20 Musculoskeletal disorders 962-1047

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Home > 2 SYSTEM-BASED DISEASES > 20 Musculoskeletal disorders
20 Musculoskeletal disorders
M. DOHERTY
P. LANYON 957
S.H. RALSTON
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Disorders of the musculoskeletal (MSK) system are prevalent throughout the world, affecting all ages and ethnic groups. The principal manifestations are pain and impairment of locomotor function.
Non-inflammatory conditions are far more prevalent than inflammatory disease (see Box 20.1). Most MSK conditions predominate in women and show a strong association with ageing. In the UK up to 1 in 4 new consultations in general practice are for MSK symptoms and as many as 40% of those aged over 65 have a significant MSK disorder. Taken together, MSK disorders are the single most common cause of physical disability in the elderly, and around one-third of all people with physical disability have an MSK disorder as the primary cause.
Most regional MSK pain arises from muscles, tendons and periarticular structures. Osteoarthritis is the most common joint disorder, with knee involvement a major cause of disability in the community. Osteoporosis is the most prevalent bone disorder and constitutes a major public health problem. In developed countries about 1 in 3 women and 1 in 6 men sustain an osteoporotic fracture at some point during their lifetime.
20.1 RELATIVE PREVALENCE OF MUSCULOSKELETAL DISORDERS
Prevalence Female:male Age association
'Non-inflammatory' conditions
Neck and back pain 20% = -
Osteoarthritis
Knee 10% F > M ++
Hip 4% = +
Osteoporosis 15% F > M ++
Regional 'soft tissue' pain 10% F > M ++
Fibromyalgia 3% F > M ++
'Inflammatory' conditions
Rheumatoid arthritis 1.5% F > M +
Gout 1.0% M > F -
Seronegative spondarthritis 0.8% = -
Polymyalgia rheumatica 0.04% F > M ++
Connective tissue diseases (mainly lupus) 0.02% F > M -


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Home > 2 SYSTEM-BASED DISEASES > 20 Musculoskeletal disorders > FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
ANATOMY AND PHYSIOLOGY
The MSK system is responsible for body movements, providing a structural framework to protect internal organs and acting as a reservoir for storage of calcium and phosphate in the regulation of mineral homeostasis. Individual components are depicted in Figure 20.1.
BONE
Embryology
Bones are divisible into two main types on the basis of their embryonic development.
Flat bones such as the skull calvariae, mandible and maxilla develop by intramembranous ossification, in which bone develops directly by differentiation of cells within condensations of mesenchymal fibrous tissue formed during early fetal life.
Other bones, including the long bones of the limbs, ribs, pelvis and vertebrae, develop by endochondral ossification, in which an initial cartilage template is invaded by vascular tissue containing osteoprogenitor cells. The cartilage is then replaced by bone that extends from centres of ossification situated in the middle and ends of the developing bone. A thin remnant of cartilage remains at each end of the bone during childhood, and is referred to as the growth plate or epiphysis. Growth depends on division of chondrocytes within the epiphysis. Cell division takes place in the proliferative zone nearest the end of the long bone, and the newly formed chondrocytes migrate downwards and enlarge in the hypertrophic zone. Chondrocyte death ensues and the surrounding matrix calcifies before being removed and replaced by mature bone. During puberty, the rise in circulating levels of sex hormones halts cell division in the growth plate. The cartilage remnant then disappears as the epiphysis fuses and longitudinal bone growth ceases.
Bone anatomy and microanatomy
Two main structural types of bone occur in the normal adult skeleton. Cortical bone has a dense compact structure and is formed from Haversian systems, which consist of concentric lamellae of bone tissue, surrounding a central canal that contains blood vessels. Cortical bone forms an envelope around the exterior of long bones, and encloses the marrow cavity. Trabecular or cancellous bone fills the centre of the bone and consists of an interconnecting meshwork of trabeculae, separated by spaces filled with bone marrow. Whilst most of the skeleton (80%) is composed of cortical bone, trabecular bone predominates at the ends of long bones, in the vertebral bodies and the calcaneus.
The skeleton is shaped and remodelled throughout life by the bone cells:
Osteoclasts are multinucleated cells derived from circulating precursors of the monocyte/macrophage lineage and are responsible for bone resorption.
Osteoblasts are mononuclear cells derived from mesenchymal cells in bone marrow stroma and are responsible for new bone formation.
Osteocytes are the most abundant cells; they derive from osteoblasts which become buried within bone matrix during bone formation. Osteocytes are thought to be responsible for sensing mechanical strain on the skeleton.

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Figure 20.1 Structure of major musculoskeletal tissues.
The main organic component of bone matrix is type I collagen, a fibrillar protein formed from two a1 peptide chains and one a2 chain wound together in a triple helix. Collagen is synthesised first as a propeptide, but following its secretion from osteoblasts, the N- and C-terminal fragments are cleaved off by proteolytic enzymes in the extracellular space. The triple helical domains that remain then self-assemble in a staggered configuration to form collagen fibrils. Subsequently, individual collagen molecules within these fibrils become linked to one another at each end by specialised pyridinium cross-links that help give bone its tensile strength. When bone is formed rapidly (for example, in Paget's disease or in bone metastases) the collagen fibrils are laid down in disorderly fashion, giving rise to 'woven bone' that is mechanically weaker than normal bone and susceptible to fracture.
Bone matrix also contains small amounts of other collagens, several non-collagenous proteins and glycoproteins. Some of these, such as osteocalcin, are specific to bone, whereas others, such as osteopontin, fibronectin and growth factors, also occur in other connective tissues. Non-collagenous bone proteins are probably involved in mediating the attachment of bone cells to the matrix and in regulating bone cell activity during bone remodelling.
The organic component of bone forms a framework upon which mineralisation occurs. Mineralisation confers upon bone the property of mechanical rigidity, which complements the tensile strength and elasticity derived from bone collagen. Bone mineral is composed mainly of calcium and phosphate laid down in the form of hydroxyapatite-[Ca10 (PO4)6 (OH2)]-crystals.
Bone remodelling
The normal skeleton is constantly being renewed and repaired by the process of bone remodelling, carried out by the coordinated actions of osteoclasts and osteoblasts (see Fig. 20.2). It is estimated that approximately 10% of the adult skeleton is remodelling at any one time.
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Figure 20.2 The bone remodelling cycle. (RANK = receptor activator of nuclear factor kappa B; RANKL = RANK ligand; OPG = osteoprotegerin)
Bone remodelling commences with the attraction of osteoclast precursors in peripheral blood to the site that is to be resorbed. The mechanisms that trigger this process are unclear, but chemotactic factors released from areas of skeletal microdamage may play a role. Once in the bone microenvironment osteoclast precursors fuse to form multinucleated osteoclasts in response to activation of the RANK (receptor activator of nuclear factor kappa B) receptor on the osteoclast precursors by RANK ligand (RANKL) expressed on osteoblasts and bone marrow stromal cells. This interaction is inhibited by a soluble protein with homology to RANK called osteoprotegerin (OPG). OPG acts as a 'decoy' receptor that inhibits osteoclast activity by binding RANKL. Mature osteoclasts attach to the bone surface by a tight sealing zone that forms around the periphery of the cell. Osteoclasts then resorb bone by secreting hydrochloric acid and proteolytic enzymes into the space beneath the sealing zone. The acid dissolves hydroxyapatite and allows proteolytic enzymes, including collagenase and cathepsin K, access to degrade components of bone matrix.
20.2 REGULATORS OF BONE REMODELLING
Factor Effect on osteoclasts Effect on osteoblasts Effect on bone mass
PTH ? ? Variable
1,25(OH)2D3 ? ? Variable
IL-1/TNF ? ? Bone loss
Thyroid hormone ? ? Bone loss
Glucocorticoids ? ? Bone loss
Calcitonin ? ? Bone gain
Oestrogen ? ? Bone gain
Testosterone ? ? Bone gain
Mechanical loading ? ? Bone gain


?= stimulates; ?= inhibits; ?= neutral.
When bone resorption is complete, osteoclasts undergo programmed cell death (apoptosis) in the 'reversal phase' that heralds the start of bone formation. Bone formation begins with the attraction of osteoblast precursors to the site that has undergone resorption. These cells then differentiate into osteoblasts by activation of the transcription factor Cbfa1. Osteoblasts lay down uncalcified bone matrix (osteoid) on to the bone surface and this subsequently calcifies after a period of about 10 days to form mature bone. The enzyme alkaline phosphatase that is produced by osteoblasts plays an important role in promoting mineralisation by degrading pyrophosphate, a naturally occurring inhibitor of mineralisation present in extracellular fluid. During bone formation, some osteoblasts become trapped within bone matrix and differentiate into osteocytes that interconnect with one another and with cells on the bone surface by long cytoplasmic processes that run through canaliculi in the bone matrix. Bone remodelling is regulated by circulating hormones and other factors (see Box 20.2). Many of these factors act by upregulating or downregulating local expression of RANKL and OPG in the bone microenvironment.
JOINTS
Bones are linked by joints. There are three main subtypes (see Box 20.3).
Fibrocartilaginous joints
Fibrous and fibrocartilaginous joints are composed of a simple bridge of fibrous or fibrocartilaginous tissue joining two bones together. They occur in the skeleton where there is little requirement for movement of one bone in relation to another. The intervertebral disc is a special type of fibrocartilaginous joint in which an amorphous area termed the nucleus pulposus lies in the centre of the fibrocartilaginous bridge. This structure has a high water content and acts as a cushion to provide the intervertebral disc with improved shock-absorbing properties compared with ordinary fibrocartilaginous joints.
20.3 TYPES OF JOINT
Type Range of movement Examples
Fibrous Minimal Skull sutures
Fibrocartilage Limited Symphysis pubis
Costochondral junctions
Intervertebral discs
Synovial Large Most limb joints
Temporo-mandibular
Costovertebral

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Synovial joints
Synovial joints are more complex structures containing several cell types. They are found in regions of the skeleton where a wide range of movement is required.
Articular cartilage
The ends of the bones in a synovial joint are covered with a layer of articular cartilage. This is an avascular tissue that consists of cartilage cells (chondrocytes) embedded in a thick matrix of proteoglycans, water, type II collagen and smaller amounts of other proteins. Although there is no cell division to speak of in normal cartilage, chondrocytes are metabolically active cells that are responsible for synthesis and turnover of cartilage matrix throughout life. The matrix consists of a meshwork of type II collagen fibrils that run through a hydrated 'gel' of proteoglycan molecules, the most important of which is aggrecan (see Fig. 20.3). Aggrecan consists of a core protein, to which several glycosaminoglycan (GAG) side-chains are attached. GAGs consist of long chains of disaccharide repeats, in which the disaccharide consists of one ordinary sugar linked to an amino sugar. The most important GAGs in aggrecan are chondroitin sulphate (glucuronic acid and sulphated N-acetylgalactosamine) and keratan sulphate (galactose and sulphated N-acetylglucosamine). Cartilage also contains hyaluronan, a long GAG consisting of multiple glucuronic acid and N-acetylgalactosamine disaccharide repeats. Hyaluronan binds several aggrecan molecules by interacting with a domain at the N-terminus of the core protein along with a small glycoprotein called link protein that acts to stabilise the complex. Large complexes of aggrecan and hyaluronan can form in cartilage with a total molecular weight in excess of 100 million. Aggrecan has a strong negative charge because of the sulphate and hydroxyl groups in the GAG residues; as a consequence, it binds large numbers of water molecules to assume a shape that occupies the maximum possible volume available. The expansive force of the charged and hydrated aggrecan, combined with the restrictive force of the collagen meshwork, gives articular cartilage excellent shock-absorbing properties.
With ageing, the amount of chondroitin sulphate in cartilage decreases, whereas that of keratan sulphate increases. Although the reasons for this are unknown, the end result is a reduction in water content and impairment of cartilage's shock-absorbing properties. Age-related changes in cartilage differ from those found in osteoarthritis, where there is abnormal chondrocyte division, loss of proteoglycan from matrix and an increase in water content.


Figure 20.3 Ultrastructure of articular cartilage.
Cartilage matrix is constantly being turned over, and in health a perfect balance is maintained between synthesis and degradation of matrix components. Matrix degradation is thought to be mediated by proteolytic enzymes such as aggrecanase and matrix metalloproteinases that degrade the core protein of aggrecan and other matrix proteins. Other enzymes termed glycosidases degrade the GAG side-chains. The importance of this system is emphasised by the occurrence of a group of diseases, termed mucopolysaccharidoses, in which genetic mutations in glycosidases occur, resulting in excessive accumulation of GAGs in various tissues. The mechanisms by which proteoglycan turnover is regulated in normal cartilage are poorly understood, but pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor (TNF) which are involved in joint inflammation are known to upregulate production of aggrecanase, metalloproteinases and other enzymes that cause matrix degradation, thereby promoting cartilage damage. This is offset by upregulation of inhibitors of proteinases in cartilage, called tissue inhibitors of metalloproteinases (TIMP), which oppose the effects of degrading enzymes and protect against matrix degradation.
Synovial fluid
The surfaces of articular cartilage are separated by a space filled with synovial fluid, a viscous liquid that lubricates the joint. Synovial fluid is basically an ultrafiltrate of plasma into which synovial cells secrete hyaluronan and proteoglycans.
Intra-articular discs
Some joints contain fibrocartilaginous discs within the joint space (for example, the menisci of the knee) that act as shock absorbers. Like articular cartilage, these structures are avascular and remain viable by diffusion of oxygen and nutrients from the synovial fluid.
The joint capsule and synovial membrane
The bones of synovial joints are connected together by the joint capsule, a fibrous structure richly supplied with blood vessels, nerves and lymphatics that encompasses the joint cavity. Ligaments are discrete, regional thickenings of the joint capsule that act to stabilise joints. The inner surface of the joint capsule is lined by the synovial membrane, which comprises an outer layer of blood vessels and loose connective tissue, and an inner layer 1-4 cells thick, consisting of two main cell types, termed type A and type B synoviocytes. Type A synoviocytes are phagocytic cells derived from the monocyte/macrophage lineage and are responsible for removing particulate matter from the joint cavity; type B cells are fibroblast-like cells that are thought to be responsible for secretion of synovial fluid. Most inflammatory and degenerative joint diseases are associated with thickening of the synovial membrane and infiltration by lymphocytes, polymorphs and macrophages.
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Many joints contain bursae, which are hollow sacs lined with synovium and filled with a small amount of synovial fluid. They help tendons and muscles move smoothly in relation to the bones and other articular structures.
SKELETAL MUSCLE
Skeletal muscles are responsible for body movements. Muscle consists of bundles of muscle cells or myocytes, embedded in a fine connective tissue containing nerves and blood vessels. Myocytes are large, elongated, multinucleated cells formed from the fusion of hundreds of mononuclear precursors termed myoblasts in early embryonic life. The nuclei in myocytes lie peripherally underneath the cell membrane, whereas the centre of the cell contains bundles of actin and myosin molecules that interdigitate with one another to form the myofibrils that are responsible for muscle contraction. The molecular mechanisms of skeletal muscle contraction are essentially as described for cardiac muscle (see p. 363). Muscle cells also contain many mitochondria which provide the large amounts of adenosine triphosphate (ATP) necessary for muscle contraction and are rich in the protein myoglobin which acts as a reservoir for oxygen during contraction.
Individual myofibrils are organised into bundles called fasciculi that are bound together by a thin layer of connective tissue termed the perimysium. The surface of the muscle is surrounded by a thicker layer of connective tissue, the epimysium, which merges with the perimysium to form the muscle tendon. Tendons are tough, fibrous structures that attach muscles to the point of insertion on bone surface that is called the enthesis.
INVESTIGATION OF MUSCULOSKELETAL DISEASE
Disease 'markers' are the pathological or physiological characteristics of an individual that assist in determining:
the diagnosis
the current activity or level of disease
the expected prognosis.
Individual markers may give information on one, two or occasionally all three of these aspects. Clinical markers are derived from enquiry and examination of the patient, and for most MSK conditions detailed clinical assessment alone gives sufficient information for diagnosis and management. Additional investigational markers can be helpful in confirming the diagnosis and in assessing activity and progression of disease. However, only a few tests are specific. The requirement for, and selection and interpretation of, investigations are principally determined by clinical assessment. Investigations are an adjunct to, never a substitute for, competent clinical assessment, and there is never a place for a battery of 'screening tests'.
In common practice the investigations of most value are synovial fluid analysis and the plain radiograph. Confirmation of clinically assessed inflammatory disease activity and its response to treatment is mainly by the full blood count and either direct or indirect measures of the acute phase response.
SYNOVIAL FLUID ANALYSIS
This is the pivotal investigation to confirm the diagnosis of septic arthritis, crystal-associated arthritis and intra-articular bleeding. It is therefore the key investigation for acute monoarthritis, especially with overlying erythema.
Synovial fluid (SF) can readily be obtained from most peripheral joints and for diagnostic purposes only a small volume is required. Normal SF is present in small volume, contains very few cells, is clear and colourless to pale yellow, and has high viscosity due to macromolecular hyaluronate. With increasing joint inflammation the volume increases, the total cell count and proportion of neutrophils rise (causing turbidity), and the viscosity lowers (due to protease degradation of hyaluronate). However, because of considerable variation and overlap between arthropathies these features have little diagnostic value. Frank pus or 'pyarthrosis' results from very high neutrophil counts and is not specific for sepsis. High concentrations of crystals, mainly urate or cholesterol, can make SF appear white.
Non-uniform blood staining of SF is common, reflecting inconsequential needle trauma to the synovium. Uniform blood staining-haemarthrosis-commonly accompanies florid synovitis but may also result from a bleeding diathesis, trauma or pigmented villonodular synovitis. A lipid layer floating above blood-stained fluid is diagnostic of intra-articular fracture.


Figure 20.4 Compensated polarised light microscopy of synovial fluids (× 400). A Monosodium urate crystals showing bright birefringence (negative sign) and needle-shaped morphology. B Calcium pyrophosphate crystals showing weak birefringence (positive sign), scant numbers and a predominantly rhomboid morphology. These are clearly more difficult to detect than urate crystals.
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If sepsis is suspected, SF should be sent for urgent Gram stain and culture in a sterile universal container. If gonococcal sepsis or uncommon organisms are suspected, especially in immunocompromised patients, the microbiologist should be consulted to ensure that optimal cultures are established and that molecular techniques of antigen detection are used if appropriate.
Identification of common SF crystals is by compensated polarised light microscopy of fresh unrefrigerated SF to avoid problems of crystal dissolution and post-aspiration crystallisation. Urate crystals are long and needle-shaped and show a strong light intensity with a negative sign of birefringence (see Fig. 20.4A). Calcium pyrophosphate crystals are smaller, rhomboid in shape, usually less numerous than urate and have weak intensity and positive birefringence (see Fig. 20.4B).
PLAIN RADIOGRAPHY
Although a static record of predominantly past events, a radiograph can show changes that reflect underlying pathological processes such as cartilage and bone erosion or calcification. The abnormalities that may be seen on a plain film include:
soft tissue swelling-seen as altered skin contours and displaced fat planes and intracapsular fat pads (fat appears dark on radiograph)
decreased or increased bone density-localised or generalised
joint erosion (non-proliferative or proliferative marginal erosion, central erosion)
joint-space narrowing (focal-osteoarthritis; generalised-inflammatory arthritis)
new bone formation (osteophyte, enthesophyte, syndesmophyte) and periosteal reaction
calcification (cartilage-chondrocalcinosis; synovium, capsule, ligament, tendon, muscle, fat, vascular, skin) and intra-articular osteochondral bodies
bone cysts and radiolucent lesions
deformity
fracture.
Although most of these abnormalities have low individual specificity, various combinations of these features, together with their selective targeting of certain joints (see Fig. 20.5), result in characteristic patterns of abnormality and distribution that have high diagnostic specificity.


Figure 20.5 The different target sites of involvement in the forefoot for arthritis.
The distribution of joint involvement is principally derived from clinical assessment, and joints to be X-rayed are usually selected on this basis. An exception is seronegative spondarthritis where sacroiliac involvement is often asymptomatic and difficult to detect clinically. For suspected seronegative spondarthritis an antero-posterior (AP) view of the pelvis and a lateral thoracolumbar spine view (i.e. two films) are usually sufficient to show sacroiliitis or syndesmophytes if they are present. Radiographs are selected to answer specific questions. For example, to determine whether a patient with inflammatory polyarthritis has erosions typical of rheumatoid arthritis, postero-anterior (PA) views of hands and feet (i.e. two films), but not radiographs of all symptomatic joints, are appropriate, since rheumatoid erosions appear first in wrists and small joints of hands and feet and may appear first in metatarsophalangeal joints even if they are asymptomatic. However, if the degree of structural damage in one large joint is a cause for concern, a radiograph of that joint will be required. Thus selection of radiographs often differs for diagnostic or disease assessment purposes.
Erosions
A hallmark of major inflammatory arthropathies is cartilage and bone erosion. Intracapsular bone erosion first occurs at the 'bare areas' of the joint margin ('marginal erosion') where bone is exposed directly to inflammatory synovium without the protection of overlying cartilage. Loss of the sharp cortical line is the first radiographic sign that precedes more definite scalloping of the bony contour (see Fig. 20.6). Cartilage erosion also starts at the margin and slowly works centrally, resulting in relatively late loss of 'joint space'. Both rheumatoid and seronegative spondarthritis (especially psoriatic arthritis) can cause marginal erosions. In rheumatoid, however, the florid synovitis is not accompanied by any bone or periosteal reaction, resulting in atrophic 'non-proliferative' erosions (see Fig. 20.6B), often with juxta-articular osteopenia and soft tissue swelling. By contrast, in seronegative spondarthritis there is often concomitant new bone formation and periosteal reaction with retained bone density, resulting in 'proliferative' erosions (see Fig. 20.6C). Accompanying ossifying enthesopathy (enthesophytes) and the targeting of different joints further assist differentiation.
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Figure 20.6 Metacarpophalangeal joint. A Early dot-dash erosion of rheumatoid arthritis. B Later definite non-proliferative erosion of rheumatoid arthritis. C The proliferative erosion of psoriatic arthritis. D The intra- and extracapsular 'pressure erosions' of gout.
In early septic arthritis the radiograph is often normal, apart from osteopenia and soft tissue swelling, for 1-2 weeks. However, erosion proceeds rapidly and results in generalised loss of joint space with loss of cortical integrity centrally-central erosion-as well as marginally. In chronic gout bony defects develop slowly as massive crystal concretions ('tophi') cause pressure necrosis to surrounding bone. Such 'pressure erosions' (see Fig. 20.6D) occur at extracapsular as well as intracapsular sites and are not accompanied by osteopenia.
Osteoarthritis


Figure 20.7 Radiograph of hip to show changes of osteoarthritis. Note the superior joint space narrowing, subchondral sclerosis, marginal osteophyte and cysts.
The changes of osteoarthritis are prevalent and highly characteristic, and contrast with those of inflammatory arthritis. The two cardinal features are narrowing and osteophyte. In contrast to inflammatory arthritis, joint space narrowing is focal not widespread (see Fig. 20.7). Bony osteophytes are most noticeable at the joint margins. Subchondral sclerosis (focal increased density of bone), 'cysts' and osteochondral 'loose' bodies within the synovium are possible additional features, and there is an increased association with chondrocalcinosis. In contrast to inflammatory arthritis, bone density is normal or increased and marginal erosions are not a feature.
Calcification
Calcification of fibrocartilage and hyaline cartilage-chondrocalcinosis-is most commonly due to calcium pyrophosphate crystals or apatite. Calcification at other sites is mainly apatite. Spotty, multiple calcification of soft tissues-calcinosis-mainly targets peripheral and intermediate sites such as finger pulps, wrists and forearms and is a feature of connective tissue disease.
OTHER IMAGING
Scintigraphy
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Figure 20.8 Comparison of bone scan appearances in Paget's disease and metastatic bone disease. A Intense homogeneous uptake throughout the affected femur (arrows) in Paget's disease. B Patchy focal uptake affecting the spine, ribs (arrows) and skull in metastatic breast cancer.
This readily available technique involves gamma-camera imaging following an intravenous injection of radioisotope, usually 99mTc-bisphosphonate. Early post-injection images reflect vascularity and can show, for example, the increased perfusion of inflamed synovium, Pagetic bone, or primary or secondary bone tumour (see Fig. 20.8). Delayed images taken a few hours later indicate bone remodelling as the bisphosphonate localises to sites of active bone turnover. Although non-specific and lacking high resolution, scintigraphy has a high sensitivity for detecting important bone and joint pathology that is not apparent on plain radiographs. It is particularly useful, following a normal or an inconclusive radiograph of a presenting painful region, as the second investigation to detect:
bone metastases-at symptomatic and clinically occult sites
bone or joint sepsis-at the presenting site and clinically occult sites
early osteonecrosis-at the presenting site and clinically occult sites
stress fracture
reflex sympathetic dystrophy (algodystrophy-see p. 1046)
hypertrophic osteoarthropathy (see p. 1045).
It is also useful in assessing the extent and activity of Paget's disease of bone.
Computerised tomography (CT)
Computerised reconstruction of multiple radiographic scan sections gives detailed information on anatomy, especially of bone, allowing three-dimensional visualisation of anatomically complex structures such as the spinal canal and facet joints which may be inadequately assessed by plain radiographs. Drawbacks include limited soft tissue resolution and a high radiation dose, and for many situations magnetic resonance imaging is now preferred.
Magnetic resonance imaging (MRI)
MRI provides detailed and sensitive information on both structure and physiology of cartilage, bone and other locomotor tissues. Further advantages are the capacity for multiplanar imaging and safety without radiation exposure. In general, T1-weighted short sequences are useful for defining anatomy and T2-weighted long sequences for assessing pathology. Other sequences are selected for special purposes; for example, the short tau inversion recovery (STIR) sequence is used to image marrow since it suppresses fat and makes the marrow appear dark. MRI, with or without enhancement with gadolinium, is particularly useful to detect and assess:
early osteonecrosis-at symptomatic and clinically occult sites
intervertebral disc disease, root entrapment and spinal cord compression
osteoarticular and soft tissue sepsis
osteoarticular and soft tissue malignancy
internal derangement of joints such as the knee
soft tissue and periarticular pathology (e.g. early synovitis, rotator cuff tears, bursitis, tenosynovitis).

Ultrasonography
This safe, accessible technique can confirm soft tissue changes such as a hip joint effusion, popliteal cyst or thickened Achilles tendon. Limited resolution, however, makes it inferior to CT or MRI for defining anatomy.
Arthrography
Injection of positive (iodinated) or negative (air) contrast, or a combination of both, can help delineate the outline of a joint or bursa. The main use of plain film arthrography is at the knee to demonstrate a ruptured popliteal ('Baker's') cyst as the cause of calf pain and swelling. It may be combined with CT or MRI to facilitate anatomical assessment.
BLOOD TESTS FOR INFLAMMATION AND SYSTEMIC DISEASE
The acute phase response
The full blood count, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may show non-specific changes that indicate inflammation. At any site of injury or inflammation macrophages and monocytes release soluble cytokines including IL-1, IL-6 and TNF-a. Some of these cytokines enter the systemic circulation and exert effects on:
the hypothalamus-to cause fever
the bone marrow-to increase production and release of neutrophils and platelets but reduce erythrocyte production
the liver-to increase production and release of acute phase proteins such as fibrinogen, clotting factors, immunoglobulin, complement and CRP, but to decrease production of negative acute phase reactants such as albumin and transferrin.

These combined systemic effects-the acute phase response (APR)-accompany chronic as well as acute inflammation. Much of the APR is beneficial for body defence and adaptation to injury. For example, thrombocytosis and increased levels of clotting factors facilitate haemostasis, while neutrophilia and increased levels of complement, immunoglobulin and CRP (an opsonin) combat infection.
The acute phase response in infection
Although the acute phase response is well recognised in inflammatory conditions such as musculoskeletal disease, it most probably evolved primarily to combat the effects of physical injury and infection.
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Certain distinctive biochemical structures, present in many microorganisms (e.g. bacterial lipopolysaccharide) can activate the production of effector acute mechanisms. Three groups of substances are produced by this mechanism:
Defensins. Alpha defensins produced by neutrophils and beta defensins produced by epithelial cells have antimicrobial properties and attract T cells.
Complement. These substances can lead to direct antibody-linked microbial disruption and also enhance opsonisation of bacteria. C5 is also a very potent neutrophil chemotaxin.
Interferons. a, ß and ? are produced by virus-infected cells and have immunomodulatory and antiproliferative functions.

C-reactive protein
Of the acute phase proteins CRP shows the greatest change from very low to very high levels, and closely mirrors the degree of inflammation, rising rapidly at the onset and falling as inflammation subsides. It is therefore the single most useful direct measure of the APR.
Erythrocyte sedimentation rate
The ESR can act as an indirect measure of the APR. Normally, erythrocytes do not clump together because their repellent electrostatic negative surface charge, or zeta potential, is greater than the attractant electrical charge (dielectric constant) of the plasma constituents. However, in the APR the altered plasma protein concentrations, chiefly fibrinogen, increase the dielectric constant sufficiently to overwhelm the zeta potential and allow erythrocytes to clump like stacks of tyres (rouleaux). Rouleaux have a higher mass/surface area ratio, so sediment faster than single red cells. This property is measured in the ESR. In the Westergren test system a 200 mm capillary tube is filled with the patient's blood and after 1 hour the sedimentation of red cells from the top is measured. In health the discrete red cells sediment slowly and the clearance is small (< 5-10 mm). However, with rouleaux formation the clearance is greater and the ESR is elevated. Therefore in a patient with an APR the ESR and CRP are both elevated, the ESR lagging behind the CRP in terms of speed of change.
The ESR, however, may be raised for reasons other than the APR. For example, the elevated levels of immunoglobulin that occur in myeloproliferative disease (e.g. multiple myeloma) and autoimmune disease (e.g. Sjögren's syndrome) can increase the dielectric constant to cause rouleaux formation. In this situation the patient may have a high ESR but normal or relatively low CRP. Such discordance between ESR and CRP should lead to consideration of such conditions and to direct measurement of immunoglobulins. The inherent number of red cells available may also modify the ESR. For example, in patients with polycythaemia the ESR is often relatively low despite a florid APR. The plasma viscosity is independent of such variation and is an alternative indirect measure of changes in serum protein concentrations.
Full blood count
The full blood count may show other changes that are non-specific but which may be characteristic of certain MSK diseases or their complications (see Fig. 20.9). For example, neutrophilia may occur in systemic vasculitis, and neutropenia in lupus. Furthermore, many slow-acting antirheumatic drugs have marrow toxicity requiring regular monitoring of the full blood count.
The typical profile of a patient with an APR is shown in Box 20.4. Such changes, of course, are not specific for inflammatory MSK disease. Also, although reasonably sensitive, they are not always present, especially in patients with connective tissue disease, seronegative spondarthritis or isolated small joint synovitis.


Figure 20.9 Some of the non-specific changes that may occur in individual elements of the full blood count in patients with systemic rheumatic disease. (JIA = juvenile idiopathic arthritis)
20.4 TYPICAL PROFILE OF A FLORID ACUTE PHASE RESPONSE
Normochromic, normocytic anaemia
Neutrophilia
Increased platelet count
High ESR
High CRP
Increased plasma viscosity
Low albumin


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Immunological tests
An increasing number of autoantibodies can be detected. Production of some of these is a common, age-related phenomenon that may be exaggerated by chronic inflammation. Their mere presence, therefore, often has low diagnostic specificity and little clinical relevance. If present in high concentrations, however, their disease specificity often increases. It is therefore important to know how much antibody is present (the titre or concentration in units) rather than just whether it is detectable. Only a few antibodies-for example, anti-dsDNA-have high diagnostic specificity. For some autoantibodies such as c-ANCA, their titre, if initially high, can be used to monitor the activity of the associated disease. Again, the correct choice and interpretation of these tests depend on detailed knowledge of the patient. Different detection and assay systems exist for many of these autoantibodies, and close liaison with the local immunology service is required.
Rheumatoid factor
A rheumatoid factor is an antibody directed against a specific region of the Fc fragment of human IgG. It may be of any immunoglobulin class, though IgM anti-IgG is the rheumatoid factor most commonly measured in the first instance. One traditional method of detecting IgM rheumatoid factor is to coat latex beads with human IgG. Adding the patient's serum to the test system allows the pentameric IgM antibody to bind with the IgG and cause the latex particles to flocculate, producing a positive 'latex fixation test'. The amount by which the serum must be diluted before this flocculation is lost is then determined; the higher this 'titre', the higher the antibody concentration.
20.5 ASSOCIATIONS WITH A POSITIVE RHEUMATOID FACTOR
Rheumatoid arthritis (c.75%)
Lupus, scleroderma, Sjögren's syndrome, dermatomyositis
Chronic infection
Bacterial endocarditis
Viruses (rubella, cytomegalovirus, infectious mononucleosis)
Parasites
Neoplasms-after irradiation or chemotherapy
Hyperglobulinaemic states
Hypergammaglobulinaemic purpura
Cryoglobulinaemia
Chronic liver disease
N.B. Normal subjects can be seropositive.

Although rheumatoid factor was so named because it was first identified in patients with rheumatoid arthritis, it also occurs in a wide variety of other conditions and in some normal adults (see Box 20.5). It therefore has low diagnostic specificity, particularly in the elderly, and is not a 'test for rheumatoid arthritis'. In terms of sensitivity, it is present in the majority of patients with erosive rheumatoid disease but may only appear after months or years of disease, once the diagnosis is beyond dispute. It is therefore neither sufficient nor necessary for the diagnosis. Its principal use is as a prognostic marker; a high titre at the onset of rheumatoid arthritis associates with a poorer prognosis. IgG rheumatoid factor has greater specificity for major rheumatic disease but the above caveats still remain.
Antinuclear antibody
An antinuclear antibody (ANA) is any autoantibody directed against one or more components of the nucleus. Immunofluorescence microscopy after serum has been applied to a nucleated tissue substrate (e.g. rodent organs) or human cell lines (e.g. Hep 2) is the standard method of detection, and four main patterns of staining are reported. As with rheumatoid factor, the higher the titre of ANA, the greater its significance, although a high titre does not necessarily imply more severe disease. The specificity and sensitivity also vary according to the antigen preparation used in the test system and whether the ANA measured is IgG or IgM. However, the tests are not universally standardised and liaison with the local laboratory is important.
The many causes of a positive ANA are outlined in Box 20.6. The most common reason to test for ANA is if lupus is suspected. For lupus, ANA has high sensitivity (virtually 100%), but because the specificity is low (10-40%) a positive result does not make the diagnosis; by contrast, a negative ANA virtually excludes the diagnosis.
If a screening ANA test is positive most laboratories attempt to establish the specific antigenic determinants, though in many cases the precise specificities remain unknown. Some determinants are soluble and can be extracted from the nucleus-'extractable nuclear antigens'. Compared to the ANA, antibodies against specific nuclear antigens may have higher specificity for certain diagnoses or for certain patterns of system involvement within the same disease. For example, ANA directed against double-stranded DNA (anti-dsDNA) is highly specific for lupus. Unfortunately, it is present in a minority of patients and those in whom it is positive often have classic severe lupus and a clear clinical diagnosis.
20.6 ASSOCIATIONS WITH A POSITIVE ANTINUCLEAR ANTIBODY
Musculoskeletal disease
Systemic lupus erythematosus (100%)
Rheumatoid arthritis
Sjögren's syndrome
Polymyositis
Polyarteritis nodosa
Juvenile idiopathic arthritis
Other disorders
Chronic active hepatitis
Autoimmune thyroid disease
Myasthenia gravis
Extensive burns
N.B. Normal subjects may be ANA-positive.

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Antibodies to Sm are almost exclusive to lupus and imply a poorer prognosis. Anti-topoisomerase 1 and anti-centromere antibodies are found exclusively in diffuse and limited scleroderma respectively. Antibodies to Ro occur predominantly in Sjögren's syndrome and systemic lupus erythematosus (SLE) and associate with a high frequency of photosensitive rashes and risk of neonatal heart block. Antibodies to ribonucleoprotein (RNP) are found in lupus but also in other conditions such as scleroderma, myositis, mixed connective tissue disease and rheumatoid arthritis. Although these antibodies may associate with disease subsets, there is little evidence that they are involved in pathogenesis.
The antiphospholipid syndrome
The antiphospholipid syndrome, defined by the occurrence of arterial and venous thromboses, recurrent fetal losses and thrombocytopenia in the presence of antiphospholipid antibodies, occurs in lupus and other autoimmune diseases and also in subjects with no other underlying disease. Antiphospholipid antibodies can be detected in assays for anticardiolipin antibodies (predominantly directed against ß2-glycoprotein 1) and in phospholipid-dependent coagulation studies to detect lupus anticoagulants (prolonged activated partial thromboplastin time (APTT) which fails to correct with the addition of normal serum). Antiphospholipid antibodies also occur in a wide variety of rheumatic, infectious (bacterial, viral, protozoal) and malignant conditions, although in these situations they are not usually associated with thromboses.
INVESTIGATION OF BONE DISEASE
X-ray examination
The most common indication for radiographs in patients with bone disease is to confirm or exclude fractures. Other indications are the investigation of MSK pain or bone deformity, where evidence of Paget's disease, primary bone tumours or metastatic bone disease may be found. Plain radiographs are of limited value in the diagnosis of osteoporosis since this has to be quite advanced before it can be detected. Although osteopenia on X-ray suggests osteoporosis, a normal result does not exclude it. Other bone diseases that may be diagnosed on plain radiographs include hyperparathyroidism (subperiosteal erosions on hand radiographs or pepperpot appearance on skull radiograph), osteopetrosis (generalised increase in radiodensity) and algodystrophy (patchy localised osteoporosis).
Bone mineral density (BMD) measurements
BMD measurement is central to the investigation of osteoporosis and is indicated in patients with risk factors for this disease (see Box 20.7). Several techniques can measure BMD, but dual energy X-ray absorptiometry (DXA) is the current method of choice because of its sensitivity and low-radiation dose. Investigation of osteoporosis is best done by measuring BMD at the spine or hip. At present it is uncertain how BMD measured at peripheral sites such as the wrist and calcaneus should be interpreted with respect to determining treatment.
DXA scanners work on the principle that bone tissue placed between an X-ray source and a detector impedes the passage of radiation in proportion to the amount of mineral present. By relating attenuation of the X-ray beam to an internal standard, the BMD can be accurately measured and is expressed in grams of hydroxyapatite per cm2 of the area scanned. Virtually all DXA machines also give results in relation to reference values to give 'Z-score' and 'T-score' readings (see Fig. 20.10). The Z-score measures by how many standard deviations the BMD deviates from the population average for the patient's age, whereas the T-score measures by how many standard deviations the patient's BMD differs from the population average for young healthy individuals who have attained peak bone mass. By convention, osteoporosis is diagnosed when the BMD T-score value falls below -2.5 (shaded red in Fig. 20.10), whereas osteopenia describes individuals whose T-scores are between -1.0 and -2.5 (shaded pink in Fig. 20.10). Note that by this definition the incidence of both osteoporosis and osteopenia increases progressively with age such that many elderly individuals with 'normal' BMD Z-score values have osteoporosis on the basis of a reduced T-score.
20.7 INDICATIONS FOR BONE DENSITOMETRY
Previous low trauma fracture (fall from standing height or less)
Clinical features of osteoporosis (height loss, kyphosis)
Radiographic evidence of osteoporosis
Corticosteroids (> 7.5 mg prednisolone daily for > 3 months)
Family history of osteoporotic fracture
Low body weight (body mass index < 19)
Early menopause (< 45 years)
Diseases associated with osteoporosis (especially if poorly controlled)
Rheumatoid arthritis
Malabsorption
Inflammatory bowel disease
Prolonged immobility
Hypogonadism in men
Assessing response of osteoporosis to treatment




Figure 20.10 Output from DXA scan of the femoral neck comparing BMD values (left axis), T-score values (right axis) and Z-score values (arrows) in patients of different ages. The solid line represents the population average plotted against age, whereas the interrupted lines are ± 2 standard deviations of the average. Patient A, aged 30, has a T-score value of -1.0 and a Z-score value of -1.0, both of which are within the normal range. Patient B, aged 80, also has a Z-score of -1.0 but has a T-score of -3.0, reflecting bone loss with age. Patient B therefore has osteoporosis, even though the BMD value is in the normal range for her age.
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Measurement of BMD is valuable not only for diagnosis but also for management of osteoporosis, since the anti-fracture efficacy of many treatments is restricted to individuals who have low spine or hip BMD values (see EBM panel). BMD measurements are also used to assess treatment response. Since changes in BMD with most osteoporosis treatments are small and occur slowly, repeat measurements should not be performed until 12-24 months after starting therapy. Measurement of spine BMD is better than hip BMD for assessing treatment response because precision is better and changes in BMD at the spine occur more quickly because of the higher content of trabecular bone.
EBM
ASSESSMENT OF OSTEOPOROSIS-role of BMD measurements in deciding upon the need for treatment
'RCTs of bisphosphonate therapy in osteoporosis have shown that the beneficial effects in preventing fractures are restricted to patients with low bone mineral density (BMD).'
Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998; 280:2077-2082.
McClung MR, Guesens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001; 344:333-340.


