19.10 Crystal- related arthropathies 4482 Edward R

19.10 Crystal- related arthropathies 4482 Edward Roddy and Michael Doherty

ESSENTIALS Many crystals have been associated with arthropathies or periarticular syndromes: only monosodium urate (gout), calcium pyrophosphate (acute calcium pyrophosphate crystal arthritis chondrocalcinosis), and basic calcium phosphates (mainly hydroxyapatite) are common. Crystals implicated in joint disease are stable, hard particles that exert biological effects via surface-​active (activation of humoral and cell-​derived mediators, interaction with cell membranes) and mech- anical properties. In general, smaller particle size, marked surface irregularity, and high negative surface charge correlate with inflam- matory potential. Gout Aetiology and pathogenesis—​gout is caused by the formation of monosodium urate crystals, and the primary risk factor for its devel- opment is hyperuricaemia. It is common (prevalence 2.49%, rising with age). Risk factors for primary gout include being male, hyperten- sion, obesity, insulin resistance, metabolic syndrome, excess alcohol consumption (especially beer), and a diet rich in purines and fruc- tose. Most act primarily by reducing efficient elimination of uric acid via the kidney. Important risk factors for secondary gout are diuretic therapy, chronic renal impairment, and osteoarthritis. Clinical features—​four clinical phases are recognized. (1) Asymptomatic hyperuricaemia:  the risk of developing gout in- creases with the degree of hyperuricaemia, but around 95% of hyperuricaemic patients remain asymptomatic throughout life. (2) Acute gout: in almost all initial episodes a single peripheral joint is involved, with the first metatarsophalangeal joint (podagra) the site of the first attack in 50% of patients. Other common sites are the midtarsal joints, ankle, knee, small hand joints, wrist, and elbow. The pain is often described as ‘the worst ever experienced’. The joint and surrounding tissues are swollen, hot, red, shiny, and extremely tender. (3) Intercritical gout: after resolution of the first attack there is a vari- able time period before the second, but this usually occurs within one year and chronic symptoms usually develop within 10 years. (4) Chronic tophaceous gout: large crystal deposits (tophi) produce irregular firm nodules and chronic joint damage. Gout is associated with renal disease; uric acid stones (10–​25% of patients) and chronic urate nephropathy (endstage renal failure occurs in up to 25% of cases of untreated chronic tophaceous gout). Diagnosis—​proof of gout requires the identification of monoso- dium urate crystals on polarized light microscopy of aspirates from synovial fluid or tophus (strongly birefringent, negative sign). Although gout is strongly associated with hyperuricaemia, serum urate is fre- quently normal during an acute attack, and hyperuricaemia per se is not a diagnostic test for gout. Management—​treatment of an acute attack aims to reduce in- flammation: options include non​steroidal anti-​inflammatory drugs, low-​dose colchicine, joint aspiration, intra-​articular (occasion- ally systemic) steroids, and ice packs. Alteration of uric acid levels is avoided until the attack has resolved. Long-​term management involves lifestyle modification advice and urate-​lowering therapy. Encouragement concerning weight loss and restriction of the con- sumption of alcohol (especially beer) and purine-​rich foods should be offered to all appropriate patients with primary gout. Urate-​ lowering therapy should be titrated with the aim of lowering the serum urate well below 360 µmol/​litre (6 mg/​dl)—​the physiological saturation point for urate crystal formation. Allopurinol, a xanthine oxidase inhibitor, is the usual drug of choice. Where allopurinol is not tolerated, options are febuxostat and the uricosuric drugs (pro- benecid, sulfinpyrazone, and benzbromarone). Calcium pyrophosphate crystal deposition Deposition of calcium pyrophosphate crystals in articular cartilage can be seen on radiographs in 4.5% of adults over the age of 40. It is almost always of unknown cause (sporadic/​idiopathic, associ- ated with osteoarthritis), but can be associated with metabolic dis- ease (hyperparathyroidism, haemochromatosis, hypophosphatasia, hypomagnesaemia) or be hereditary. Clinical features, diagnosis, and management—​the following are common presentations. (1)  Acute calcium pyrophosphate crystal arthritis (acute pseudogout) —​one of the commonest causes of acute monoarthritis in older people. A typical attack develops rapidly (6–​ 24 h)—​usually in the knee—​with severe pain, stiffness and swelling, and a florid synovitis on examination. Fluid aspirated from the joint is often turbid or bloodstained with an elevated cell count, and po- larized light microscopy reveals calcium pyrophosphate crystals (weakly birefringent, positive sign). Local therapy is preferred with ice packs and aspiration (combined with intra-​articular steroid in florid cases). (2) Osteoarthritis with calcium pyrophosphate deposition—​a common condition that affects mainly elderly women and targets 19.10 Crystal-​related arthropathies Edward Roddy and Michael Doherty