Quantitative ultrasound examination
Quantitative ultrasound examination is usually performed at the heel and provides an alternative to DXA for assessment of osteoporotic fracture risk. Although almost as good as DXA at predicting fracture risk in population-based studies, it cannot be used to diagnose osteoporosis (which is defined by a low BMD) and has not yet been accepted as a method of selecting patients for anti-osteoporotic treatments.
Radionuclide bone scanning
Radionuclide bone scanning is of value in the differential diagnosis of bone pain, particularly when metastatic bone disease or Paget's disease is the suspected cause (see Fig. 20.8). Bone scans are generally more sensitive than radiographs in detecting metastatic disease, but negative results can occur in multiple myeloma where disease suppression of osteoblastic activity reduces uptake of tracer in lytic lesions.
Bone biopsy
Bone biopsy is helpful in the diagnosis of metabolic bone diseases when other tests have proved inconclusive. The biopsy is taken using a large diameter (8 mm) trephine needle from the iliac crest under local anaesthetic. Samples are then processed for histology, without decalcification, and analysed for the presence of mineralisation defects (e.g. osteomalacia), marrow infiltrates (e.g. mastocytosis, secondary tumours) and abnormalities of bone turnover or structure (e.g. renal osteodystrophy, Paget's disease).
Biochemical tests
Some metabolic bone diseases, such as Paget's disease, renal bone disease and osteomalacia, give a characteristic pattern of abnormalities on routine biochemical tests (see Box 20.8). Other biochemical markers are also available with which to assess bone turnover. Markers of bone resorption include serum or urinary levels of pyridinium cross-links, and cross-linked collagen telopeptides. These derive from degradation of bone collagen during bone remodelling. Markers of bone formation include serum osteocalcin and serum bone-specific alkaline phosphatase, both released from osteoblasts, and serum collagen propeptide fragments that are cleaved from newly synthesised collagen molecules laid down during matrix deposition. These assays can be used to assess levels of bone turnover, but they are not useful diagnostically. Their use is currently restricted to research.
INVESTIGATION OF SUSPECTED MUSCLE DISEASE
There are three main investigations for diagnosis and monitoring of muscle disease: serum creatine kinase (CK), electromyography (EMG) and muscle histology. None is 100% sensitive so that each may be normal despite abnormality detected by one or both of the others. CK is the most indirect marker but is readily available and often measured first. Elevation of CK, however, may result from a variety of causes (see Box 20.9) and some ethnic groups such as Afro-Caribbeans have high normal values. An EMG or muscle biopsy is often undertaken next, the choice depending on local availability and expertise. How much information is gained from the first two tests often determines whether the third is also undertaken. The test that is most abnormal is then often used for subsequent monitoring of disease activity.
20.8 BIOCHEMICAL ABNORMALITIES IN VARIOUS BONE DISEASES
Serum calcium Serum phosphate Serum alkaline phosphatase (AP) Serum PTH Serum 25(OH)D
Osteoporosis N N N N N
Paget's disease N N ?? N or ? N
Osteomalacia N or ? N or ? ? ? ?
Renal osteodystrophy ? ?? ? ?? N
Primary hyperparathyroidism ? N or ? N or ? ? N


(PTH = parathyroid hormone; 25(OH)D = 25-hydroxyvitamin D; N = normal)
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20.9 CAUSES OF AN ELEVATED SERUM CREATINE KINASE
Inflammatory myositis ± vasculitis
Muscular dystrophy
Motor neuron disease
Alcohol, drugs
Trauma, strenuous exercise
Myocardial infarction
Hypothyroidism, metabolic myopathy


The EMG measures the action potentials produced at rest and during voluntary contraction. Normal muscle is electrically silent at rest. On slight contraction motor-unit potentials of 500-1000 uV in amplitude and 4-8 ms in duration are recorded. On maximal contraction, as many motor units as possible are recruited and an interference pattern develops. With inflammatory polymyositis the EMG may show a diagnostic triad of:
spontaneous fibrillation
short-duration action potentials in a polyphasic disorganised outline
repetitive bouts of high-voltage oscillations produced by needle contact with diseased muscle.

Needle muscle biopsy of the quadriceps or deltoid is a simple procedure requiring local anaesthetic, a small skin incision (no stitches afterwards), a UCH (University College Hospital) or other muscle biopsy needle, and no subsequent limitation of activity. It can be repeated for serial monitoring of treatment response. Immunohistochemical staining, together with plain histology, gives considerable information on primary and secondary muscle and neuromuscular disease. Although open biopsy yields more muscle, only a small amount of tissue is required and serial open biopsy is clearly problematic.

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Home > 2 SYSTEM-BASED DISEASES > 20 Musculoskeletal disorders > MAJOR MANIFESTATIONS OF MUSCULOSKELETAL DISEASE
MAJOR MANIFESTATIONS OF MUSCULOSKELETAL DISEASE
JOINT PAIN
ACUTE MONOARTHRITIS
Acute monoarthritis should always lead to consideration of sepsis and crystals, but other causes are listed in Box 20.10. Monoarthritis can be the presentation of what subsequently evolves into oligo- or polyarthritis, and atypical presentation of common disease is more prevalent than rare disease.
20.10 PRINCIPAL CAUSES OF ACUTE MONOARTHRITIS IN A PREVIOUSLY NORMAL JOINT
Septic arthritis
Crystal synovitis-gout, pseudogout
Monoarticular presentation of oligo- or polyarthritis
Reactive, psoriatic or other seronegative spondarthritis
Erythema nodosum
Rheumatoid arthritis
Juvenile idiopathic arthritis (JIA)
Trauma-especially if associated with haemarthrosis
Haemarthrosis associated with clotting abnormality
Foreign body reaction (e.g. plant thorn)


Consideration of the following features often reduces the differential diagnosis and suggests the most likely diagnosis:
Age and gender of the patient. Juvenile idiopathic arthritis (JIA) is restricted to children, haemophilia to boys; reactive arthritis is the most common cause in young men; gout presents in middle-aged men; pseudogout mainly targets older women.
Joint involved. Almost every joint disease can affect the knee, but classic target sites typical of certain conditions include the first metatarsophalangeal joint (gout); the big toe interphalangeal joint (reactive/psoriatic arthritis); the elbow and ankle (haemarthrosis, seronegative spondarthritis); the wrist and shoulder (pseudogout); finger joints (psoriasis, plant thorn synovitis).
Speed of onset. Crystal synovitis develops very rapidly, often reaching maximum severity with extreme pain within just 2-12 hours, whereas sepsis is more subacute and continues to progress until treated.
Associated periarticular inflammation. Acute synovitis with surrounding soft tissue swelling and overlying erythema is a classic feature of sepsis and crystals but may also occur with seronegative spondarthritis and erythema nodosum. Haemarthrosis can cause a very tense effusion, often splinting the joint in its loose-pack position, but there is no surrounding swelling or skin change. The combination of small joint synovitis and firm periarticular swelling in a digit-'dactylitis'-is characteristic of psoriasis (fingers, toes) or reactive arthritis (toes).
Additional circumstances surrounding the onset of pain. These include preceding dysentery or new sexual contact with reactive arthritis; intercurrent illness or surgery triggering crystal synovitis; clinical features or a family history of psoriasis; streptococcal sore throat triggering erythema nodosum.

The differential diagnosis differs when acute monoarthritis occurs in a joint that is already abnormal because of damage, most commonly osteoarthritis, or through involvement by inflammatory disease (see Box 20.11). A common situation is an acute flare of inflammation in a single joint of a patient with known rheumatoid disease. Rheumatoid has a strong negative association with crystal deposition, and disproportionate inflammation in one or even two joints in this situation, especially with overlying erythema, should always suggest sepsis.
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20.11 COMMON CAUSES OF ACUTE ARTHRITIS IN A PREVIOUSLY ABNORMAL JOINT
Damaged joint
Pseudogout in association with osteoarthritis
Bone problem
Secondary avascular necrosis
Subchondral collapse or fracture
Cartilage problem
Fibrocartilage tear, cartilage debris
Haemarthrosis
Septic arthritis

Existing inflammatory disease (with or without damage)
Septic arthritis
Exacerbation of underlying disease


Investigation of acute monoarthritis varies according to the clinical situation, but aspiration of the joint is required if there is a possibility of sepsis or crystals.
CHRONIC INFLAMMATORY MONOARTHRITIS
Chronic inflammatory monoarthritis that persists for more than 6 weeks may be due to a variety of causes (see Box 20.12). The knee is the most common site but almost any joint may be involved. If no cause is apparent by 6 months, or if there are radiographic signs of osteopenia, erosion or periostitis, synovial biopsy is usually undertaken to exclude chronic infection or rare causes that have specific treatments. Retrospective studies suggest that about 25% of cases evolve to osteoarthritis and about 25% to rheumatoid arthritis but that 30% remain undiagnosed, especially when the knee is involved.
20.12 CAUSES OF CHRONIC SINGLE SITE SYNOVITIS
Foreign body (e.g. plant thorn)
Infection, including tuberculosis, fungi
Chronic sarcoidosis
Enteropathic arthritis (mainly Crohn's)
Amyloidosis
Pigmented villonodular synovitis
Synovial chondromatosis
Synovial sarcoma
Monoarticular presentation of oligo-/polyarticular disease
Rheumatoid arthritis
Seronegative spondarthritis
Juvenile idiopathic arthritis


OLIGOARTHRITIS
Oligo- or pauciarticular disease is arthritis affecting two, three or four joints or joint groups (for example, the wrist or midfoot, which have many joints but are counted as a single site). By far the most common cause is osteoarthritis, which associates with non-inflammatory symptoms that usually affect just one or a few sites at any one time, even though more asymptomatic multiple joint osteoarthritis may be apparent on examination.
20.13 CAUSES OF INFLAMMATORY OLIGOARTHRITIS
Seronegative spondarthritis
Reactive
Psoriatic
Ankylosing spondylitis
Enteropathic arthritis
Erythema nodosum
Juvenile idiopathic arthritis
Oligoarticular presentation of polyarthritis
Infection, including
Bacterial endocarditis
Neisseria
Mycobacteria


Acute or subacute inflammatory oligoarthritis mainly targets lower limb joints and is usually asymmetrical; it is a common presentation of JIA in children, especially girls, and of seronegative spondarthritis in adults (see Box 20.13). Sequential joint involvement that ascends a limb-for example, a midfoot, followed by the ankle and then the knee on the same side-should always suggest sepsis.
POLYARTHRITIS
Polyarthritis is involvement of five or more joints or joint groups. In determining the cause it is helpful to consider whether the polyarthritis:
is symmetrical (approximately) or asymmetrical
shows predominant or equal involvement for upper and lower limbs
shows predominant or equal involvement for large and small joints
has accompanying periarticular involvement
has accompanying extra-articular features as clues to the diagnosis (see Box 20.14).

A large number of viral infections may cause arthralgia (joint pain with no abnormal examination findings) and rapid onset of an acute symmetrical inflammatory polyarthritis affecting small and large joints of upper and lower limbs that is usually self-limiting within 6 weeks. These include parvovirus B19, hepatitis B and C, mumps, rubella, chickenpox and infectious mononucleosis. The rapidity of onset, the presence of fever and the characteristic rash usually suggest the diagnosis. Arthritis usually precedes jaundice from hepatitis B. Rubella arthritis mainly affects girls and women, occurring 1-7 days after the rash or 2-6 weeks after vaccination. Rubella is exceptional in that, although the symmetrical polyarthritis settles, oligoarthritis may persist for some months.
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20.14 EXAMPLES OF EXTRA-ARTICULAR FEATURES THAT ASSOCIATE WITH INFLAMMATORY OLIGO- OR POLYARTHRITIS
Clinical feature Disease association
Skin, nails and mucous membranes
Psoriasis, nail pitting Psoriatic arthritis and dystrophy
Raynaud's Lupus, scleroderma
Photosensitivity Lupus
Livedo reticularis Lupus
Splinter haemorrhages, Vasculitis nail-fold infarcts
Oral ulcers Lupus, reactive arthritis, Behçet's
Large nodules (mainly Rheumatoid arthritis, gout extensor surfaces)
Clubbing Enteropathic arthritis, metastatic lung cancer, endocarditis
Eyes
Uveitis Seronegative spondarthritis
Conjunctivitis Reactive arthritis
Episcleritis, scleritis Rheumatoid arthritis, vasculitis
Urethritis Reactive arthritis
Heart, lungs
Pleuro-pericarditis Lupus, rheumatoid arthritis
Fibrosing alveolitis Rheumatoid arthritis, lupus, other connective tissue disease
Abdominal organs
Hepatosplenomegaly Rheumatoid arthritis, lupus
Haematuria, proteinuria Lupus, vasculitis, scleroderma
Urethritis Reactive arthritis
Fever, lymphadenopathy Infection, systemic JIA



Figure 20.11 Contrasting patterns of involvement in polyarthritis. A Rheumatoid arthritis (symmetrical, small and large joints, upper and lower limbs). B Seronegative psoriatic arthritis (asymmetrical, large > small joints, associated periarticular inflammation giving dactylitis). C Seronegative inflammatory spondylitis (axial involvement, large > small joints, asymmetrical).
20.15 CAUSES OF POLYARTHRITIS
Cause Characteristics
Non-inflammatory
Generalised osteoarthritis Very common, symmetrical, small and large joints, Heberden's nodes, only a few joints symptomatic at any one time
Haemochromatosis Rare, small and large joints
Acromegalic arthropathy Rare, mainly large joints, spine
Inflammatory
Viral arthritis Very acute, self-limiting
Rheumatoid arthritis Symmetrical, small and large joints, upper and lower limbs
Seronegative spondarthritis (Psoriasis, reactive, ankylosing spondylitis, enteropathic arthropathy) Asymmetrical, large > small joints, lower > upper limbs, spondylitis
Lupus Symmetrical, small > large joints, joint damage uncommon
Chronic gout Distal > proximal joints, preceded by acute attacks
Juvenile idiopathic arthritis Symmetrical, small and large joints, upper and lower limbs
Chronic sarcoidosis Symmetrical, small and large joints
Scleroderma and polymyositis Rare, small and large joints
Hypertrophic osteoarthropathy Rare, large > small joints, clubbing

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Polyarthritis that persists for more than 6 weeks is unlikely to be viral (see Box 20.15). A definitive diagnosis may be difficult in the first few months of onset but often becomes firmer as more characteristic features develop with time. However, certain patterns are characteristic and may be present at or soon after presentation (see Fig. 20.11). Rheumatoid arthritis is by far the most common cause of chronic inflammatory, symmetrical polyarthritis affecting small and large joints of upper and lower limbs. Tenosynovitis and bursitis (i.e. synovial inflammation) are the main periarticular manifestations. Marked asymmetry, lower limb predominance and involvement of large more than small joints are all more characteristic of seronegative spondarthritis. Concurrence of enthesitis, associated diffuse periarticular swelling and inflammatory spondylitis may be further clinical markers of spondarthritis. Lupus usually causes more arthralgia and wrist extensor tenosynovitis than overt synovitis. Chronic polyarthritis due to gout is inevitably preceded by a long history of acute attacks. Other causes of polyarthritis are rare.
A detailed history and examination often reveal the likely diagnosis and direct investigation. For inflammatory polyarthritis present for less than 6 weeks the full blood count, liver function tests and viral serology are often appropriate. For early persistent polyarthritis of indeterminate cause appropriate initial investigation should include the full blood count, ESR, CRP, liver function, rheumatoid factor and antinuclear antibody, and radiographs of hands and feet.
REGIONAL PERIARTICULAR PAIN
SINGLE REGIONAL PAIN
This usually results from an over-usage strain or injury affecting a periarticular structure. The patient can often state the day or week that it started and may be able to name an obvious provoking event or injury. The pain is non-progressive and reproduced by just one or a few movements. Apart from the pain, the patient feels normal. Examination reveals localised periarticular tenderness and no, or only mild, signs of inflammation, and the pain may be reproduced by resisted active movement or by a stress test for the involved structure. Increasing age, obesity and generalised hypermobility are predisposing constitutional factors and occupational and recreational usage may be relevant to causation.
The duration of symptoms is variable. Muscle injuries usually repair rapidly within days, whereas fibrous structures such as tendons and ligaments may take weeks or months to return to normal. The diagnosis is usually made clinically, though imaging, especially ultrasound and MRI, may be required to define the anatomy of more severe or resistant lesions. Management is aimed towards:
identifying and avoiding, if possible, predisposing or adverse mechanical factors
pain relief (topical and/or oral analgesics, local injection for severe pain)
appropriate exercise and rehabilitation to restore movement and function.
Surgery is only occasionally required for very resistant or disabling lesions.
Shoulder pain
Shoulder pain is a very common MSK complaint in men and women over the age of 40 years, principally due to rotator cuff lesions (see Box 20.16). Varying pain patterns of common lesions are shown in Figure 20.12.
20.16 EXAMINATION FINDINGS IN COMMON PERIARTICULAR LESIONS AT THE SHOULDER
Rotator cuff lesion
Pain reproduced by resisted active movement
Abduction-supraspinatus
External rotation-infraspinatus, teres minor
Internal rotation-subscapularis
Subacromial bursitis
No pain on resisted active abduction (cf. supraspinatus lesion-the other cause of a painful middle arc)
Bicipital (long head) tendinitis
Tender over bicipital groove
Pain reproduced by resisted active wrist supination or elbow flexion




Figure 20.12 Pain patterns around the shoulder.
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Adhesive capsulitis ('frozen shoulder') is an ill-understood condition which presents with upper arm pain that progresses over 4-10 weeks before levelling and then receding over a similar time course. Glenohumeral restriction is present from the outset, but progresses and reaches its maximum as the pain is receding. In the early phase there is marked anterior joint/capsular tenderness and stress pain in a capsular pattern; later there is painless restriction, often of all movements. Frozen shoulder is more common in diabetics and may be triggered by a rotator cuff lesion, local trauma, myocardial infarction or hemiplegia. Treatment in the early stage is with analgesics, intra- and extracapsular corticosteroid injection and regular 'pendulum' exercises of the arm to prevent the capsule from over-tightening. Mobilising and strengthening exercises are the sole treatment in the painless 'frozen' stage. The natural history is for slow but complete recovery, the complete cycle sometimes taking as long as 2 years.
Elbow pain
Pain from the three joint compartments is felt maximally at the elbow, close to its origin, with occasional radiation down the forearm. Lateral epicondylitis is the most common periarticular lesion (see Box 20.17). Olecranon bursitis can follow local repetitive trauma but infection, gout and rheumatoid also commonly affect this bursa.
Hand and wrist pain
Joint disease in the hand produces pain well localised to the involved joints. Pain from the first carpometacarpal joint, commonly targeted by osteoarthritis, is maximal at the thumb base but often radiates down the thumb and back over the radial wrist. Non-articular causes of hand pain include:
tenosynovitis-flexor or extensor (pain, swelling ± fine crepitus on volar or extensor aspect) and de Quervain's
median nerve compression (carpal tunnel syndrome)
Raynaud's phenomenon
C8/T1 radiculopathy
algodystrophy (reflex sympathetic dystrophy).

Trigger finger results from stenosing tenosynovitis in the flexor tendon sheath, with intermittent locking of the finger in flexion. A local corticosteroid injection often relieves the problem and surgical decompression is only occasionally required.
20.17 PERIARTICULAR LESIONS PRESENTING AS ELBOW PAIN
Lesion Pain Examination findings, tests
'Tennis elbow' Lateral epicondyle Tender over epicondyle
Radiation to extensor forearm Pain reproduced by resisted active wrist extension
'Golfer's elbow' Medial epicondyle Tender over epicondyle
Radiation to flexor forearm Pain reproduced by resisted active wrist flexion
Olecranon bursitis Olecranon Fluctuant tender swelling over olecranon

De Quervain's tenosynovitis, involving the tendon sheaths of abductor pollicis longus and extensor pollicis brevis, produces pain maximal over the radial aspect of the distal forearm and wrist. There is tenderness (± warmth, linear swelling, fine crepitus) over the distal radius and marked pain on forced ulnar deviation of the wrist with the thumb held in the patient's palm (Finkelstein's sign). It is usually caused by repetitive over-usage, but bilateral symptoms may occur with gonococcal infection.
Dupuytren's contracture results from fibrosis and contracture of the superficial palmar fascia. Inability to extend the fingers fully is associated with puckering of the skin and the presence of palpable nodules. The ring and little fingers are usually the first and worst affected. It is usually painless and the main symptoms relate to the curled fingers becoming snagged in pockets or poking the eye during face-washing. It is age-related and usually bilateral, strongly predominates in men, and is often familial with a dominant inheritance. Occasional associations include plantar fibromatosis, Peyronie's disease, alcohol misuse and chronic vibration injury. It is very slowly progressive and fasciotomy is seldom necessary.
Hip pain


Figure 20.13 Pain patterns of hip disease and trochanteric bursitis.
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Hip pain is usually maximal deep in the anterior groin, with variable radiation to the buttock, anterolateral thigh, knee or shin (see Fig. 20.13). Sacroiliac pain is maximal in the buttock, with radiation down the posterior thigh, worse on standing on that leg.
Trochanteric bursitis is the most common periarticular lesion (see Box 20.18). It predominates in older, especially obese, women as an isolated lesion or secondary to other problems, such as hip or knee osteoarthritis, that cause an abnormal gait.
Referred pain from other structures may require differentiation. Back pain commonly radiates to the buttock and posterior thigh but the site of maximal pain is close to the spine or pelvic brim. Root entrapment can cause pain to the lateral thigh (T12-L1) or to the inguinal region and lateral thigh (L2-4) but is worsened by coughing and straining more than by movement, and is often accompanied by sensory disturbance. A psoas abscess, retroperitoneal haemorrhage or pelvic inflammation can cause inguinal and lateral thigh pain that is aggravated by resisted hip flexion.
Knee pain
20.18 PERIARTICULAR LESIONS AT THE HIP
Lesion Pain Examination findings, tests
Trochanteric bursitis Upper lateral thigh, worse on lying on that side at night Tender over greater trochanter
Gluteal enthesopathy Upper lateral thigh, worse on lying on that side at night Tender over greater trochanter
Pain reproduced by resisted active hip abduction
Adductor tendinitis Upper inner thigh Tender over adductor origin/tendon/muscle
Usually clearly sports-related Pain reproduced by resisted active hip adduction
Ischiogluteal bursitis Buttock, worse on sitting Tender over ischial prominence
Iliopectineal bursitis Anterior groin Tender (± fluctuant swelling) lateral to femoral pulse, not worsened by internal rotation of hip (cf. hip pain)

The knee is a common target site for arthritis but also a common site for trauma and periarticular lesions. Pain arising from the three knee compartments (arthritis or internal derangement) is anterior and well localised to the involved compartment. Patello-femoral pain is worse going down and up stairs or inclines. Locking-sudden painful inability to extend fully that often spontaneously unlocks and is followed by aching-reflects a mechanical derangement such as a meniscal tear or osteochondritis dissecans. Referred pain from the hip may present at the knee but is more diffuse and often relieved by rubbing; on examination hip not knee movement reproduces it.
Pain from periarticular lesions is well localised to the involved structure (see Box 20.19). Inflammation of any of the three bursae around the patella usually results from repetitive occupational kneeling, but infection and gout may need consideration.
Anterior knee pain syndrome is a common problem, especially in adolescent girls. The pain has patello-femoral characteristics and is often aggravated by sports. In a small proportion there is evidence of non-progressive fibrillation of the retro-patellar cartilage ('chondromalacia patellae'). The condition is usually self-limiting and treatment should be conservative.
The anterior tibial compartment syndrome is characterised by severe pain in the front of the lower leg, aggravated by exercise and relieved by rest. Symptoms result from fascial compression of the muscles in the anterior tibial compartment and may be associated with a foot drop. Treatment is urgent surgical decompression.
20.19 PERIARTICULAR LESIONS AT THE KNEE
Lesion Pain Examination findings, tests
Prepatellar bursitis Anterior patella Tender fluctuant swelling in front of patella
Superficial and deep Infrapatellar bursitis Anterior knee, inferior to patella Tender fluctuant swelling in front of (superficial) or behind (deep) patella tendon
Anserine bursitis Upper medial tibia Tenderness (± warmth, swelling) over upper medial tibia
Inferior medial collateral Upper medial tibia Localised tenderness of upper medial tibia
ligament enthesopathy Pain reproduced by valgus stress on mildly flexed knee
Popliteal ('Baker's') cyst Popliteal fossa Tender swelling of popliteal fossa, usually reducible by massage with knee in mid-flexion
Patella tendon enthesopathy (Osgood-Schlatter disease) Anterior upper tibia Tenderness and firm swelling of tibial tubercle
Mainly energetic adolescents Pain on resisted active knee extension

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Foot and ankle pain
Pain arising from articular and periarticular structures is usually well localised. Pain from the ankle joint is felt anteriorly between the two malleoli and is worse on standing or walking. Subtalar pain is mainly posterior between the malleoli and particularly aggravated by walking on uneven surfaces, requiring eversion/inversion. Periarticular lesions that cause hindfoot pain are listed in Box 20.20.
Midtarsal disease causes pain in the 'bootlace' area, mainly during the late stance and toe-off phase of walking. Loss of the normal arches-pes planus ('flat foot')-may cause pain in the mid-sole. Pes planus is often congenital, but acquired causes include trauma, constitutional hypermobility, rheumatoid arthritis and neuropathic arthropathy. Medial arch supports in well-fitting shoes and/or intrinsic muscle-strengthening exercises usually relieve symptoms but rigid orthotics may be required for hyperpronated feet, provided the foot is not rigid from fusion of the tarsal bones (tarsal coalition).
Metatarsophalangeal (MTP) joint pain is felt below the metatarsal heads (metatarsalgia) and is often described as 'like walking on marbles'. Hallux valgus deformity with secondary bursitis (bunions) and osteoarthritis of the first MTP joint often associates with flattening of the transverse metatarsal arch and is a common cause of forefoot pain. It predominates in women as a consequence of wearing narrow high-heeled shoes. Severe restriction of first MTP joint extension (hallux rigidus), usually due to osteoarthritis, may cause marked pain during attempted toe-off. For both hallux problems, conservative treatment and appropriate footwear usually suffice, although surgery is required for a minority.
Pes cavus ('claw foot') is characterised by a high medial arch, secondary clawing of toes and metatarsal callosities. Rarely, it associates with neurological disorders such as Friedreich's ataxia, spina bifida or poliomyelitis. Associated pain is often helped by medial arch supports and metatarsal insoles, and fasciotomy or osteotomy is rarely indicated.
20.20 PERIARTICULAR LESIONS CAUSING HINDFOOT PAIN
Lesion Pain Examination findings, tests
Plantar fasciitis Under heel, worse on standing and walking Tender under distal calcaneus/plantar fascia insertion site
Subcalcaneal bursitis Under heel, worse on standing and walking Tender under middle of calcaneus
Achilles tendinitis Localised to tendon Tender on squeezing tendon, ± swelling of tendon
Pain reproduced by standing on toes or resisted plantar flexion
Achilles enthesopathy Localised to tendon insertion Tender over insertion site, ± firm swelling
Pain reproduced by standing on toes or resisted plantar flexion
Retro-Achilles bursitis Posterior heel Tenderness and soft swelling posterior to tendon
Pre-Achilles bursitis Posterior heel Tenderness and fluctuant swelling anterior to tendon

Morton's neuroma is an entrapment neuropathy of the interdigital nerves, mostly between the third and fourth metatarsal heads in middle-aged women with ill-fitting shoes. The neuralgic, lancinating pain occurs mainly when the patient is wearing shoes and may associate with local sensory loss and a palpable tender swelling between the metatarsal heads. Footwear adjustment, with or without a local corticosteroid injection, is often sufficient but excision is occasionally required.
MULTIPLEREGIONAL PAIN
Multiple regional 'soft tissue' pain is most commonly due to fibromyalgia. People with this prevalent condition may present with pain at one or a few index sites but enquiry establishes the widespread nature of their pain, often with other typical symptoms, and examination reveals multiple hyperalgesic tender sites.
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Other causes of multiple regional pain without arthropathy include:
Seronegative spondarthritis. Enthesopathy may affect several regions prior to the onset of more characteristic features. Chest wall pains, Achilles enthesopathy and plantar fasciitis are particularly common. Clues may lie in the marked inflammatory component (marked morning stiffness), coexistent back pain and stiffness, preceding uveitis or a strong family history.
Generalised hypermobility. Joint mobility is variable but in general is greater in women than men and in Afro-Caribbeans than in whites, and declines with age. The 10% of adults at the lax end of the spectrum of joint mobility are predisposed to ligament strain, traumatic enthesopathy, mechanical back pain, arthralgia and dislocation (mainly glenohumeral). Such generalised hypermobility may be the explanation of recurrent pain at several regions and is recognised in adults by a modified Beighton score (see Box 20.21). Within this 10% are individuals with disease-associated hypermobility such as in Marfan's syndrome, Ehlers-Danlos syndrome and acromegaly.
Endocrine disease. Hyperparathyroidism and hypothyroidism may both cause ill-defined, widespread pains.
Parkinsonism. This may cause ill-defined regional pain, stiffness and disability. Rigidity, tremor, bradykinesia and other features are usually apparent.
Polymyalgia rheumatica and polymyositis. These may both cause multiple regional symptoms with no clear examination findings. However, marked early morning stiffness and systemic upset are usually prominent.

20.21 RECOGNITION OF GENERALISED HYPERMOBILITY IN ADULTS
Extend little finger > 90° (1 point each side)
Bring thumb back parallel to/touching forearm (1 point each side)
Extend elbow > 10° (1 point each side)
Extend knee > 10° (1 point each side)
Touch floor with flat of hands, legs straight (1 point)
Hypermobile = 6 or more out of a possible 9 points.

BACK AND NECK PAIN
LOW BACK PAIN
Back pain is a 'human condition', with 60-80% of the world's population experiencing pain at some time in their lives. Although there is no evidence that back pain prevalence has increased, reported disability due to back pain, particularly work absence, has increased significantly in the last 30 years. In Western countries, back pain is the most common cause of sickness-related absence from work. In the UK, 7% of the adult population consult their GP each year with back pain, at a cost of £500 million and 80 million working days lost.
Only a small number of patients with back pain have a pathologically definable problem. All structures in the spinal column, other than cartilage, are pain-sensitive, but the exact mechanism of pain production within individual structures is unknown. Amongst patients presenting with back pain, the main role of history and examination is to identify the small number who have a serious or specific spinal disorder. The initial assessment should address the questions in Figure 20.14.
Non-mechanical pain
Non-mechanical pain is constant and has little variation in intensity or with activity. Anorexia, dyspepsia, change in bowel habit, prostatism or abnormal per vagina bleeding may indicate gastric, pancreatic, colonic, prostatic or uterine/ovarian malignancies respectively. Other 'red flags' for possible serious spinal pathology are indicated in Box 20.22. If there is evidence of a spinal cord or cauda equina lesion, this needs urgent neurosurgical assessment (see Box 20.23).


Figure 20.14 Initial triage assessment of back pain.
20.22 RED FLAGS FOR POSSIBLE SPINAL PATHOLOGY
History
Age-presentation under age 20 or over age 50
Character-constant, progressive pain unrelieved by rest
Location-thoracic pain
Past medical history-carcinoma, tuberculosis, human immunodeficiency virus (HIV), systemic steroid use
Constitutional-sweats, malaise, weight loss
Major trauma

Examination
Painful spinal deformity
Severe/symmetrical spinal deformity
Saddle anaesthesia
Progressive neurological signs/muscle-wasting
Multiple levels of root signs


20.23 FEATURES OF CAUDA EQUINA SYNDROME
Difficulty with micturition
Loss of anal sphincter tone or faecal incontinence
Saddle anaesthesia
Progressive motor weakness/gait disturbance
Sensory level


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Mechanical pain
Mechanical pain accounts for more than 90% of back pain episodes, usually affecting patients aged 20-55 years. Onset is often acute, associated with lifting or bending. Mechanical pain is related to activity and is generally relieved by rest (see Box 20.24). It is usually confined to the lumbosacral region, buttock or thigh, is asymmetrical, and does not radiate beyond the knee (this implies nerve root irritation). On examination there may be asymmetric local paraspinal muscle spasm and tenderness, and painful restriction of some but not all movements. Back pain precipitated by extension may relate to facet joint hypertrophy or spinal stenosis. Low back pain is more common in heavy manual workers, particularly occupations that involve heavy lifting and twisting (e.g. construction, mining, agriculture and nursing). Psychological factors (e.g. job dissatisfaction, perceived inadequacy of income, depression, anxiety) are important risk factors for both acute back pain and the transition to chronic pain and disability.
20.24 FEATURES OF SIMPLE MECHANICAL LOW BACK PAIN
Pain varies with physical activity (improved with rest)
Sudden onset, precipitated by lifting or bending
Recurrent episodes
Age 20-55
Pain limited to back or upper leg
No clear-cut nerve root distribution
Systemically well
Prognosis good (90% recovery at 6 weeks)


Radicular pain
Radicular (nerve root) pain has a severe, sharp, lancinating quality, radiates down the back of the leg beyond the knee and is aggravated by coughing, sneezing and straining at stool more than by back movement. On examination, there are signs of lumbar nerve root irritation (see Box 20.25). In contrast, referred pain is usually a dull, deep ache, poorly localised with indistinct boundaries.
20.25 FEATURES OF NERVE ROOT PAIN
Unilateral leg pain worse than low back pain
Pain radiates beyond knee
Paraesthesia in same distribution
Nerve irritation signs (reduced straight leg raising which reproduces leg pain)
Motor, sensory or reflex signs (limited to one nerve root)
Prognosis reasonable (50% recovery at 6 weeks)


Inflammatory pain
Inflammatory pain due to spondylitis has a more gradual onset and often occurs before the age of 30. It is usually axial and symmetrical and spread over many segments which may include the thoracic region. Pain from sacroiliitis is maximal in the buttock, with radiation down the posterior thigh. Inflammatory pain associates with marked morning and inactivity stiffness and improves rather than worsens with activity.
Investigations
Plain radiographs are rarely helpful in patients with acute mechanical low back pain, unless red flags are present (see Box 20.22). By the age of 50, 60% of women and 80% of men have radiographic features of 'spondylosis' (vertebral sclerosis and osteophyte, and osteoarthritis of apophyseal facet joints). However, there is no clear correlation between these universal degenerative changes and back pain. Although advanced lumbar spondylosis frequently associates with low back pain, the clinical features are variable and there is a poor correlation with the degree of radiographic changes. Similarly, minor congenital abnormalities, such as spina bifida occulta and transitional vertebrae, are not associated with low back pain.
Plain radiographs may be helpful in persistent pain in a young patient to help confirm a diagnosis of ankylosing spondylosis, and in an older patient to detect vertebral osteoporotic fracture, particularly if there is a history of trauma, prolonged steroid use or known osteoporosis.
If red flags are present, MRI should be undertaken even if plain radiographs are normal. CT is inferior to MRI for assessing soft tissue structures and nerves but is useful for detecting minor abnormalities of bone architecture and when MRI is contraindicated (e.g. pacemaker or metallic clips).
A low haemoglobin and raised CRP or ESR may heighten a clinical suspicion of inflammation or malignancy. A raised acid phosphatase or prostate-specific antigen (PSA) is associated with metastatic carcinoma of the prostate, and raised alkaline phosphatase with other bone metastases and Paget's disease. Myeloma is associated with a monoclonal band on immunoelectrophoresis and the presence of urine light chains (Bence Jones proteinuria). EMG and nerve conduction studies, with or without measurement of somatosensory evoked responses, are occasionally required to confirm the localisation of nerve root lesions.
Management
Most episodes of mechanical low back pain settle spontaneously with explanation, reassurance and simple analgesics. After 2 days, 30% are better and at 6 weeks 90% have recovered. Recurrences of pain are common, however, and the 10-15% of patients with acute back pain who develop chronic pain consume 85% of back pain resources.
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Patient education is paramount and should emphasise that hurt does not imply harm to the underlying structures and that exercise is helpful not damaging. Regular analgesia and/or non-steroidal anti-inflammatory drugs (NSAIDs) may be required to improve mobility and facilitate exercise. Return to work and normal activity should take place as soon as possible. Bed rest is not helpful and may increase the risk of chronic disability. Referral for physiotherapy (e.g. McKenzie technique of passive extension and postural correction) or manipulation should be considered if a return to normal activities has not been achieved by 6 weeks. Low-dose tricyclic drugs also provide analgesic benefits in addition to effects on sleep and mood.
Other treatment modalities occasionally used for acute or chronic low back pain include epidural and facet joint injection, spinal manipulation, traction and lumbar supports. There is currently no RCT evidence to support these interventions (see EBM panel). Surgery is required in fewer than 1% of patients with low back pain.
The management of serious spinal pathology will be dictated by the cause.
EBM
MANAGEMENT OF LOW BACK PAIN
'For acute or recurrent low back pain with or without referred leg pain, bed rest for 2-7 days is worse than placebo or ordinary activity. Continuation of ordinary activity gives equivalent or faster symptomatic recovery and less chronic disability than rest.'
'There is no evidence to support the use of traction, lumbar corsets and support, plaster jackets or facet joint injections for acute low back pain.'
Waddell G, Feder G, McIntosh A, et al. Low back pain evidence review. London: Royal College of General Practitioners; 1996.
Further information: www.cochrane.co.uk

Spondylolysis and spondylolisthesis
Spondylolysis describes any situation where there is a break in the integrity of the neural arch. The principal cause is an acquired defect in pars interarticularis due to a fracture, mainly in gymnasts, dancers and long-distance runners in whom it is an important cause of back pain. Spondylolisthesis is where a defect causes slippage of a vertebra on the one below. This may be congenital, post-traumatic or degenerative. Rarely, it can result from metastatic destruction of the posterior elements.
Uncomplicated spondylolysis does not associate with symptoms but spondylolisthesis can variably associate with low back pain aggravated by standing and walking. More severe cases can result in nerve root compression or a lumbar stenosis syndrome and the vertebral slip is occasionally palpable. Spondylolysis and spondylolisthesis can usually be diagnosed from lateral radiographs of the lumbar spine (see Fig. 20.15). MRI may be required if there is nerve root involvement.
Advice on posture and muscle-strengthening exercises are required in mild cases. Surgical fusion is indicated for severe and recurrent low back pain, and surgical decompression is mandatory prior to fusion in patients with significant lumbar stenosis or symptoms of cauda equina compression.


Figure 20.15 Lumbar spondylolisthesis. Lateral radiograph showing L5/S1 spondylolisthesis with disc space narrowing, sclerosis and a defect in the posterior element (spondylolysis).
Spinal stenosis
Symptoms of spinal stenosis occur due to limitation of space in the vertebral canal. The most common presentation is 'pseudoclaudication' with discomfort in the legs on walking that is relieved by rest, bending forwards or walking uphill. Patients may adopt a characteristic simian posture, with a forward stoop and slight flexion at the hips and knees. Diagnosis is confirmed by CT/MRI. Decompression is indicated if mobility or quality of life is significantly impaired.
Prolapsed intervertebral disc
Age-related reduction in proteoglycan size within the nucleus pulposus diminishes its viscoelasticity, leading to focal damage and disc herniation. These changes occur most frequently at L4 and L5 due to the increased mechanical forces across this area. Most patients have their first episode between the ages of 20 and 30 years. Presentation is with radicular pain (invariably felt below the knee) in combination with evidence of root involvement (sensory deficit, motor weakness, asymmetrical reflexes) and a positive sciatic or femoral stretch test. About 70% of patients improve by 4 weeks. Persistent neurological deficit at 6 weeks is an indication to consider surgery.
Arachnoiditis
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Chronic inflammation of nerve root sheaths in the spinal canal can cause severe low back pain, sometimes combined with nerve root symptoms. Arachnoiditis can complicate meningitis or spinal surgery, but most frequently occurs as a late complication of myelography with oil-based contrast agents. MRI or radiculography can confirm the diagnosis but no satisfactory treatment is available.
Scheuermann's osteochondritis
This disorder predominates in adolescent boys who develop a painless dorsal kyphosis in association with irregular radiographic ossification of the vertebral end plates. Back pain, aggravated by exercise and relieved by rest, may occur if upper lumbar vertebrae are affected, and secondary spondylosis can follow in middle age. Excessive exercise and heavy manual labour before epiphyseal fusion has occurred may aggravate the symptoms. Treatment is avoidance of excessive activity and protective postural exercises. The deformity seldom warrants corrective surgery.
Diffuse idiopathic skeletal hyperostosis (DISH)


Figure 20.16 Diffuse idiopathic skeletal hyperostosis (DISH). Radiograph of thoracolumbar spine showing flowing ossification joining more than four contiguous vertebrae. The disc spaces are preserved and the sacroiliac joints are normal.
DISH ('Forrestier's disease') is a common disorder in the elderly, affecting 10% of men and 8% of women over the age of 65. It associates with obesity, hypertension, type II diabetes mellitus and hyperinsulinaemia. DISH is characterised by florid new bone formation along the anterolateral aspect of at least four contiguous vertebral bodies (see Fig. 20.16). It is distinguished from lumbar spondylosis by the absence of disc space narrowing and marginal vertebral body sclerosis, and from spondylitis by the absence of sacroiliitis or apophyseal joint fusion. It rarely associates with pain and is usually an asymptomatic radiographic finding. Ossifying enthesopathy at peripheral sites may cause pain-for example, under the heel with calcaneal spur formation.
NECK PAIN
Neck pain is less common than back pain as a cause of disability in the working population but is a significant problem in the elderly. Neck pain is usually due to mechanical or degenerative problems, although serious spinal disease needs to be excluded using the same principles as for back pain. Most episodes of transient mechanical neck pain are not associated with demonstrable spinal pathology. Other causes of neck pain are listed in Box 20.26.
20.26 CAUSES OF NECK PAIN
Mechanical
Postural
Whiplash injury
Disc prolapse
Cervical spondylosis
Inflammatory
Infections
Spondylitis
Juvenile idiopathic arthritis
Rheumatoid arthritis
Polymyalgia rheumatica
Metabolic
Osteoporosis
Osteomalacia
Paget's disease
Neoplasia
Metastases
Myeloma
Reticuloses
Intrathecal tumours
Other
Fibromyalgia
Torticollis
Referred pain
Pharynx
Cervical lymph nodes
Teeth
Angina pectoris
Aortic aneurysm
Pancoast tumour
Diaphragm


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Pain arising from neck structures is often poorly localised but maximal close to the neck. Pain from upper segments may radiate to the occiput, temple or face, and pain from lower segments to the scapula, shoulder, arm and occasionally chest wall. Mechanical neck pain is often acute in onset and associated with asymmetrical restriction of neck movements and a history of awkward posture or trauma. Radicular pain may arise from compression from osteophyte or disc prolapse. Most prolapse (70%) affects the C6 disc, compressing the C7 root; 20% affects C5. Massive cervical osteophytes or DISH occasionally cause dysphagia due to oesophageal indentation.
The principles of investigation and management are identical to those for low back pain. Surgery is only required when there are neurological signs of radiculopathy or progressive cervical myelopathy (see p. 1190).
BONE PAIN
CHRONIC BONE PAIN
Subacute or chronic bone pain usually has the following characteristics:
well localised to the site of origin (no radiation)
predominant at or confined to night-time
not clearly worsened by movement or usage (unlike joint or periarticular pain)
not readily reproduced by clinical examination.

Such pain may result from a variety of causes, most notably:
secondary (less commonly, primary) bone tumours
chronic infection (osteomyelitis)
Paget's disease
osteonecrosis
metabolic bone disease (e.g. osteomalacia, hyperparathyroidism).

Other features in the enquiry usually point to the most likely cause. For example, slowly but relentlessly progressive pain with these characteristics suggests destructive disease-malignancy or chronic infection. Malignancy may associate with weight loss, fatigue and symptoms relating to the primary site. Pain that is experienced over a wider area and accompanied by bone deformity strongly suggests Paget's disease. Osteomalacia very commonly associates with limb girdle weakness. Pain from osteonecrosis is initially bony and progressive but then may develop superadded features of joint pain (worse on usage or weight-bearing, ± radiation, reproduced by examination) as the adjacent joint cartilage collapses and the joint is involved (mainly hips, shoulders, elbows). Investigation of bony pain always includes plain radiographs of the symptomatic site and commonly a radioisotope bone scan, with other tests directed by the presumptive diagnosis.
Severe arthropathy with subchondral bone attrition and collapse, most commonly osteoarthritis, may also cause bone pain, though this is inevitably superimposed upon a chronic history of usage-related joint pain.
ACUTE BONE PAIN: FRACTURE
Sudden-onset pain that is very well localised, severe and worsened by even slight movement should always suggest a fracture. This is the major clinical manifestation of metabolic bone disease. From a clinical and aetiological standpoint, fractures are divisible into several subtypes:
Fragility fractures result from relatively minor trauma and are typical of osteoporosis. With vertebral fractures the precipitating factor is often bending or lifting and with long bone fractures the trigger is usually a simple fall (from standing height or less).
Pathological fractures occur in bone that is structurally abnormal, such as in Paget's disease, osteomalacia, bone metastases and parathyroid bone disease. Like fragility fractures, they often occur spontaneously or follow minor trauma.
High-energy fractures result from major trauma (e.g. car crash, falls from a height) and can affect normal bones. The same is true of stress (fatigue) fractures in healthy individuals such as athletes and military recruits who are exposed to minor but repetitive trauma.

Differential diagnosis
Long bone fractures present with acute pain and swelling following trauma. The main differential diagnosis is soft tissue injury, but fracture should be suspected when there is marked pain and swelling, abnormal movement of the affected limb, crepitus or deformity. Femoral neck fractures typically produce a shortened, externally rotated leg that is painful to move. Presentation of vertebral fractures is more variable. Some cause acute severe back pain with radiation to the anterior chest wall, mimicking acute myocardial infarction or pulmonary embolism. Many cause no symptoms or only minor ones, and present with more insidious or intermittent back pain and height loss. The differential diagnosis for chronic back pain is potentially wide (see pp. 981-984), but significant loss of height and acquired structural kyphosis should always suggest osteoporosis as a predisposing cause. Rib fractures often cause pleuritic-type pain that may suggest intrathoracic disease, especially in patients with chronic respiratory disease and associated steroid-induced osteoporosis. Osteoporotic rib fractures are suggested by aggravation of the pain by movement, local tenderness and pain on springing the rib cage.
Investigations and diagnosis
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For suspected fracture, plain radiographs of the affected bone should be taken in at least two perpendicular planes and examined for discontinuity of the cortical outline. This is usually sufficient for diagnosis. If the radiographs are normal but clinical suspicion remains high, other imaging may be used-for example, radioisotope bone scans for fatigue fractures or scaphoid fractures, and CT or MRI scans for fractures of the pelvis or spine. CT or MRI can also help differentiate pathological fractures of the spine due to tumour from fractures due to osteoporosis.
Management
The principles of management are outlined in Box 20.27. Femoral neck fractures present a special management problem since non-union and avascular necrosis are common complications, especially with intracapsular fractures; surgical treatment of these fractures often entails replacing the femoral head with a prosthetic joint.
Rehabilitation is as important as reduction and fixation in determining outcome. A supervised exercise programme is important to avoid muscle-wasting and joint stiffness, both of which impair long-term mobility, especially in the elderly. Older patients with hip fracture also benefit from nutritional supplementation during their hospital stay, and this should be instituted routinely.
Investigating and treating the cause of fracture
20.27 PRINCIPLES OF FRACTURE MANAGEMENT
Action Long bone fractures Vertebral fractures
1. Provide pain relief v v
2. Reduce the fracture and correct deformity v n/a
3. Immobilise the fracture site v n/a
4. Rehabilitate and mobilise v v
5. Investigate and treat the underlying cause v v


(n/a = not applicable)
Patients with high-energy and fatigue fractures generally require nothing further once the fracture has healed. Those with fragility fractures of long bones or vertebral fractures, however, require BMD measurement, especially if other risk factors for osteoporosis are present (see Box 20.7, p. 972), and treatment if it is confirmed (see p. 1027). A radionuclide bone scan should be performed on patients with pathological fracture due to Paget's disease or metastases to define the extent of the disease, and a radiograph taken of any lower limb metastases to assess the likelihood of fracture. Lytic lesions that have eroded more than 50% of the cortex are likely to fracture and should be considered for prophylactic surgical fixation. Patients with metastases may also need treatment with prophylactic bisphosphonates, radiotherapy or chemotherapy, depending on the tumour type (see p. 1033). Fractures associated with hyperparathyroidism and Paget's disease require no special treatment, but patients with these diseases should be kept well hydrated and their serum calcium monitored post-operatively because they are at risk of hypercalcaemic crisis. Patients with fractures due to osteogenesis imperfecta or fibrous dysplasia should be considered for intravenous bisphosphonate treatment, since this appears to reduce the risk of new fractures.
MUSCLE PAIN AND WEAKNESS
Acute muscle weakness can arise from a variety of metabolic, endocrine, infective and neurological causes. It is important to distinguish between:
a subjective feeling of generalised weakness or fatigue
objective 'true' weakness with loss of muscle power and function.
The former is often a non-specific manifestation of many organic diseases and also psychological distress. Conversely, the diagnosis of muscle disease may be delayed because weakness is misinterpreted as fatigue.
Proximal muscle weakness
This usually indicates a proximal myopathy which typically causes difficulty with standing from a seated position, squatting and lifting overhead. Distal power, such as grip, is usually preserved. The causes of proximal myopathy (see Box 20.28) are either inflammatory (myositis) or non-inflammatory (due to endocrine or metabolic abnormalities or toxins).
20.28 CAUSES OF PROXIMAL MUSCLE PAIN AND WEAKNESS
Inflammatory
Polymyositis
Dermatomyositis
Inclusion body myositis

Endocrine
Hypothyroidism
Hyperthyroidism
Addison's
Cushing's
Steroid therapy

Metabolic
Myophosphorylase deficiency
Phosphofructokinase deficiency
Carnitine deficiency
Myoadenolate deaminase deficiency

Drugs/toxins
Alcohol
Cocaine
Fibrates
Statins
Penicillamine
Zidovudine

Infections
Viral (HIV, cytomegalovirus, rubella, Epstein-Barr, echo)
Bacterial (clostridia, staphylococci, tuberculosis, mycoplasma)
Parasitic (schistosomiasis, cysticercosis, toxoplasmosis)


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Hypothyroidism can cause myopathy, usually with CK elevation; in Cushing's disease and steroid myopathy the CK is usually normal. A history of exercise intolerance, with post-exertional cramps (± a family history), suggests a metabolic myopathy, the most common being the glycogen storage disorders. A strong family history and onset in early adulthood are suggestive of a muscular dystrophy. A drug history is important, notably alcohol, which can cause both an inflammatory myopathy and muscle atrophy of type 2 fibres. Myopathy can be associated with several viral infections, including HIV, due to either the virus itself or drug therapy with zidovudine.
Distal or generalised weakness
This usually indicates a neurological cause (e.g. motor neuron disease), which is even more likely if there are sensory abnormalities or if the weakness is unilateral or focal. The weakness of myasthenia gravis is characteristically worsened by repeated exertion (fatigability) and improved by rest, and usually involves the ocular muscles.
Investigations (see p. 973)
Physical examination should establish the presence, pattern and severity of muscle weakness, graded according to the MRC (Medical Research Council) 1-5 scale. General examination should assess for fasciculation, evidence of endocrine disease, malignancy, arthropathy and connective tissue disease.
The most sensitive biochemical test of muscle injury is CK. A raised level confirms the clinical suspicion of muscle inflammation or necrosis but does not establish the cause. Occasionally, the CK is normal, particularly if muscle changes are focal. Because the differential diagnosis of muscle pain and weakness and raised CK is wide, muscle biopsy and EMG are usually required for a precise diagnosis. Using MRI to identify focal areas of muscle abnormality can increase the diagnostic yield from muscle biopsies. In inflammatory myositis, the typical features are muscle fibre necrosis and regeneration in the presence of focal lymphocytic infiltration. Atrophy of grouped fibres suggests a neuromyopathic cause such as denervation. Atrophy of type 2 fibres is a non-specific finding, and may occur with disuse and steroid therapy as well as with a variety of connective tissue diseases.
Management
This is determined by the underlying cause, discussed further in other relevant sections. In all patients with muscle disease, physical therapy to maximise current muscle ability and to improve muscle conditioning may be helpful.
SYSTEMIC ILLNESS
Systemic illness may be the dominant presenting feature of multisystem MSK disease. The essential features are arthralgia and myalgia in combination with weight loss, night sweats, fever, skin rashes, raised inflammatory markers and abnormal urinalysis.
The differential diagnosis is potentially wide but the most important diagnosis to consider is sepsis, particularly bacterial endocarditis and meningococcal infection. If the patient is febrile, unwell or hypotensive, empirical broad-spectrum antibiotics should be initiated after appropriate samples have been taken for culture.
The next important group of conditions to consider is systemic vasculitis. This may require urgent treatment prior to full diagnostic confirmation, particularly if there is evidence of critical organ inflammation. Additional symptoms that may point towards a diagnosis of vasculitis are shown in Box 20.29. Further investigation should include urine microscopy, ANCA and biopsy of accessible affected organs. Immediate empirical management of vasculitis with critical organ involvement is with 1 g i.v. methylprednisolone on 3 consecutive days.
A number of other conditions may mimic both sepsis and vasculitis, including disseminated malignancy, lymphoma, atrial myxoma, cholesterol emboli and the antiphospholipid syndrome.
20.29 CLINICAL FEATURES THAT MAY ACCOMPANY MULTISYSTEM MSK DISEASE
Systemic
Malaise
Fever
Night sweats
Weight loss in combination with arthralgia and myalgia

Skin rashes
Palpable purpura
Pulp infarcts
Ulceration
Livedo reticularis

ENT
Epistaxis
Recurrent sinusitis
Deafness
Respiratory cough
Haemoptysis
Wheeze (uncontrolled asthma)

Gastrointestinal
Mouth ulcers
Diarrhoea
Abdominal pain (due to mucosal inflammation or enteric ischaemia)

Neurological
Sensory or motor neuropathy



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Home > 2 SYSTEM-BASED DISEASES > 20 Musculoskeletal disorders > PRINCIPLES OF MANAGEMENT OF MUSCULOSKELETAL DISORDERS
PRINCIPLES OF MANAGEMENT OF MUSCULOSKELETAL DISORDERS
For the majority of MSK conditions the aims of management are to:
educate the patient
control pain
optimise function
beneficially modify the disease process.
These aims are interrelated and success in one area often benefits the others. Successful management inevitably requires careful assessment of the person as well as his or her MSK system. The management plan needs to be individualised and patient-centred, taking into account holistic factors such as:
the person's daily activity requirements, and work and recreational aspirations
risk factors and associations of the MSK condition (e.g. obesity, muscle weakness, non-restorative sleep)
the person's perceptions and knowledge of his or her condition
medications and coping strategies already tried by the patient
comorbid disease and its therapy
the availability, costs and logistics of appropriate evidence-based interventions.

The plan needs to be agreed and understood by both patient and practitioner. Simple and safe interventions should be tried first. The patient's symptoms and signs will change with time, and require review and readjustment rather than rigid continuation of a single plan or algorithm. The wide variety of treatment approaches may require the expertise of a number of health professionals, necessitating a coordinated multidisciplinary team approach for some patients.
20.30 INTERVENTIONS FOR PATIENTS WITH MUSCULOSKELETAL PAIN
Core
Education
Exercise
Aerobic conditioning
Strengthening
Reduction of adverse mechanical factors
Pacing of activities
Appropriate footwear
Weight reduction if obese
Simple analgesia
Other options
Other analgesic drugs
Oral NSAIDs
Topical creams
Opioid analgesics
Amitriptyline
Slow-acting antirheumatic drugs
Corticosteroids
Local injections
Physical treatments
Aids, appliances
Surgery
Coping strategies


The principal core interventions that should be considered for every patient with a painful MSK condition are listed in Box 20.30. In addition, there are other non-pharmacological and drug options from which to select, the choice depending largely on the nature and severity of the MSK diagnosis.
CORE INTERVENTIONS
Education
It is every doctor's responsibility to inform patients about the nature of their condition and its investigation, treatment and prognosis. As well as this being a professional responsibility, education can improve outcome.
Information access and therapist contact can reduce pain and disability, improve self-efficacy and reduce the health-care costs of many MSK conditions, including osteoarthritis and rheumatoid arthritis. This is by unknown mechanisms other than improved adherence to the management plan. Such benefits are modest but potentially long-lasting, safe and cost-effective (see EBM panel). Education can be provided in various ways, including one-to-one discussion with health professionals, written literature, patient group education classes (with patients leading the sessions) and interactive computer programs. Inclusion of the patient's partner or carer is often appropriate; this is clearly essential for childhood conditions but also beneficial for many chronic adult conditions such as rheumatoid arthritis or fibromyalgia.
EBM
MANAGEMENT OF ARTHRITIS-role of education
'RCTs have shown that education as an intervention results in substantial and prolonged benefits in terms of perceived ability to manage arthritis, reduction in pain and improved psychological well-being.'
Barlow JH, Turner AP, Wright CC. Long-term outcomes of an arthritis self-management programme. Br J Rheumatol 1998; 37:1315-1319.
Fries JF, Carey C, McShane DJ. Patient education in arthritis: randomized controlled trial of a mail-delivered program. J Rheumatol 1997; 24:1378-1383.
Mazzuca SA, Brandt KD, Katz BP, et al. Reduced utilization and cost of primary care clinic visits resulting from self-care education for patients with osteoarthritis of the knee. Arthritis Rheum 1999; 42:1267-1273.
Further information: www.cochrane.co.uk

Exercise
MSK tissues require regular movement for their health. If compromised by disease, it is even more important to maintain movement. Two types of exercise commonly require prescription:
Aerobic fitness training can produce long-term reduction in MSK pain and disability. It improves well-being, encourages restorative sleep and benefits common comorbidity such as obesity, diabetes, chronic heart failure and hypertension.
Local strengthening exercise for muscles that act over compromised joints also reduces pain and disability, with accompanying improvements in the reduced muscle strength, proprioception, coordination and balance that associate with chronic arthritis. 'Small amounts, often' of strengthening exercise are better than protracted episodes performed infrequently.

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Reduction of adverse mechanical factors
Excessive impact-loading and adverse repetitive usage of a compromised joint or periarticular tissue can often be reduced through discussion with the patient: for example, cessation of avoidable activities such as contact sports, or altered use of machinery or tools at the workplace. Simple 'pacing' of activities-dividing physically onerous tasks into shorter segments with brief breaks in between-is relevant to any patient with MSK pain. Use of shock-absorbing footwear with thick soft soles can reduce impact-loading through feet, knees, hips and back, and improve symptoms at these sites. A walking-stick held on the contralateral side takes weight off a painful hip, knee or foot.
Advice on weight loss if obese
Obesity aggravates pain at most sites of the body through increased mechanical strain, and is a risk factor for more rapid progression of joint damage in patients with arthritis. Obese subjects should receive an explanation of the mechanical effects and health implications of their weight and be offered strategies on how to lose weight initially and then maintain an appropriate weight.
Simple analgesia
Paracetamol (1 g 6-8-hourly) is the oral analgesic of choice and, if successful, the preferred long-term oral analgesic. This is because of its efficacy, lack of contraindications or drug interactions, long-term safety, low cost and availability. Paracetamol inhibits prostaglandin synthesis centrally in the brain but has no effect on peripheral production of prostaglandins.
OTHER TREATMENTS
PHARMACOLOGICAL OPTIONS FOR DIRECT SYMPTOM CONTROL
Non-steroidal anti-inflammatory drugs (NSAIDs)
These are among the top five most prescribed drugs in many countries. Oral NSAIDs are often effective for the pain and stiffness of inflammatory disease. Long-acting NSAIDs given at night are particularly helpful for marked inflammatory early morning stiffness. NSAIDs also often reduce bone pain due to secondary malignant lesions. For chronic symptoms they may need to be taken for 2-3 weeks before their optimal effect is seen. Although NSAIDs show similar overall efficacy, there is marked variability in individual patient tolerance and response; patients who do not respond to one may still experience symptom relief from another.
NSAIDs reduce prostaglandin levels through inhibition of prostaglandin H synthase or cyclo-oxygenase (COX). Arachidonic acid, derived from membrane phospholipids, is catalysed to prostaglandins and leukotrienes by the COX and 5-lipoxygenase pathways respectively (see Fig. 20.17). There are two isoforms of COX, encoded by distinct genes and differing in their distribution and expression. COX-1 is constitutively expressed and functions largely as a 'housekeeping' enzyme in tissues such as the gastric mucosa, platelets and kidneys. In contrast, the 'inflammatory' enzyme COX-2, although constitutively expressed in some tissues (brain, ovary, uterus, cartilage, bone, kidney), is largely induced at sites of inflammation, producing prostaglandins that are involved in peripheral inflammation and pain. In response to inflammation COX-2 is also upregulated in the central nervous system, where it plays an essential role in the central mediation of pain and production of fever. Although NSAIDs inhibit both COX enzymes, COX-2 inhibition is largely responsible for their analgesic, anti-inflammatory and antipyretic effects. Whilst NSAIDs have 'anti-inflammatory' activity they do not reduce peripheral cytokine production, acute phase reactants or ESR.
Side-effects of NSAIDs
The major drawback of NSAIDs is gastrointestinal toxicity. They can damage the gastric mucosal barrier and are an important aetiological factor in up to 30% of gastric ulcers. These drugs also reduce the integrity of the duodenal mucosa but are probably responsible for only a small proportion of duodenal ulcers. They greatly increase the risk of bleeding or perforation from pre-existing gastric and duodenal ulcers.
Mechanisms of NSAID toxicity. Prostaglandins of the E series also play a major role in the maintenance of gastroduodenal defence mechanisms. By depleting mucosal prostaglandin levels, aspirin and NSAIDs impair this 'cytoprotection', resulting in mucosal injury, erosions and ulceration. The risks are appreciable.


Figure 20.17 COX-1 and COX-2 pathways.
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20.31 SOME COMMONLY USED NSAIDs AND THEIR RELATIVE RISK OF GASTRODUODENAL BLEEDING AND PERFORATION
Drug Daily dose Doses/day Idiosyncratic side-effects, comments
Low risk
Ibuprofen < 1.6 g 3-4 Weak anti-inflammatory effect at this dose
Etodolac 600 mg 1 Partially selective COX-2 inhibitor
Meloxicam 7.5-15 mg 1 Partially selective COX-2 inhibitor
Nabumetone 500-1500 mg 1-2 Partially selective COX-2 inhibitor
Medium risk
Ibuprofen 1600-2400 mg 3-4
Naproxen 500-1000 mg 1-2
Diclofenac 75-100 mg 2-3 Abnormal liver function tests
High risk
Indometacin 50-200 mg 3-4 High incidence of dyspepsia and CNS side-effects (headache, dizziness, confusion)
Ketoprofen 100-200 mg 2-4
Highest risk
Piroxicam 10-30 mg 1-2 Restricted use, especially in those over 60 years
Azapropazone 1200 mg 2-4 Marked uricosuric action
Restricted use, especially in those over 60 years

For example:
Approximately 1% of patients with rheumatoid arthritis or osteoarthritis are hospitalised each year because of NSAID-associated gastroduodenal bleeding.
Endoscopic evidence of peptic ulceration is found in 20% of NSAID users even in the absence of symptoms.
The annual mortality from NSAID-associated bleeding/perforation is estimated to be about 16000 people in the US and 2000 in the UK (i.e. higher than deaths from diseases such as myeloma, asthma, cervical cancer or Hodgkin's disease).

The adjusted increased risk (odds ratio) of bleeding or perforation from all NSAIDs is 4-5, though differences exist between NSAIDs (see Box 20.31).
Dyspepsia is no guide to the presence of NSAID-associated ulceration, or to the risk of complications. Principal risk factors for NSAID-associated bleeding and perforation are shown in Box 20.32, the most important being ageing and previous history of peptic ulceration. The main risk of dying from bleeding or perforation is in the elderly and in those with comorbidity, especially cardiovascular disease. Co-prescription of omeprazole (20 mg daily) or misoprostol (200 µg 8-12-hourly) can reduce the incidence of NSAID-associated ulceration and complications, but H2 antagonists are ineffective in this respect.
Recently, highly selective COX-2 inhibitors with no physiologically evident COX-1 inhibition have been developed ('coxibs'-celecoxib 100-200 mg 12-hourly, rofecoxib 12.5-25 mg once daily). These associate with no increased risk of gastroduodenal ulceration. They do, however, have other NSAID side-effects and currently are relatively expensive.
Management of NSAID-induced ulcers. Where possible, the offending drug should be stopped. If an NSAID must be continued, then one with a lower risk of complications, e.g. ibuprofen or diclofenac, should be used at the lowest effective dose. Co-prescription of a proton pump inhibitor (e.g. omeprazole 40 mg daily) will heal most, but not all, ulcers.
20.32 RISK FACTORS FOR NSAID-INDUCED ULCERS
Age > 60 years
Past history of peptic ulcer
Past history of adverse event with NSAIDs
Concomitant corticosteroid use
High-dose or multiple NSAIDs
Individual NSAID-highest with azapropazone, piroxicam, ketoprofen; lower with ibuprofen


EBM
NSAID-INDUCED PEPTIC ULCER-role of omeprazole
'Omeprazole is more effective than either misoprostol or ranitidine in healing peptic ulcers in patients taking NSAIDs. Omeprazole reduces the risk of new ulcer formation in patients taking NSAIDs.'
Yeomans ND, Tulassay Z, Juhasz L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med 1998; 33:719-726.
Hawkey CJ, Karrasch JA, Szczepanski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med 1998; 338:727-734


Other important common side-effects of NSAIDs. These include fluid retention (renal effects of COX-1 and COX-2 inhibition), non-ulcer-associated dyspepsia, abdominal pain and altered bowel habit, and rashes. Interstitial nephritis, asthma and anaphylaxis are rare. There are concerns that long-term NSAIDs may hasten cartilage and bone damage in osteoarthritis, but human data on this are sparse. Unlike other NSAIDs aspirin causes irreversible, rather than reversible, inhibition of platelet COX-1, even at low doses (which have little effect on most tissue COX-2). Higher doses of aspirin or salicylate are required for effective anti-inflammatory (COX-2) activity, but because of frequent toxicity at such doses they have been superseded by other NSAIDs for relief of MSK symptoms.
Advice on NSAID prescribing is summarised in Box 20.33.
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20.33 RECOMMENDATIONS FOR THE USE OF NSAIDs
Current use of anticoagulants is a contraindication to NSAID use
Try to avoid the use of NSAIDs in the elderly and in those with important comorbidity
Start with the lowest dose of one of the safer established NSAIDs (e.g. ibuprofen) and only increase the dose if required
If an unsatisfactory result is obtained with one NSAID, a trial of another NSAID may still be warranted
Never prescribe more than one NSAID at a time
Allow a 2-3-week trial to assess efficacy of any particular NSAID or dose
For a patient with recognised risk factors for GI ulceration (see Box 20.32) consider co-prescription with omeprazole or misoprostol or use of a coxib


ISSUES IN OLDER PEOPLE
USE OF ORAL NSAIDs
Age is a strong risk factor for major gastrointestinal complications (bleeding, perforation) of NSAID-associated peptic ulceration.
Older people, especially those with cardiovascular comorbidity, are more likely to die if they suffer NSAID-associated bleeding or perforation.
Older people are at greater risk of renal and cardiovascular side-effects of NSAIDs (peripheral oedema, cardiac failure).
Co-prescription of proton pump inhibitors or misoprostol reduces, but does not eliminate, the risk of life-threatening GI complications, and is relatively expensive.
Coxibs have a better GI safety profile than other oral NSAIDs but still associate with renal and cardiovascular complications in the elderly.
For many elderly people oral paracetamol is as effective as oral NSAID for pain relief; because of its greater safety and low expense it remains the oral analgesic of choice.


Nutripharmaceuticals
A wide variety of compounds are available as food supplements and 'health foods' for relief of MSK symptoms. Their rationale for treatment is not always clear, though some, such as glucosamine sulphate and chondroitin sulphate, are normal constituents of cartilage, and others (e.g. selenium, zinc, manganese, copper, and vitamins C, D and E) are trace or oligo-elements required for normal health. Evidence from clinical trials is largely absent, though there are some data that glucosamine, chondroitin and avocado/soybean may provide a slow onset (after several weeks) of modest pain relief in knee osteoarthritis, and that regular glucosamine may slow further structural damage. Interest in such apparently safe compounds is growing and large independent clinical trials to determine the extent of their efficacy are in progress. Currently, however, these agents remain unlicensed and are available for self-medication only.
Topical agents
NSAID creams and gels and capsaicin (chilli extract) cream (0.025%) are both often effective for pain relief from arthritis, especially osteoarthritis, and superficial periarticular lesions affecting hands, elbows and knees. Topical NSAIDs can penetrate to superficial tissues and even to the joint capsule, though intrasynovial levels mainly reflect secondary blood-borne delivery. Topical capsaicin causes pain fibres to discharge substance P. Initial application causes a burning sensation, but continued use 6-hourly depletes substance P, with subsequent pain reduction that is optimal after 1-2 weeks. Topical NSAIDs and capsaicin are extremely safe and may be used as monotherapy or as adjunctive treatment with paracetamol or other oral analgesics. They are particularly suited to patients with just one or a few painful regions but not for multiple regional or deep-seated axial pain. Topical rubefacients may act through counter-irritation. They often contain several compounds (e.g. nicotinates, camphor, diethylamine, chilli extract) and are mainly available over the counter for self-medication.
Opioid analgesics
Stronger analgesics are sometimes required for moderate to severe pain which is unresponsive to other drug and non-pharmacological approaches. The non-opioid nefopam (30-90 mg 8-hourly) can help moderate MSK pain, though sympathomimetic and antimuscarinic side-effects (nausea, nervousness, dry mouth) often limit its use. Codeine, dihydrocodeine and dextropropoxyphene are relatively mild analgesics, but when combined with paracetamol may give better analgesia than paracetamol alone. Any benefit, however, is often offset by side-effects such as constipation, headache and confusion, especially in the elderly. Because dependence and tolerance may develop with continuous use such combinations are mainly reserved for intermittent control of painful 'flares'.
The centrally acting analgesics tramadol and meptazinol may be useful for temporary, but not long-term, control of severe pain unresponsive to other measures. The opioid analogue tramadol (50-100 mg up to 4-hourly, maximum 400 mg/day) may produce analgesia by several mechanisms-as a non-selective agonist at opioid (mainly µ) receptors, by inhibiting neuronal re-uptake of noradrenaline, and by enhancing 5-hydroxytryptamine (5-HT, serotonin) release. Meptazinol (200 mg 6-hourly) has mixed agonist and antagonist actions at opioid receptors with highest affinity for µ receptors. Both drugs have poor tolerability due to nausea, bowel upset, dizziness and somnolence, and withdrawal symptoms after chronic use. Patients who appear to require such opioids for MSK pain merit assessment by specialist teams.
Amitriptyline
This tricyclic antidepressant with sedative properties prevents neuronal re-uptake and hence inactivation of noradrenaline and 5-HT. When given at lower doses (25-75 mg at night) than are used for depression it can be an effective adjunctive treatment for chronic MSK pain, especially when accompanied by non-restorative sleep. It is the primary drug treatment for fibromyalgia.
SLOW-ACTING ANTIRHEUMATIC DRUGS
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There are an increasing number of drugs that, like corticosteroids, non-specifically suppress chronic inflammatory disease. In contrast to corticosteroids, these drugs have a delayed action and must be taken for weeks or months before benefit occurs. Their precise mode of action is unclear. Nevertheless, such slow-acting drugs can reduce clinical signs of inflammation and improve or normalise objective parameters of the acute phase response. For some agents there is evidence that a successful response may reduce target tissue damage, hence the alternative name 'disease-modifying antirheumatic drug' (DMARD).
Slow-acting drugs are commonly indicated for rheumatoid arthritis, seronegative spondarthritis, juvenile idiopathic arthritis and connective tissue diseases (see Box 20.34). The main indications for use are:
persistent synovitis (>6 weeks)
severe extra-articular disease (e.g. vasculitis, scleritis, renal involvement)
steroid-sparing effect (e.g. polymyalgia rheumatica resistant to low-dose steroid)
inflammatory myositis.

20.34 EXAMPLES OF MORE COMMONLY USED SLOW-ACTING ANTIRHEUMATIC DRUGS
Drug Disease indications Usual maintenance dose Principal side-effects Monitoring requirement Frequency
Hydroxychloroquine RA, lupus retinopathy (rare) 200-400 mg/day corneal deposits, Rash, nausea, diarrhoea, headache, fundoscopy Visual acuity, Amsler chart, 6-12-monthly
Sulfasalazine RA, seroneg 2-3 g/day Nausea, GI upset, rash, hepatitis, neutropenia, pancytopenia (rare) FBC, LFT Monthly for 3 months, then 3-monthly
D-penicillamine RA 250-750 mg/day Rash, stomatitis, metallic taste, proteinuria, thrombocytopenia FBC, urine (protein) Initially 1-2-weekly; 4-6-weekly for maintenance
Gold RA 50 mg/month by i.m. injection Rash, stomatitis, alopecia, proteinuria, thrombocytopenia, myelosuppression FBC, urine (protein) Each injection
Methotrexate RA, seroneg, lupus, CTD, vasculitis, PMR 5-25 mg/week GI upset, stomatitis, rash, alopecia, hepatotoxicity, acute pneumonitis FBC, LFT Monthly
Azathioprine RA, seroneg, lupus, CTD, vasculitis, PMR 50-150 mg/day GI upset, stomatitis, hepatitis, myelosuppression FBC, LFT Initially weekly, then monthly
Leflunomide RA 20 mg/day hypertension Nausea, GI upset, rash, alopecia, hepatitis, FBC, LFT, blood pressure 2-4-weekly
Cyclophosphamide Vasculitis, lupus, myositis 0.5-1 g by i.v. injection, 1-4-weekly Nausea, GI upset, alopecia, cystitis, myelosuppression, azoospermia, anovulation FBC, urine (blood) Each i.v. injection
Chlorambucil RA 4-8 mg/day Nausea, GI upset, myelosuppression, azoospermia, anovulation FBC, LFT Monthly
Ciclosporin (cyclosporin) RA, psoriasis, lupus 150-300 mg/day Nausea, GI upset, hepatotoxicity, renal impairment, hypertension FBC, LFT, creatinine, blood pressure 2-4-weekly


(RA = rheumatoid arthritis; PMR = polymyalgia rheumatica; seroneg = peripheral arthritis due to seronegative spondarthritis; CTD = connective tissue disease; FBC = full blood count; LFT = liver function tests)
All such drugs require regular monitoring for recognised side-effects and are contraindicated in pregnancy, especially the first trimester. They are mainly used as monotherapy, though certain combinations are increasingly used for rheumatoid arthritis. Slow-acting drugs are taken in addition to the patient's pain-relieving drugs, but if successful may reduce analgesic and NSAID requirements. Average doses, principal toxicity and monitoring requirements of slow-acting drugs are summarised in Box 20.34.
Hydroxychloroquine
This antimalarial is often effective for mild to moderate lupus, especially when skin or locomotor involvement predominates. It is a relatively weak antirheumatic drug for rheumatoid arthritis, with a slower than usual onset of action (2-4 months). Despite a wide range of potential side-effects it is usually well tolerated.
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Sulfasalazine
This compound has a good benefit-to-risk profile and is often a first-choice agent for rheumatoid and for the peripheral (not axial) arthritis of seronegative spondarthritis. Nausea and gastrointestinal intolerance are usually avoided by using enteric-coated tablets (500 mg), always taken with food, starting with one tablet daily and building up to the full dose over 2 weeks. The patient should be warned of possible orange staining of urine and contact lenses.
D-penicillamine and intramuscular gold
These old-established treatments are now not first-choice drugs for rheumatoid arthritis because of their high incidence of side-effects. Their main toxicity is marrow suppression, immune-complex nephritis (proteinuria, nephrotic syndrome), rashes and mouth ulcers.
D-penicillamine is started at 125-250 mg daily, away from food, with 125 mg increments every 6 weeks until benefit occurs (maximum 750 mg/day). Reversible metallic taste, rashes, nausea and febrile reactions may occur early; later side-effects include mouth ulcers and nephritis. Very rarely, the drug induces disease resembling lupus, myasthenia gravis or pemphigus. Thrombocytopenia and pancytopenia can develop at any time and are the major concerns. Proteinuria, mild thrombocytopenia, or dropping platelet counts on sequential tests are indications to stop the drug. It may be slowly reintroduced if the abnormalities disappear but should be withdrawn altogether if they recur. Pancytopenia and febrile reactions are absolute indications for drug withdrawal.
Gold (sodium aurothiomalate) is given by deep intramuscular injection. After a small test dose (10 mg) injections of 50 mg are given weekly until benefit occurs, usually by 2-3 months. Injections are then spaced to fortnightly and then monthly. If there is a flare a temporary return to weekly frequency may recapture control. If there is no initial benefit after 6 months, it is abandoned. Any side-effect that develops is potentially serious and precludes further therapy. Pruritic rashes may respond to antihistamines but corticosteroids are indicated for severe exfoliative rashes, marrow suppression and nephropathy. Patients with agranulocytosis usually recover if appropriately managed, but aplastic anaemia carries a significant mortality.
Non-specific anti-inflammatory immunosuppressive drugs
Several cytotoxic and immunomodulatory drugs have slow-acting antirheumatic actions at low doses. Their use is mainly limited by toxicity. Because they often impair immunocyte number and function, they may compromise immunosurveillance and increase the risk of neoplasia, especially solid tumours and lymphomas. Such risks are difficult to estimate, especially since the primary condition itself may have an increased risk. In general, risk of drug-induced neoplasia is lower in patients with rheumatic disease compared to organ transplant patients, possibly reflecting the lower doses used. Evidence for a significant risk of neoplasia mainly relates to cyclophosphamide and chlorambucil. Another generic side-effect is increased risk of infection, bacterial and/or viral (e.g. zoster), though this needs balancing against the increased risk of infection in patients with uncontrolled systemic inflammatory disease.
Methotrexate
This antimetabolite competitively inhibits dihydrofolate reductase, interfering with DNA synthesis and cell division and causing cytotoxicity at high doses. It is often the first-choice slow-acting drug (or second after sulfasalazine or hydroxychloroquine) for rheumatoid arthritis, peripheral synovitis of seronegative spondarthritis, lupus or connective tissue disease. It works relatively quickly, often within 1-2 months. It is usually given as a weekly oral dose starting at 5 mg and increasing in 2.5 mg increments every 3-4 weeks until benefit occurs (maximum 30 mg). It is usually well tolerated but can cause nausea and malaise for 24-48 hours after ingestion. Marrow suppression is rare but hepatotoxicity and hepatic fibrosis may occur, especially at higher doses. Folic acid (5 mg/day) reduces the incidence of adverse effects without reducing efficacy. Patients should be warned of drug interaction with sulphonamides and to avoid excess alcohol, which enhances methotrexate hepatotoxicity. Acute pulmonary toxicity is rare but can occur at any time during treatment. Patients should therefore be warned to seek early advice if they develop unexplained breathlessness.
Azathioprine
Following absorption, azathioprine is metabolised to 6-mercaptopurine (6-MP), which is then converted intracellularly to active purine thioanalogues. These purine antimetabolites remain in the cell and inhibit DNA and RNA biosynthesis. The oral dose range is 1.5-2.5 mg/kg/day with food. Common adverse effects are nausea, diarrhoea and mouth ulcers; hepatitis and marrow suppression are less common. Since 6-MP requires oxidation by xanthine oxidase before renal excretion, coadministration of allopurinol increases its toxicity; if both drugs are required, azathioprine should be reduced to 25% of the original dose.
Leflunomide
This novel isoxazole inhibits both uridine monophosphate production and tyrosine kinases and is an effective inhibitor of activated lymphocytes. It is currently only indicated for rheumatoid arthritis. It is given orally as a loading dose for 3 days (100 mg daily), followed by a daily dose of 20 mg. It is usually well tolerated, with low marrow toxicity.
Cyclophosphamide and chlorambucil
These alkylating agents directly bind DNA, RNA and other proteins. Both are potentially mutagenic and teratogenic. Cyclophosphamide is the most commonly used. It is inactive until converted by the cytochrome P-450 oxidase system to phosphoramide mustard and acrolein. It may be given daily as tablets (1-2 mg/kg/day) or more commonly, for induction of remission, as 'pulse' intravenous injections (0.5-1.5 g/m2) weekly or monthly. Common adverse effects include nausea, vomiting, reversible alopecia and susceptibility to infection. The incidence of acrolein-related haemorrhagic cystitis is reduced by good hydration and ingestion of mesna. Because of the high risk of azoospermia and anovulation, which may be permanent, pre-treatment sperm or ova collection and storage may need consideration.
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Ciclosporin (cyclosporin) A
This is a fungal cyclic polypeptide that blocks resting lymphocytes in the G0 or G1 phase of the cell cycle, inhibiting lymphokine production and release. It is toxic and expensive and usually reserved for patients resistant to other slow-acting agents. Its dose range is 2.5-4 mg/kg daily given in two divided doses 12-hourly.
TARGETED ANTICYTOKINE TREATMENT
A number of agents with specific actions to inhibit the effects of individual cytokines are now being developed. Tumour necrosis factor alpha (TNF-a) and interleukin-1 (IL-1) are central mediators of inflammation and joint tissue destruction in rheumatoid arthritis. Two anti-TNF biological agents have recently been licensed in several countries for the treatment of active rheumatoid disease. Etanercept is a recombinant protein consisting of a dimer of the extracellular portion of two p75 TNF receptors fused to the Fc portion of human IgG1, administered subcutaneously twice weekly. Infliximab is a chimeric human-murine monoclonal antibody to TNF, administered by i.v. infusion every 1-2 months. Methotrexate is co-prescribed to reduce immunogenicity of infliximab. Whilst both drugs appear to be more effective than standard DMARDs, in view of their cost (approximately £8000-£10 000 per patient per year) their use is currently recommended only when an adequate trial of at least two other DMARDs has failed. The main potential side-effect is a risk of serious infection, particularly reactivation of latent tuberculosis. There is a theoretical risk of immunosuppression-related malignancy, but there are as yet no long-term studies to quantify these risks. Subcutaneous daily injection of IL-1 receptor antagonist has also proved effective in reducing symptoms and radiographic damage in rheumatoid arthritis but is not yet licensed. It is hoped that in the near future a variety of biological anticytokine agents will individually, or in combination, prove very effective treatments for severe inflammatory MSK disease.
CORTICOSTEROIDS
Corticosteroids have a very rapid and dramatic anti-inflammatory action. However, the doses required to maintain adequate symptomatic relief are accompanied by an unacceptable level of side-effects. Furthermore, whether corticosteroids have any disease-modifying antirheumatic activity remains in question. Indications for their use are therefore restricted. Since the incidence of steroid-related side-effects are largely dose- and duration-dependent, the aim is always to use the smallest amount for the shortest time possible to achieve the therapeutic goal.
The main indications for oral or parenteral steroid are listed in Box 20.35. In most cases steroid is initiated for rapid control of inflammatory disease at the same time as commencing a slow-acting antirheumatic drug. After just a few months, when the slow-acting drug is exerting benefit, the steroid is withdrawn. It is usual to gain control with a high initial dose of steroid that is then rapidly reduced to the lowest dose that will maintain control.
20.35 PRINCIPAL INDICATIONS FOR ORAL OR PARENTERAL CORTICOSTEROID
For rapid, short-term (1-3 months) control of marked synovitis or systemic inflammation while awaiting efficacy from slow-acting antirheumatic agent
For life-threatening (e.g. vasculitis) or organ-threatening (e.g. kidney, lung, eye) inflammatory multisystem disease
For primary treatment of polymyalgia rheumatica
For control of inflammatory disease during pregnancy


Prednisolone has predominantly glucocorticoid activity and is the oral steroid of choice. To minimise hypothalamo-pituitary-adrenal axis suppression it should be given as a single morning dose to coincide with peak levels of endogenous cortisol. Initial dosage is up to 10-20 mg daily (45-60 mg for very severe disease). The dose can often be reduced after just a few days and the aim for maintenance is a dose of 7.5 mg daily or less. If higher doses are being required, institution of a slow-acting antirheumatic drug should always be considered. Potential side-effects are numerous (see Box 20.36), although steroid-induced osteoporosis, infection and increased mortality from ischaemic heart disease are the major concerns. Patients receiving oral corticosteroid should be given appropriate bone prophylaxis (see p. 1028) and have any infections treated promptly.
Intramuscular injection of methylprednisolone (80-120 mg) may quickly and effectively control inflammation for variable periods (2-6 weeks). Such an approach, repeated if necessary at 3-6-week intervals, may provide equivalent short-term control whilst avoiding some of the problems of daily prednisolone.
LOCAL INJECTIONS
Intra-articular injections
Injection of a long-acting steroid (e.g. triamcinolone acetonide or hexacetonide) may be useful adjunctive therapy for short-term pain relief (osteoarthritis, inflammatory arthritis) and for temporary control of synovitis of just one or a few joints. The duration of benefit varies according to joint size and the nature and severity of the arthritis, but is in the order of 2-8 weeks. Frequently repeated injections may result in joint tissue atrophy and Cushing's syndrome, and some advise no more than four injections per year into a large joint like the knee. The following simple precautions should be observed:
Never inject if the diagnosis is in doubt.
Do not inject if there is local or systemic infection.
Use an aseptic technique-single ampoules, sterile needle and syringe, clean hands, clean skin (alcohol/antiseptic).
If aspirated fluid is turbid, send it for culture.