19.10  Crystal-related arthropathies 4483 the same large and medium-​sized joints as acute calcium pyrophos- phate crystal arthritis. Presentation is with chronic pain, stiffness, and functional impairment, with or without superimposed acute attacks. Affected joints show signs of osteoarthritis with varying de- grees of synovitis. There is no specific therapy and treatment of any underlying metabolic disease does not influence outcome, which is generally good. (3) Asymptomatic calcium pyrophosphate depos- ition may be an incidental radiographic finding. Apatite-​associated syndromes Apatites, or basic calcium phosphates, are the usual minerals de- posited in extraskeletal tissues (e.g. in arterial walls or tuberculous lesions). Apatite deposition in the supraspinatus tendon is a not un- common incidental finding, occasionally resulting in severe acute inflammation (acute calcific periarthritis). Introduction Diversity and terminology Many crystals have been associated with acute synovitis, chronic arthropathy, or periarticular syndromes (Box 19.10.1). In practice only monosodium urate, calcium pyrophosphate, and basic calcium phosphates (mainly hydroxyapatite) are commonly encountered. The taxonomy of these conditions is not universally agreed. Difficulties arise from our poor understanding of pathogenesis, his- torical extrapolation from gout to other crystal-​related conditions, and multiple terms for the same clinical syndrome. Possible rela- tionships between crystals and disease are outlined in Fig. 19.10.1. A ‘crystal deposition disease’ is defined as a pathological condition associated with mineral deposits that contribute directly to the path- ology. This is probably the situation for all manifestations of gout, for acute syndromes associated with calcium pyrophosphate, and for acute apatite periarthritis. However, the role of nonurate crystals in chronic arthropathy is unclear and confounded by the following observations: • Most crystals lack disease specificity and occur in a variety of clinical settings, often unaccompanied by symptoms or other abnormality. • Crystal deposition may coexist with other rheumatic disease, most commonly osteoarthritis, and often follows, rather than precedes, articular damage. • Combined deposition of several crystal species is common (mixed crystal deposition). For descriptive purposes, confusion may be avoided by specifying the crystal, the site of involvement, and the clinical syndrome (e.g. chronic urate olecranon bursitis, acute calcium pyrophosphate crystal arthritis of the knee). Crystal deposition and clearance Many factors determine crystal formation and dissolution (Fig. 19.10.2). High solute concentrations alone are often insufficient to initiate crystal formation, and the presence of nucleating factors that aid initial particle formation and the balance of growth-​promoting and inhibitory factors are probably more important. Little is known of such tissue factors, although they may in part explain: • the characteristic, limited distribution of different crystals Box 19.10.1  Crystalline particles associated with joint disease Intrinsic • Monosodium urate • Calcium pyrophosphate (monoclinic, triclinic) • Calcium phosphates — Basic: hydroxyapatite, octacalcium phosphate, tricalcium phosphate — Acidic: brushite, monetite • Calcium oxalate • Lipids • Cholesterol • Lipid liquid crystals • Charcot–​Leyden (phospholipase) crystals • Cystine • Xanthine, hypoxanthine • Protein precipitates (e.g. cryoglobulins) Extrinsic • Synthetic corticosteroids • Plant thorns (semicrystalloid cellulose), especially blackthorn, rose, dried palm fronds • Sea urchin spines (crystalline calcium carbonate) • Methylmethacrylate Crystals X Crystals Joint disease Crystals Joint disease Crystals Joint disease Joint disease Fig. 19.10.1  Possible relationships between crystals and joint disease. Solute excess (pH) Dissolution Inhibitory factors Nucleating factors Growth promoting factors CRYSTALS (slow transition to stable forms) Enzymic degradation Reduced solute concentration (temperature) (pressure) Fig. 19.10.2  Factors affecting crystal formation.