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If sensible precautions are taken, the incidence of iatrogenic infection is extremely low. Other unwanted effects are:
facial flushing 24-72 hours post-injection
local skin atrophy, telangiectasia and permanent fat atrophy due to leakage along needle track (especially with fluorinated triamcinolone preparations)
post-injection 'flare' with temporary (1-3 days) symptom exacerbation.

20.36 SIDE-EFFECTS OF CORTICOSTEROIDS
Endocrine
Moon face
Truncal obesity
Hirsutism
Impotence
Menstrual irregularity
Suppression of hypothalamo-pituitary-adrenal axis
Growth suppression

Metabolic
Negative calcium, potassium and nitrogen balance
Sodium and fluid retention
Hyperglycaemia
Hyperlipoproteinaemia

Musculoskeletal
Osteoporosis
Proximal myopathy
Avascular necrosis

Skin
Acne
Thin skin, easy bruising
Facial erythema, telangiectasia
Striae
Impaired wound healing

Immunological
Susceptibility to infection
Suppression of delayed hypersensitivity
Lymphopenia
Possible reactivation of TB

Gastrointestinal
Impaired healing of NSAID-induced peptic ulcers
Pancreatitis

Cardiovascular
Hypertension
Ischaemic heart disease
Congestive heart failure

Ocular
Glaucoma
Cataracts (posterior, subcapsular)

CNS
Changes in mood and personality
Hyperactivity, insomnia
Psychosis
Benign intracranial hypertension


In knee osteoarthritis intra-articular injection of one of several forms of hyaluronan (polymers of hyaluronate) given as a course of weekly injections for 3-5 weeks can give modest pain relief that may be more prolonged (3-6 months) than following a single injection of steroid. Intra-articular injection of radiocolloid (e.g. 90yttrium silicate for large to medium joints, 159erbium for small joints) can give prolonged control of synovitis ('medical' or 'radiation' synovectomy) but should be avoided in patients under the age of 45. Joints are immobilised for 24-72 hours post-injection to reduce spread to regional lymph nodes. The synovium often recovers with return of synovitis after 1-3 years. Indications include: inflammatory synovitis (e.g. rheumatoid) where just one or a few joints are resistant to other measures; synovitis of chronic haemophilic arthropathy; and pigmented villonodular synovitis.
Periarticular injections
Injection of local steroid and/or anaesthetic may give rapid, effective control of pain from periarticular lesions (e.g. bursitis, tenosynovitis, enthesopathy). Such injection will not hasten healing (steroid may retard healing) but its analgesic effect may extend beyond the natural history of the lesion. The rationale for injection is therefore relief of severe or resistant pain. Non-fluorinated steroid should be used for superficial lesions (e.g. lateral epicondylitis, anserine bursitis) to avoid fat and skin atrophy. If anaesthetic is combined with the steroid, quick relief of pain confirms both the diagnosis and accurate placement of the injection. Injection of steroid into, or even adjacent to, certain tendons (e.g. long head of biceps tendon) can predispose to rupture and should be avoided. Steroid injection may also be used to confirm and temporarily benefit peripheral nerve entrapment (e.g. carpal tunnel injection for median nerve entrapment at the wrist).
Nerve blocks
Nerve blocks using steroid and/or long-acting anaesthetics may be helpful for control of severe chronic arthritis or periarticular pain resistant to other means (e.g. suprascapular nerve block for severe glenohumeral arthritis or chronic rotator cuff pain). Epidural injections of corticosteroid may also give temporary relief of troublesome root entrapment symptoms.
PHYSICAL TREATMENTS
Local heat, ice packs, wax baths and other local external applications can induce muscle relaxation and temporary relief of symptoms. Hydrotherapy permits muscle relaxation and enhanced movement in a warm, pain-relieving environment without the restraints of gravity and normal load-bearing. Various manipulative techniques may also help improve restricted movement. Such therapies are often combined with education and therapist contact and this enhances their benefits.
Splints can give temporary rest and support for painful joints and periarticular tissues, and prevent disadvantageous involuntary postures during sleep. Prolonged rest, however, must be avoided. Orthoses are more permanent appliances used to reduce instability and excessive abnormal movement. Examples include working wrist splints, knee orthoses, and iron and T-straps to control ankle instability. Orthoses are particularly suited for severely disabled patients in whom a surgical option is inappropriate, and often need to be custom-made for the individual.
For those with severe disabilities it may be more appropriate to modify the environment around the patient than to try to restore irreversibly damaged joints to normal usage. A variety of simple aids and appliances may transform the lives of disabled patients, permitting dignity and independence with respect to the activities of daily living. Common examples are a raised toilet seat, high rather than low chairs, extended handles on taps, a shower instead of a bath, thick-handled cutlery, and extended 'hands' to pull on tights and socks. Full assessment and advice from an occupational therapist can maximise the benefits from such adaptations.
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SURGERY
There are a variety of surgical interventions that may relieve pain and conserve or restore function in patients with joint and periarticular disease (see Box 20.37).
Soft tissue release and tenosynovectomy may reduce inflammatory symptoms, improve function and prevent or retard tendon damage for variable periods, sometimes indefinitely. Synovectomy of joints does not prevent disease progression but may be indicated for pain relief when drugs, physical therapy and intra-articular injections have provided insufficient relief. Tendon repairs and transfers may also prove useful. The main approaches for damaged joints are osteotomy (cutting bone to alter joint mechanics and load transmission), excision arthroplasty (removing part or all of the joint), joint replacement (insertion of prosthesis in place of the excised joint) and arthrodesis (joint fusion).
20.37 EXAMPLES OF COMMON USEFUL SURGICAL PROCEDURES
Procedure Indication
Soft tissue release (decompression)
Carpal tunnel Median nerve compression
Tarsal tunnel Posterior tibial nerve entrapment
Flexor tenosynovectomy Relief of 'trigger' fingers
Ulnar nerve transposition Ulnar nerve entrapment at elbow
Fasciotomy Severe Dupuytren's contracture
Tendon repairs and transfers
Hand extensor tendons Extensor tendon rupture
Thumb and finger flexor tendons Flexor tendon rupture
Synovectomy
Wrist and extensor tendon sheath (+ excision of radial head) Pain relief and prevention of extensor tendon rupture in rheumatoid arthritis
Knee synovectomy Resistant inflammatory synovitis
Osteotomy
Femoral osteotomy Early osteoarthritis of hip
Tibial osteotomy Unicompartmental knee osteoarthritis
Excision arthroplasty
First metatarsophalangeal joint (Keller's procedure) Painful hallux valgus
Radial head Painful distal radio-ulnar joint
Lateral end of clavicle Painful acromioclavicular joint
Metatarsal head Painful subluxed metatarsophalangeal joints
Joint replacement arthroplasty
Knee, hip, shoulder, elbow Established, successful procedures for painful damaged joints (mainly osteoarthritis)
Arthrodesis
Wrist Damaged joint-pain relief, improvement of grip
Ankle/subtalar joints Damaged joint-pain relief, stabilisation of hindfoot

The main aims of such operations are pain relief and improvements in function and quality of life. Patient expectations need to be realistic. If surgery is to be successful, the aims and consequences of each operation should be carefully explained and considered as part of an integrated programme of management and rehabilitation. This is often best achieved by multidisciplinary teams of surgeons, allied health professionals and physicians. Assessment of motivation, social support and environment are no less important than careful consideration of patients' general health, their risks for major surgery, the extent of disease in other joints and their ability to mobilise following the operation. In particular, it must be appreciated that for some severely compromised people pain relief and functional independence are better served by provision of a suitable wheelchair, home adjustments, physical aids and social services than by surgery that is technically successful but from which the patient cannot mobilise.
COPING STRATEGIES
These are approaches that help patients to cope better with, and to adjust to, their chronic pain and disability. They may be useful at any stage but should be considered particularly for patients with incurable problems who have received all other available treatment options. The aim is to increase self-management through self-assessment, information and problem-solving. This involves patients recognising negative but potentially remediable aspects of their psyche (stress, frustration, anger, low self-esteem or prestige) and their situation (e.g. physical, social, financial). These may then be addressed by changes in attitude and behaviour; for example:
learning yoga and relaxation techniques to reduce stress
avoiding negative situations or activities that regularly produce stress and increasing pleasant activities that give satisfaction
altering beliefs about and perspectives on disease through information and discussion
learning to reduce or avoid catastrophising and maladaptive pain behaviour
learning imagery and distraction techniques for pain
expanding social contact and better utilising social services.

Involvement of the spouse or partner in mutual goal-setting can improve partnership adjustment for individuals with persistent pain. Such approaches are often an element of group education classes and pain clinics, but may require more formal explanation from psychologists or cognitive behavioural therapists.

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Home > 2 SYSTEM-BASED DISEASES > 20 Musculoskeletal disorders > OSTEOARTHRITIS
OSTEOARTHRITIS
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Osteoarthritis (OA, osteoarthrosis) is by far the most common form of arthritis. It shows a strong association with ageing and is a major cause of pain and disability in the elderly. Pathologically, it may be defined as a condition of synovial joints characterised by:
focal loss of articular hyaline cartilage
simultaneous proliferation of new bone with remodelling of joint contour.
Inflammation is not a prominent feature. OA, however, is not a disease or a single condition. It is best viewed as the dynamic repair process of synovial joints that may be triggered by a variety of insults, some but not all of which result in symptomatic 'joint failure'.




Integration link: Osteoarthritis

Taken from Robbins Basic Pathology 7e




Epidemiology
Radiographic and autopsy studies show that OA preferentially targets only certain small and large joints (see Fig. 20.18). There is a steady rise in overall prevalence from age 30 such that by 65, 80% of people have some radiographic evidence of OA, though only 25-30% have associated symptoms. The knee and hip are the principal large joints affected and the principal sites of significant disability. Knee OA is more prevalent than hip OA, but taken together they affect 10-25% of those aged over 65 years. Although joints not targeted by OA are in comparison rarely affected, OA remains the most common cause of arthritis at sites such as the elbow, glenohumeral joint or ankle because it is far more prevalent than are inflammatory arthropathies.


Figure 20.18 The distribution of osteoarthritis. Although osteoarthritis can affect any synovial joint, those shown in red are the most commonly targeted.
Both generalised constitutional and local biomechanical risk factors may predispose to development of OA (see Fig. 20.19). Their relative importance differs at each joint site and between individuals. Twin and family studies show that inheritance is a major attributable factor, particularly for hand and generalised OA but also for hip and knee OA, although the responsible genes have yet to be determined. Knee OA is prevalent in all racial groups but hip, hand and generalised OA are only prevalent in Caucasians. OA is more prevalent and more commonly associates with symptoms in women, except at the hip where both genders are equally affected. Although overt trauma is a commonly recognised local predisposing factor, more subtle repetitive adverse loading of joints during occupation or competitive sports also appears important. Recognised occupational risks for OA include farming (hip OA), mining (knee OA) and professional football (knee OA).
The correlation between the presence of structural OA (clinical signs, radiographic changes) and pain and disability varies according to site. Correlation is stronger at the hip than the knee, and poor at most small joint sites. Risk factors for pain and disability may differ from those for structural change. At the knee, for example, reduced quadriceps muscle strength and adverse psychosocial factors (anxiety, depression) correlate more strongly with pain and disability than the degree of radiographic change. Such factors are potentially modifiable, giving optimism with respect to treatment.
Aetiology and pathogenesis


Figure 20.19 Risk factors for the development of osteoarthritis.
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A variety of mechanical, metabolic, genetic or constitutional insults may damage a synovial joint and trigger the need for repair. Most often the insult remains unclear ('primary' OA) but sometimes a clear cause such as trauma or ligament rupture may be apparent ('secondary' OA). All the joint tissues (cartilage, bone, synovium, capsule, ligament, muscle) depend on each other for health and function. Insult to any one tissue impacts on the others, resulting in a common OA phenotype affecting the whole joint. The OA process is metabolically active, involving new tissue production and remodelling of joint shape. Often the slow but efficient OA process compensates for the insults, resulting in an anatomically altered but pain-free functioning joint ('compensated' OA). Sometimes, however, because of either overwhelming or chronic insult or an inherently poor repair response, it fails, resulting in progressive tissue damage, more frequent association with symptoms, and presentation as an OA patient with 'joint failure'. Such a perspective readily explains the clinical heterogeneity of OA and the variable outcome observed.
Cartilage changes in OA are highly characteristic. There is enzymatic degradation of the major structural components aggrecan and collagen, principally by aggrecanase, collagenase and stromelysin. The chondrocytes increase their production of matrix components and divide to produce clones or nests of metabolically active chondrocytes. Although the turnover of aggrecan components is increased, the concentration of aggrecan eventually falls. The decrease in size of the hydrophilic aggrecan molecules increases the water concentration and swelling pressure in cartilage, further disrupting the retaining scaffolding of type II collagen and making the cartilage vulnerable to load-bearing injury. There is eventual fissuring of the cartilage surface ('fibrillation'), development of deep vertical clefts, localised chondrocyte death and decrease in cartilage thickness. Cartilage loss is focal rather than widespread and usually restricted to the maximum load-bearing part of the joint (see Fig. 20.20). The changes in OA cartilage encourage deposition of calcium pyrophosphate and apatite crystals, especially in the mid- and superficial zones.


Figure 20.20 Pathological changes in osteoarthritis.
The bone immediately below the compromised cartilage increases its trabecular thickness. In some cases this reflects healed trabecular microfractures. Holes ('cysts') often develop, possibly the result of small areas of osteonecrosis caused by the increased pressure in bone as the cartilage fails in its load-transmitting function. At the margins of the joint there is production of new fibrocartilage that then undergoes endochondral ossification to form osteophyte. Despite central and marginal new bone formation, with severe cartilage loss there may be attrition of bone as the two unprotected bone ends wear on each other. Such wear may ablate the trabeculae and lead to a smooth, shiny surface ('eburnation'), often with deep linear grooves. Bone remodelling and cartilage thinning slowly alter the shape of the OA joint, increasing its surface.
The synovium undergoes variable degrees of hyperplasia. Sometimes histological changes are as florid, though not as widespread, as those of rheumatoid arthritis. Osteochondral bodies commonly occur within the synovium, reflecting chondroid metaplasia within the synovium or secondary uptake and growth of damaged cartilage fragments. The outer capsule also thickens and contracts, usually retaining the stability of the remodelling joint. The muscles that act over the joint commonly show non-specific type II fibre atrophy.
Clinical features
The main presenting symptoms of OA are pain and functional restriction. Pain may directly relate to the OA process through increased pressure in subchondral bone (mainly causing night pain), trabecular microfractures, capsular distension and low-grade synovitis, or result from bursitis and enthesopathy secondary to the altered joint mechanics. OA pain typically has the characteristics listed in Box 20.38. For many people functional restriction of the hands, knees or hips is an equal problem to, if not greater problem than pain. The clinical findings vary according to severity but are principally those of joint damage.
It should be remembered that OA is prevalent in middle-aged and elderly subjects, and commonly asymptomatic. Therefore the presence of OA cannot necessarily be taken as an explanation of the patient's problem.
Nodal generalised OA
This common form of OA is characterised by:
polyarticular finger interphalangeal joint (IPJ) OA
Heberden's (± Bouchard's) nodes
marked female preponderance
peak onset in middle age
good functional outcome for hands
predisposition to OA at other joints, especially knees
strong genetic predisposition.

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20.38 TYPICAL CHARACTERISTICS OF PAIN AND CLINICAL SIGNS OF OSTEOARTHRITIS
Pain
Patient over age 45 (often over age 60)
Insidious onset over months or years
Variable or intermittent over time ('good days, bad days')
Mainly related to movement and weight-bearing, relieved by rest
Only brief (< 15 minutes) morning stiffness and brief (< 1 minute) 'gelling' after rest
Usually only one or a few joints painful (not multiple regional pain)

Clinical signs
Restricted movement (capsular thickening, blocking by osteophyte)
Palpable, sometimes audible, coarse crepitus (rough articular surfaces)
Bony swelling (osteophyte) around joint margins
Deformity, usually without instability
Joint-line or periarticular tenderness
Muscle weakness, wasting
No or only mild synovitis (effusion, increased warmth)


Presentation is typically in middle-aged women (in their forties or fifties) who develop pain, stiffness and swelling of one or a few finger IPJs. Gradually, over many months, more finger IPJs (distal > proximal) are recruited. Affected joints develop posterolateral swellings each side of the extensor tendon. They slowly enlarge and harden to become Heberden's (distal IPJ) and Bouchard's (proximal IPJ) nodes (see Fig. 20.21). Typically each joint goes through a phase of episodic symptoms (1-5 years) while the node evolves and OA develops in the underlying IPJ. Once fully established, however, symptoms usually subside and hand function often remains relatively unimpaired. Affected IPJs often show characteristic lateral deviation, reflecting the asymmetric focal cartilage loss of OA. Involvement of the first carpometacarpal joint is also common. At this site marked osteophyte and subluxation may result in 'thumb-base squaring'. Thumb-base OA occasionally causes more chronic symptoms and functional impairment than IPJ OA.


Figure 20.21 Nodal osteoarthritis. Heberden's nodes and lateral deviation of distal interphalangeal joints, with mild Bouchard's nodes at the proximal interphalangeal joints.
People who develop nodal OA are at increased risk of subsequently developing OA at other sites ('generalised OA'), especially the knee. Nodal generalised OA has a very strong genetic predisposition, probably the strongest of all major rheumatic conditions. Many patients give a clear family history, especially in their female relatives, and the daughter of an affected mother has a 1 in 3 chance of developing nodal OA herself. Nodal OA with multiple nodes and symptom onset in middle age should not be confused with just one or two asymptomatic nodes related to past trauma, a very common finding, particularly in the elderly. Some patients with otherwise typical nodal OA have a more prolonged symptom phase and more overt IPJ inflammation, and subsequently develop IPJ instability in some fingers, with subchondral erosions on radiographs. Such 'erosive' OA is uncommon and is probably part of the spectrum of nodal OA rather than a distinct subset.
Knee OA
OA principally targets the patello-femoral and medial tibio-femoral compartments of the knee. It may be isolated or occur as part of nodal generalised OA. Trauma is a more important risk factor in men and may result in unilateral OA. Most knee OA, particularly in women, is bilateral and symmetrical.
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Most knee OA pain is well localised to the anterior or medial aspect of the knee and upper tibia. Patello-femoral pain is usually worse going up and down stairs or inclines. Posterior knee pain suggests a complicating popliteal 'cyst'. Common functional difficulties are prolonged walking, rising from a chair, getting in or out of a car, or bending to put on shoes and socks. Local examination findings may include:
a jerky, asymmetric 'antalgic' gait (see p. 961)-less time weight-bearing on the painful side
a varus (see Fig. 20.22), less commonly valgus, and/or fixed flexion deformity
joint-line and/or periarticular tenderness (secondary anserine bursitis and medial ligament enthesopathy are common, giving tenderness of the upper medial tibia)
weakness and wasting of the quadriceps muscle
restricted flexion/extension with coarse crepitus
bony swelling around the joint line.



Figure 20.22 Typical varus deformity resulting from marked medial tibio-femoral osteoarthritis.
It is at the knee that predisposition to calcium pyrophosphate dihydrate (CPPD) crystal deposition by OA is most evident. Such coexistent crystal deposition may result in a more overt inflammatory component (stiffness, effusions) and superadded acute attacks of synovitis ('pseudogout'-see p. 1018). The presence of knee effusion, increased warmth, CPPD crystal deposition and obesity are suggested risk factors for more rapid radiographic progression and a worse clinical outcome.
Hip OA
Hip OA most commonly targets the superior aspect of the joint (see Fig. 20.23). Such 'superior pole' OA is the usual pattern in men and the predominant pattern in women, and includes most OA that is secondary to structural abnormality. It is often unilateral at presentation, often progresses with superolateral migration of the femoral head, and has a poor prognosis. The less common central (medial) OA shows more central cartilage loss and is largely confined to women. It is often bilateral at presentation, may associate with nodal generalised OA, uncommonly progresses with axial femoral migration, and has a better prognosis.
The hip shows the best correlation between symptoms and radiographic change. Hip pain is usually maximal deep in the anterior groin, with variable radiation to the buttock, antero-lateral thigh, knee or shin. Lateral hip pain, worse on lying on that side with tenderness over the greater trochanter, suggests secondary trochanteric bursitis. Common functional difficulties are the same as for knee OA; in addition, restricted hip abduction in women may cause pain on intercourse.
Examination may reveal:
an antalgic gait
weakness and wasting of quadriceps and gluteal muscles
pain and restriction of internal rotation with the hip flexed-the earliest and most sensitive sign of hip OA; other movements may subsequently be restricted and painful
anterior groin tenderness just lateral to the femoral pulse
fixed flexion, external rotation deformity of the hip
ipsilateral leg shortening with severe joint attrition and superior femoral migration.



Figure 20.23 Patterns of hip osteoarthritis.
Although obesity is not a risk factor for development of hip OA, it is a risk factor for its more rapid progression. The superior pole pattern is also a risk factor.
Young-onset OA
Sometimes patients present with typical symptoms and clinical signs of OA but are younger than expected (<45 years of age). In most cases they have OA at a single joint such as the knee and the explanation of previous overt trauma is apparent in their history. However, in people with apparently young-onset OA affecting several or many joints, especially those not normally targeted by OA, rare causes need to be considered (see Box 20.39). Patients with endemic OA, due to unknown environmental cartilage toxins, will have grown up in just a few specific areas of the world: for example, eastern Russia and northern China ('Kashin-Beck disease').
20.39 CAUSES OF YOUNG-ONSET OSTEOARTHRITIS (< 45 YEARS)
Monoarticular
Previous trauma, localised instability

Pauciarticular or polyarticular
Prior joint disease (e.g. juvenile idiopathic arthritis)
Metabolic or endocrine disease
Haemochromatosis (see p. 870)
Ochronosis
Acromegaly (see p. 742)
(Spondylo-)epiphyseal dysplasia
Late avascular necrosis
Neuropathic joint
Endemic OA


Investigations
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The diagnosis and assessment of common OA are purely clinical. A plain radiograph is the only useful but non-essential investigation. This may show one or more of the typical features of OA, namely focal narrowing of joint space, marginal osteophyte, subchondral sclerosis, cysts, osteochondral ('loose') bodies and deformity (see Fig. 20.7, p. 968). Chondrocalcinosis may be an additional feature, particularly at the knee. The main use of a radiograph is to assess severity of structural change, an issue if surgery is being considered. Although a non-weight-bearing PA view of the pelvis is adequate for assessment of hip OA, standing (stressed) AP radiographs are needed to assess tibio-femoral cartilage loss, and a flexed skyline view is best for patello-femoral OA.
OA does not trigger the acute phase response and therefore has no impact on the full blood count, ESR or CRP. Synovial fluid aspirated from OA knees shows variable characteristics but is predominantly viscous with low turbidity; CPPD crystals may be identified in up to 50% of knee OA fluids. Radioisotope bone scans performed for other reasons often show, as an incidental finding, discrete increased uptake in OA joints due to bone remodelling.
Unexplained young-onset OA requires investigation. Radiographs are often helpful-for example, in showing typical features of dysplasia or avascular necrosis, widening of joint spaces in acromegaly, multiple cysts and chondrocalcinosis in haemochromatosis, or disorganised architecture in neuropathic joints. Other tests are specific to the condition (e.g. serum ferritin and liver function for haemochromatosis, serum growth hormone and skull radiograph for acromegaly, urine homogentisic acid for ochronosis).
Management
Treatment aims are to educate the patient, control pain, minimise disability and handicap, and reduce further structural progression. Management always requires:
Full explanation of the nature of OA (± support literature). This should include risk factors relevant to that individual (e.g. obesity, heredity, trauma); the fact that established structural changes are permanent but that pain and function can improve; discussion of prognosis (good for hand OA, more optimistic for knee than hip OA); and the fact that appropriate action can improve the prognosis of large joint OA.
Advice and instruction on appropriate exercise. This should cover both strengthening and aerobic, preferably with reinforcement by a physiotherapist (see EBM panel).
Reduction of any adverse mechanical factors. These could include weight loss if obese, shock-absorbing footwear, pacing of activities, use of a walking-stick for painful knee or hip OA, or provision of built-up shoes to equalise leg lengths.
Initial trial of paracetamol. Consider the addition of a topical NSAID, and then capsaicin, for knee and hand OA. If required, consider the ascending use of opioid (including combined) analgesics and oral NSAIDs, bearing in mind the side-effects of such agents, especially in the elderly and in those with comorbidity.

EBM
KNEE OR HIP OA-benefit of exercise
'RCTs have shown that both aerobic and strengthening exercise produce modest but long-term improvements in pain, disability and physical performance in people with knee or hip OA, even in older disabled subjects.'
FAST (Fitness Arthritis and Seniors Trial). Ettinger WH, Burns R, Messier SP, et al. A randomised trial comparing aerobic exercise and resistance exercise with a health education program in older adults with knee osteoarthritis. JAMA 1997; 277:25-31.
Van Baar ME, Dekker J, Oostendorp RAB, et al. The effectiveness of exercise therapy in patients with osteoarthritis of the hip or knee: a randomized clinical trial. J Rheumatol 1998; 25:2432-2439.


For temporary benefit of moderate to severe pain consider intra-articular injection of steroid (particularly for knee and thumb-base OA) and hyaluronan (knee OA), and local physical therapies such as heat or cold.
At present there are no disease-modifying drugs for OA. Although there are data from in vitro and animal experiments which show that certain NSAIDs, tetracycline and other agents are 'chondroprotective', there is no convincing evidence for such beneficial effects in human OA. However, lifestyle alteration (reducing obesity, good nutrition, regular appropriate exercise) may reduce structural progression as well as benefit symptoms.
Surgery should be considered if conservative measures fail, the main indications being uncontrolled pain and progressive immobility and functional impairment. Osteotomy may prolong the life of malaligned joints and relieve pain by reducing intraosseous pressure. Joint replacement, however, can effectively transform the quality of life of people with severe knee or hip OA. Factors that influence patient selection for joint replacement are:
pain severity (walking limited to 10 minutes, severe rest/night pain)
age (the older, the better since prostheses have a limited lifespan of approximately 15 years)
fitness for surgery and anaesthesia (especially lung and heart disease), although surgery can be performed under local anaesthesia
exclusion of patients with an unacceptable risk of complications (e.g. active sepsis, leg ulcers or severe peripheral vascular disease).
Contrary to popular opinion, total joint replacements are required for the minority of people with large joint OA. The failure rate for replacements (mainly loosening) is about 15% at 15 years for hip replacements, and 10% at 15 years for knee replacements.
ISSUES IN OLDER PEOPLE
OSTEOARTHRITIS
OA is the major MSK cause of pain and disability in the elderly.
The reduced muscle strength, reduced proprioception and impaired balance that accompany ageing all associate with and contribute to pain and disability from knee and hip OA.
Coexistent calcium pyrophosphate crystal deposition is an age-associated phenomenon that may result in superimposed acute attacks of synovitis ('pseudogout').
Regular strengthening exercise can safely reduce the pain and disability of knee OA with accompanying improvements in lower limb muscle strength, proprioception and balance.
Ageing is not a contraindication to strengthening and aerobic exercise.
Oral paracetamol and topical NSAIDs are safe in the elderly, have no important drug interactions or contraindications and are often effective for pain relief.
Total joint replacement with appropriate rehabilitation is an excellent cost-effective treatment for severe disabling knee or hip OA in the elderly.



pages 996 - 1001


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Home > 2 SYSTEM-BASED DISEASES > 20 Musculoskeletal disorders > INFLAMMATORY JOINT DISEASE
INFLAMMATORY JOINT DISEASE
RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is the most common inflammatory arthritis and hence an important cause of potentially preventable disability. Many of the clinical features and management strategies in RA are relevant across the spectrum of inflammatory joint disease. The typical clinical phenotype of RA is a symmetrical, deforming, small and large joint polyarthritis, often associated with systemic disturbance and extra-articular disease features. The clinical course is usually life-long, with intermittent exacerbations and remissions. Some patients have mild disease; in others it is more severe. It is currently not possible to predict prognosis at presentation accurately, so caution and appropriate treatment are needed in all patients.




Integration link: Rheumatoid arthritis

Taken from Robbins & Cotran's Pathologic Basis of Disease 7e




Epidemiology
RA occurs throughout the world and in all ethnic groups. The prevalence is lowest in black Africans and Chinese, and highest in Pima Indians. In Caucasians it is around 1.0-1.5% with a female:male ratio of 3:1. Prevalence increases with age, with 5% of women and 2% of men over 55 years being affected. RA is uncommon in men under the age of 45, where there is a 6:1 female excess.
Aetiology


Figure 20.24 Pathogenesis of rheumatoid arthritis. Possible sequence of events with network of cells, cytokines and mediators. (IL = interleukin; TNF-a = tumour necrosis factor-a; Th1 and Th2 = Th1 and Th2 lymphocyte subsets; IFN = interferon; MMPs = metalloproteinases; PGE2 = prostaglandin E2)
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No single factor has been identified to date. Evidence for the importance of genetic susceptibility comes from higher concordance rates in monozygotic (12-15%) than in dizygotic twins (3%) and an increased frequency of disease in first-degree relatives of patients with RA. Up to 50% of the genetic contribution to susceptibility is due to genes in the HLA region. HLA-DR4 is the major susceptibility haplotype in most ethnic groups, occurring, for example, in 50-75% of Caucasian patients with RA compared to 20-25% of the normal population. However, DR1 is more important in Indians and Israelis and DW15 in Japanese. It is likely that genetic factors influence both susceptibility and severity, with DR4 positivity more common in those with severe erosive disease.
More specifically, disease susceptibility is associated with a 'shared epitope (SE)' of specific amino acid sequences on the beta 1 chain of a number of class II alleles located in the third allelic hypervariable region of HLA-DR ß1, between amino acid residues 67 and 74, which flank the T-cell recognition site. Population variation in the frequency of SE-positive alleles may explain some of the geographical variation in the frequency of RA.
Female gender is a risk factor and this susceptibility is increased post-partum and by breastfeeding. No infectious agents have been consistently isolated and there is no evidence of disease clustering. Cigarette smoking is a risk factor for RA and for positivity for rheumatoid factor in non-RA subjects. Whatever the initiating stimulus, RA is characterised by persistent cellular activation, autoimmunity and the presence of immune complexes at sites of articular and extra-articular lesions (see Fig. 20.24). This leads to chronic inflammation, granuloma formation and joint destruction.
Pathology
The earliest change is swelling and congestion of the synovial membrane and the underlying connective tissues, which become infiltrated with lymphocytes (especially CD4 T cells), plasma cells and macrophages. Effusion of synovial fluid into the joint space takes place during active phases of the disease. Hypertrophy of the synovial membrane occurs, with the formation of lymphoid follicles resembling an immunologically active lymph node. Inflammatory granulation tissue (pannus) spreads over and under the articular cartilage, which is progressively eroded and destroyed. Later, fibrous or bony ankylosis may occur. Muscles adjacent to inflamed joints atrophy and there may be focal infiltration with lymphocytes.
Subcutaneous nodules consist of a central area of fibrinoid material surrounded by a palisade of proliferating mononuclear cells. Similar granulomatous lesions may occur in the pleura, lung, pericardium and sclera. Lymph nodes are often hyperplastic, showing many lymphoid follicles with large germinal centres and numerous plasma cells in the sinuses and medullary cords. Immunofluorescence confirms rheumatoid factor synthesis by plasma cells in synovium and lymph nodes.
Clinical features
20.40 CRITERIA FOR DIAGNOSIS OF RHEUMATOID ARTHRITIS
Morning stiffness (> 1 hour)
Arthritis of three or more joint areas
Arthritis of hand joints
Symmetrical arthritis
Rheumatoid nodules
Rheumatoid factor
Radiological changes
Duration of 6 weeks or more
N.B. Diagnosis of RA is made with four or more criteria.

The diagnosis of RA can only be established by an accurate and careful history and physical examination. Only limited help is provided by laboratory tests. The clinical hallmark of inflammatory joint disease is persistent synovitis. In patients with isolated small joint synovitis the acute phase response may be normal, because the magnitude of this response is correlated with the amount of inflammatory activity (synovitis bulk). A set of classification criteria for epidemiological purposes is shown in Box 20.40. However, these criteria were designed to distinguish patients with RA from those with other arthropathies in a clinical population, and for comparative epidemiological studies. They are not intended to be used dogmatically for clinical diagnosis in individual cases, and their sensitivity to diagnose early inflammatory disease in a primary care setting is unknown. The requirement for symptoms to persist beyond 6 weeks is a useful cutoff to ensure that self-limiting or viral arthritis is not labelled prematurely as RA. However, irreversible damage occurs early in RA and diagnosis and treatment should not be delayed.
The most common presentation is with a gradual onset of symmetrical arthralgia and synovitis of small joints of the hands, feet and wrists. This insidious onset has traditionally been considered to imply a poor prognosis, possibly because of the delay in presenting for medical advice. A dramatic acute onset, sometimes over just a few days, with florid morning stiffness, polyarthritis and pitting oedema, occurs more commonly but not exclusively in the elderly. Some elderly patients present acutely with an initial polymyalgic illness with marked proximal muscle stiffness, the synovitis appearing only after several months as the steroid dose is reduced. Occasionally the onset is palindromic, with recurrent symmetrical acute episodes of joint pain and swelling which last only for a few hours or days. Whatever the pattern, most patients have evidence of morning and inactivity stiffness and stress pain. Involvement of other synovial structures (tenosynovium, bursae) is common but, unlike in seronegative spondarthritis, the entheses are not targeted.
Specific joints
The hand is crucial to overall patient function and provides a good reflection of overall disease activity. The typical features are symmetrical swelling of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints. These and other joints are considered to be actively inflamed if they are tender on pressure, and have stress pain on passive movement or non-bony effusion/swelling. Note that erythema is not a feature of rheumatoid arthritis and usually implies coexistent sepsis. Specific hand abnormalities include 'swan neck' deformity, the boutonnière or 'button hole deformity', and a Z deformity of the thumb (see Fig. 20.25). Dorsal subluxation of the ulnar styloid of the wrist is common and may contribute to rupture of the fourth and fifth extensor tendons. Triggering of fingers may occur due to nodules in the flexor tendon sheath.
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Figure 20.25 The hand in rheumatoid arthritis. A Ulnar deviation of the fingers with wasting of the small muscles of the hands and synovial swelling at the wrists, the extensor tendon sheaths, the metacarpophalangeal and proximal interphalangeal joints. B 'Swan neck' deformity of the fingers.
In the forefoot dorsal subluxation of the metatarsophalangeal (MTP) joints results in 'cock-up' toe deformities. This causes pain on weight-bearing on the exposed MTP heads and development of secondary adventitious bursae and callosities. In the hindfoot, calcaneovalgus (eversion) is the most common deformity, reflecting damage to the ankle and subtalar joint. This is often associated with loss of the longitudinal arch (flat foot) due to rupture of the tibialis posterior tendon.
Popliteal ('Baker's') cysts usually occur in combination with knee synovitis, with synovial fluid communicating with the cyst but being prevented from returning to the joint by a valve-like mechanism. Rupture, often induced by knee flexion in the presence of a large effusion, leads to calf pain and swelling. Differentiation from a deep vein thrombosis (DVT) can usually be made by the presence of pre-existing joint problems, but a Doppler ultrasound or arthrogram is required to establish the correct diagnosis, since DVT and Baker's cyst may coexist. It is important to be aware of this differential diagnosis, as anticoagulating a Baker's cyst can cause further leg swelling and lead to a compartment syndrome (see Fig. 20.26).
Extra-articular features
RA is a systemic disease. Anorexia, weight loss and fatigue are the most common non-articular symptoms, which may occur throughout the disease course. Generalised osteoporosis and muscle-wasting occur due to systemic inflammation. Extra-articular features are more common in patients with long-standing seropositive erosive disease but may occasionally occur at presentation, especially in men. Most features are due to serositis, granuloma/nodule formation or vasculitis (see Box 20.41).
Cutaneous features


Figure 20.26 Ruptured Baker's cysts in rheumatoid arthritis. Arthrogram showing radio-opaque contrast medium in popliteal cysts and tissues of the calf.
Subcutaneous rheumatoid nodules occur almost exclusively in seropositive patients, usually at sites of pressure or friction such as the extensor services of the forearm, sacrum, Achilles tendon and toes (see Fig. 20.27). They may be complicated by ulceration and secondary infection. Systemic rheumatoid vasculitis usually occurs in elderly seropositive patients in the context of systemic symptoms and multiple extra-articular features. The cutaneous clinical manifestations vary from relatively benign nail-fold infarcts to widespread cutaneous ulceration with skin necrosis. Involvement of medium-sized arteries may lead to mesenteric, renal or coronary artery occlusion.
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20.41 EXTRA-ARTICULAR MANIFESTATIONS OF RHEUMATOID DISEASE
Systemic
Fever
Weight loss
Fatigue
Susceptibility to infection
Musculoskeletal
Muscle-wasting
Tenosynovitis
Bursitis
Osteoporosis
Haematological
Anaemia
Thrombocytosis
Eosinophilia
Lymphatic
Splenomegaly
Felty's syndrome
Nodules
Sinuses
Fistulae
Ocular
Episcleritis
Scleritis
Scleromalacia
Keratoconjunctivitis sicca
Vasculitis
Digital arteritis
Ulcers
Pyoderma gangrenosum
Mononeuritis multiplex
Visceral arteritis
Cardiac
Pericarditis
Myocarditis
Endocarditis
Conduction defects
Coronary vasculitis
Granulomatous aortitis
Pulmonary
Nodules
Pleural effusions
Fibrosing alveolitis
Bronchiolitis
Caplan's syndrome
Neurological
Cervical cord compression
Compression neuropathies
Peripheral neuropathy
Mononeuritis multiplex
Amyloidosis



Figure 20.27 Rheumatoid nodules and olecranon bursitis. Nodules were palpable within as well as outside the bursa.
Ocular features
The most common symptom is dry eyes (keratoconjunctivitis sicca) due to secondary Sjögren's syndrome. Painless episcleritis frequently accompanies nodular seropositive disease; it may cause intense redness but the conjunctival vessels remain normal. It is not usually associated with visual disturbance. If treatment is required, local steroids or systemic NSAIDs are usually effective.
Scleritis is more serious and potentially sight-threatening; the eye is red and painful, with inflammatory changes throughout the sclera and uveal tract. The pupil may appear irregular due to adhesions (synechiae) that can lead to secondary glaucoma and visual impairment. NSAIDs may be effective but if no response is obtained oral steroids are required.
Scleromalacia is painless bilateral thinning of the sclera, with the affected area appearing blue or grey (the colour of the underlying choroid). No specific treatment is required.
Corneal melting is a rare but devastating manifestation. It usually occurs in long-standing disease and is associated with systemic vasculitis. The clinical features are pain, redness and blurred vision with corneal thinning. If untreated, progression to perforation is common. Immunosuppression with steroids and ciclosporin or cyclophosphamide is usually required.
Cardiovascular features
Asymptomatic pericarditis occurs in approximately 30% of patients with seropositive RA, with pericardial effusions and constrictive pericarditis being rare complications. Occasionally, granulomatous lesions result in heart block, cardiomyopathy, coronary artery occlusion or aortic regurgitation.
Pulmonary features
See page 559.
Neurological features
Entrapment neuropathies result from compression of peripheral nerves due to hypertrophied synovium or joint subluxation. Median nerve compression in the carpal tunnel is the most common, and bilateral compression may be an early clinical manifestation of RA. Other common features include ulnar nerve compression at the elbow, compression of the lateral popliteal nerve at the head of the fibula, and tarsal tunnel syndrome (entrapment of the posterior tibial nerve in the flexor retinaculum) which causes burning, tingling and numbness in the distal sole and toes.
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Figure 20.28 Subluxation of cervical spine. A Flexion. B Extension.
Diffuse symmetrical peripheral neuropathy and mononeuritis multiplex may occur due to a vasculitic neuropathy. Cervical cord compression can result from subluxation of the cervical spine at the atlantoaxial joint or at a subaxial level (see Fig. 20.28). Atlantoaxial subluxation is a common finding in long-standing RA and is due to erosion of the transverse ligament around the posterior aspect of the odontoid peg. On neck flexion, this leads to the peg moving posteriorly and indenting the cord. If unrecognised, it can lead to cord compression or sudden death following minor trauma or manipulation. Atlantoaxial subluxation should be suspected in any RA patient who describes new onset of occipital headache, particularly if symptoms of paraesthesia or electric shock are present in the arms. Alternatively, onset may be insidious, with subtle loss of function that is initially attributed to active disease. Reflexes and power can be very difficult to assess in the presence of marked joint damage, and therefore sensory or upper motor signs are the most important to elicit. Lateral radiographs should be taken in flexion and extension, and the degree of compression established with MRI. Operative stabilisation and fixation may be required, though the outcome is poor if the patient already has tetraparesis.
Haematological features
20.42 FELTY'S SYNDROME
Risk factors
Age of onset 50-70
F > M
Caucasians > blacks
Incidence < 1% RA patients
Long-standing RA
Deforming but inactive disease
Seropositive for rheumatoid factor
Common clinical features
Splenomegaly
Lymphadenopathy
Weight loss
Skin pigmentation
Keratoconjunctivitis sicca
Nodules
Vasculitis, leg ulcers
Recurrent infections
Laboratory findings
Anaemia (normochromic, normocytic)
Neutropenia
Thrombocytopenia
Impaired T and B cell immunity
Abnormal liver function


Microcytic iron deficiency anaemia due to NSAID-induced gastrointestinal blood loss and normochromic, normocytic anaemia (± thrombocytosis) due to active disease may both occur, the latter being unresponsive to oral iron. Felty's syndrome is the association of splenomegaly and neutropenia with RA (see Box 20.42). Lymphadenopathy may be found in nodes draining actively inflamed joints, but generalised lymphadenopathy should be investigated by biopsy since there is an increased risk of lymphoma in patients with long-standing disease. Amyloidosis is a rare complication of prolonged active disease and usually presents with nephrotic syndrome.
Investigations
The diagnosis should be confirmed according to clinical criteria (see Box 20.43). The acute phase response is usually elevated in patients with widespread disease, but may be normal in isolated small joint synovitis. Rheumatoid factor is only present in 60-80% of patients so its absence does not exclude the diagnosis. Conversely, rheumatoid factor is present in 10% of the normal population.
The typical radiographic appearances of RA are periarticular osteopenia and marginal non-proliferative erosions. Although osteopenia may be present within the first 6 months, erosions are uncommon within the first year. Therefore it is not appropriate to await radiographic changes before making the diagnosis.
20.43 INVESTIGATIONS AND MONITORING OF RHEUMATOID ARTHRITIS
To establish diagnosis
Clinical criteria
Acute phase response
Serological tests
Radiographs

To monitor disease activity and drug efficacy
Pain (visual analogue scale)
Early morning stiffness (minutes)
Joint tenderness (number of inflamed joints, articular index)
Acute phase response

To monitor disease damage
Radiographs
Functional assessment

To monitor drug safety
Urinalysis
Biochemistry
Haematology


Management
The following are the key management goals in RA:
relief of symptoms
suppression of inflammation
conservation and restoration of function in affected joints (joint protection)
environmental modification if appropriate.
Physical rest, targeted anti-inflammatory therapy and passive exercises are the mainstay of treatment for acute RA. Hospital admission in order to undergo multiple intra-articular injections, joint splinting, regular hydrotherapy, physiotherapy and education may be beneficial. However, most flares can be managed out of hospital by judicious use of either intramuscular or intra-articular steroids, oral analgesics and NSAIDs, and adjustment of DMARDs. Periodic assessment of disease activity, progression (damage) and disability is required. Patient education, counselling and a coordinated multidisciplinary approach are required for successful management.
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Drug therapy
Prompt introduction of DMARDs, either singly or in combination, is central to the modern management of RA. These drugs do not have immediate anti-inflammatory or analgesic effects but will improve symptoms and acute phase response, and reduce radiographic progression, at least in the medium term (see EBM panel). They are likely to be most useful when started early in disease before irreversible damage has occurred. Methotrexate and sulfasalazine are current first-choice DMARDs for RA. If they fail to control disease or are not tolerated due to side-effects, other DMARDs should be used, either sequentially or in combination. The addition of a fixed dose of 7.5 mg prednisolone daily to NSAID and DMARD therapy may slow the rate of radiological progression over 2 years in patients with early RA. Symptomatic management with continued use of NSAIDs and analgesics may also be required.
EBM
DMARD THERAPY FOR RHEUMATOID ARTHRITIS
'Radiographically detectable articular damage can be favourably influenced by the early use of DMARDs. Methotrexate and sulfasalazine have the most favourable toxicity/efficacy ratios. It is impossible to predict the response in an individual patient.'
Felson DT, Andersen JJ, Meenan RF. Use of short term efficacy/toxicity ratios to select second line drugs in RA. Arthritis Rheum 1992; 35:117-125.
Further information: www.cochrane.co.uk

Surgery
Synovectomy of the wrist or finger tendon sheaths of the hands may be required for pain relief or to prevent tendon rupture when other medical interventions have failed. In later stages of the disease osteotomy, arthrodesis or arthroplasties play a major part in patient rehabilitation (see Box 20.37, p. 996).
Progression and prognosis
Past views about the treatment of RA were based on the concept that it was a benign, non-fatal and slowly evolving disease, often responsive to simple therapy. This led to a conservative management approach, predominantly based on the use of NSAIDs, that has been challenged by the following findings:
There is increased mortality in RA patients, highest in those with the most severe disease. Average lifespan is reduced by 8-15 years by RA and the 5-year survival for patients with severe disease is only 50%.
Around 40% of patients will be registered disabled within 3 years.
Around 80% will be moderately to severely disabled within 20 years and 25% will have required a large joint replacement.

Functional capacity decreases most rapidly at the beginning of disease and it is therefore essential to control disease as soon as possible. Joint damage and erosions occur early, and the functional status of patients after only 1 year of RA is often predictive of long-term outcome. It is not possible to predict the outcome accurately at the time of diagnosis, so caution and careful follow-up are needed in all patients. However, the following factors at presentation are associated with a poor prognosis:
higher baseline disability
female gender
involvement of MTP joints
positive rheumatoid factor
disease duration of over 3 months.

ISSUES IN OLDER PEOPLE
RHEUMATOID ARTHRITIS
Presentation may be atypical-for example, with an initial polymyalgic picture or with synovitis and marked peripheral oedema.
Increasing age and comorbidity (e.g. cardiac, renal, gastrointestinal tract disease) increase the risks of NSAID gastrotoxicity; comorbidity can also make overall management more difficult.
Patients aged over 65 years are at an increased risk of steroid-induced osteoporosis; prophylaxis should be considered at doses of = 7.5 mg for >3 months (HRT, bisphosphonates or calcitriol).
Age alone is not a contraindication to slow-acting antirheumatic drug therapy.


SERONEGATIVE SPONDARTHRITIS
This term is applied to a group of inflammatory joint diseases, distinct from rheumatoid arthritis, that are thought to share a similar pathogenesis. They all show considerable overlap and similarity of articular and extra-articular clinical features (see Box 20.44). The diseases that fall within the group are:
ankylosing spondylitis
reactive arthritis, including Reiter's syndrome
psoriatic arthritis
arthropathy associated with inflammatory bowel disease (Crohn's, ulcerative colitis).
In addition to their clinical similarities they share a common pathology and a striking genetic association with the histocompatibility antigen HLA-B27.
20.44 CLINICAL FEATURES COMMON TO SERONEGATIVE SPONDARTHRITIS
Asymmetrical inflammatory oligoarthritis (lower > upper limb)
Sacroiliitis and inflammatory spondylitis
Inflammatory enthesitis
Tendency for familial aggregation
No association with seropositivity for rheumatoid factor
Absence of nodules and other extra-articular features of rheumatoid arthritis
Overlapping extra-articular features typical of the group:
Mucosal surface inflammation-conjunctivitis, buccal ulceration, urethritis, prostatitis, bowel ulceration
Pustular skin lesions, nail dystrophy
Anterior uveitis
Aortic root fibrosis (aortic incompetence, conduction defects)
Erythema nodosum


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Pathology
The pathology of the synovitis that occurs in this group is non-specific and, apart from the absence of granulomata, is often indistinguishable from rheumatoid synovitis. However, the distinctive feature for the group is the marked degree of extrasynovial inflammation, especially of the enthesis but also affecting capsule, periarticular periosteum, cartilage and subchondral bone. Large central cartilaginous joints (sacroiliac, intervertebral, symphysis pubis) are particularly involved, but even when synovial joints are affected (often spinal apophyseal joints, hips, knees, shoulders) extrasynovial inflammation is still prominent. Apart from targeting entheses, two other characteristic features are:
resolution of inflammation by extensive fibrosis
a tendency for resultant scar tissue to calcify and ossify.
In seronegative spondarthritis, therefore, chronic inflammation that predominately targets extrasynovial tissue may characteristically lead to joint fusion in the relative absence of joint synovitis. Similarly, periarticular osteitis and periostitis may result in bony spurs that bridge adjacent vertebral bodies (syndesmophytes) or protrude at sites of ligament attachment (e.g. calcaneal or olecranon 'spurs').
Association with HLA-B27
Within the group, disease association with HLA-B27 is striking, particularly for ankylosing spondylitis (> 95%) and Reiter's disease (90%), and when there is sacroiliitis, uveitis or balanitis. The mechanism of this disease association, however, is unclear.
The suggested pathogenesis for the seronegative spondarthritides is that they are caused by an aberrant response to infection in genetically predisposed persons-the 'reactive' concept. In some situations a triggering organism can be identified, as in Reiter's disease following bacterial dysentery or chlamydial urethritis, but in others the environmental trigger remains obscure.
A further feature to support the seronegative spondarthritis group concept is the strong aggregation of these conditions within families, each syndrome showing an increased familial incidence of the other conditions. It is tempting to speculate that such families share an inherited 'reactive' potential but the phenotypic expression is modified according to the inciting trigger and other genetic and constitutional features of the individual.
ANKYLOSING SPONDYLITIS
This prototype of the seronegative spondarthritis group is a chronic inflammatory arthritis with a predilection for the sacroiliac joints and spine. It is characterised by progressive stiffening and fusion of the axial skeleton.
Epidemiology
The disease has a peak onset in the second and third decades, with a male:female ratio of about 3:1. In Europe more than 90% of affected persons are HLA-B27-positive. The overall prevalence is around 0.5% in most communities, but is much greater in the Pima and Haida Indians who have a high prevalence of HLA-B27.
Infective triggers have not clearly been linked to causation. Chronic prostatitis is more common than expected but appears non-infective. Increased faecal carriage of Klebsiella aerogenes occurs in patients with established ankylosing spondylitis and may relate to exacerbation of both joint and eye disease.
Clinical features
The onset is usually extremely insidious, over months or years, with recurring episodes of low back pain and marked stiffness. Radiation to the buttocks or posterior thighs is not uncommon and is often misdiagnosed as sciatica. Unlike common mechanical back pain, symptoms extend over many segments and are axial and symmetrical in distribution. Symptoms are most marked in the early morning and after inactivity and are relieved by movement. Although the lumbosacral area is usually the first and worst affected region, some patients present with mainly thoracic or neck symptoms. The disease tends to ascend the spine slowly and, eventually, after several years, the whole spine may be affected. As the spine becomes progressively ankylosed, spinal rigidity and secondary osteoporosis predispose to spinal fracture, presenting as acute, severe, well-localised pain. Secondary spinal cord compression is a rare complication.
Most patients have additional locomotor symptoms reflecting the widespread nature of the condition. 'Pleuritic' chest pain aggravated by breathing is common and results from involvement of the costovertebral joints. Plantar fasciitis, Achilles tendinitis and tenderness over bony prominences such as the iliac crest and greater trochanter are common, reflecting inflammatory enthesopathy. Fatigue is often a major complaint and may result from both chronic interruption of sleep due to pain as well as chronic systemic inflammation.
Up to 40% of patients have extraspinal joint involvement. This is usually asymmetrical at first and may cause inflammatory symptoms mainly affecting hips, knees, ankles or shoulders. Involvement of a peripheral joint, most commonly ankle, knee or elbow, may precede the development of spinal symptoms in around 10% of cases. In a further 10% symptoms begin in childhood as one variety of pauciarticular juvenile idiopathic arthritis.
Early physical signs include failure to obliterate the lumbar lordosis on forward flexion, pain on sacroiliac compression, and restriction of movements of the lumbar spine in all directions. As the disease progresses, stiffness increases throughout the spine, and chest expansion frequently becomes restricted. Spinal fusion varies in its extent and in most cases does not associate with gross flexion deformity. A few patients, however, develop marked kyphosis of the dorsal and cervical spine that may interfere with forward vision. This may prove incapacitating, especially when associated with fixed flexion contractures of hips or knees.
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20.45 EXTRA-ARTICULAR FEATURES OF ANKYLOSING SPONDYLITIS
Anterior uveitis (25%) and conjunctivitis (20%)
Prostatitis (80% men)-usually asymptomatic
Cardiovascular disease
Aortic incompetence
Mitral incompetence
Cardiac conduction defects
Pericarditis
Amyloidosis
Atypical upper lobe pulmonary fibrosis


Acute anterior uveitis is the most common extra-articular feature, affecting up to 25% of patients. Occasionally, this precedes joint disease. Other extra-articular features are rare (see Box 20.45).
Investigations
The ESR and CRP are usually raised but may be normal. Serum rheumatoid factor is usually negative; if positive, it is not present in high titre.
Radiographic signs provide the strongest investigational evidence but may take years to develop. Sacroiliitis is often the first abnormality, beginning in the lower synovial parts of the joints with irregularity and loss of cortical margins, widening of the joint space and subsequently marginal sclerosis, narrowing and fusion. Lateral views of the thoraco-lumbar spine may show anterior 'squaring' of the vertebrae owing to erosion and sclerosis of the anterior corners and periostitis of the waist. Bridging syndesmophytes are fine and symmetrical and follow the outermost fibres of the annulus (see Fig. 20.29). Ossification of the anterior longitudinal ligament and facet joint fusion may also be visible. The combination of all these features may result in the typical 'bamboo' spine (see Fig. 20.30). Erosive changes may be seen in the symphysis pubis, the ischial tuberosities and peripheral joints. Osteoporosis and atlantoaxial dislocation can occur.


Figure 20.29 Radiographic syndesmophytes. A Fine symmetrical marginal syndesmophytes typical of ankylosing spondylitis. B Coarse, asymmetrical non-marginal syndesmophytes typical of psoriatic/Reiter's spondylitis.


Figure 20.30 'Bamboo' spine of severe late ankylosing spondylitis. Note the symmetrical marginal syndesmophytes, sacroiliac joint fusion and generalised osteopenia.
Management
The aims are to relieve pain and stiffness, maintain a maximal range of skeletal mobility and avoid the development of deformities. Education and appropriate physical activity are the cornerstones of management. Early in the disease patients should be taught to perform regular daily back extension exercises, including a morning 'warm-up' routine, and to punctuate prolonged periods of inactivity (e.g. driving, computer work) with regular breaks. Swimming is ideal exercise and should be encouraged on a regular basis. Poor bed and chair posture must be avoided.
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NSAIDs are often effective in relieving symptoms but do not alter the course of the disease. A long-acting NSAID at night is often particularly helpful for marked morning stiffness. The slow-acting antirheumatic drugs sulfasalazine, methotrexate or azathioprine may be effective for control of persistent peripheral joint synovitis but appear to have little or no impact in suppressing axial disease.
Local corticosteroid injections can be useful for persistent plantar fasciitis and the management of other enthesopathies. Oral steroid may occasionally be required for acute uveitis but should otherwise be avoided. Severe hip, knee or shoulder restriction may require surgery. Total hip arthroplasty has largely obviated the need for difficult spinal surgery in those with advanced deformity.
Around 75% or more of patients with ankylosing spondylitis are able to remain in employment and enjoy a good quality of life. Even if severe ankylosis develops, functional limitation may not be marked as long as the spine is fused in an erect posture. Severe hip, knee or shoulder disease carries a worse prognosis.
REACTIVE ARTHRITIS
Reiter's disease is the classic triad of non-specific urethritis, conjunctivitis and reactive arthritis that follows:
bacterial dysentery-mainly Salmonella, Shigella, Campylobacter or Yersinia, or
sexually acquired infection with Chlamydia.
Incomplete forms with just one or two of these features, however, are more frequent than the full syndrome.
Epidemiology
Reactive arthritis is predominantly a disease of young men with a sex ratio of 15:1 and is possibly the most common cause of inflammatory arthritis in men aged 16-35; however, it may occur at any age. Between 1% and 2% of patients with non-specific urethritis seen at clinics for sexually acquired diseases have reactive arthritis. Following an epidemic of Shigella dysentery, 20% of HLA-B27-positive men develop reactive arthritis.
Clinical features
The onset of classic Reiter's is typically acute, with development of urethritis, conjunctivitis (in about 50%) and an inflammatory oligoarthritis affecting the large and small joints of the lower limbs 1-3 weeks following sexual exposure or an attack of dysentery. There may be considerable systemic disturbance with fever, weight loss and vasomotor changes in the feet.
Less classic attacks may be subacute or more insidious. Many patients present with single joint involvement that over several days turns into an asymmetric oligoarthritis. Symptoms and signs of urethritis or conjunctivitis may be minimal or absent and there may be no clear history of prior dysentery. In such cases the coexistence of both synovitis and periarticular inflammation, marked asymmetry and lower limb predominance all suggest seronegative spondarthritis. Achilles tendinitis or plantar fasciitis may be present as further locomotor clues.
In addition to urethritis and conjunctivitis the following extra-articular features may develop 1-3 weeks following the initiating infection:
Circinate balanitis (20-50%). This is characteristic, starting as vesicles on the coronal margin of the prepuce and glans and later rupturing to form superficial erosions with minimal surrounding erythema, some coalescing to give the circular pattern. Lesions are often painless and may escape notice.
Keratoderma blennorrhagica (15%). These skin lesions appear as discrete waxy yellow-brown vesico-papules with desquamating margins, occasionally coalescing to form large crusty plaques. Palms and soles are particularly affected but spread may occur to the scrotum, scalp and trunk. Clinically and histologically, these lesions are indistinguishable from pustular psoriasis.
Nail dystrophy with subungual hyperkeratosis. This is indistinguishable from psoriatic nail dystrophy.
Buccal erosions (10%). These shallow red patches on tongue, palate, buccal mucosa and lips are painless and last only a few days.

The first attack of arthritis is usually self-limiting, with spontaneous remission of symptoms within 2-4 months of onset. However, recurrent or chronic arthritis develops in more than 60% of patients and is not necessarily related to further infection. In chronic arthropathy low back pain and stiffness from sacroiliitis are common and 15-20% of patients develop spondylitis. Ankles, midtarsal joints, metatarsophalangeal joints and knees are usually the other target sites. Uveitis is rare with the first attack but occurs in 30% of patients with recurring arthritis. Other features are uncommon but include:
cardiac abnormalities-aortic incompetence, conduction defects, pleuro-pericarditis
peripheral neuropathy-foot drop, ulnar neuritis
CNS disease-seizures, meningoencephalitis.

Investigations
The acute phase response is usually evident from a raised ESR and CRP and subsequently from a normochromic, normocytic anaemia. Aspirated synovial fluid is inflammatory (low viscosity, turbid) and often contains giant macrophages (Reiter's cells). Urethritis may be confirmed in the 'two-glass test' by demonstration of mucoid threads in the first void specimen that clear in the second. High vaginal swabs may reveal Chlamydia on culture. Except for post-Salmonella arthritis, stool cultures are usually negative by the time the arthritis presents; serum agglutinin tests, however, may help confirm previous dysentery. Serum tests for rheumatoid factor and antinuclear factor are negative.
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In most cases there are no radiographic changes in the acute attack other than soft tissue swelling. However, mild periarticular osteopenia, joint space narrowing and marginal proliferative erosions may develop with chronic or recurrent disease. There may also be periostitis, especially of metatarsals, phalanges and pelvis, and large 'fluffy' calcaneal spurs. In contrast to changes in ankylosing spondylitis, radiographic sacroiliitis is often asymmetrical and sometimes unilateral, and syndesmophytes are predominantly coarse, asymmetrical and beyond the contours of the annulus fibres (i.e. 'non-marginal'). The radiographic changes in the peripheral joints and spine are identical to those seen with psoriasis.
Management
In the first attack this is mainly symptomatic and supportive. NSAIDs are often helpful during the acute phase, together with judicious aspiration of joints and intra-articular or other local steroid injections. Systemic corticosteroids are rarely required. Severe progressive arthritis and intractable keratoderma blennorrhagica occasionally warrant antirheumatic therapy with azathioprine or methotrexate. Non-specific chlamydial urethritis is usually treated with a short course of tetracycline and this may reduce the frequency of arthritis in sexually acquired cases. Anterior uveitis is a medical emergency requiring topical, subconjunctival or systemic corticosteroids.
Around 10% of patients have evidence of active disease 20 years after the onset. Spondylitis, chronic erosive arthritis, recurrent acute arthritis and uveitis are the major causes of long-term morbidity.
PSORIATIC ARTHROPATHY
This seronegative inflammatory arthritis usually presents in patients with current or previous psoriasis (70%), but in some cases (20%) it predates the onset of psoriasis. Synchronous onset is unusual (5%). The association with nail dystrophy is stronger than with skin plaques.
Epidemiology
Psoriatic arthritis occurs in about 1 in 1000 of the general population and in 7% of patients with psoriasis. Approximately 20% of all patients with seronegative polyarthritis have psoriasis, while the prevalence of psoriasis in seropositive rheumatoid arthritis is no higher than that in the general population, suggesting that the association of the skin disease with seronegative arthritis does not arise by chance alone. The onset is usually between 25 and 40 years of age.
Clinical features
A wide spectrum of joint disease is seen but five major presentations are recognised:
1. Asymmetrical inflammatory oligoarthritis (40%). This may affect lower and upper limb joints and commonly demonstrates the combination of joint synovitis and periarticular inflammation. This is most characteristic when a finger or toe is involved by synovitis of its joints and tenosynovitis, enthesitis and inflammation of intervening tissue to give a 'sausage digit' or dactylitis (see Fig. 20.31). Usually only one or two large joints are involved, mainly knees, with often very large effusions. Onset is often abrupt but symptoms are often mild and systemic features absent. Dactylitis particularly often settles, with a good outcome after several months.
2. Symmetrical polyarthritis (25%). This predominates in women and may strongly resemble rheumatoid arthritis, with symmetrical involvement of small and large joints in both upper and lower limbs. However, nodules and other extra-articular features of rheumatoid are absent and joint disease is generally less extensive and more benign. Much of the hand deformity often results from tenosynovitis and soft tissue contractures.
3. Predominant distal interphalangeal joint (DIPJ) arthritis (15%). This is a very characteristic form that mainly affects men and predominantly targets finger DIPJs and surrounding periarticular tissues, almost invariably with accompanying nail dystrophy (see Fig. 20.32).
4. Psoriatic spondylitis (15%). This presents a similar clinical picture to ankylosing spondylitis but with a tendency to less severe involvement. It may occur alone or with any of the other clinical patterns of peripheral arthritis.


Figure 20.31 'Sausage' middle finger of a patient with psoriatic arthritis.


Figure 20.32 Psoriatic arthritis. Note the typical distal interphalangeal joint pattern with accompanying nail dystrophy (pitting and onycholysis).
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5. Arthritis mutilans (5%). This deforming erosive arthritis targets fingers and toes. Marked cartilage and bone attrition results in loss of the joint and marked instability. The encasing skin appears invaginated and 'telescoped' ('main en lorgnette') and traction can pull the finger back to its original length. Other joints in the hand or foot may show ankylosis.
The general pattern of psoriatic arthritis is one of intermittent exacerbation followed by varying periods of complete or near-complete remission. Residual damage and disability in many cases, except arthritis mutilans, is relatively mild.
Extra-articular features are limited to:
Nail changes. These include pitting, onycholysis, subungual hyperkeratosis and horizontal ridging, and may be present in the absence of skin lesions. They are found more commonly in psoriatic arthritis (85%) than in uncomplicated psoriasis (30%).
Skin lesions. These may be widespread scaling lesions, typically over extensor surfaces, or insignificant lesions confined to such areas as the scalp, natal cleft and umbilicus, where they are easily overlooked (see p. 1075).
Conjunctivitis and uveitis. Conjunctivitis is most common. Uveitis is mainly in HLA-B27-positive individuals with sacroiliitis and spondylitis.

Investigations
The ESR and CRP may be raised, especially with polyarticular disease, but are often unimpressive. Tests for rheumatoid factor and antinuclear antibody are generally negative. Radiographs may be normal or show erosive change with joint space narrowing. Features that may permit distinction from rheumatoid arthritis include marginal proliferative erosions, retained bone density, and increased sclerosis of small bones ('ivory phalanx'). Arthritis mutilans and peripheral joint ankylosis can occur in both conditions. The changes in the axial skeleton resemble those of chronic reactive arthritis, specifically coarse, asymmetrical, non-marginal syndesmophytes and asymmetrical sacroiliitis.
Management
The prognosis in general is better than for rheumatoid arthritis, with the exception of those with arthritis mutilans. Symptomatic agents such as simple analgesics, topical or oral NSAIDs are usually all that is required to control symptoms. Intra-articular injections may help to control florid synovitis temporarily. In general, splints and prolonged rest are avoided because of the increased tendency to fibrous and bony ankylosis. The same regime of regular exercise and attention to posture should be prescribed as to those with spondylitis.
For persistent peripheral arthritis sulfasalazine, methotrexate or azathioprine may be required but these have little or no benefit for axial disease. Methotrexate and azathioprine may also help severe skin psoriasis. Antimalarials should be avoided since they can give exfoliative reactions. The retinoid acitretin (20 mg daily-see p. 1079) is effective in treating the arthritis as well as the skin lesions but must be avoided in young women because of its teratogenicity. Its use is complicated by mucocutaneous side-effects, hyperlipidaemia, myalgias and extraspinal calcification. Photochemotherapy with methoxypsoralen and long-wave ultraviolet light (PUVA) is primarily used for patients with severe skin lesions but can also help some patients with synchronous exacerbations of inflammatory arthritis.
ARTHRITIS ASSOCIATED WITH INFLAMMATORY BOWEL DISEASE
Two patterns of seronegative inflammatory arthritis are associated with ulcerative colitis and Crohn's disease.
Enteropathic arthritis
This is an acute inflammatory oligoarthritis that occurs in 12% of patients with ulcerative colitis and 20% of those with Crohn's disease. Large lower limb joints (knees, ankles, hips) are most commonly affected but the wrists and small joints of the fingers and toes can also be involved. The arthritis coincides with exacerbations of the underlying bowel disease, sometimes in association with aphthous mouth ulcers, iritis and erythema nodosum. It ceases to be a problem following total colectomy for ulcerative colitis. The higher prevalence of arthritis in Crohn's disease may reflect the greater difficulty in eradicating the bowel problem.
Sacroiliitis and ankylosing spondylitis
Sacroiliitis (16%) and ankylosing spondylitis (6%) are disease associations that may predate or follow the onset of bowel disease. There is no correlation between the inflammatory activity of the spondylitis and bowel disease and they pursue independent courses. Clinically and radiologically, such axial disease is indistinguishable from classic ankylosing spondylitis.
CRYSTAL-ASSOCIATED DISEASE
20.46 CRYSTAL-ASSOCIATED ARTHRITIS AND DEPOSITION IN CONNECTIVE TISSUE
Crystal Associations
Common
Monosodium urate monohydrate Acute gout
Chronic tophaceous gout
Calcium pyrophosphate dihydrate Acute 'pseudogout'
Chronic (pyrophosphate) arthropathy
Chondrocalcinosis
Basic calcium phosphates Calcific periarthritis
Calcinosis
Uncommon
Cholesterol Chronic effusions in rheumatoid arthritis
Calcium oxalate Acute arthritis in dialysis patients
Extrinsic crystals/semi-crystalline particles
Synthetic crystals Acute synovitis
Plant thorns/sea urchin spines Chronic monoarthritis, tenosynovitis

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A variety of crystals can deposit in and around joints and associate with both acute inflammatory and chronic syndromes (see Box 20.46). In some instances crystals are the primary pathogenic agents-true 'crystal deposition disease' (e.g. gout). In other situations MSK disease predisposes to secondary crystal formation (e.g. predisposition to calcium pyrophosphate and apatite crystal formation in osteoarthritis). Such crystals may subsequently amplify symptoms and damage, or be an incidental epiphenomenon of no clinical consequence.
A variety of factors influence crystal formation (see Fig. 20.33). Firstly, there must be sufficient concentration of the chemical components (ionic product). Whether a crystal then forms, however, depends on the balance of tissue factors that promote or inhibit crystal nucleation and growth. Many of our tissues are supersaturated for various products but depend on natural inhibitors to prevent crystallisation. Lack of such natural inhibitors, presence of abnormal promoters, or both, may allow crystallisation. Crystals can also dissolve and the yield of crystals at any one time will depend on the relative rates of crystallisation, growth and dissolution.


Figure 20.33 Factors relating to crystal formation and tissue concentration at any one time.
The inflammatory potential of crystals resides in the physical irregularity and high negative charge of their surface. This can:
activate inflammatory mediators such as complement and Hageman factor directly, or indirectly via adsorbed immunoglobulin
stimulate and subsequently disrupt surface membranes of neutrophils, synoviocytes and other cells.
Because of their hard particulate nature they may also mechanically damage the tissues in which they lie and act as wear particles at the joint surface. Crystals forming deep within cartilage or tendon are prevented from interaction with proteins and cells and can paradoxically reside in MSK tissues for years without causing inflammation or symptoms. It is only when they are released from their protected sites of origin ('crystal shedding') that they trigger acute attacks of inflammation. Such attacks may occur spontaneously, result from mechanical loosening (local trauma), partial dissolution and reduced crystal size (e.g. initiation of hypouricaemic treatment), or occur in association with an acute phase response due to intercurrent illness or surgery (mechanism unknown).
GOUT
Gout is a true crystal deposition disease. It can be defined as the pathological reaction of the joint or periarticular tissues to the presence of monosodium urate monohydrate (MSUM) crystals. Clinically, this may present as inflammatory arthritis, bursitis, tenosynovitis, cellulitis or as nodular ('tophaceous') crystal deposits. Prolonged hyperuricaemia is necessary, but is alone not sufficient, for development of gout.




Integration link: Gout - classification and pathogenesis

Taken from Robbins Basic Pathology 7e








Integration link: Gout - morphology

Taken from Robbins Basic Pathology 7e




Epidemiology
The prevalence of gout varies between populations but is around 1% with a strong male predominance (>10:1). Prevalence increases with age and increasing serum uric acid concentration. 'Primary' gout is almost exclusively a male disease and the most common cause of inflammatory arthritis in men over the age of 40. 'Secondary' gout, due to renal impairment or drug therapy, mainly affects people over the age of 65 and is the form most usually seen in women.
Serum uric acid levels are distributed in the community as a continuous variable and are determined by a number of variables of which gender, age, body bulk and genetic constitution are the most important. Levels are higher in men than women; they rise from the twenties in men and after the menopause in women, positively correlate with obesity, and vary according to ethnicity (being highest in New Zealand Maoris). Hyperuricaemia can be defined in two ways:
as a serum uric acid level above the theoretical solubility of MSUM in physiological conditions (0.42 mmol/l)
as a serum uric acid level greater than 2 standard deviations above the mean for the population (c. 0.40 mmol/l for men, 0.35 mmol/l for women).
Probably 95% of hyperuricaemic subjects never develop gout.
Aetiology and pathogenesis
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Figure 20.34 The uric acid pool. Origins and disposal of uric acid in normal humans.
About one-third of the body uric acid pool is derived from dietary sources and two-thirds from endogenous purine metabolism (see Fig. 20.34). The concentration of uric acid in body fluids depends on the balance between its synthesis and its elimination via the kidneys (two-thirds) and gut (one-third). Purine nucleotide synthesis and degradation are regulated by a network of enzyme pathways; xanthine oxidase catalyses the end conversion of hypoxanthine to xanthine and then xanthine to uric acid.
Various genetic, constitutional and environmental factors can cause hyperuricaemia by decreasing renal elimination of uric acid and/or by increasing its production (see Box 20.47). In over 75% of primary gout patients hyperuricaemia results from an inherited isolated renal defect in fractional uric acid excretion which impairs their ability to increase renal excretion in response to a purine load ('under-excretors'). About 20% of primary gout patients are intrinsic 'over-producers' of uric acid through no identifiable cause. Rare individuals, however (<1% primary gout patients), have a specific inherited enzyme defect of purine synthesis. They should be suspected:
if gout develops at a very early age (<25)
if urolithiasis (uric acid stones) is the presenting feature
if there is a strong family history of early-onset gout.

Apart from hyperuricaemia, other risk factors and inter-related associations for primary gout include:
obesity
high alcohol (predominantly beer) intake
type IV hyperlipoproteinaemia, hypertension and ischaemic heart disease
unidentified inherited alteration in tissue factors relating to inhibition/promotion of crystal formation.

20.47 FACTORS THAT PREDISPOSE TO CHRONIC HYPERURICAEMIA AND GOUT
Diminished renal excretion-common
Inherited isolated renal tubular defect ('under-excretors')
Renal failure
Chronic drug therapy
Thiazide and loop diuretics
Low-dose aspirin
Ciclosporin
Pyrazinamide
Lead toxicity (e.g. in 'moonshine' drinkers)
Lactic acidosis (alcohol)

Increased production of uric acid-uncommon
Increased purine turnover
Chronic myeloproliferative or lymphoproliferative disorders (e.g. polycythaemia, chronic lymphatic leukaemia)
Increased de novo synthesis ('over-producers')
Unidentified abnormality (most common)
Specific enzyme defect (rare)
Hypoxanthine-guanine phosphoribosyl transferase deficiency
Phosphoribosyl pyrophosphate synthetase over-activity
Glucose-6-phosphatase deficiency


Secondary gout results from chronic hyperuricaemia due to renal impairment or chronic diuretic use. In diuretic-induced gout nodal generalised OA is a further risk factor, especially in women. This presumably relates to a non-specific predisposition to crystallisation in osteoarthritic cartilage, possibly due to reduced levels of proteoglycan and other inhibitors of crystal formation.
MSUM crystals preferentially deposit in peripheral connective tissues in and around synovial joints, initially favouring lower rather than upper limbs, and especially targeting the first metatarsophalangeal and small joints of feet and hands. As the crystal deposits slowly increase and enlarge there is progressive involvement of more proximal sites and the potential for cartilage and bone damage, from both inflammation and mass pressure effects, and development of 'secondary' osteoarthritis. MSUM crystals take months or years to grow to a detectable size, implying a long asymptomatic phase.
Clinical features
Acute gout
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Figure 20.35 Podagra. Acute gout causing swelling, erythema and extreme pain and tenderness of the first metatarsophalangeal joint.
In almost all first attacks a single distal joint is affected. The first metatarsophalangeal joint is affected in over 50% of cases-'podagra' (see Fig. 20.35). Other common sites (in order of decreasing frequency) are the ankle, midfoot, knee, small joints of hands, wrist and elbow. The axial skeleton and large proximal joints are rarely involved and never as the first site. Typical attacks have the following characteristics:
extremely rapid onset, reaching maximum severity in just 2-6 hours, often waking the patient in the early morning
severe pain, often described as the 'worst pain ever'
extreme tenderness-the patient is unable to wear a sock or to let bedding rest on the joint
marked swelling with overlying red, shiny skin
self-limiting over 5-14 days, with complete return to normality.
During the attack the joint shows signs of marked synovitis but also periarticular swelling and erythema. The attack may be accompanied by fever, malaise and even confusion, especially if a large joint such as the knee is involved. As the attack subsides pruritus and desquamation of overlying skin are common. The main differential diagnosis is septic arthritis, infective cellulitis or another crystal disease. Sepsis, however, is usually more subacute in onset and progresses in severity until treated.
Acute attacks may also manifest as bursitis, tenosynovitis or cellulitis. These attacks have the same characteristics-rapid onset, severe pain, florid inflammation and erythema. Many patients describe milder episodes lasting just a few days ('petite attacks'). Some have attacks in more than one joint, and sometimes one attack, by triggering the acute phase response, triggers attacks in other joints a few days later ('cluster attacks'). Polyarticular attacks are rare.
Intercritical periods
These are asymptomatic periods between attacks. Some people never have a second attack; in others the next episode occurs after years. In most, however, a second attack occurs within 1 year. Subsequently, the frequency of attacks and number of sites involved gradually increase with time. Later attacks are more likely to involve several joints and to be more severe. Eventually, continued MSUM deposition causes joint damage and chronic pain. The interval between the first attack and the development of chronic symptoms is variable, but averages around 10 years. The main determinant is the uric acid level-the higher it is, the earlier and more extensive the development of joint damage and MSUM deposits.
Chronic tophaceous gout


Figure 20.36 Tophus with white MSUM crystals visible beneath the skin. This was diuretic-induced gout in a patient with pre-existing nodal osteoarthritis.
Large MSUM crystal deposits produce irregular firm nodules ('tophi') at the usual sites for nodules around extensor surfaces of fingers, hands, forearm, elbows, Achilles tendons and sometimes the helix of the ear. Marked asymmetry, locally and between sides, is characteristic. The white colour of MSUM crystals may be evident and permit distinction from rheumatoid nodules (see Fig. 20.36). Large nodules may ulcerate, discharging white gritty material and associating with local inflammation (erythema, pus) even in the absence of secondary infection. Although tophi are usually a very late feature, they may appear surprisingly rapidly, in under 1 year, in patients with chronic renal failure.
The joints most commonly involved with signs of damage and varying degrees of synovitis are the first metatarsophalangeal joint, midfoot, finger joints and wrists, occasionally with severe deformity and marked functional impairment, especially of feet and hands. As with tophi, asymmetry is characteristic.
Secondary gout may present with painful, sometimes discharging tophi without preceding acute attacks. This is particularly seen in older, mainly female patients with nodal osteoarthritis who develop tophi in and around their osteoarthritic finger joints as a consequence of chronic (> 1-2 years) diuretic therapy (see Fig. 20.36).
Urolithiasis
Uric acid (not MSUM) stones cause renal colic in around 10% of gout patients in Europe. The incidence is higher in hot climates and is favoured by:
purine over-production
uricosuric drugs and defects in tubular reabsorption of uric acid
dehydration and lowering of urine pH (e.g. chronic diarrhoea, ileostomy).

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Chronic urate nephropathy
Progressive renal disease is an important complication confined to untreated severe chronic tophaceous gout. This results from MSUM crystal deposition in the interstitium of the medulla and pyramids with consequent chronic inflammation, giant-cell reaction, fibrosis, glomerulosclerosis and secondary pyelonephritis.
Investigations
Definite confirmation of diagnosis is by identification of MSUM crystals in the aspirate from a joint, bursa or tophus. In acute gout synovial fluid shows increased turbidity due to the greatly elevated cell count (>90% neutrophils); chronic gouty fluid is more variable but occasionally appears white due to the high crystal load. During an intercritical period aspiration of an asymptomatic first metatarsophalangeal joint or knee still often permits crystal identification.
Although hyperuricaemia is usually consistently present, it does not confirm gout. Equally, a normal uric acid level, especially during an attack, does not exclude gout (uric acid is a negative acute phase reactant). Measurement of 24-hour urinary uric acid excretion on a low purine diet will identify an over-producer. Assessment of renal function (serum creatinine, urine testing) should always be undertaken. Fasting lipoproteins should be checked in those with primary gout. An intercritical full blood count and ESR should detect myeloproliferative disorders. During an attack a marked acute phase response (elevated CRP, neutrophilia) is usual; the ESR is often modestly raised in tophaceous gout.
Radiographs can assess the degree of joint damage. In early disease they are usually normal, but narrowing of joint space, sclerosis, cysts and osteophyte (changes of osteoarthritis) may develop in affected joints with time, or be present as a predisposing factor in secondary gout. Gouty 'erosions' (bony tophi) are a less common but more specific feature occurring as para-articular 'punched-out' defects with well-delineated borders and retained bone density. Tophi may also be visible as eccentric soft tissue swellings. In late disease changes may be hard to distinguish from other forms of inflammatory polyarthritis.
Management
The acute attack
A quick-acting oral NSAID (e.g. naproxen, diclofenac, indometacin) can give effective pain relief and is the standard treatment. Patients can keep a supply of an NSAID with which they are familiar and take it as soon as the first symptoms are noticed, continuing for the duration of the attack. Oral colchicine (a potent inhibitor of neutrophil microtubular assembly) can be very effective, but unfortunately often causes vomiting and severe diarrhoea at the doses needed for rapid relief (1 mg loading dose, then 0.5 mg 6-hourly until symptoms abate). The compromise is to try lower doses (0.5 mg 8-12-hourly) for a slower onset of benefit. Aspiration of the joint will give instant relief and, when combined with an intra-articular steroid injection to prevent fluid reaccumulation, often effectively aborts the attack.
Long-term management
Patient education is critical. The nature of gout and the aims and mechanisms of treatment require careful explanation if a cure is to be achieved.
Correction of any predisposing factors should always be attempted. Lifestyle alteration to correct obesity and reduce excess beer consumption may significantly reduce hyperuricaemia. In those with diuretic-induced gout it may prove possible to stop their diuretic, depending on the reasons for its use. Although a very high purine diet (large amounts of offal and meat) should be tempered, there is no need for a specific highly restrictive diet.
Prolonged hypouricaemic drug treatment is indicated for:
recurrent attacks of acute gout
tophi
evidence of bone or joint damage
associated renal disease
gout with greatly elevated serum uric acid.

Allopurinol is the usual drug of choice because of its once-daily convenience and low incidence of side-effects. It inhibits xanthine oxidase and reduces conversion of hypoxanthine and xanthine to uric acid. The usual starting dose is 100-300 mg daily but lower doses (100 mg or less) should be used in older patients or if renal function is impaired. The sharp reduction in tissue uric acid levels that follows initiation of treatment can partially dissolve MSUM crystals and trigger acute attacks. The patient should be warned of this and told to continue treatment even if an attack occurs. This tendency can be minimised by using a lower starting dose (100 mg) or by concurrent administration of oral colchicine (0.5 mg 12-hourly) for the first few weeks. Initiation of treatment during an attack can exacerbate and prolong the episode so it is prudent to wait until the attack settles.
The aim of treatment is to bring the serum uric acid level into the lower half of the normal range to ensure dissolution of crystals and to prevent new crystals forming. The serum uric acid should therefore be measured every 6 weeks and the dose of allopurinol increased in 100 mg increments until this is achieved. Infrequent (e.g. yearly) monitoring is advised to ensure maintenance of effective treatment. In most cases allopurinol will need to be continued indefinitely.
Uricosuric drugs can achieve equivalent reductions in serum uric acid to allopurinol. Probenecid (0.5-1 g 12-hourly) or sulfinpyrazone (100 mg 8-hourly) are effective uricosurics but have the disadvantage of requiring several doses each day and maintenance of a high urine flow (to avoid uric acid crystallisation in renal tubules). Salicylates antagonise the uricosuric action of these drugs and should be avoided. Uricosurics are contraindicated:
in over-producers (they already have gross uricosuria)
in patients with renal impairment (ineffective)
in patients with urolithiasis (increased stone formation).
The uricosuric benzbromarone (100 mg daily) is effective in patients with mild to moderate renal impairment but has limited availability in most countries.
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Asymptomatic hyperuricaemia
There is no evidence that hyperuricaemia itself is damaging. Treatment is therefore unnecessary unless there is a strong family history of gout, urolithiasis or persistently very high levels (>0.6 mmol/l). Causes of secondary hyperuricaemia should be considered.
ISSUES IN OLDER PEOPLE
GOUT
This is never primary but usually secondary to chronic (>18 months) diuretic therapy (thiazides, loop diuretics) or, less commonly, chronic renal failure.
In the older person on long-term diuretic therapy nodal generalised osteoarthritis is an important additional risk factor for developing gout.
In contrast to primary gout, secondary gout in the elderly often presents as painful tophi rather than as acute attacks. Hands, not feet, are the target site of involvement in this age group.
Because of increased toxicity in the elderly allopurinol should be started at the low dose of 100 mg/day.
Acute attacks in the elderly are best treated by aspiration and intra-articular injection of long-acting steroid followed by early mobilisation. Oral NSAID and colchicine are best avoided because of increased incidence and severity of toxicity.


CALCIUM PYROPHOSPHATE DIHYDRATE (CPPD) CRYSTAL DEPOSITION
CPPD crystal deposition in hyaline and fibrocartilage of joints (chondrocalcinosis) is a common age-associated phenomenon (> 55) that particularly targets the knee. Sporadic, familial and metabolic disease-associated forms are recognised. It is often clinically occult, but can cause acute self-limiting synovitis ('pseudogout') or occur as a chronic arthritis showing a strong association/overlap with osteoarthritis.
Epidemiology
Radiographic chondrocalcinosis is more common in women and shows a striking association with age, being rare under the age of 55, but rising from 10-15% in those aged 65-75 to 30-60% in those over 85. The knee (hyaline cartilage and menisci) is by far the most prevalent site, followed by the wrist (triangular fibrocartilage) and pelvis (symphysis pubis). There is an increased association with radiographic osteoarthritis, especially at the knee (see Fig. 20.37).
Aetiology
CPPD deposition is most commonly sporadic, occurring as an isolated phenomenon in aged but otherwise apparently normal fibrocartilage and hyaline cartilage in knees and just one or two other sites. Apart from ageing, the strongest association is with osteoarthritis (see Box 20.48). The changes in osteoarthritic cartilage that may encourage CPPD crystal deposition are:
reduction in concentration of proteoglycan and other natural inhibitors of crystal formation
increased extracellular pyrophosphate levels due to upregulated chondrocyte metabolism.



Figure 20.37 Knee radiograph showing chondrocalcinosis of the fibrocartilaginous menisci and articular hyaline cartilage. There is also narrowing and osteophyte of the medial tibio-femoral compartment.
20.48 ASSOCIATIONS OF CPPD CRYSTAL DEPOSITION
Chondrocalcinosis Structural arthritis
Ageing (sporadic)--most common + -
Osteoarthritis, joint damage--common + +
Familial predisposition--rare + Variable
Metabolic disease--rare
Haemochromatosis + +
Hyperparathyroidism + 0
Hypophosphatasia + 0
Hypomagnesaemia + 0
Wilson's disease + 0

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Rare families have been described from many countries and racial groups in which florid polyarticular chondrocalcinosis develops in the third and fourth decades in association with acute attacks and variable degrees of 'osteoarthritis'. All show an autosomal dominant pattern of inheritance; in some an abnormality of pyrophosphate metabolism has been implicated, though the causal genes remain unknown. A variety of metabolic diseases may also predispose to chondrocalcinosis and recurrent acute attacks due to CPPD, though only haemochromatosis additionally predisposes to osteoarthritis-like structural change. All these diseases elevate extracellular levels of pyrophosphate in joint tissues, mainly through reduced concentration or activity of alkaline phosphatase and other pyrophosphatases, so an increase in ionic product appears to be the principal mechanism of predisposition.
Clinical features
Acute synovitis: 'pseudogout'
This is the most common cause of acute monoarthritis in the elderly. The knee is by far the most common site, followed by the wrist, shoulder, ankle and elbow. It may be the first presentation of previously asymptomatic CPPD, or occur on a background of chronic symptomatic arthritis. Triggering factors include direct trauma and intercurrent illness or surgery.
The typical attack resembles acute gout and develops rapidly, with severe pain, stiffness and swelling, maximal within 6-24 hours of onset. Overlying erythema is common and examination reveals a very tender joint held in the flexed 'loose-pack' position with signs of marked synovitis (large/tense effusion, warmth, restricted movement with stress pain). Fever is common and the patient may appear confused and ill. The attack is self-limiting but may take 1-3 weeks to resolve.
Sepsis and gout are the main differential diagnoses. Although sepsis is often more subacute in onset and is progressive, it often needs exclusion, especially when pseudogout has been triggered by chest infection or surgery and if the patient is unwell. It is noteworthy, however, that sepsis and pseudogout can coexist (infection 'strip-mining' CPPD crystals from cartilage). Gout is unlikely in patients over the age of 65 without a preceding history of primary gout or chronic diuretic therapy and seldom involves the knee in a first attack.
Chronic ('pyrophosphate') arthritis
Most patients with chronic symptoms are elderly women. The distribution is similar to that of pseudogout, with knees being the worst affected, then wrists, shoulders, elbows, hips and midtarsals. In the hand the second and third metacarpophalangeal joints are often the ones most affected. Symptoms are chronic pain, variable early morning and inactivity stiffness, and functional impairment. Acute attacks may be superimposed on this chronic history. Symptoms usually target just a few joints, though single or multiple joint involvement can occur. Affected joints show features of osteoarthritis (bony swelling, crepitus, restriction) with varying degrees of synovitis. Effusion and synovial thickening are usually most apparent at knees and wrists; wrist involvement may result in carpal tunnel syndrome. Examination often reveals more widespread but asymptomatic signs of osteoarthritis, and Heberden's nodes and generalised osteoarthritis commonly coexist.
Inflammatory features may be sufficiently pronounced to suggest rheumatoid arthritis. However, the absence of tenosynovitis and extra-articular involvement, and targeting of large and medium rather than small joints usually permit distinction. Severe damage and instability of knees or shoulders may occasionally lead to consideration of a neuropathic joint, though neurological findings are normal.
Incidental finding
Because of its high age-associated prevalence radiographic chondrocalcinosis is often seen as an incidental finding in older subjects. As with uncomplicated osteoarthritis, asymptomatic clinical and radiographic features of 'pyrophosphate' arthritis are also not uncommon in the elderly. A thorough history and examination are always required to determine the relevance of such findings to symptom causation.
Investigations
In acute pseudogout examination of synovial fluid using compensated polarised microscopy will demonstrate CPPD crystals (see Fig. 20.4B, p. 966) and permit distinction from urate gout. The aspirated fluid is often turbid and may be uniformly blood-stained, reflecting the severity of inflammation. Gram stain and culture of the fluid will exclude sepsis. CPPD crystals may also be identified in smaller numbers in the less inflammatory fluids aspirated from chronic pyrophosphate arthritis.
Radiographs may show chondrocalcinosis in hyaline cartilage and/or fibrocartilage (occasionally capsule or ligament) with or without associated structural changes of osteoarthritis (see Fig. 20.37). Chondrocalcinosis is not always evident, especially in joints showing some degree of cartilage loss, and its absence does not exclude the diagnosis of pseudogout. Synovial fluid crystal identification (and negative culture) is the principal diagnostic test.
Screening for metabolic or familial predisposition should be undertaken in patients who show:
early-onset CPPD deposition, <55 years old
florid polyarticular, as opposed to pauciarticular, chondrocalcinosis
recurrent acute attacks without chronic arthropathy
additional clinical or radiographic features of predisposing disease.
Metabolic screening includes serum calcium, alkaline phosphatase, magnesium, ferritin and liver function. If positive, some metabolic disease (hypomagnesaemia, haemochromatosis, hypophosphatasia) requires examination of first-degree relatives. For investigation of non-metabolic familial CPPD, a bilateral knee radiograph is an appropriate screen. If there is no chondrocalcinosis at the knee, it is extremely unlikely to be elsewhere.
Management
For acute pseudogout, aspiration quickly reduces pain and may alone be sufficient. Fluid reaccumulation, however, is common, particularly early in an attack, and for florid pseudogout intra-articular injection of steroid is usually required. Oral NSAIDs and colchicine are also effective, as in gout, but should be avoided if possible in the elderly. Early active mobilisation is also important in this age group.
For chronic arthropathy management is the same as for osteoarthritis (see p. 1001).
BASIC CALCIUM PHOSPHATE (BCP) DEPOSITION
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Hydroxyapatite (apatite) is the principal mineral in bone and teeth. Apatite and other BCPs (octacalcium phosphate, tricalcium phosphate) are also the usual minerals to deposit in extraskeletal tissues. In MSK tissues abnormal deposition may occur in:
periarticular tissues, particularly tendon
hyaline cartilage in association with osteoarthritis
subcutaneous tissue and muscle, principally in connective tissue diseases.

Aetiology
The ionic product of [calcium] × [phosphate] must be kept high to maintain skeletal integrity. Specific cellular mechanisms activate calcification where it is appropriate: for example, around matrix vesicles of growing cartilage. Other mechanisms, such as local concentrations of pyrophosphate and proteoglycan, inhibit calcification elsewhere. In general, abnormal calcification due to BCP results from:
elevation of the calcium phosphate product, causing widespread 'metastatic' calcification (e.g. hyperparathyroidism, chronic dialysis, vitamin D intoxication), or
alteration in the local balance of tissue inhibitors and promoters of crystal formation, causing local 'dystrophic' calcification (e.g. atherosclerotic arteries, fibrotic lymph nodes, scarred lung parenchyma).

In most situations such calcification is of no consequence, possibly because of protein coating or surrounding fibrous tissue that protects BCP crystals from contact with inflammatory mediators. However, BCP crystals have inflammatory potential and in some MSK situations their deposition associates with clinical problems.
Individual apatite crystals are too small to be viewed by light microscopy but their aggregated spherulites can be seen using calcium stains. Sophisticated analytical techniques are required to identify individual BCPs but for clinical purposes presumptive diagnosis based on radiographic calcification or non-specific calcium staining of synovial fluid or histological tissue is sufficient.
Calcific periarthritis
Deposition of apatite in the supraspinatus tendon (see Fig. 20.38) is a relatively common incidental radiographic finding in around 7% of adults. It occasionally results in severe acute inflammation of the subacromial bursa and periarticular tissues through crystal shedding from the tendon into and around the bursa. Periarticular sites around the greater trochanter of the hip, foot or hand are less common sites. Men and women are equally affected, usually as young or middle-aged adults.
The acute episode may occur spontaneously or follow local trauma. Within just a few hours shoulder pain and tenderness are extreme and the area appears swollen, hot and sometimes red. Modest systemic upset and fever are common. Radiographs confirm the diagnosis by showing tendon calcification. If the subacromial bursa is aspirated, thick white fluid containing many calcium-staining (alizarin red S) aggregates may be obtained.


Figure 20.38 Shoulder radiograph showing supraspinatus tendon calcification (arrow).
The condition usually resolves spontaneously over 1-3 weeks, often accompanied by radiographic dispersal and disappearance of small to modest-sized deposits (i.e. complete crystal shedding). Calcific periarthritis may result from metabolic abnormality (renal failure, hyperparathyroidism, hypophosphatasia) but measurements of serum creatinine, calcium and alkaline phosphatase are usually normal. The CRP is elevated during the episode.
Oral analgesics and NSAIDs ameliorate symptoms and the attack may be abbreviated by aspiration and injection of steroid. Exceptionally large deposits may cause mechanical blocking and painful impingement on abduction rather than acute periarthritis, and require surgical removal.
Osteoarthritis and BCP crystal deposition
Modest amounts of BCP aggregates are commonly found in synovial fluid from osteoarthritic joints, either alone or with CPPD crystals ('mixed crystal deposition'). Whether they contribute to joint damage or cause minor inflammatory episodes remains unclear. Large amounts of BCP, however, have been associated with an uncommon but distinctive form of osteoarthritis characterised by:
presence in elderly people (>75), predominantly women
involvement of knee, hip or shoulder (large joints) only
rapid progression, often leading to severe pain and disability in just a few months
development of marked instability and large effusions of knees or shoulders
an atrophic radiographic appearance with marked loss of cartilage and bone and minimal osteophyte or remodelling.

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Aspiration yields large volumes of relatively non-inflammatory fluid containing abundant BCP aggregates and often cartilage fragments. The differential diagnosis of such rapidly destructive arthropathy is end-stage avascular necrosis, chronic sepsis or neuropathic joint. Unlike sepsis, the acute phase response is not triggered and synovial fluid cultures are negative.
Treatment is with analgesics, intra-articular injection of steroids, local physical treatments and physiotherapy. The clinical outcome, however, is poor and most patients require joint replacement surgery. It is most likely that the BCP aggregates, rather than being causal pathogenic agents, are a marker of the speed of joint damage in such 'apatite-associated destructive arthritis' which represents the most severe end of the spectrum of osteoarthritis.
JOINT INFECTION
SEPTIC ARTHRITIS
Septic arthritis is a medical emergency. It is the most rapid and destructive joint disease and has a significant morbidity and a mortality of 10%. This has not improved over the last 20 years despite advances in antimicrobial therapy. The incidence is 2-10 per 100 000 in the general population and 30-70 per 100 000 in those with pre-existing joint disease or joint replacement.
Patients with septic arthritis have, by definition, a bacteraemia. Haematogenous spread from either skin or upper respiratory tract is the most common mode of entry. Acquisition of infection from direct puncture wounds secondary to joint aspiration is uncommon. Risk factors for septic arthritis include increasing age, pre-existing joint disease (principally rheumatoid arthritis), diabetes mellitus and immunosuppression (through drugs or disease). Additional factors in patients with rheumatoid arthritis include maceration of skin between the toes due to joint deformity, compounded by difficulties in washing and drying the feet due to hand deformities, with breakdown of skin a frequent portal of entry.
Lyme disease (see p. 21) may present with monoarthritis, often with other features including headaches, neurological signs and fatigue. There is usually a history of skin rash (erythema migrans) occurring 7-10 days after tick bite. Diagnosis is confirmed by Borrelia serology, although false positives may occur.
Clinical features
The usual presentation is with acute or subacute monoarthritis. The joint is usually swollen, hot and red and held in the 'loose-pack' position, with rest pain and stress pain on movement. Although any joint can be affected, the lower limb, particularly knee and hip, is the most common site. In patients with pre-existing arthritis involvement of one or more joints is not uncommon and a full MSK examination should be undertaken.
In adults the most likely organism is Staphylococcus aureus, particularly in patients with rheumatoid arthritis and diabetes. In young, sexually active adults disseminated gonococcal infection is an important cause. Disseminated infection occurs in up to 3% of untreated gonorrhoea. The usual presentation is with migratory arthralgia, low-grade fever and tenosynovitis, which may precede the development of oligo- or monoarthritis. Painful pustular skin lesions may also be present. Amongst the elderly or those who misuse intravenous drugs, Gram-negative bacilli or group B, C and G streptococci are important causes. Other organisms that are occasionally isolated include group A streptococci, pneumococci, meningococci and Haemophilus influenzae.
Investigation
Joint aspiration is essential whenever septic arthritis is suspected. Synovial fluid should be sent for Gram stain and culture. Aspirated fluid often looks turbid or blood-stained but may appear more normal. Blood cultures should also be taken. If the joint is not readily accessible (e.g. hip, spine, sacroiliac joint), aspiration should be performed under image guidance or in theatre. Prosthetic joints should only be aspirated in theatre.
Synovial fluid culture is positive in around 90% of cases of septic arthritis, though in only 50% of these is the initial Gram stain positive. By contrast, synovial fluid culture is positive in only 30% of gonococcal infections, making it important to obtain concurrent cultures from the genital tract (positive in 70-90% of cases). Although fever with peripheral leucocytosis and raised ESR occur in most patients, these may be absent in elderly or immunocompromised patients or early in the disease course.
Management
Hospitalisation is essential. The principles of management are:
pain relief
parenteral antibiotics
adequate drainage
early active rehabilitation.

The recommended first-line antibiotic regime treatment in adults is flucloxacillin (2 g i.v. 6-hourly), which will cover both staphylococcal and streptococcal infection until identification and antibiotic sensitivities are available. Intravenous treatment is usually continued for 2-3 weeks followed by oral treatment for 6 weeks in total. Initially, the joint should be aspirated daily to keep the effusion at a minimum. If this proves unsuccessful or the joint is inaccessible, surgical drainage may be required. Regular passive movement should be undertaken from the outset, and active movements encouraged once the condition has stabilised.
VIRAL ARTHRITIS
Most forms of viral arthritis are self-limiting. The usual presentation is with acute polyarthritis, fever or viral prodrome and rash. Parvovirus arthropathy is the most common and unlike children, adults may not have the characteristic facial rash. Diagnosis is confirmed by a rise in specific IgM. Polyarthritis may also rarely occur with hepatitis B and C, rubella and HIV infection.
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ISSUES IN OLDER PEOPLE
BONE INFECTION
Vertebral infection is more common in older people and recognition is often delayed as symptoms may be attributed to compression fractures caused by osteoporosis.
Peripheral vascular disease leads to more frequent involvement of the bones of the feet, and diabetic foot ulcers are also commonly complicated by osteomyelitis.
Prosthetic joint infections are now more common because of the increased frequency of trauma and prosthetic joint insertion in older people. Most prosthetic joint infections are delayed several months after surgery, and are difficult to treat.
Gram-negative bacilli are a more frequent pathogen in old age than in youth.


JUVENILE IDIOPATHIC ARTHRITIS
Although MSK pain is prevalent in children, inflammatory arthritis is relatively rare compared to adults (<0.01%>6 weeks) inflammatory arthritis that begins before age 16 for which no specific cause can be found. There are no specific diagnostic or investigational features for JIA and it is basically a diagnosis of exclusion. A list of some of the alternative diagnoses that may require consideration in a child with MSK pain and apparent joint swelling is shown in Box 20.49.
The aetiology of JIA is unknown, though both genetic and environmental factors are thought to be involved. JIA is classified according to the pattern of onset of arthritis in the first few months. This simple descriptive classification has prognostic significance and helps guide treatment selection. The most recent classification agreed by the International League against Rheumatism (ILAR) is shown in Box 20.50.
20.49 DIFFERENTIAL DIAGNOSIS OF JUVENILE IDIOPATHIC ARTHRITIS
Anxiety
Rickets/metabolic-scurvy, storage diseases
Tumour
Haematological-leukaemia, haemophilia, sickle-cell disease
Reactive-reactive arthritis, rheumatic fever
Immunological disease-lupus, immunodeficiency, serum sickness
Trauma, hypermobility
Injury (non-accidental)
Sepsis
Septic arthritis, bacterial endocarditis, meningococcus
Viral arthritis (including rubella, mumps, parvovirus, glandular fever)


20.50 INTERNATIONAL LEAGUE AGAINST RHEUMATISM (ILAR) CLASSIFICATION OF JUVENILE IDIOPATHIC ARTHRITIS*
Pattern Definition Main target
Oligoarthritis
Persisting Arthritis of 1-4 joints in first 6 months of disease Young girls
Extending Arthritis restricted to 1-4 joints in first 6 months that subsequently develops into polyarthritis Young girls
Polyarthritis
Rheumatoid factor (RF)-negative Arthritis of > 4 joints in first 6 months Young girls
Rheumatoid factor (RF)-positive Arthritis of > 4 joints in first 6 months, ×2 positive serum rheumatoid factor tests 3 months apart Older, adolescent girls
Psoriatic arthritis Arthritis + psoriasis, or Older girls and boys equally
Arthritis + family history of psoriasis and either dactylitis or nail pitting/onycholysis
Enthesitis-related arthritis Arthritis + enthesitis, or Older boys
Arthritis + two of:
Sacroiliac joint tenderness
Inflammatory spinal pain
HLA-B27
Anterior uveitis
Family history of uveitis, spondarthritis or inflammatory bowel disease
Systemic arthritis Arthritis + fever > 2 weeks, evanescent skin rash Under 2, girls and boys equally
Other arthritides Patients who fit no category or more than one category


* Children under the age of 16 at onset of symptoms with persistent features of arthritis for at least 6 weeks.
Oligoarthritis
This is the most common form, typically affecting pre-school girls and targeting lower limb joints, mainly knees. There is rarely any systemic upset. The MSK prognosis is usually excellent if it remains limited to oligoarthritis (oligoarthritis persisting) but 30% of cases progress to severe polyarthritis (oligoarthritis extending). Antinuclear antibodies and HLA-DR5 are present in 50% and such children are at high risk of asymptomatic chronic anterior uveitis.
Polyarthritis
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This accounts for 30-40% of JIA. Those who are seronegative for rheumatoid factor (90%) can be any age but pre-school girls are most commonly affected. There is symmetrical involvement of small and large joints in both upper and lower limbs, with common involvement of the cervical spine. Early cervical fusion and under-development of the mandible can give the stiff neck, receding chin and dental problems characteristic of adults who have had this form of JIA. The prognosis is less favourable than oligoarthritis; two-thirds have residual problems into adult life and 10% have severe joint damage.
Less commonly (10%), a similar presentation occurs in older (>8) or adolescent girls who are rheumatoid factor-positive. They often follow an aggressive course similar to severe adult rheumatoid arthritis with erosions, joint damage, nodules and vasculitis, and show increased association with HLA-DR4.
Psoriatic arthritis
This usually presents as an asymmetrical oligoarthritis. The diagnosis is made on the presence of skin plaques, or on a family history of psoriasis together with accompanying nail dystrophy or dactylitis ('sausage digit'). The prognosis for both the arthritis and uveitis tends to be worse than for non-psoriatic oligoarthritis.
Enthesitis-related arthritis
Older children and adolescents, especially boys, may develop lower limb mono- or oligoarthritis (hips, knees, ankles) with enthesitis (e.g. Achilles insertion, plantar fasciitis). Sacroiliitis is common and there may be a family history of seronegative spondarthritis, uveitis or inflammatory bowel disease. Around 75% are HLA-B27-positive and in most the disease gradually evolves into adult ankylosing spondylitis. The prognosis is worse than for adult-onset spondylitis.
Systemic arthritis
This pattern is the least common. It equally affects boys and girls and can occur at any age, though very young (< 2 years old) children are mostly affected. The diagnosis can be difficult since systemic upset and extra-articular features are initially often more dominant than the arthritis. Lymphadenopathy, hepatosplenomegaly, pleuro-pericarditis and high fevers often make malignancy or sepsis the main differential diagnoses. The intermittent nature of the fever and its accompaniment by an evanescent faint pink macular rash are helpful clues to the diagnosis. Remission of initial systemic inflammation usually occurs within 6 months, but over half the children have recurrent episodes and 30% develop severe chronic polyarthritis that is often resistant to treatment and may lead to subsequent secondary amyloidosis.
Complications
There is considerable physical, social and psychological morbidity with JIA. Special features of childhood arthritis include:
Uveitis. Chronic anterior uveitis is asymptomatic and potentially blinding. It is often bilateral, can develop in the absence of active synovitis and is detectable only by slit lamp examination. The greatest risk is with early-onset (<6 years old) oligoarthritis in young girls who are ANA-positive.
Growth disturbance. There may be a generalised suppressive effect due to active inflammation, compounded by use of systemic corticosteroids, as well as localised effects of synovitis that may lead to accelerated or retarded epiphyseal growth (e.g. long leg or short limbs and fingers) or early fusion of epiphyses (e.g. short limbs, micrognathia).
Loss of schooling and family disruption. The social and psychological consequences of chronic disease in childhood for both the child and the family should not be underestimated.

Management
Successful management of the interlinked educational, social, psychological and physical problems requires the skills of an experienced multidisciplinary team comprising rheumatologists, paediatricians, physiotherapists, occupational therapists, nurses, ophthalmologists, dentists/orthodontists, psychologists, social workers and teachers. Treatment usually includes education, regular exercise and physical therapy, NSAIDs, intra-articular steroid injections and antirheumatic drugs. Schooling should be integrated with healthy peers wherever possible, requiring close cooperation with community professionals.
Active physiotherapy is of great importance to reduce deformities and maintain muscle strength. Rest may be required when joints are acutely inflamed, but care must be taken to avoid development of flexion deformities, especially of hips and knees, by encouraging regular prone lying and the use of appropriate lightweight splints. Whenever possible, the child should be kept mobile and ambulant, and daily physiotherapy given to maintain a good range of joint movements and muscle strength. Hydrotherapy in a warm pool is particularly useful. Special consideration needs to be given to maintaining the child's education and helping parents to develop a sensible, vigilant but not over-protective approach.
Drug therapy
NSAIDs are useful symptomatic drugs and may be the only medication required for oligoarthritis. NSAIDs are safer and better tolerated in children than in adults, perhaps reflecting more rapid hepatic metabolism and urinary excretion and greater ability to repair mucosal surfaces. They are used at higher doses than in adults. For example, initial and maximum doses of commonly used NSAIDs include: naproxen 10-30 mg/kg/day, ibuprofen 30-60 mg/kg/day, tolmetin 20-30 mg/kg/day, and piroxicam 0.3-0.6 mg/kg/day. Aspirin should be avoided because of the risk of Reye's syndrome. If NSAIDs fail to settle the arthritis, intra-articular steroid injections are used to treat resistant joints (often delivered under short-acting general anaesthesia or relaxants), with or without parenteral bolus injections for multiple joint involvement. Joint injections in children can have long-lasting benefits compared with adults. If patients with oligoarthritis fail to respond, methotrexate is added for at least 2 years. Combined therapy with hydroxychloroquine or ciclosporin A may be considered if methotrexate alone is insufficient.
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Slow-acting antirheumatic drugs should be considered early in the disease course for all children with polyarthritis. Poor prognostic features include positive rheumatoid factor, systemic arthritis that evolves into polyarthritis, extended oligoarthritis and psoriatic polyarthritis. Methotrexate and sulfasalazine are the most effective agents; gold, d-penicillamine and hydroxychloroquine have no significant benefit.
Long-term corticosteroids are reserved for children with severe systemic disease, for those with chronic uveitis not responding to local therapy and where very active joint disease does not respond to other measures. The use of alternate-day corticosteroids should always be considered since doses of prednisolone as low as 3 mg/day can inhibit growth in children under 5 years. Corticosteroids do not arrest the progression of disease.
In children with systemic arthritis who fail to respond to steroids or NSAIDs for at least 2 years, combination therapy including methotrexate, cyclophosphamide and prednisolone may be considered. The balance is swinging in favour of early aggressive treatment in children with risk factors for poor outcome with the hope that this will achieve better long-term results. Chlorambucil is used in children with secondary amyloidosis.
Surgery
Surgery is usually limited to the rehabilitation of children with deformities. Soft tissue release operations may be helpful in eliminating difficult flexion contractures, and osteotomies may be required when joints have been allowed to fuse in poor positions. Total hip arthroplasty can be considered for severely damaged joints as soon as growth has ceased.

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Home > 2 SYSTEM-BASED DISEASES > 20 Musculoskeletal disorders > FIBROMYALGIA
FIBROMYALGIA
This is a very common cause of multiple regional MSK pain and disability. There is no associated pathology but physiological abnormalities of sleep and pain processing are both recognised. It commonly associates with medically unexplained symptoms in other systems and shows considerable overlap with, and similar risk factors to, other syndromes of 'functional disturbance' (see Ch. 8).
Epidemiology
The crude prevalence in UK and US communities is 2-3%. There is a strong female predominance of around 10:1. Although fibromyalgia can occur at any age, including in teenagers, it shows a progressive increase with age, reaching a maximum prevalence of 7% in women aged over 70. The condition appears ubiquitous and is reported in a wide variety of racial groups and cultural settings.
Recognised risk factors other than ageing and female gender include a wide variety of life events that all associate with psychosocial distress: for example, divorce, marital disharmony, alcoholism in the family, traumatic injury or assault, low income and self-reported childhood abuse.
Aetiology
The condition is poorly understood. Despite intensive and invasive investigation no structural, inflammatory, metabolic or endocrine abnormality has been identified. Two abnormalities, however, have consistently been reported:
Sleep abnormality. Delta waves are characteristic of the deep stages of non-rapid eye movement (non-REM) sleep. Most delta sleep usually occurs in the first few hours and is thought to have primarily a restorative function. People with fibromyalgia have difficulty quickly entering delta sleep and obtain reduced amounts during the night. This pattern differs from sleep abnormalities associated with clinical depression alone. Furthermore, deprivation of delta but not REM sleep in normal volunteers produces the symptoms and signs of fibromyalgia, supporting the concept of fibromyalgia as a non-restorative sleep disorder.
Abnormal pain processing. A reduced threshold to pain perception and tolerance at characteristic sites throughout the body is a central feature of fibromyalgia. Affected people also have spinal cord 'wind-up' (pain amplification), as evidenced by the exaggerated skin flare response to topically applied capsaicin and frequent occurrence of dermatographism and allodynia (when normally non-noxious stimuli become painful). Other observations to support abnormal pain processing include altered cerebrospinal fluid levels of substance P (increased) and 5-HT (reduced) and reduced regional cerebral blood flow in the caudate and thalamus.

Both these abnormalities may interrelate. Poor sleep may impair normal descending inhibition to the spinal cord centres that gate pain and, equally, chronic pain may interrupt sleep. The strong association with distressing life events might also explain initial disruption of normal sleep and restoration. A current hypothesis to explain these interrelations is outlined in Figure 20.39.


Figure 20.39 Possible mechanisms involved in fibromyalgia.
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Epidemiological studies have confirmed the clustering of poor sleep, multiple regional pain, widespread hyperalgesia and low scores on anxiety and depression ratings, giving some credence to 'fibromyalgia' as a descriptive term to characterise people with the combination of such problems (see EBM panel).
EBM
FIBROMYALGIA-evidence for associations
'Epidemiological community studies have shown that widespread body pain, fatigue, psychological distress and multiple hyperalgesic tender sites cluster together and associate with increased odds ratios of various stressful life events.'
Wolfe F, Ross K, Anderson J, et al. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum 1995; 38:19-28.
Croft P, Schollum J, Silman A. Population study of tender point counts and pain as evidence of fibromyalgia. BMJ 1994; 309:696-699.


Clinical features
20.51 SYMPTOMS OF FIBROMYALGIA
Usual symptoms
Multiple regional pain
Marked fatigability
Marked disability
Broken non-restorative sleep
Low affect, irritability, weepiness
Poor concentration, forgetfulness
Variable locomotor symptoms
Early morning stiffness
Swelling of hands, fingers
Numbness, tingling of all fingers
Additional, variable, non-locomotor symptoms
Non-throbbing bifrontal headache ('tension headache')
Colicky abdominal pain, bloating, variable bowel habit ('irritable bowel syndrome')
Bladder fullness, nocturnal frequency ('irritable bladder')
Hyperacusis, dyspareunia, discomfort when touched (allodynia)
Common side-effects with drugs ('chemical sensitivity')


The main presenting feature is multiple regional pain, often focusing on the neck and back (see Box 20.51). At presentation just one or a few regions may dominate the picture, but over the preceding months pain will have affected all body quadrants-both arms, both legs, neck and back. The pain is characteristically unresponsive to traditional measures (analgesics, NSAIDs) and physiotherapy often makes it worse. Fatigability, most prominent in the morning, is the second major problem. Reported disability is often marked. Although people can usually dress, feed and groom themselves, they may be unable to perform daily tasks such as shopping, housework or gardening. They may have experienced major difficulties at work or even given up employment because of pain and fatigue.


Figure 20.40 Major tender sites that become hyperalgesic with fibromyalgia.
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Examination usually reveals no abnormality of the MSK system in terms of joint synovitis or damage and no overt neurological defect or wasting. Depending on their age, people may have signs of osteoarthritis or other prevalent MSK conditions, but of insufficient severity to explain such widespread symptoms and severe disability. The principal finding is hyperalgesia at recognised natural tender sites in the body (see Fig. 20.40). Moderate digital pressure at each site may be uncomfortable in a normal subject but in fibromyalgia it produces a wince/withdrawal response. Metered dolorimeters are available for research purposes but moderate digital pressure, sufficient to just whiten the nail, is sufficient for clinical diagnosis.
To fulfil the criteria for fibromyalgia the person requires:
the appropriate symptoms, including pain affecting all body quadrants
positive hyperalgesic tender sites in each arm and leg and axially (i.e. widespread)
negative control tender sites (pressure on forehead, squeezing across the distal radius and ulna, pressure over the proximal fibular head).

If someone exhibits hyperalgesia wherever pressure is applied, he or she is likely to have severe psychological disturbance or be malingering.
People with recognised MSK or other disease (e.g. rheumatoid arthritis, lupus, cancer) are not exempt from developing fibromyalgia. Assessment of people with coexistent rheumatoid arthritis or lupus may prove challenging since many of the symptoms could relate to activity of their multisystem disease. Marked discordance between the severity of reported and observed abnormality, however, is an important feature to suggest fibromyalgia, and widespread hyperalgesic tender sites are not explained by polyarticular disease.
Investigations
Fibromyalgia does not associate with any abnormality of routine testing. However, it is important to screen for alternative conditions that may account for some of the symptoms without producing overt clinical signs (see Box 20.52).
20.52 A MINIMUM INVESTIGATION SCREEN IN PEOPLE WITH FIBROMYALGIA
Test Condition screened
Full blood count Anaemia, lymphopenia of lupus
ESR, CRP Inflammatory Disease
Thyroid function Hypothyroidism
Calcium, alkaline phosphatase Hyperparathyroidism, osteomalacia
Antinuclear antibody Lupus

Management
The aims of management are education concerning the nature of the problem, pain control and improvement of sleep.
Education is central. Wherever possible, discussion should include the spouse, family or carer so that the same information is shared. The fact that the person's chronic pain does not reflect inflammation, damage or disease is a vital but difficult concept to explain. Repeat or drawn-out investigation may reinforce beliefs in occult serious pathology and should be avoided. The central importance of sleep and the fact that selective sleep deprivation can cause these symptoms in anyone deserves emphasis. Ascribing the symptoms to a cause for which the patient cannot be blamed, and knowing that it is very common often help. The fact that we recognise the condition but have no clear medical explanation for it should be admitted. The model of a self-perpetuating cycle of poor sleep causing body pain that limits activity, that then worsens sleep, that then makes pain worse is often readily accepted and is a useful framework for a problem-based management strategy.
The two evidence-based interventions that may help some individuals are:
1. Low-dose amitriptyline (25-75 mg nocte) for a limited trial of 2-3 weeks, continuing thereafter if pain and fatigue are improved. Combination with fluoxetine (20 mg in the morning) may increase the benefit. Many people with fibromyalgia, however, are intolerant of even small doses of amitriptyline.
2. A graded increase in aerobic exercise to improve well-being and sleep quality. This often requires regular supervision if it is to succeed.
The use of self-help strategies should be encouraged. A cognitive behavioural approach, with relaxation techniques and other coping strategies, may help the person better deal with symptoms. Many people with chronic pain 'for no obvious cause' adopt maladaptive illness behaviour patterns and these can sometimes be modified with resultant improved coping. Sublimated anxiety relating to distressing life events should be specifically explored and addressed by appropriate counselling. Literature is available and there are patient organisations from which to obtain additional information and support.
The prognosis for hospital-diagnosed fibromyalgia is poor. Although treatment may improve their quality of life and ability to cope, most people do not lose their symptoms or diagnostic criteria over 5 years. Subjects diagnosed in primary care, or who have sublimated anxiety that can be successfully addressed, may fare better.

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Home > 2 SYSTEM-BASED DISEASES > 20 Musculoskeletal disorders > DISEASES OF BONE
DISEASES OF BONE
OSTEOPOROSIS
Osteoporosis is a common disease characterised by reduced bone mass, microarchitectural deterioration of bone tissue and an increased risk of fracture. The prevalence of osteoporosis and osteoporosis-related fractures both increase with age in women and men, reflecting age-related decline in bone mass. Fractures related to osteoporosis are a major public health problem in all developed countries, and are estimated to affect up to 30% of women and 12% of men at some time in their life. In the UK alone osteoporotic fractures affect over 200 000 individuals annually, with treatment costs of about £1.4 billion.
Pathogenesis
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One of the defining features of osteoporosis is reduced bone mass. In normal individuals bone mass increases during skeletal growth to reach a peak between the ages of 20 and 25 but falls thereafter in both sexes, with an accelerated phase of more rapid bone loss in women due to the effects of oestrogen deficiency at the menopause. This loss of bone mass is caused by an imbalance between bone resorption and bone formation (see Fig. 20.41). Individuals who have normal peak bone mass are protected against osteoporosis, even though they suffer age-related bone loss (panel A) whereas patients with low peak bone mass are at risk of developing osteoporosis from age-related bone loss (panel B). Osteoporosis can also occur in patients with normal peak bone mass if bone resorption substantially exceeds bone formation (panel C). Patients with low peak bone mass in whom bone resorption substantially exceeds bone formation are at risk of severe osteoporosis (panel D).


Figure 20.41 Mechanisms of osteoporosis. The panels on the far right depict changes in bone mineral density with age under various scenarios for peak bone mass and bone remodelling. The green shaded area represents the 'normal range' in young healthy individuals.
Many factors regulate bone mass and bone loss in normal individuals. They include genetic influences and environmental factors such as exercise, smoking and diet. Twin and family studies have shown that heredity accounts for 70-85% of individual variance in bone mass and also contributes to other determinants of fracture risk such as bone loss and body weight. The genetic mechanisms are incompletely understood, but appear to involve subtle variations (polymorphism-see p. 347) in several genes that regulate bone cell activity and composition of bone matrix. Rarely, osteoporosis may result from single gene disorders. Environmental factors such as exercise and calcium intake during growth and adolescence are also important in maximising peak bone mass and in regulating rates of post-menopausal bone loss. Finally, bone loss may occur as a complication of various endocrine, inflammatory and neoplastic conditions, in hypogonadism and as the result of various drug treatments, especially corticosteroids (see Box 20.53). The pathogenesis of corticosteroid-induced osteoporosis involves reduced bone formation, impaired calcium absorption, increased urinary loss of calcium and hypogonadism.
Clinical features
Clinical presentation is with fragility fractures (see p. 985). These can affect virtually any bone, but the most common sites are the forearm (Colles fracture), spine (vertebral fracture) and femur (hip fracture) (see Fig. 20.42). Colles and vertebral fractures typically occur in women aged 55 and above, whereas hip fractures mainly affect individuals aged 70 and above. Since low bone density alone does not cause symptoms, patients with advanced osteoporosis may be completely asymptomatic until a fracture occurs.
Investigations and diagnosis
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20.53 RISK FACTORS FOR OSTEOPOROSIS AND OSTEOPOROTIC FRACTURES
Genetic
Race
Low body weight
Family history
Lifestyle
Diet/calcium intake
Exercise/immobility
Highly trained athletes
Endocrine
Pituitary disease
Early menopause
Thyrotoxicosis
Hyperparathyroidism
Inflammatory disease
Ankylosing spondylitis
Rheumatoid arthritis
Inflammatory bowel disease
Gastrointestinal disease
Malabsorption
Chronic liver disease
Drugs
Corticosteroids
Anticonvulsants
Sedatives
Gonadotrophin-releasing hormone (GnRH) agonists
Substance misuse
Alcoholism
Smoking
Others
Anorexia nervosa
Myeloma
Mastocytosis
Homocystinuria
Gaucher's disease


Patients with suspected osteoporosis should undergo bone densitometry at the spine and hip (see p. 972). If this shows a BMD T-score value of -2.5 or less at either site, the diagnosis is confirmed. Secondary causes of osteoporosis should be sought by clinical history and physical examination, supplemented by biochemical screening for thyrotoxicosis (see p. 691), myeloma (ESR, serum protein electrophoresis) and primary hyperparathyroidism (see p. 718). When osteoporosis occurs in men and pre-menopausal women, hypogonadism should be excluded by measurement of sex hormones and gonadotrophins. Routine biochemistry is usually normal in post-menopausal osteoporosis but serum alkaline phosphatase can be raised transiently following a fracture. Bone biopsy is not required for diagnosis but can be helpful in identifying unusual causes and in excluding osteomalacia.
Management
An algorithm for the management of patients with suspected osteoporosis is shown in Figure 20.43. Individuals with a normal BMD can be reassured. Those with mild osteopenia (T-score -1.0 to -2.0) should be given general advice on lifestyle factors such as smoking (stop), alcohol (limit to < 20 units/week), dietary calcium intake (aim for 1500 mg daily) and exercise (encourage), and reassessed after 3-5 years. Specific pharmacological therapy should be considered in addition to lifestyle advice in patients with more severe osteopenia (T-score -2.0 to -2.5) and in those with osteoporosis (T-score values of -2.5 and below). Pharmacological treatment (see Box 20.54) is especially indicated in those patients with osteoporosis who have suffered fragility fractures since their risk of further fracture is high.
20.54 EFFICACY OF DRUG TREATMENT OF OSTEOPOROSIS
?BMD ?Risk of vertebral fracture ?Risk of non-vertebral fracture
Bisphosphonates + + +
Hormone replacement therapy + + +
Raloxifene + + -
Calcium + vitamin D + n/a +
Calcium + + -
Calcitonin + + -
Tibolone + n/a n/a


(+ = proven efficacy in RCT; - = ineffective in RCT; n/a = data not available)


Figure 20.42 Common osteoporotic fractures. A Colles fracture. B Vertebral fractures. C Hip fracture.
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Figure 20.43 Diagnosis and management of suspected osteoporosis. Numbers needed to treat (NNTs) are derived from randomised clinical trials (RCTs) of bisphosphonate therapy in osteoporosis.
Bisphosphonates
These are the most effective agents for the prevention and treatment of osteoporosis. Bisphosphonates are stable, synthetic analogues of pyrophosphate that adsorb on to bone surfaces and become incorporated within bone matrix beneath the resorbing osteoclasts. When bone that contains bisphosphonate is ingested by osteoclasts, the drug is released within the cell at high concentration to cause osteoclast death, thereby inhibiting bone resorption. Bisphosphonates do not directly stimulate bone formation but long-term treatment typically increases BMD by 5-10%. This is thought to be due to filling of resorption sites with new bone and increased mineralisation of existing bone.
EBM
PREVENTION OF OSTEOPOROTIC FRACTURES-role of bisphosphonates
'Large-scale RCTs have shown that the aminobisphosphonates aledronate and residronate reduce the risk of osteoporotic fractures by about 50% when administered to patients with post-menopausal osteoporosis.'
Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348:1535-1541.
Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis. JAMA 1999; 282:1344-1352.


Etidronate was the first bisphosphonate to be used for the treatment of osteoporosis. It is given as an oral daily dose of 400 mg for 2 weeks, followed by a 13-week phase of calcium supplements (500-1000 mg daily). This regimen is repeated cyclically on a long-term basis. Cyclical etidronate has been shown to prevent post-menopausal bone loss and to reduce the risk of osteoporotic vertebral fractures in postmenopausal women with established osteoporosis. It is also effective in the prevention and treatment of corticosteroid-induced osteoporosis. Amino-substituted bisphosphonates such as alendronate (10 mg daily, or 70 mg once weekly) and risedronate (5 mg daily) are more potent than etidronate and are clinically superior at preventing post-menopausal bone loss, in treating established post-menopausal osteoporosis and in preventing and treating corticosteroid-induced osteoporosis. Alendronate has also been shown to increase BMD and reduce the risk of fractures in men with osteoporosis; there is also evidence that alendronate and risedronate reduce the risk of both vertebral and non-vertebral fractures in post-menopausal women (see EBM panel). All bisphosphonates should be taken on an empty stomach with a glass of water since their absorption is poor and inhibited by food. They are generally well tolerated, but upper gastrointestinal upset can occur with alendronate and this agent should be used with caution or avoided in patients with gastro-oesophageal reflux disease.
Hormone replacement therapy (HRT)
HRT (see p. 713) is effective in preventing post-menopausal bone loss and long-term treatment reduces the risk of fracture. HRT is most commonly used in early menopausal women with climacteric symptoms such as hot flushes, but has also been shown to be effective in older women with established osteoporosis. Side-effects, however, are more common in older women and many cannot tolerate HRT because of weight gain, fluid retention, menstrual bleeding or breast tenderness.
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Calcium
Calcium supplements (500-1000 mg daily) slow post-menopausal bone loss, especially in people whose dietary calcium intake is low. Calcium supplements have been shown to reduce the risk of vertebral fracture in some studies, but they do not increase bone mass or reduce the risk of non-vertebral fractures. Because of this, calcium supplements are mainly given in combination with other agents such as bisphosphonates, HRT and calcitonin in the management of osteoporosis.
Calcitonin
Calcitonin prevents bone loss in post-menopausal osteoporosis and is also effective in the secondary prevention of osteoporotic vertebral fractures. It may also have an analgesic effect when given to patients with acute vertebral fractures. Traditionally, calcitonin has been given daily by subcutaneous or intramuscular injections (100-200 U) in the treatment of osteoporosis, but recently a formulation has been developed which is given by intranasal spray (200 U/day). The inconvenience of frequent injections, coupled with side-effects such as flushing and nausea, has so far limited the use of calcitonin injections in the long-term treatment of osteoporosis, but many of these problems have been circumvented by the intranasal formulation, which seems to be better tolerated.
Calcium and vitamin D
Calcium (500-1000 mg daily) and vitamin D supplements (20 µg daily) have an established role in the primary prevention of fractures in the elderly, irrespective of whether or not BMD values are reduced. This treatment has been shown to be effective in reducing the risk of hip fractures and other non-vertebral fractures in both institutionalised patients and community-living individuals.
Raloxifene
Raloxifene belongs to a class of compounds termed selective oestrogen receptor modulators (SERMs), which act as oestrogen receptor agonists in some tissues and antagonists in others. Raloxifene (60 mg daily, with calcium and vitamin D supplements) has been found to increase bone mass and reduce the risk of vertebral fractures in post-menopausal women with osteoporosis. Raloxifene treatment is associated with an increased risk of DVT, but apart from the occurrence of muscle cramps in some patients is otherwise well tolerated. In addition to its beneficial effects on the skeleton, raloxifene has been found in short-term studies to reduce the risk of women developing breast cancer. The long-term impact of raloxifene on breast cancer mortality is as yet unclear.
Other agents
Anabolic steroids such as stanozolol have been found to increase BMD in osteoporosis, but there are no data on fracture prevention and adherence to therapy is poor because of side-effects such as hirsutism, weight gain, fluid retention and disturbance of liver function. Testosterone treatment has been found to increase BMD in hypogonadal males with osteoporosis and should be given routinely in this situation. Tibolone is a hormone receptor modulator that acts as a partial agonist at the oestrogen, progestogen and androgen receptors. It increases BMD in post-menopausal osteoporosis but there are no data on fracture prevention. Calcitriol and alphacalcidol, the active metabolites of vitamin D, have been found to be effective when given along with calcium in secondary prevention of vertebral fractures in some studies, but not in others. This therapy must be closely monitored in view of the risk of hypercalcaemia and hypercalciuria. Sodium fluoride differs from most of the other agents discussed so far in having a specific stimulatory effect on bone formation. Sodium fluoride can give impressive increases in bone mass (30% or more), but the therapeutic window is narrow since fluoride can promote formation of woven bone with reduced mechanical strength. In view of this, the role of fluoride in the treatment of osteoporosis is controversial.
Monitoring therapy
ISSUES IN OLDER PEOPLE
OSTEOPOROSIS
Fractures due to osteoporosis are a common cause of morbidity and mortality in the elderly, although fracture healing is not delayed by age.
There is an age-associated increase in parathyroid hormone (PTH) secretion which leads to increased bone turnover, and as there is also an age-related defect in osteoblast function, the outcome is bone loss.
Elderly patients who suffer fragility fractures are at increased risk for further fracture. They should be investigated for evidence of osteoporosis and treated if the diagnosis is confirmed.
Risk factors for falls (such as visual and neuromuscular impairments) are independent risk factors for hip fracture in elderly women, so intervention to prevent falls is as important as treatment of osteoporosis (see Ch. 7, p. 241).
Bisphosphonates are the most effective agents currently available for the prevention of osteoporotic fractures, but their use should be restricted to patients in whom bone densitometry has shown low BMD values (T-score below -2.5).
Calcium and vitamin D supplements are a safe and effective way of reducing the risk of hip and other non-vertebral fractures in elderly housebound or institutionalised individuals, irrespective of BMD values.


The response of osteoporosis to treatment should ideally be monitored by repeating spine BMD measurements between 12 and 24 months after starting therapy. Increases in BMD of between 5 and 8% are expected with HRT and bisphosphonates, whereas other agents have a lesser effect (1-3%). If BMD measurements are not available, then progression of spinal osteoporosis can be monitored by changes in height. The development of fractures during treatment is not necessarily a reason for stopping therapy since even the most potent agents only reduce the risk of fracture by 50%.
OSTEOMALACIA AND RICKETS
Osteomalacia is characterised by defective bone mineralisation, bone pain, muscle weakness and pathological fractures. Osteomalacia is now relatively rare in developed countries, but remains common in high-risk subgroups such as female Muslim immigrants to Western societies and elderly housebound people. Rickets is the clinical syndrome that results when osteomalacia occurs in the growing skeleton.
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Pathogenesis
The most common cause is vitamin D deficiency. This can occur through reduced dietary intake, vitamin D malabsorption or reduced sunlight exposure. Reduced sunlight exposure may cause osteomalacia because the precursor of vitamin D-cholecalciferol-is synthesised from cholesterol in skin that is exposed to ultraviolet light (see Fig. 16.13, p. 715). Osteomalacia is therefore more common in housebound individuals and in Muslim women who cover their skin for cultural reasons.
The low levels of circulating 25(OH) vitamin D cause reduced production of the biologically active metabolite 1,25(OH) vitamin D by the kidney and this causes a reduction in calcium absorption from the intestine. The low calcium absorption stimulates parathyroid hormone (PTH) secretion, which restores serum calcium levels towards normal by increasing bone resorption and renal tubular calcium reabsorption. The high level of PTH also promotes phosphaturia, however, and causes phosphate depletion. It is the combination of calcium loss from bone and phosphate depletion that causes impaired mineralisation of bone, which is the defining feature of osteomalacia.
20.55 CAUSES OF OSTEOMALACIA
Type Causal factors Mechanism
Vitamin D deficiency
Classical Lack of sunlight exposure/dietary lack of meat and dairy products Reduced cholecalciferol synthesis in the skin/low levels of vitamin D in diet
Gastrointestinal disease Malabsorption Malabsorption of dietary vitamin D and calcium
Failure of 1,25 vitamin D synthesis
Chronic renal failure Hyperphosphataemia and kidney damage Impaired conversion of 25(OH)D3 to 1,25(OH)2D
Vitamin D-dependent rickets type I (autosomal recessive) Mutation in renal 25(OH)D-1-a-hydroxylase enzyme
Vitamin D receptor defects
Vitamin D-dependent rickets type II (autosomal recessive) Inactivating mutations in vitamin D receptor Impaired response to 1,25(OH)2D
Defects in phosphate and pyrophosphate metabolism
Hypophosphataemic rickets X-linked dominant mutations in PHEX gene Hypophosphataemia
Autosomal dominant mutations in FGF23
Oncogenic hypophosphataemic osteomalacia Tumour-produced FGF23
Hypophosphatasia Mutations in bone-specific alkaline phosphatase Inhibition of bone mineralisation due to pyrophosphate accumulation
Iatrogenic
Bisphosphonate therapy Etidronate/pamidronate Drug-induced impairment of mineralisation
Aluminium Use of aluminium-containing phosphate binders or aluminium in dial Aluminium-induced impairment of mineralisation

Osteomalacia also occurs with various inherited and acquired metabolic defects (see Box 20.55). The most common is chronic renal failure where there is failure of renal 1,25(OH) vitamin D synthesis due to hyperphosphataemia (which directly inhibits 25(OH) vitamin D-1-a-hydroxylase) and loss of functioning renal tissue. A similar mechanism occurs in vitamin D-resistant rickets type I caused by inactivating mutations in the renal 25(OH) vitamin D-1-a-hydroxylase enzyme. Another type of vitamin D-resistant rickets (type II) results from mutations in the vitamin D receptor rendering it resistant to activation by 1,25(OH)D. X-linked hypophosphataemic rickets (XLH) is caused by inactivating mutations in the PHEX gene whose normal function is to degrade a circulating hormone which promotes phosphaturia. Deficiency of PHEX causes profound renal phosphate wasting due to the unopposed action of this factor. Autosomal dominant hypophosphataemic rickets is a related disorder, caused by activating mutations of fibroblast growth factor 23 (FGF23), which acts on the kidney to promote phosphaturia. Osteomalacia caused by renal phosphate wasting can also occur as a complication of tumours due to 'ectopic' production of FGF23 by tumours. In hypophosphatasia, the bone-specific alkaline phosphatase gene is mutated, resulting in failure of pyrophosphate breakdown, accumulation of pyrophosphate in bone and osteomalacia due to the inhibitory effect of pyrophosphate on mineralisation. Osteomalacia that results from bisphosphonate and aluminium toxicity also occurs through a direct inhibitory effect on mineralisation.
Clinical features
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Infants with rickets exhibit delayed development and muscle hypotonia. Other signs include craniotabes (small unossified areas in membranous bones of the skull that yield to finger pressure with a cracking feeling); 'bossing' of the frontal and parietal bones and delayed anterior fontanelle closure; enlargement of epiphyses at the lower end of the radius; and swelling of the rib costochondral junctions (rickety rosary). Deformities of the long bones, chest, spine and pelvis may also occur. Severe rickets may be associated with hypocalcaemic tetany that presents with spasm of the hands, feet and vocal cords, resulting in a high-pitched distressing cry or laryngeal stridor. Epileptic seizures due to hypocalcaemia also occur. Mild osteomalacia in adults can be asymptomatic, but bone pain, pathological fractures and malaise occur as the disease progresses. Muscle weakness is prominent and the patient may walk with a waddling gait and experience difficulty in climbing stairs or getting out of a chair. Bone and muscular tenderness on pressure is common and focal bone pain may occur in association with fissure fractures of the ribs and pelvis.
Investigations and diagnosis
A routine biochemical screen should be performed, along with estimation of 25(OH)D and PTH levels. The combination of raised alkaline phosphatase, raised PTH and low 25(OH)D levels is virtually diagnostic, although transiliac bone biopsy may be required in cases of doubt. Radiological examination may show pathognomonic features in rickets and osteomalacia, but only in advanced disease. Abnormalities include thickening and widening of the epiphyseal plate in children and focal radiolucent areas (pseudofractures or Looser's zones) in the ribs, pelvis and long bones.
Patients with osteomalacia secondary to chronic renal disease show grossly elevated PTH and raised alkaline phosphatase levels. Patients with chronic renal failure (CRF) are unable to excrete aluminium effectively; it may accumulate in bone and cause a mineralisation defect. Possible sources of aluminium include aluminium hydroxide (often used as an oral phosphate-binding drug in patients with CRF, or as an antacid) and the water used to make up dialysis fluid. Careful monitoring of aluminium levels in blood and dialysis fluid have rendered this a rare condition. Patients are often hypercalcaemic, but alkaline phosphatase and PTH are usually not elevated. Diagnosis requires a bone biopsy. Treatment consists of removal from aluminium exposure, and desferrioxamine, a chelating agent which removes aluminium from tissues.
Bisphosphonate-induced osteomalacia is transient, often asymptomatic and mainly occurs in Pagetic patients given high doses of etidronate or pamidronate. The diagnosis can only be made by bone biopsy. Vitamin D-resistant rickets (VDRR) is usually suspected when rachitic patients fail to respond to vitamin D and calcium. In type I VDRR, 25(OH)D levels are normal and 1,25(OH)D levels are undetectable, whereas in type II VDRR, 25(OH)D levels are normal and 1,25(OH)D levels are raised. Osteomalacia due to hypophosphatasia also fails to respond to vitamin D but is differentiated from VDRR by the finding of very low alkaline phosphatase levels. Osteomalacia resulting from hypophosphataemic rickets is characterised by severe hypophosphataemia, renal phosphate wasting and normal 25(OH)D and 1,25(OH)D levels. The diagnosis is usually obvious when the above features are combined with a positive family history. Acquired hypophosphataemic rickets due to ectopic secretion of FGF23 presents with similar biochemical features in the absence of a family history.
Management
This depends on the underlying cause. Vitamin D-deficient rickets and osteomalacia respond rapidly to 25(OH) vitamin D (10-50 µg daily) or active vitamin D metabolites (1-a-hydroxyvitamin D 0.5-2 µg daily or 1,25 dihydroxyvitamin D 0.25-1.5 µg daily) and calcium supplementation (500-1000 mg daily). Higher doses of vitamin D may be required in patients with malabsorption. Healing of the bone disease is accompanied by rapid clinical improvement, normalisation of biochemical abnormalities and radiographic improvement. After 3-4 months, treatment can generally be stopped or the dose of vitamin D reduced to a maintenance level for those with underlying disease or lifestyle factors which put them at risk of recurrence.
Osteomalacia in chronic renal failure requires treatment with active vitamin D metabolites (1-a-hydroxyvitamin D or 1,25 dihydroxyvitamin D) rather than 25(OH)D since these metabolites bypass the metabolic defect in 1-a-hydroxylation of 25(OH)D. Although VDRR type I responds well to active vitamin D metabolites, VDRR type II responds poorly and often presents an intractable management problem despite parenteral calcium, phosphate and high doses of active vitamin D metabolites. The same applies to hypophosphatasia for which there is no specific treatment. Hypophosphataemic rickets usually responds well to phosphate supplements (2-4 g daily) and active vitamin D metabolites.
Monitoring of calcium, phosphate, alkaline phosphatase and renal function is important in patients with osteomalacia who are undergoing long-term treatment with vitamin D or its metabolites. Healing of osteomalacia is usually reflected by a return of alkaline phosphatase values to normal. Monitoring serum phosphate is of value in hypophosphataemic rickets to judge the adequacy of phosphate replacement.
ISSUES IN OLDER PEOPLE
OSTEOMALACIA
Elderly housebound individuals are at increased risk of osteomalacia due to lack of sunlight exposure and poor diet. Around 15% of older people in the community in the UK and USA have low levels of 25(OH)D.
The diagnosis should be considered in patients with bone pain and muscular weakness who have low serum levels of 25(OH)D and raised alkaline phosphatase levels.
The diagnosis can be confirmed by bone biopsy, which should be considered in patients where the investigations above are inconclusive.
The symptoms and signs of osteomalacia respond rapidly to treatment with calcium and small doses of vitamin D.


PAGET'S DISEASE
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Paget's disease of bone is characterised by increased, disorganised bone remodelling on a focal or multifocal basis at various sites in the skeleton. The pelvis, femur, tibia, lumbar spine, skull and scapula are principally affected; involvement of small bones of hands and feet is rare. Paget's disease rarely spreads to new bones once the diagnosis is made, suggesting that affected bones are targeted by the disease relatively early in life. Paget's disease is seldom diagnosed before the age of 40 but gradually increases in incidence thereafter to affect up to 10% of the UK population by the age of 85. The disease is common in Caucasians from Western and Southern Europe but rare in Scandinavians, Asians, Chinese and Japanese. These ethnic differences persist after emigration, highlighting the importance of genetic factors in aetiology.
Pathogenesis
The primary abnormality is increased osteoclastic bone resorption, which is accompanied by marrow fibrosis, increased vascularity of bone and increased osteoblast activity. These abnormalities result in architecturally abnormal bone with reduced mechanical strength. As well as being increased in number, the osteoclasts are abnormally large and can contain up to 100 nuclei. Genetic factors are clearly important in pathogenesis and a positive family history is obtained in about 15% of patients. Families are described in which Paget's is inherited as an autosomal dominant trait. In some families with severe early-onset disease (familial expansile osteolysis) activating mutations of the RANK gene are responsible, though different unidentified genes are involved in late-onset familial Paget's disease. Environmental factors, however, may also be important. Localisation of Paget's disease to bones or limbs that have been subjected to heavy repetitive use suggests that biomechanical factors may help trigger the disease.
Clinical features
The classic presentation of Paget's disease is with bone pain, bone deformity, deafness and pathological fractures. Nowadays, however, it is more often discovered as an incidental finding on biochemical testing or radiographic examination. Clinical signs of Paget's include bone deformity and expansion, increased warmth over affected bones, and pathological fracture. Pagetic deformity is usually most evident in weight-bearing bones such as the femur and tibia and in the skull where the cranium becomes enlarged. Neurological problems such as deafness, other cranial nerve defects, nerve root pain, spinal cord compression and spinal stenosis may occur with involvement of the skull and spine because the affected bones enlarge and encroach upon the spinal cord and nerve foramina. Increased vascularity of Pagetic bone can precipitate high-output cardiac failure in elderly patients with limited cardiac reserve. Osteosarcoma is a rare but serious complication of Paget's disease that has a poor prognosis. It should be suspected in a patient with Paget's who suffers a sudden increase in pain or swelling of an affected bone.
Investigations and diagnosis


Figure 20.44 Paget's disease. A Radiographic features, illustrating bone expansion and osteosclerosis with pseudofractures breaching the bone cortex (arrows). B Radiograph from the same patient who developed a pathological fracture (arrow) at the site of a pre-existing pseudofracture while walking down the street.
The diagnosis is usually suspected by the finding of a raised serum alkaline phosphatase but normal liver function tests. Confirmation is by typical features on radiograph (see Fig. 20.44) or isotope bone scan (see Fig. 20.8, p. 969). Bone scans are useful in documenting the extent of disease and in helping to assess whether symptoms such as pain are due to Paget's disease of a specific bone. Radiographs should be taken of symptomatic bones to look for deformity, to screen for coexisting osteoarthritis and to document whether fractures or pseudofractures are present, since all of these can contribute to bone pain. Rarely, osteosclerotic metastases can mimic Paget's disease on biochemical and radiological grounds. If this diagnosis is suspected, bone biopsy is required for accurate differentiation.
Management
20.56 MEDICAL MANAGEMENT OF PAGET'S DISEASE
Drug Route of administration Dose
Etidronate Oral 400 mg daily for 3-6 months
Tiludronate Oral 400 mg daily for 3-6 months
Risedronate Oral 30 mg daily for 2 months
Alendronate* Oral 40 mg daily for 3 months
Pamidronate Intravenous 60 mg on 1-6 occasions
Calcitonin Subcutaneous 100-200 U 3 times weekly for 2-3 months

* Not licensed in the UK for treatment of Paget's disease.
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Bisphosphonates are the treatment of choice since they effectively reduce bone turnover and improve bone pain (see Box 20.56). Potent bisphosphonates such as alendronate may also heal osteolytic lesions and improve bone architecture, but the long-term effects of anti-Pagetic therapy on complications such as deafness, bone deformity and fracture are unknown. Calcitonin can also be used but is less potent than bisphosphonates. The main indication for anti-Pagetic treatment is bone pain thought to be due to active disease. Whilst the primary effect of anti-Pagetic therapy is inhibition of osteoclastic resorption, this is coupled to bone formation; measurement of serum alkaline phosphatase can therefore be used to monitor the response to treatment.
Etidronate is moderately effective and well tolerated but should be avoided in patients with pseudofractures and deformities of weight-bearing limb bones, since it can cause osteomalacia and increase the risk of pathological fracture. Tiludronate is more effective than etidronate and does not cause osteomalacia, but it seldom restores bone turnover to normal in severe or extensive disease. Severe disease is best treated with potent bisphosphonates such as risedronate, alendronate or pamidronate. These frequently restore bone turnover to normal and also work in patients who have become resistant to weaker bisphosphonates like etidronate.
Bone pain of active Paget's disease usually improves within 1-2 months of starting therapy. If pain recurs in association with a re-elevation of alkaline phosphatase values, then further courses of treatment can be given as necessary. If pain persists after biochemical suppression of Paget's disease has been achieved, other causes should be sought. The most common of these is osteoarthritis since this has an increased incidence in joints adjacent to Pagetic bone. This is managed along the usual lines (see p. 1001), but if joint replacement is required anti-Pagetic drug therapy is often given beforehand to reduce the bone vascularity in the hope that this will reduce intra-operative blood loss.
ISSUES IN OLDER PEOPLE
PAGET'S DISEASE
Paget's disease affects about 3% of individuals over the age of 55 in the UK.
The condition is usually asymptomatic and is often discovered by the finding of an elevated serum alkaline phosphatase in patients with otherwise normal biochemistry.
The diagnosis is usually obvious on radiograph but can be confirmed by radionuclide bone scan, which also gives information on the extent of the disease.
No treatment is required in those who are asymptomatic.
Anti-Pagetic therapy with bisphosphonates is the treatment of choice in patients with bone pain that does not respond to analgesics.


CANCER-ASSOCIATED BONE DISEASE
Hypercalcaemia is a common metabolic complication of malignancy; in most cases this is due to excessive release of parathyroid hormone-related protein (PTHrP) by solid tumours such as carcinoma of the lung, breast and genitourinary system. Less commonly, osteomalacia can complicate malignancy, particularly mesenchymal tumours, through ectopic release of FGF23, which promotes phosphaturia (see p. 1030).
Bone metastases are a common complication of tumours of the bronchus, breast and prostate, and of multiple myeloma. Metastatic bone disease typically presents with bone pain, pathological fracture or neurological symptoms due to nerve root compression or spinal cord compression. The diagnosis is suspected on the basis of clinical history and typical appearances of local osteolytic lesions on radiographic examination. Osteosclerotic metastases also occur and are particularly characteristic of prostatic carcinoma. A radionuclide bone scan is a more sensitive means of detecting bone metastases, but in myeloma osteolytic lesions can occur in the absence of new bone formation, leading to a false negative result.
The treatment of metastatic bone disease is interdisciplinary and four broad approaches can be identified (see Box 20.57). The most effective means of treating bone metastases is with antitumour therapy but in cases where this does not work efforts should focus on control of pain with analgesics/NSAIDs, nerve blockade or local radiotherapy. Orthopaedic surgery may also be required for pathological fractures or to stabilise local osteolytic lesions that are likely to progress to fracture. Surgical decompression may also be indicated as a palliative manoeuvre in the treatment of spinal metastases that are encroaching on the spinal cord.
Most tumours cause osteolytic lesions by local release of factors that increase osteoclast formation and activity. Bisphosphonates inhibit osteoclast activity so that the bone surrounding tumour deposits is protected from resorption, and have been shown to prevent the development of pathological fractures, improve bone pain and reduce skeletal morbidity in patients with breast carcinoma and multiple myeloma (see EBM panel). The efficacy of bisphosphonates in preventing progression of bone disease in other tumours has not yet been demonstrated, although they do appear to improve bone pain.
20.57 MANAGEMENT OF METASTATIC BONE DISEASE
Treatment of the primary tumour
Chemotherapy
Hormone therapy
Radiotherapy

Treatment of local lesions
Fixation of fractures
Spinal cord decompression
Radiotherapy

Inhibition of osteoclastic bone resorption
Bisphosphonates

Treatment of pain
Analgesics/NSAIDs
Nerve blocks
Radiotherapy


EBM
CANCER PAIN AND SKELETAL EVENTS-role of bisphosphonates
'RCTs have shown that prophylactic bisphosphonate therapy can prevent skeletal morbidity and improve bone pain in patients with breast cancer and myeloma who have metastatic bone disease.'
Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 1996; 334:488-493.
Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 2000; 88:1082-1090.


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Primary bone tumours are far less common than metastases. They present with local pain and swelling. Treatment depends on histological tumour type, but often involves surgical removal of the tumour followed by chemotherapy and radiotherapy.

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Home > 2 SYSTEM-BASED DISEASES > 20 Musculoskeletal disorders > SYSTEMIC CONNECTIVE TISSUE DISEASE
SYSTEMIC CONNECTIVE TISSUE DISEASE
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
SLE is the most common multisystem connective tissue disease. It is characterised by a wide variety of clinical features and a diverse spectrum of autoantibody production. The prevalence varies according to geographical and racial background, from 30/100 000 in Caucasians to 200/100 000 in Afro-Caribbeans. Around 90% of affected individuals are women, with peak onset in the second and third decades.
Aetiology and pathogenesis
At least 50 autoantigenic targets for autoantibody production are described in SLE. However, none of the diverse manifestations of SLE can be attributed to a single antigenic stimulus, and it is likely that this wide spectrum of autoantibody production results from polyclonal B and T cell activation. Many autoantigens in SLE are components of the intracellular and intranuclear machinery. In normal health these antigens are 'hidden' from the immune system and do not provoke an immune response. Although the triggers that lead to autoantibody production in SLE are unknown, one mechanism may be expression of novel antigens on the cell surface during apoptosis. This hypothesis is supported by the fact that environmental factors that associate with flares of lupus increase oxidative stress and subsequent apoptosis. Such factors include exposure to sunlight and artificial ultraviolet (UV) light, pregnancy and infection.
Diagnosis
Diagnosis depends on the recognition of specific symptoms and identification of autoantibodies. To fulfil current classification criteria, 4 of 11 factors must be present or have occurred in the past (see Box 20.58). Patients who are ANA-negative are very unlikely to have SLE unless they are extractable nuclear antigen (Ro)-positive; most Ro-positive patients also have skin rashes. Anti-dsDNA antibodies occur in only 30-50% of patients.
Clinical features
Raynaud's phenomenon
20.58 REVISED AMERICAN RHEUMATISM ASSOCIATION CRITERIA FOR SLE1
Features Characteristics
Malar rash Fixed erythema, flat or raised, sparing the nasolabial folds
Discoid rash Erythematous raised patches with adherent keratotic scarring and follicular plugging
Photosensitivity Skin rash as a result of unusual reaction to sunlight
Oral ulcers Oral or nasopharyngeal ulceration, may be painless
Arthritis Non-erosive, involving two or more peripheral joints
Serositis (a) Pleuritis (convincing history of pleuritic pain, rub or pleural effusion), or
(b) Pericarditis (rub, ECG evidence or effusion)
Renal disorder (a) Persistent proteinuria > 0.5 g/day, or
(b) Cellular casts (red cell, granular or tubular)
Neurological disorder Seizures or psychosis, in the absence of offending drugs or metabolic derangement
Haematological disorder (a) Haemolytic anaemia, or
(b) Leucopenia2 (< 4000/mm3), or
(c) Lymphopenia2 (< 1500/mm3), or
(d) Thrombocytopenia2 (< 100000/mm3) in the absence of offending drugs
Immunology disorder (a) Anti-DNA antibodies in abnormal titre, or
(b) Presence of antibody to Sm antigen, or
(c) Positive antiphospholipid antibodies
Antinuclear antibody disorder Abnormal titre of ANA by immunofluorescence


2On two separate occasions.
1For the purpose of identifying patients for clinical studies, a person must have SLE if any 4 out of 11 are present serially or simultaneously.
Arthralgia or arthritis in combination with Raynaud's phenomenon (see p. 446) is the most common presentation (see Fig. 20.45). It is important to elicit a history of Raynaud's since it is very uncommon for this to associate with other arthropathies such as RA. Raynaud's phenomenon in a teenage girl, with no other associated symptoms, especially if there is a family history, is likely to be idiopathic primary Raynaud's. By contrast, onset in a male, or in a woman over the age of 30 years suggests a secondary cause, usually underlying connective tissue disease. Examination of capillary nail-fold loops using an ophthalmoscope may help distinguish primary from secondary Raynaud's. Loss of the normal loop pattern and capillary 'fallout' with haemorrhage and dots indicate underlying disease.


Figure 20.45 Severe secondary Raynaud's phenomenon leading to digital ulceration.
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Figure 20.46 Butterfly (malar) rash of systemic lupus erythematosus, sparing the nasolabial folds.
Musculoskeletal features
A variety of joint problems may occur, including migratory arthralgia with mild morning stiffness, tenosynovitis and small joint synovitis that may mimic rheumatoid. In contrast to RA, joint deformities are rare. Deformities that do occur result from tendon inflammation and damage rather than from bone erosion ('Jaccoud's arthropathy').
Mucocutaneous features
Painful oral ulcers are common in SLE. In comparison with aphthous ulceration, they usually last longer and may scar. Diffuse, usually non-scarring alopecia may occur with active disease. There are three main types of rash in SLE:
The classic butterfly facial rash (20-30% of patients) is raised and painful or pruritic and occurs in a photosensitive distribution that spares the nasolabial folds (see Fig. 20.46).
Subacute cutaneous lupus erythematosus (SCLE) rashes are migratory, non-scarring and are either papulosquamous (psoriaform) or annular.
Discoid lupus lesions are characterised by hyperkeratosis and follicular plugging and may cause scarring alopecia if present on the scalp (see Fig. 20.47).
Other skin manifestations include periungual erythema, vasculitis and livedo reticularis, the latter also being a common feature of the antiphospholipid antibody syndrome (see Fig. 20.48).
Renal features


Figure 20.47 Scarring alopecia due to discoid lupus.


Figure 20.48 Livedo reticularis in systemic lupus erythematosus.
Renal involvement is one of the main determinants of prognosis, and regular monitoring of urinalysis and blood pressure is essential. The typical renal lesion is a proliferative glomerulonephritis (see p. 612), characterised by heavy haematuria, proteinuria, and casts on urine microscopy.
Cardiopulmonary features
The most common manifestation is chest pain from pleurisy or pericarditis. Myocarditis and sterile endocarditis (Libman-Sacks endocarditis) may also occur. SLE patients with antiphospholipid antibodies are at increased risk of venous thromboembolism, which should always be considered in the presence of chest pain or dyspnoea. Alveolitis and lung fibrosis occur, particularly in overlap connective tissue diseases.
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Central nervous system features
Fatigue, headache, poor concentration and other non-specific features similar to fibromyalgia are common accompaniments of SLE and often occur in the absence of active disease. Specific features of cerebral lupus include visual hallucinations, chorea (also associated with antiphospholipid antibody syndrome-APL), organic psychosis, transverse myelitis and lymphocytic meningitis.
Haematological features
Antibody-mediated destruction of peripheral blood cells may cause neutropenia, lymphopenia, thrombocytopenia or haemolytic anaemia. The degree of leucopenia, most commonly lymphopenia, is often a good guide to disease activity. Although the ESR is usually elevated, CRP is often normal unless there is serositis or infection.
Other manifestations
Fever, weight loss and mild lymphadenopathy commonly accompany active disease. Gastrointestinal involvement is rare and other causes of abdominal pain should always be considered, i.e. appendicitis, perforation secondary to drugs, or infection.
Management
All patients require education on the importance of avoiding sun and UV light exposure, and the use of high-factor sun blocks (sun protection factor 25-50). Many patients have mild disease requiring only intermittent analgesics or NSAIDs. Hydroxychloroquine (200-400 mg daily) is often effective for more troublesome cutaneous and joint symptoms. Short courses of oral steroids may be required for mild to moderate disease activity (e.g. rashes, synovitis, pleuro-pericarditis). With the availability of immunosuppressive agents maintenance with oral steroid is less commonly needed.
EBM
MANAGEMENT OF LUPUS NEPHRITIS
'RCTs have shown that pulse i.v. cyclophosphamide is more effective than pulse i.v. methylprednisolone alone for SLE nephritis. Combination therapy is more effective than either treatment alone. Continuing quarterly i.v. treatment for 1 year after renal remission decreases the risk of renal flares.'
Boumpas DT, Austin HA, Vaughn EM, et al. Controlled trial of pulse methylprednisolone versus two regimes of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992; 340:741-745.
Gourley MF, Austin HA, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 1996; 125:549-557.


Acute or life-threatening disease (i.e. renal, cerebral) requires high-dose steroids (e.g. oral prednisolone 40-60 mg daily or i.v. methylprednisolone 500 mg-1 g) in combination with pulse i.v. cyclophosphamide (see EBM panel). Other immunosuppressive drugs (azathioprine, methotrexate, ciclosporin, tacrolimus, mycophenolate mofetil) are useful either alone or in combination with steroids for severe but non-life-threatening manifestations or as step-down therapy after cyclophosphamide. Lupus patients with the antiphospholipid antibody syndrome who have had previous thrombosis will require life-long warfarin. If repeated thromboses occur despite warfarin, the international normalised ratio (INR) target range should be increased to 3-4.
Prognosis
Overall 5-year survival is greater than 90%. Early mortality within 5 years of diagnosis is usually due to organ failure or overwhelming sepsis, both of which are modifiable by early effective intervention. However, compared to the normal population, patients with lupus have a fivefold increased late mortality. This mainly results from premature cardiovascular disease to which chronic steroid therapy makes a major contribution. To reduce this, steroids should be used at the lowest effective dose and for the shortest period possible; combination therapy with immunosuppressive drugs may help to achieve this.
There is also a significant late morbidity due to symptoms of chronic fatigue and other features of fibromyalgia, which affect up to 80% of patients. These symptoms are typically unresponsive to steroids and should be managed according to standard fibromyalgia protocols, e.g. low-dose amitriptyline, graded exercise therapy and cognitive behavioural interventions if appropriate.
SCLERODERMA
Scleroderma is a generalised disorder of connective tissue affecting the skin, internal organs and vasculature. The clinical hallmark is the presence of sclerodactyly in combination with Raynaud's or digital ischaemia. The peak age of onset is in the fourth and fifth decades, and overall prevalence is 10-20 per 100 000 with a 4:1 female:male ratio. It is subdivided into diffuse and limited disease, the latter also termed 'CREST syndrome' (Calcinosis, Raynaud's, oesophageal involvement, Sclerodactyly, Telangiectasia).
Aetiology and pathogenesis
The aetiology is unknown, with no consistent genetic, geographical or racial associations. Environmental factors are important in isolated cases that result from exposure to silica dust, vinyl chloride, hypoxia resins and trichloroethylene.
Early in the disease there is skin infiltration by T lymphocytes and abnormal fibroblast activation that leads to increased production of extracellular matrix in the dermis, primarily type I collagen. This results in symmetrical thickening, tightening and induration of the skin (sclerodactyly). In addition to skin changes there is arterial and arteriolar narrowing due to intimal proliferation and vessel wall inflammation. This endothelial injury causes release of vasoconstrictors and platelet activation, resulting in further ischaemia.
Clinical features and diagnosis
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Figure 20.49 Systemic sclerosis. Hands showing tight shiny skin, sclerodactyly, flexion contractures of the fingers and thickening of an extensor tendon sheath.
Scleroderma is predominantly a clinical diagnosis based on the presence of sclerodactyly proximal to the metacarpophalangeal joints (see Fig. 20.49). Most patients are ANA-positive, and approximately 30% of patients with diffuse disease and 60% with limited disease have antibodies to topoisomerase 1 and centromere respectively.
Cutaneous changes
Raynaud's phenomenon is universal and may precede other clinical features.
The initial phase of skin disease is characterised by non-pitting oedema of the fingers and flexor tendon sheaths. Subsequently, the skin becomes shiny and taut, and distal skin creases disappear. There is usually erythema and tortuous dilatation of capillary loops in the nail-fold bed, readily visible with an ophthalmoscope set to +20. The face and neck are usually involved next, with thinning of the lips and radial furrowing. In some patients skin thickening stops at this stage. Skin involvement restricted to sites distal to the elbow or knee is classified as 'limited disease' or CREST syndrome (see Fig. 20.50). Involvement proximal to the knee and elbow and on the trunk is classified as 'diffuse disease'. In the distal extremities, the combination of intimal fibrosis and vessel wall inflammation may cause critical tissue ischaemia, leading to skin ulceration over pressure areas, localised areas of infarction and pulp atrophy at the fingertips.
Musculoskeletal features


Figure 20.50 Typical facial appearance in the CREST syndrome.
Arthralgia, morning stiffness and flexor tenosynovitis are common. Restricted hand function is due to skin rather than joint disease and erosive arthropathy is uncommon. Muscle weakness and wasting are usually due to myositis.
Gastrointestinal features
Gut involvement is common. Smooth muscle atrophy and fibrosis in the lower two-thirds of the oesophagus lead to reflux with erosive oesophagitis. Since this may lead to further fibrosis, adequate treatment of reflux (usually with proton pump inhibitors) is important. Dysphagia and odynophagia may also occur. Involvement of the stomach causes early satiety and occasionally outlet obstruction. Recurrent occult upper gastrointestinal bleeding may indicate a watermelon stomach, which occurs in up to 20% of patients. Small intestine involvement may lead to malabsorption due to bacterial overgrowth and intermittent bloating, pain or constipation. Dilatation of large or small bowel due to autonomic neuropathy may cause pseudo-obstruction.
Cardiorespiratory features
Pulmonary involvement is a major cause of morbidity and mortality. Fibrosing alveolitis mainly affects patients with diffuse disease, particularly those with antibodies to topoisomerase 1. Pulmonary hypertension is a complication of long-standing disease and is six times more prevalent in limited than in diffuse disease. The clinical features are rapidly progressive dyspnoea (more rapid than interstitial lung disease), right heart failure and angina, often in association with rapidly progressing digital ischaemia. Treatment strategies include vasodilators, continuous infusions of prostacyclin and heart-lung transplantation.
Renal features
One of the main causes of death is hypertensive renal crisis characterised by rapidly developing malignant hypertension and renal failure. Treatment is by angiotensin-converting enzyme (ACE) inhibition even if renal impairment is present.
Management and prognosis
Five-year survival is approximately 70%. Risk factors at presentation that associate with a poor prognosis include older age, diffuse skin disease, proteinuria, high ESR, a low TLCO (gas transfer factor for carbon monoxide), and pulmonary hypertension.
Self-management to maintain core body temperature and avoid peripheral cold exposure is important. Infection of ulcerated skin should be treated with prompt antibiotic therapy. Antibiotics penetrate poorly into scleroderma skin lesions and therefore need to be given at higher dose for longer periods (e.g. flucloxacillin 500 mg 6-hourly for 14 days). Calcium antagonists (e.g. nifedipine, amlodipine) or angiotensin II receptor antagonists (e.g. valsartan) may be effective for Raynaud's symptoms. For severe digital ischaemia, intermittent infusions of prostacyclin may be helpful.
Steroids and cytotoxic drugs are indicated in patients with myositis or alveolitis. No agent has demonstrated efficacy in arresting or improving skin changes. Agents that have been shown to be ineffective include d-penicillamine and interferon gamma. Other novel agents currently under study include mycophenolate mofetil and tacrolimus.
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MIXED CONNECTIVE TISSUE DISEASE
This is an overlap connective tissue disease with features of SLE, scleroderma and myositis. The usual clinical features include synovitis and oedema of the hands in combination with Raynaud's phenomenon and muscle pain/weakness. Most patients have anti-ribonucleoprotein (RNP) antibodies, although these also occur in SLE without overlap features.
SJÖGREN'S SYNDROME
This is an autoimmune disorder of unknown aetiology characterised by lymphocytic infiltration of salivary and lachrymal glands, leading to glandular fibrosis and exocrine failure. Age of onset is usually in the fourth and fifth decades with a female:male ratio of 9:1. The disease may be primary or secondary in association with other autoimmune disease such as rheumatoid, SLE, thyroiditis or primary biliary cirrhosis.
Clinical features
The eye symptoms, termed keratoconjunctivitis sicca, are due to a lack of tears and lubrication. Conjunctivitis and blepharitis are frequent manifestations, and may lead to filamentary keratitis due to tenacious mucous filaments binding to the cornea and conjunctiva. Oral involvement typically leads to the patient needing water to swallow food, and there is a high incidence of dental caries. Other sites of extraglandular involvement are listed in Box 20.59.
20.59 FEATURES OF SJÖGREN's SYNDROME
Risk markers
Age of onset 40-60
F > M
HLA-B8/DR3

Common clinical features
Keratoconjunctivitis sicca
Xerostomia
Salivary gland enlargement
Non-erosive arthritis
Raynaud's
Fatigue

Less common features
Low-grade fever
Interstitial lung disease
Anaemia, leucopenia
Thrombocytopenia
Cryoglobulinaemia
Vasculitis
Peripheral neuropathy
Lymphadenopathy
Lymphoreticular malignancy
Glomerulonephritis
Renal tubular acidosis

Autoantibodies frequently detected
Rheumatoid factor
ANA
SS-A (anti-Ro)
SS-B (anti-La)
Gastric parietal cell
Thyroid

Associated autoimmune disorders
SLE
Progressive systemic sclerosis
Primary biliary cirrhosis
Chronic active hepatitis
Myasthenia gravis


The disease is associated with a 40-fold increased lifetime risk of lymphoma and can be viewed as being at the crossroads of autoimmunity and malignancy.
Investigations
Most patients will have an elevated ESR secondary to hypergammaglobulinaemia and one or more autoantibodies, of which antinuclear factor (ANF) and rheumatoid factor are the most common. Sicca can be established by the Schirmer tear test, which measures flow over 5 minutes using absorbent paper strips placed in the lower lachrymal sac; a normal result is greater than 6 mm of wetting. If diagnosis is still in doubt, it can be confirmed by finding focal lymphocytic infiltrate in the minor salivary glands on lip biopsy.
Management
Artificial lubrication is the mainstay of symptomatic treatment. Lachrymal substitutes such as hypromellose should be used during the day in combination with more viscous lubricating ointment at night. Soft contact lenses can be useful for corneal protection in patients with filamentary keratitis, and occlusion of the lachrymal ducts is occasionally needed. Artificial saliva and oral gels can be tried for xerostomia, but are often not effective. Stimulation of saliva flow by sugar-free chewing gum or lozenges may be helpful. Adequate post-prandial oral hygiene and prompt treatment of oral candidiasis are essential. Vaginal dryness is treated with lubricants such as K-Y jelly.
Extraglandular and musculoskeletal manifestations may respond to steroids and, if so, other immunosuppressive drugs such as azathioprine can be added for steroid-sparing effect. One of the most difficult symptoms to treat is fatigue; this is usually due to non-restorative sleep (often because of xerostomia) and is unresponsive to steroids. Immunosuppression does not improve sicca symptoms. If massive lymphadenopathy or salivary gland enlargement develops during the disease course, biopsy should be performed to exclude malignancy.
POLYMYOSITIS AND DERMATOMYOSITIS
The idiopathic inflammatory myopathies (IIMs) are rare connective tissue disorders defined by the presence of muscle weakness and inflammation. The incidence is 2-10 per million/year with no significant world-wide variation. The aetiology is unknown and genetic associations differ amongst ethnic groups. The most common clinical forms of IIM are polymyositis, dermatomyositis and inclusion body myositis. Other systemic autoimmune diseases such as SLE or vasculitis can also cause myositis, whilst organ-specific autoimmune disease (e.g. thyroid) may impair muscle function without causing muscle inflammation. Usually only skeletal muscle is affected. Occasionally, the distribution is focal (e.g. orbital myositis).
Adult polymyositis
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Figure 20.51 Typical eyelid appearance in dermatomyositis. Note the oedema and telangiectasia.
The typical presentation is with symmetrical proximal muscle weakness, usually affecting the lower extremities first. Patients report difficulty rising from a chair, climbing stairs and lifting, sometimes in combination with muscle pain. The onset is usually between 40 and 60 years of age and is typically gradual, over a few weeks, although an explosive and more insidious onset may also occur. Systemic features of fever, weight loss and fatigue are common. Respiratory or pharyngeal muscle involvement leading to ventilatory failure/aspiration is ominous and requires urgent treatment. Interstitial lung disease occurs in up to 30% of patients and is strongly associated with the presence of antisynthetase (e.g. Jo1) antibodies.
Adult dermatomyositis
The muscle manifestations are identical to polymyositis, but occur in combination with characteristic cutaneous manifestations. Gottron's papules are scaly erythematous/violaceous plaques or papules occurring over the extensor surfaces of the proximal and distal interphalangeal joints. The heliotrope rash is a violaceous discoloration of the eyelid in combination with periorbital oedema (see Fig. 20.51). Similar rashes occur on the upper back, chest and shoulders ('shawl' distribution). Periungual nail-fold capillaries are often abnormal. Other systemic manifestations include arthralgia, weight loss and fever.
Childhood dermatomyositis
This is three times more common in girls than in boys and mainly affects 6-9-year-olds. The presentation is similar to adult dermatomyositis except that cutaneous manifestations are more common. These include cutaneous ulceration, lipodystrophy and dystrophic calcification (calcinosis) in the skin, subcutaneous tissue and muscle fascia.
Investigations


Figure 20.52 Muscle biopsy from a patient with inflammatory myositis. The sample shows an intense inflammatory cell infiltrate in an area of degenerating and regenerating muscle fibres.
These conditions should be suspected in anyone who presents with proximal muscle weakness without evidence of neuropathy, particularly if there is evidence of systemic disease. Creatine kinase (CK) is usually raised and is a guide to disease activity. However, a normal CK does not exclude the diagnosis, particularly in juvenile myositis where only 70% of patients have a raised CK at the time of diagnosis. Electromyography (EMG) may confirm the presence of myopathy and exclude neuropathy. Most patients will then need a muscle biopsy to look for the typical features of fibre necrosis, regeneration and inflammatory cell infiltrate (see Fig. 20.52). Occasionally, a biopsy may be normal, particularly if myositis is patchy. MRI is a useful means of identifying areas of abnormal muscle that are amenable to biopsy. There is an increased risk of malignancy in patients with dermatomyositis (about a threefold increase) and polymyositis (an increase of about 30%) (see EBM panel). This risk is highest within the first 5 years, and malignancy may be apparent at the time of diagnosis. Current recommended screening investigations when malignancy is suspected should include chest/abdomen/pelvis CT, gastrointestinal tract imaging and mammography.
EBM
RELATIONSHIP BETWEEN MALIGNANCY AND INFLAMMATORY MUSCLE DISEASE
'Dermatomyositis is strongly associated with malignant disease (standard incidence ratio 3.0), particularly ovarian, lung, pancreatic, stomach and colorectal. There is a modest increased risk in polymyositis, mainly non-Hodgkin's lymphoma, lung and bladder. Risk of malignancy is highest at time of diagnosis.'
Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population based study. Lancet 2001; 357:96-100.


Management
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Oral steroids (e.g. prednisolone 40-60 mg daily) are the mainstay of initial treatment. Patients with severe weakness or evidence of respiratory or pharyngeal weakness may need methylprednisolone 1 g daily for 3 days. If there is a good response, steroids should be reduced by approximately 25% per month down to a maintenance dose of 5-7.5 mg. Although most patients have an initial response to steroids, many will need additional immunosuppressive therapy. Azathioprine and methotrexate are the initial agents of choice. If these are ineffective or not tolerated, then ciclosporin, cyclophosphamide or tacrolimus is an alternative. Relapses may occur, associated with a rising CK, and this is an indication for additional therapy. If the patient fails to respond clinically to treatment, this may be due to steroid-induced myopathy or the development of inclusion body myositis. Further biopsy is indicated at this stage. If active necrosis and regeneration are present, then the disease is still active, whereas the presence of type 2 fibre atrophy is consistent with steroid myopathy but also occurs with active disease.
INCLUSION BODY MYOSITIS
Inclusion body myositis is the most common disease of muscle in patients over the age of 50 and predominates in men. Although proximal weakness does occur, distal involvement is more common and may be asymmetrical. Evaluation is along the same lines as for IIM. CK may be marginally elevated and neuropathic changes may be present on EMG. The characteristic findings on muscle biopsy are abnormal fibres containing rimmed vacuoles and filamentous inclusions in the nucleus and cytoplasm. These inclusions contain paired helical filaments that resemble those seen in the brain in Alzheimer's disease. Treatment is controversial and not as successful as in IIM. Some patients do have an inflammatory component and are steroid-responsive; a trial of steroids is therefore warranted, and if a response occurs then immunosuppressive therapy should be substituted.
SYSTEMIC VASCULITIS
The vasculitides are a heterogeneous group of diseases characterised by inflammation and necrosis of blood vessel walls, often with associated organ involvement. The spectrum of disease ranges from benign and self-limiting (e.g. cutaneous leucocytoclastic vasculitis limited to skin) to life-threatening (e.g. fulminant Wegener's granulomatosis with renal failure and pulmonary haemorrhage).
Clinical features
The clinical features of vasculitis are due to local tissue ischaemia and the systemic effects of widespread inflammation. The symptoms may mimic those of widespread malignancy or emboli, or of occult sepsis. These varied manifestations may be confusing and lead to diagnostic delay, but early diagnosis and management are essential to prevent irreversible organ damage. The key to recognition is the presence of multisystem involvement. Systemic vasculitis should be considered in any patient with fever, weight loss, fatigue, evidence of multisystem involvement, skin rashes, raised inflammatory markers and abnormal urinalysis. Specific symptoms, which should be sought if vasculitis is suspected, are shown in Box 20.29, page 987.
Vasculitis may occur in many types of inflammatory or infectious diseases, such as SLE, rheumatoid arthritis, endocarditis and hepatitis B and C. In these situations, the vasculitis is a secondary manifestation of the primary disease. Primary systemic vasculitis is less common, with an annual incidence of approximately 18-40 new cases per million, which peaks in the 65-74-year age group. The aetiology remains unclear, although geographic, environmental and genetic factors are important. Classification is based on vessel size (see Box 20.60).
20.60 SIZE OF VESSEL INVOLVEMENT IN VASCULITIS
Large vessel
Giant cell arteritis
Takayasu's arteritis
Medium vessel
Classical polyarteritis nodosa
Kawasaki disease
Small vessel
Microscopic polyangiitis
Wegener's granulomatosis
Churg-Strauss syndrome
Henoch-Schönlein purpura
Mixed essential cryoglobulinaemia


A number of important conditions may mimic vasculitis; these include sepsis (particularly subacute bacterial endocarditis and meningococcaemia), malignancy, cholesterol emboli, atrial myxoma and the antiphospholipid syndrome. Careful physical history and examination usually lead to their exclusion.
Investigations
If vasculitis is suspected, the diagnosis should ideally be confirmed by tissue biopsy, in order to determine the vessel size involved and guide therapy. Skin biopsies are easily obtained, but will not help to determine whether the disease is systemic or limited to the skin. Nasal septal tissue can be obtained from areas of ulceration or granulation. Muscle biopsy is positive in about 50% of patients with muscle pain. The most important bedside test is the urine dip test for protein and blood and subsequent microscopy, since the prognosis of vasculitis is often determined by the degree of renal involvement. In patients with abnormal renal function and active urinary sediment, renal biopsy should be considered. Visceral angiography to detect microaneurysms (e.g. classical polyarteritis nodosa) is most useful where involved tissue is not available to biopsy. Antineutrophil cytoplasmic antibodies (ANCA) are directed against enzymes present in neutrophil granules. Two main patterns of immunofluorescence are distinguished: cytoplasmic (c-ANCA) and perinuclear (p-ANCA), specific for the enzymes proteinase 3 and myeloperoxidase respectively. While c-ANCA is particularly associated with Wegener's granulomatosis, p-ANCA is associated with microscopic polyangiitis. However, positive ANCAs occur in many other diseases, including malignancy, infection (bacterial and HIV), inflammatory bowel disease, rheumatoid arthritis, lupus and pulmonary fibrosis. Therefore, the diagnosis of these conditions cannot be made or refuted on the ANCA test alone.
LARGE VESSEL VASCULITIS
Polymyalgia rheumatica (PMR)
PMR is a clinical syndrome of muscle pain and stiffness and, classically, an increased ESR. It is not a true vasculitis but there is a close association with giant cell arteritis. It is predominately a disease of the elderly, with a prevalence of approximately 20 per 100 000 over the age of 50 years. The mean age of onset is 70, and diagnosis is rarely made in patients under 60. Women are affected more often than men by a ratio of 3:1.
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Clinical features
The cardinal features are muscle stiffness and pain, symmetrically affecting the proximal muscles of the neck, upper arms and, less commonly, the buttocks and thighs. There is marked early morning stiffness, often with night pain. Constitutional features of weight loss, fatigue, depression and night sweats also occur. Most patients have a rapid onset of symptoms, sometimes overnight, although occasionally the onset is more insidious. On examination there may be stiffness and painful restriction of active shoulder movement but passive movements are preserved. Muscles may be tender to palpation but there should not be muscle-wasting; if there is, then primary muscle or neurological disease is more likely.
Investigations
In the majority of patients the ESR is elevated above 40 mm/hour and there may be a normochromic, normocytic anaemia. Very occasionally the ESR is low, usually in the acute situation where there has not been sufficient time for it to rise. In this situation the CRP may be elevated prior to the ESR.
Management
The only effective treatment is corticosteroids, and prednisolone should be started at a maximum dose of 15 mg. The majority of patients should have a dramatic response within 72 hours. If there is no response by 72 hours or an incomplete response by 7 days, then the diagnosis is not PMR. Other conditions that may mimic PMR are shown in Box 20.61.
If there has been a good response, the dose should be reduced to 10 mg after 4 weeks and then by 1 mg per month, assuming that symptoms remain controlled. If symptoms recur, the dose should be increased to that which previously controlled the symptoms, and reduction attempted in another few months. Most patients need steroids for an average of 18 months and osteoporosis prophylaxis with bisphosphonates should be considered. Some patients require steroid-sparing agents such as methotrexate or azathioprine, particularly if steroids cannot be withdrawn at 2 years or are needed at doses greater than 7.5 mg.
Occasionally, rheumatoid arthritis presents with a polymyalgic illness. This is more common in men and is usually revealed by the appearance of peripheral synovitis when steroid doses are reduced below 10 mg. Approximately 15-20% of patients develop features of giant cell arteritis at some point in the course of their disease. All patients should therefore be instructed to seek prompt medical advice if such symptoms occur.
20.61 CONDITIONS THAT MAY MIMIC POLYMYALGIA RHEUMATICA
Fibromyalgia
Hypothyroidism
Cervical spondylosis
Rheumatoid arthritis
Inflammatory myopathy (particularly inclusion body myositis)
Systemic vasculitis
Malignancy


Giant cell arteritis (GCA)
Giant cell arteritis is a large vessel vasculitis predominately affecting branches of the temporal and ophthalmic arteries. The mean age of onset is 70 years with a 4:1 female:male ratio.
Clinical features
As with PMR symptoms may be abrupt but are often insidious over the course of several weeks or months. The most important clinical features are:
Headache. This is usually the first symptom and is often localised to the temporal or occipital region, with scalp tenderness.
Jaw pain. This is brought on by chewing or talking and is due to ischaemia of the masseters.
Visual disturbance. The optic nerve head is supplied by the posterior ciliary artery, vasculitis of which leads to occlusion and acute anterior ischaemic optic neuropathy. Damage to the optic nerve results in loss of visual acuity and field, reduced colour perception and papillary defects. Sudden visual symptoms in one eye, leading rapidly to blindness, constitute the most common pattern. On fundoscopy the optic disc may appear pale and swollen with haemorrhages, but these changes may take 24-36 hours to develop and the fundi may initially appear normal. Once blindness has occurred steroids have a negligible effect other than preventing blindness in the other eye.

There may be associated constitutional symptoms of anorexia, fatigue, weight loss, fever, depression and general malaise. Occasionally presentation is with neurological complications that include transient ischaemic attacks, brain-stem infarcts and hemiparesis.
Investigations
The ESR is usually elevated above 50 mm/hour. In some the ESR is normal, mainly in those with acute presentation where the ESR has not yet had time to rise; in this situation the CRP may be more helpful. If GCA is suspected, systemic steroid (prednisolone 60 mg daily) should be started immediately to prevent visual loss. Ideally, a temporal artery biopsy should also be obtained. However, steroid treatment should not be delayed whilst this is organised; diagnostic information will still be present on biopsies taken a week later. Characteristic biopsy findings are fragmentation of the internal elastic lamina with necrosis of the media in combination with a mixed inflammatory cell infiltrate (lymphocytes, plasma cells and eosinophils). However, 'skip' lesions are common and a negative biopsy does not exclude the diagnosis.
Management
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Steroid reduction should be guided by symptoms and ESR, aiming for approximately 10 mg daily by 6 weeks. Thereafter, doses should be reduced by 1 mg per month. Patients with known GCA should be advised to take 60 mg prednisolone and seek prompt medical advice should they experience any recurrence of headache or visual disturbance. Maintenance therapy is required for at least 1 year, and rarely for the rest of the patient's life. Relapse occurs in 30%, and is an indication to restart high-dose steroids with additional immunosuppressive agents, typically azathioprine or methotrexate.
Takayasu's arteritis
Takayasu's disease is a chronic inflammatory granulomatous panarteritis of elastic arteries-the aorta, its major branches and occasionally the pulmonary arteries. It most commonly affects women (female:male ratio 8:1) with a typical age of onset at 25-30 years. It has a world-wide distribution but is most common in Asia. The aetiology is unknown. In contrast to other vasculitides Takayasu's is characterised by thickened and inflamed intima without fibrinoid degeneration.
The usual presentation is with claudication and systemic symptoms of fever, arthralgia and weight loss. The vessels most commonly involved are the carotid, ulnar, brachial, radial and axillary arteries. Clinical examination may reveal loss of pulses, bruits, hypertension and aortic incompetence.
Laboratory investigations are usually non-specific, with high ESR and normocytic, normochromic anaemia. Diagnosis is usually based on angiographic findings of coarctation, occlusion and aneurysmal dilatation. The distribution of involvement can be classified into four types:
Type 1 is localised to the aorta and its branches.
Type 2 is localised to the descending thoracic and abdominal aorta.
Type 3 combines features of 1 and 2.
Type 4 involves the pulmonary artery.

The 5-year survival rate is 83%. Most patients respond to initial high-dose oral prednisolone (1-2 mg/kg daily). Additional therapy with methotrexate or cyclophosphamide is usually required. Reconstructive vascular surgery should be avoided during periods of active inflammation but may benefit selected patients, especially those with hypertension secondary to aortic or renal lesions.
MEDIUM-SIZED ARTERIES
Classical polyarteritis nodosa (PAN)
Classical PAN is a necrotising vasculitis characterised by transmural inflammation of medium-sized to small arteries. PAN is a rare disorder with an annual incidence of 2 per million in most populations. All age groups can be affected, with a peak incidence in the fourth and fifth decades, and a male:female ratio of 2:1. Hepatitis B is a risk factor, and the incidence of PAN is 10 times higher in the Inuit population of Alaska, where hepatitis B infection is endemic.


Figure 20.53 Rash of systemic vasculitis (palpable purpura).
Characteristic presentation is with myalgia, arthralgia, fever and weight loss in combination with manifestations of multisystem disease. The most common skin lesions are palpable purpura, ulceration, infarction and livedo reticularis (see Fig. 20.53). In 70% of patients arteritis of the vasa nervorum leads to neuropathy which is typically symmetrical and affects both sensory and motor function. Severe hypertension and/or renal impairment may occur due to multiple renal infarctions; glomerulonephritis is rare (in contrast to microscopic polyangiitis). Diagnosis is confirmed by finding multiple aneurysms and smooth narrowing of either the mesenteric, hepatic or renal systems on angiography. Tissue biopsy may be definitive (muscle or sural nerve), even in the absence of angiographic abnormality.
Treatment for hepatitis B-related disease is to remove the source of the antigen, i.e. antiviral therapy. Steroids and cyclophosphamide are the treatment of choice for idiopathic disease. Mortality is less than 20%, although relapse occurs in up to 50% of patients.
Kawasaki disease (mucocutaneous lymph node syndrome)
Kawasaki disease (KD) is an acute systemic disorder of childhood that predominately occurs in Japan (800 cases per million in children under the age of 5). The disease resembles a viral exanthem or Stevens-Johnson syndrome. Although the causative trigger is unknown, it has been associated with Mycoplasma and HIV infection in some cases. The principal clinical features, which often develop abruptly, are shown in Box 20.62. Cardiovascular complications include myocarditis, pericarditis, coronary aneurysms, transient coronary artery dilatation, myocardial infarction due to coronary thrombosis, peripheral vascular insufficiency and gangrene.
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20.62 FEATURES OF KAWASAKI DISEASE
Fever persisting > 5 days
Bilateral conjunctival congestion
Erythema of lips, buccal mucosa and tongue
Acute non-purulent cervical lymphadenopathy
Polymorphous exanthema
Erythema of palms and soles (oedema followed by desquamation)
Coronary dilatation


The differential diagnosis is wide. Investigations that favour KD include a polymorphonuclear leucocytosis, thrombocytosis, raised ESR and CRP and circulating anti-endothelial cell antibodies. Treatment is with aspirin (5 mg/kg daily for 14 days) and intravenous gammaglobulin (400 mg/kg daily for 4 consecutive days). Steroids should be avoided because of the risk of worsening the coronary artery dilatation. Coronary artery changes are usually monitored weekly by two-dimensional echo for 4 weeks, by which stage most children have recovered. The overall mortality is less than 2%. Relapse is rare, but if there is coronary artery involvement long-term follow-up is necessary.
SMALL VESSEL DISEASE OF ARTERIOLES, VENULES AND CAPILLARIES
Microscopic polyangiitis, Wegener's granulomatosis and Churg-Strauss syndrome can be grouped together as 'ANCA-associated vasculitis', although not all patients are ANCA-positive at diagnosis. All patients may present similarly with arthralgia, myalgia and evidence of multisystem disease, the precise 'subtype' being determined by other specific clinical features.
Microscopic polyangiitis (MPA)
MPA is more common than PAN, with an annual incidence of 8 per million in the UK. Classic presentation is with rapidly progressive glomerulonephritis often associated with alveolar haemorrhage. Cutaneous and gastrointestinal involvement, similar to PAN, is common. Less usual features include neuropathy (15%) and pleural effusions (15%). Patients are usually p-ANCA (myeloperoxidase)-positive.
Wegener's granulomatosis (WG)
The incidence of WG is 5-10 per million. The most common presentation is with upper airway involvement (typically epistaxis, nasal crusting and sinusitis), haemoptysis, mucosal ulceration and deafness due to serous otitis media. Symptoms may have been present for several months, and erroneously attributed to infection or allergy. The most common ocular abnormality is proptosis, due to inflammation of the retro-orbital tissue. This may cause diplopia due to entrapment of the extraocular muscles, or loss of vision due to optic nerve compression, the earliest feature of which is usually disturbance of colour vision (see Fig. 20.54). Untreated nasal disease ultimately leads to destruction of bone and cartilage. Migratory pulmonary infiltrates and nodules occur in 50% of patients. A minority of patients present with glomerulonephritis. Patients are usually c-ANCA-positive.
Churg-Strauss syndrome (CSS)


Figure 20.54 Eye involvement in Wegener's granulomatosis.
The annual incidence is 1-3 per million in the UK. Most patients have a prodromal period for many years characterised by allergic rhinitis, nasal polyposis and late-onset asthma that is often difficult to control. The typical acute presentation is with a triad of skin lesions (purpura or nodules), asymmetric mononeuritis multiplex and eosinophilia on a background of resistant asthma. Pulmonary infiltrates and pleural or pericardial effusions due to serositis may be present. Up to 50% of patients have abdominal symptoms due to mesenteric vasculitis. Either c-ANCA or p-ANCA is present in around 40% of cases.
Management of MPA, WG and CSS
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Treatment should be instituted as early as possible to prevent irreversible damage. If there is life-threatening or critical organ involvement, treatment may need to be given prior to biopsy confirmation. The aims of treatment are to induce a remission, and then to maintain remission with minimum drug toxicity. Remission can be induced either with oral high-dosage prednisolone (1 mg/kg daily) and continuous oral cyclophosphamide (2 mg/kg daily) or with bolus i.v. methylprednisolone (10 mg/kg) and cyclophosphamide (15 mg/kg), initially fortnightly and subsequently monthly. Doses of cyclophosphamide should be reduced in the elderly and those with renal impairment. The dose of oral prednisolone is rapidly reduced once remission has occurred. Cyclophosphamide is usually continued for 6-12 months in total, followed by maintenance with azathioprine. Co-trimoxazole is usually given at a prophylactic dose (960 mg thrice weekly) in conjunction with cyclophosphamide to prevent Pneumocystis pneumonia, unless there is a history of drug allergy. Mesna is used with bolus cyclophosphamide to reduce the risks of haemorrhagic cystitis. Occasionally, cyclophosphamide fails to induce a remission, in which case the diagnosis should be reconsidered. Other treatment strategies for resistant vasculitis include plasma exchange and daily oral etoposide.
Henoch-Schönlein purpura
This small vessel vasculitis usually occurs in children and young adults and often has a good prognosis. Typical presentation is with purpura over the buttocks and lower legs, abdominal symptoms (pain and bleeding) and arthritis (knee or ankle) following an upper respiratory tract infection. Nephritis occurs in 40% of patients and may occur up to 4 weeks after the onset of other symptoms. The diagnosis can only be confirmed by demonstrating IgA deposition within and around blood vessel walls. Prognosis is determined by the degree and severity of renal involvement. Although only 1% of patients develop end-stage renal failure, adverse features at presentation in adults include hypertension, abnormal renal function and proteinuria > 1.5 g/day. Corticosteroids alone are effective for gastrointestinal and joint involvement but nephritis usually requires treatment with both pulse i.v. steroids and immunosuppression.
Cryoglobulinaemic vasculitis
Cryoglobulins are circulating immunoglobulins that precipitate out in the cold. They are classified into three types (see Box 20.63); types II and III are associated with cryoglobulinaemic vasculitis. The typical clinical features are palpable purpura over the lower extremities, arthralgia, Raynaud's phenomenon and neuropathy. Type II cryoglobulinaemia is secondary to hepatitis C virus (HCV) infection in most patients, the virus being present in the vasculitic lesions complexed with IgG and IgM. For HCV-positive patients, interferon-alpha is currently the treatment of choice; for high HCV loads, combination with ribavirin may be more effective (see p. 865).
20.63 CLASSIFICATION OF CRYOGLOBULINS
Type Antibody type Associations
I Monoclonal IgM Malignant B-cell disease, e.g. Waldenstr[scaron]m's, lymphoma, myeloma
II ('mixed essential') Monoclonal IgM and anti-IgG antibody (RhF) Hepatitis C, SLE, B-cell malignancy
III Polyclonal IgM and anti-IgG antibody (RhF) RA, SLE, chronic infections

OTHER FORMS OF VASCULITIS
Behçet's syndrome
This is a vasculitis of unknown aetiology that characteristically targets venules. It is rare in Western Europe but more common in 'Silk Route' countries around the Mediterranean and Japan where there is a strong association with HLA-B51.
There is a wide range of clinical features, and the disease is characterised by unpredictable exacerbations. There are no defining investigations and the diagnosis is made on clinical features (see Box 20.64). Oral ulcers are universal (see Fig. 20.55). Unlike aphthous ulcers they are usually deep and multiple, and last for 10-30 days. Genital ulcers are less common (60-80%). The usual skin lesions are erythema nodosum or acneiform lesions but migratory thrombophlebitis and vasculitis also occur. The pathergy reaction is hyper-reactivity at the site of minor trauma. A formal pathergy test involves intradermal skin pricking with a needle, and is positive if a pustule develops within 48 hours. Ocular involvement is usually bilateral and may include anterior or posterior uveitis or retinal vasculitis. Neurological involvement occurs in 5% and mainly involves the brain stem, although the meninges, hemispheres and cord can also be involved to cause pyramidal signs, cranial nerve lesions, brain-stem symptoms or hemiparesis. Recurrent thromboses also occur. Renal involvement is extremely rare.
Oral ulceration can be managed with topical steroid preparations (e.g. soluble prednisolone mouthwashes, steroid pastes). Colchicine is sometimes effective for erythema nodosum and arthralgia. Thalidomide (100-300 mg per day for 28 days initially) is very effective for resistant oral and genital ulceration but is teratogenic and neurotoxic. Systemic disease is more problematic and usually requires oral steroids in combination with other immunosuppressive drugs.
20.64 CRITERIA FOR THE DIAGNOSIS OF BEHÇET's SYNDROME
Recurrent oral ulceration-minor aphthous, major aphthous or herpetiform ulceration at least three times in a 12-month period

Plus two of:
Recurrent genital ulceration
Eye lesions-anterior uveitis, posterior uveitis, or cells in vitreous on slit lamp examination, or retinal vasculitis
Skin lesions-erythema nodosum, pseudofolliculitis, or papulopustular lesions, or acneiform nodules
Positive pathergy test




Figure 20.55 Oral ulceration in Behçet's syndrome.

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Home > 2 SYSTEM-BASED DISEASES > 20 Musculoskeletal disorders > MUSCULOSKELETAL MANIFESTATIONS OF DISEASE IN OTHER SYSTEMS
MUSCULOSKELETAL MANIFESTATIONS OF DISEASE IN OTHER SYSTEMS
Many systemic diseases result in MSK symptoms and signs and in some cases this may be the presentation of the disease. Furthermore, drugs used for other system disease may result in MSK complications (see Box 20.65). The following examples illustrate the variety of conditions that may be encountered but are not exhaustive.
20.65 EXAMPLES OF DRUG-INDUCED EFFECTS ON THE MUSCULOSKELETAL SYSTEM
Musculoskeletal problem Principal drug
Secondary gout Diuretic-thiazide, loop diuretic
Osteoporosis Corticosteroids, heparin
Osteomalacia Anticonvulsants
Osteonecrosis Corticosteroids
Drug-induced lupus syndrome Procainamide, hydralazine, isoniazid, chlorpromazine
Arthralgias or arthritis Steroid withdrawal, glibenclamide, methyldopa, ciclosporin, isoniazid, barbiturates
Myalgias Steroid withdrawal, L-tryptophan, clofibrate, statins
Myopathy Corticosteroid, chloroquine
Myositis, myasthenia Penicillamine
Cramps Corticosteroid, ACTH, diuretics, carbenoxolone
Vasculitis Amphetamines, thiazides

MALIGNANT DISEASE
Progressive 'bone' pain may result from skeletal metastases or invasion by myeloma (see p. 985) in adults. Polyarthritis may be the presentation of acute leukaemia (see p. 931), especially in children.
Dermatomyositis/polymyositis may be the presentation of occult malignancy. This should be suspected in those over the age of 50 with marked skin involvement and resistance to treatment. Polymyalgia rheumatica, but not temporal arteritis, may similarly be the presentation of neoplastic disease. Apart from a screening chest radiograph, other investigations are largely guided by symptoms.
Hypertrophic osteoarthropathy comprises clubbing, painful swelling of distal limbs (usually symmetrical), periosteal new bone formation and arthralgia/arthritis. Many causes of clubbing can result in this uncommon syndrome but it mainly occurs with bronchial carcinoma (5%; the most common cause-see p. 544) and mesothelioma (40%-see p. 573). The pain is characteristically worsened by dependency and relieved by elevation. Bone scans show increased periosteal activity before new bone is apparent on radiograph. The course follows that of the underlying malignancy and eradication can effect a cure.
ENDOCRINE DISEASE
Hypothyroidism (see p. 691) may present with carpal tunnel syndrome. A severely painful, symmetrical proximal myopathy with muscle hypertrophy is an occasional presentation. All MSK lesions show excellent recovery following thyroxine replacement.
Hyperparathyroidism (see p. 718), both primary and secondary, may cause bone disease through accelerated bone turnover, usually presenting as ill-defined aching. There is predisposition to radiographic chondrocalcinosis, pseudogout attacks due to calcium pyrophosphate crystals and, especially with disease secondary to renal failure, calcific periarthritis.
Diabetes mellitus (see Ch. 15) commonly causes diabetic 'stiff hands' (cheiroarthropathy) due to tightening of skin and periarticular structures, giving flexion deformities of many fingers which is sometimes painful. Diabetic osteopathy presents as forefoot pain and shows radiographic progression from osteopenia to complete osteolysis of the phalanges and metatarsals. There is also predisposition to 'frozen shoulder', Dupuytren's contracture, septic arthritis and neuropathic joints.
MSK symptoms are common presenting features of acromegaly (see p. 742) and include:
low mechanical back pain, with normal or excessive (not restricted) movement
carpal tunnel syndrome and late-onset Raynaud's phenomenon (25%)
acromegalic arthropathy (50%), mainly affecting knees, hips and shoulders, with non-inflammatory usage pain and coarse crepitus, suggesting osteoarthritis, but normal or increased (not restricted) movement. Radiographic signs may include widening of joint spaces, squaring of bone ends, generalised osteopenia and tufting of terminal phalanges.

METABOLIC DISEASE
Approximately 50% of people with haemochromatosis (see p. 870) develop arthropathy, usually in their forties or fifties, which may predate other classic features. Presentation is usually with pain and stiffness of wrists, fingers and metacarpophalangeal joints, though hips, shoulders and knees are also commonly affected. Radiographic changes resemble osteoarthritis with narrowing, sclerosis and cysts, but cysts are often multiple and prominent, there is little osteophyte, and atypical sites for osteoarthritis (e.g. radiocarpal joint, metacarpophalangeal joints) are targeted. About 30% have superimposed pseudogout attacks and radiographic chondrocalcinosis as additional clues. Treatment of the haemochromatosis does not influence the arthropathy.
SARCOIDOSIS
Acute self-limiting arthritis, presenting as polyarthralgia and erythema nodosum, may accompany the onset of acute sarcoidosis (see p. 552). Chronic sarcoidosis may associate with a more persistent arthritis that targets the same joints.
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NEUROPATHIC (CHARCOT) JOINTS
Neurological disease (see Ch. 22) may result in rapidly destructive arthritis of joints, first described by Charcot in association with syphilis. Although repetitive microtrauma following sensory loss was one popular explanation, the more likely pathogenesis is altered blood flow secondary to impaired sympathetic nervous system control. The following are the principal predisposing diseases and principal sites of involvement:
diabetic neuropathy (hindfoot)
syringomyelia (shoulder, elbow, wrist)
leprosy (hands, feet)
tabes dorsalis (knees, spine).
Presentation is usually with chronic monoarthritis or dislocation. Pain can be a feature, especially at the onset, but the striking clinical feature is that signs are disproportionately greater than symptoms would suggest. The joint is often grossly swollen, with effusion, crepitus, marked instability and deformity, though usually no increased warmth. It may eventually become flail and be complicated by peripheral nerve entrapment or spinal cord compression. Radiographic features are gross loss of cartilage and bone, with disorganisation of normal architecture and often multiple loose bodies, and either no (atrophic) or gross (hypertrophic) new bone formation. Management principally involves orthoses and occasionally arthrodesis.

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Home > 2 SYSTEM-BASED DISEASES > 20 Musculoskeletal disorders > MISCELLANEOUS RARE MUSCULOSKELETAL CONDITIONS
MISCELLANEOUS RARE MUSCULOSKELETAL CONDITIONS
ALGODYSTROPHY (REFLEX SYMPATHETIC DYSTROPHY)
This disorder usually affects a single, mainly peripheral, region with severe burning pain and tenderness, vasomotor changes (abnormal sweating, colour and temperature change, oedema) and associated localised regional osteoporosis. It may be triggered by trauma, pregnancy or intercurrent illness, or arise spontaneously. It is thought to result from abnormal sympathetic vasomotor control that causes local vasodilatation and increased osteoclastic bone resorption. It is diagnosed on the basis of clinical features, regional patchy osteoporosis on radiograph, increased uptake on radioisotope bone scanning, and absence of an acute phase response. Various treatments have been tried, including active mobilisation, calcitonin, corticosteroids and sympathetic blockade, though bisphosphonates appear the most beneficial in improving pain and swelling. The sooner any treatment is started, the better its effect. The prognosis is variable but often poor. Shoulder-hand syndrome is one form of complex algodystrophy that affects two regions simultaneously.
INHERITED CONNECTIVE TISSUE DISEASE
Marfan's syndrome is characterised by skeletal disproportion (arm span greater than height), arachnodactyly (long, thin, 'spider' fingers), sternal depression, generalised hypermobility of joints, lens dislocation and a high arched palate. It results from mutations of the fibrillin gene, a component of extracellular matrix. The most serious complications are in the cardiovascular system, with mitral valve prolapse, aortic incompetence and aortic dissection (see p. 447). Ehlers-Danlos syndrome is characterised by generalised hypermobility, skin laxity and easy bruising, with scoliosis, short stature, ocular fragility and visceral vascular catastrophes. It may result from mutations in several genes including COLIA2, lysyl oxidase, fibronectin and elastin. Osteoporosis and a Marfanoid appearance occur in homocystinuria, which is due to deficiency of the enzyme cystathionine synthetase. Other features include mental retardation, and venous and arterial thrombosis. The diagnosis is confirmed by finding homocystine in the urine, and patients respond to treatment with pyridoxine.
OSTEOGENESIS IMPERFECTA (OI)
OI is a rare disease that usually presents with severe osteoporosis and multiple fractures in infancy and childhood. Other variable features include blue sclerae and abnormal dentition. Most cases are due to mutations of type I collagen genes (COLIA1, COLIA2), with either reduced collagen production or formation of abnormal molecules that rapidly degrade. Disease severity varies from neonatal lethal (type II), through very severe with multiple fractures in infancy and childhood (types III and IV), to mild (type I) which can present in adults and mimic osteoporosis. Severe OI is diagnosed on clinical grounds or by specialised analysis of collagen produced by cultured skin fibroblasts. There is no cure, but physiotherapy and occupational therapy may help the associated disability. Surgery is often required for fracture fixation and correction of deformity. HRT is advised for perimenopausal women with OI to prevent post-menopausal bone loss. Intravenous pamidronate may improve bone pain and reduce fracture incidence in severe OI.
OSTEOPETROSIS AND OSTEOSCLEROSIS
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Osteopetrosis is a group of rare inherited diseases characterised by defects in osteoclast function and generalised osteosclerosis. The phenotype varies from a severe disorder that presents with marrow failure in childhood to a milder, often asymptomatic form in adults. Childhood cases may show failure to thrive, delayed dentition, cranial nerve palsies (due to absent cranial foramina formation), anaemia and recurrent infections (due to bone replacing the marrow cavity). The adult-onset type may present with bone pain, cranial nerve palsies and osteoarthritis or be discovered as an incidental radiographic finding. Defects identified include deficiency of carbonic anhydrase II (the enzyme that permits osteoclasts to produce acid), defects in the osteoclast proton pump and deficiency of cathepsin K (a bone matrix degrading protease). For severe cases interferon gamma treatment can improve blood counts and reduce frequency of infections. Cure, however, can be effected by bone marrow transplantation which provides a source of healthy osteoclast precursors that resorb bone normally.
Osteosclerosis describes disorders characterised by focal increases in bone density. Acquired forms are described in intravenous drug users with hepatitis C infection, in patients with lymphoma and myelosclerosis, and in fibrogenesis imperfecta ossium-an idiopathic disorder causing intractable bone pain, mixed sclerotic/lytic lesions on radiograph and multiple fractures. Engelmann's disease is an autosomal dominant disorder causing severe pain and osteosclerosis of long bones. It is due to activating mutations of the transforming growth factor beta 1 gene. There is no cure but the pain may be improved by corticosteroid.
RELAPSING POLYCHONDRITIS
Relapsing polychondritis (RP) is an idiopathic condition classically presenting as acute pain and swelling of one or both ear pinnae, which spares the non-cartilaginous portion. Around 30% of patients have coexisting autoimmune or connective tissue disease. In 25% of patients inflammation of the tracheobronchial tree leads to hoarse voice, cough, stridor or expiratory wheeze. Manifestations at other cartilage sites include collapse of the bridge of the nose, scleritis, hearing loss and cardiac valve dysfunction. Diagnosis may be confirmed by auricular cartilage biopsy. Pulmonary function tests, including flow volume loops, should be performed to assess the degree of laryngotracheal disease since this is an important cause of mortality. Mild ear disease usually responds to low-dose steroids or NSAIDs. Major organ involvement requires high-dose steroids in combination with cytotoxic drugs. Rarely, tracheostomy or tracheal stents are required.
FAMILIAL PERIODIC FEVERS
These are characterised by recurrent attacks of fever and organ inflammation. Familial Mediterranean fever (FMF) is largely restricted to Armenians, Sephardic Jews and other ethnic groups originating from the Middle East and Mediterranean, and results from mutations of the pyrin gene. Painful febrile attacks affect joints, skin and serosal cavities and last from a few hours to 4 days.
Hyperimmunoglobulinaemia D periodic fever syndrome (HIDS) is an autosomal recessive disorder that causes attacks every 4-8 weeks of abdominal pain, diarrhoea, lymphadenopathy, arthralgia and skin lesions. Serum IgD is persistently elevated. Most patients originate from the Netherlands and northern France.
TNF receptor-associated periodic syndrome (TRAPS) is an autosomal dominant syndrome causing recurrent periodic fever, arthralgia, myalgia, serositis and rashes with a marked acute phase response. FMF and TRAPS may both result in amyloidosis, and colchicine is the first-line treatment. Therapy with monoclonal anti-TNF receptor therapy (e.g. etanercept) may be effective in TRAPS.
FURTHER INFORMATION
Bone health in the balance. Science 2000; 289:1497-1514. A series of reviews on basic aspects of bone cell biology and bone turnover.
Brandt KD, Doherty M, Lohmander LS, eds. Osteoarthritis. Oxford: Oxford University Press; 1998.
Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 2001; 27:165-176. Medline Similar articles Full article
Cush JJ, Kavanaugh AF, Olsen N, et al. Rheumatology diagnosis and therapeutics. Baltimore: Williams & Wilkins; 1999. Full article
Delmas PD, Meunier PJ. The management of Paget's disease of bone [review]. N Engl J Med 1997; 336(8):558-566. Medline Similar articles Full article
Doherty M, Hazleman BL, Huttin CW, et al. Rheumatology examination and injection techniques. London: WB Saunders; 1999. Full article
Eastell R. Treatment of postmenopausal osteoporosis. N Engl J Med 1998; 33(8):736-746. Full article
Firestein GS, Panayi GS, Wollheim FA, eds. Rheumatoid arthritis: new frontiers in pathogenesis and treatment. Oxford: Oxford University Press; 2000. Full article
Maddison PJ, Isenberg DA, Woo P, Glass DN, eds. Oxford textbook of rheumatology. 2nd edn. Oxford: Oxford University Press; 1998.
www.eBandolier.com Updates on management.
www.ectsoc.org/reviews Reviews on various aspects of bone disease, both clinical and basic.
www.rheumatology.com Updates on management. Full article

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