section 19  Rheumatological disorders 4484 • the frequency of mixed crystal deposition (via epitaxial nucleation and growth of one crystal on another) • non​specific predisposition to crystal formation in osteoarthritic tissues (via accompanying alterations in proteoglycan, collagen, and lipid) Formation of crystals in vivo is a dynamic process, although usually slow. At any time the crystal load will depend on the rate of forma- tion, the rate of dissolution, and trafficking of crystals away from their site of formation (via shedding from preformed deposits with secondary uptake by synovial and other cells). Crystal-​induced inflammation and tissue damage Crystals implicated in joint disease are stable, hard particles that exert biological effects via surface-​active and mechanical properties. With respect to acute inflammation, they are all markedly phlogistic agents in a wide range of in vitro and in vivo systems. Surface-​active interaction has been demonstrated with: • humoral mediators (e.g. complement activation via classical and alternative pathways, activation of Hageman factor) • cell-​derived mediators (e.g. superoxide production and release of lysozymes, chemotactic factor, and lipoxygenase-​derived prod- ucts of arachidonic acid by neutrophils, release of interleukin l (IL-​1), IL-​6, and tumour necrosis factor (TNF) by monocytes and synoviocytes) • cell membranes (e.g. membranolysis of lysosomes, erythrocytes, and neutrophils, non-​lytic platelet, and neutrophil secretory responses) In general, monosodium urate is the most inflammatory, followed by calcium pyrophosphate, then apatite and the less common crys- tals. In general, smaller particle size, marked surface irregularity, and high negative surface charge correlate with inflammatory po- tential. Some surface effects result from direct crystal contact, but others are mediated via adsorbed protein, particularly immuno- globulin. Although adsorbed IgG may enhance inflammation, most other protein binding is inhibitory. A key recent development has been the identification of the role played by the intracellular NLRP3 inflammasome in crystal-​induced inflammation. Both monoso- dium urate and calcium pyrophosphate crystals stimulate this to ac- tivate and release interleukin-​1β. Less is known of chronic crystal-​induced tissue damage. Postulated effects include persistent synovial inflammation, altered cell metab- olism (ingested calcium crystals may stimulate mitogenesis, fibrosis, and calcium-​related cellular effects), and deleterious mechanical effects from large deposits. Evidence for activation of inflamma- tory mediators in chronic crystal-​associated synovitis is lacking, although a chronic ‘granulomatous’ reaction often occurs around large accretions. The physicochemical effects of hard, highly charged crystals embedded within cartilage, or occurring as wear particles at the surface, are largely unknown.  Gout Monosodium urate crystals are undoubted causal agents in gout, which arises following supersaturation of body tissues with mono- sodium urate. Subsequently the deposition of crystals in previously normal tissues may elicit acute inflammation and eventual tissue damage. Their effective removal halts progression and results in cure. In these respects, gout is a true crystal deposition disease. Both the incidence and prevalence of gout are rising. In the United Kingdom, its incidence increased from 1.36 to 1.77 per 1000 person-​ years between 1997 and 2012. Similarly, prevalence rose from 1.52% in 1997 to 2.49% in 2012 in the United Kingdom, and from 2.64% in 1988–​1994 to 3.76% in 2007–​2010 in the United States. Prevalence rises with age and there is strong predominance in men (male:female approximately 4:1), particularly under 65 years of age. Untreated gout evolves slowly through four clinical phases: asymp- tomatic hyperuricaemia, acute gout, intercritical gout, and chronic tophaceous gout. Clinical features Asymptomatic hyperuricaemia Hyperuricaemia is the primary risk factor for the development of gout and arises from either overproduction or renal underexcretion of uric acid, or a combination of both (see Chapter 12.4). Although hyperuricaemia and gout are strongly linked, they are not syn- onymous. Around 95% of hyperuricaemic subjects remain asymp- tomatic throughout life. The risk of developing gout increases with the degree of hyperuricaemia, but even in patients with the highest levels of serum urate (>540 µmol/​litre (9.0 mg/​dl)) annual incidence is less than 5%, emphasizing the importance of local tissue factors in crystal nucleation/​growth. Ultrasound studies suggest that up to one in three hyperuricaemic patients have occult monosodium urate deposits. Monosodium urate crystals preferentially deposit in peripheral connective tissues in and around synovial joints. Deposits occur first in articular cartilage, most commonly the first metatarsophalangeal and small joints of the feet, developing later in synovium, capsule, and periarticular soft tissues. Crystals probably take months if not years to grow in vivo to detectable size, implying a long asymptom- atic phase. Absence of inflammation during this period may relate to low crystal yield, positioning within hypovascular tissues, or in- hibitory protein coating. Acute attacks The classical attack In almost all initial episodes, a single peripheral joint is involved. The first metatarsophalangeal joint (podagra) is the site of the first attack in 50% of patients and is affected at some point in over 70%. This may relate to the common occurrence of osteoarthritis at this joint. Other common sites are the midtarsal joints, ankle, knee, small hand joints, wrist, and elbow. The axial skeleton and large central joints are rarely involved and never as the first site. Attacks often wake the patient in the early morning with local- ized irritation and aching. Within just a few hours the joint and sur- rounding tissues are swollen, hot, red, shiny, and extremely painful. The patient cannot bear even bedclothes to touch the joint and it is often described as ‘the worst pain ever experienced’. Inflammation is maximal within 24 h and is often associated with pyrexia and mal- aise. Examination reveals florid synovitis and swelling, extreme ten- derness, and overlying erythema. If left untreated, the attack resolves spontaneously over 5–​15 days, often with pruritus and desquam- ation of overlying skin.

19.10  Crystal-related arthropathies 4485 Although many attacks occur spontaneously, some situations encourage shedding of preformed monosodium urate crystals and triggering of acute attacks. Suggested mechanisms include mechan- ical loosening (local trauma), partial dissolution and reduction of crystal size (initiation of hypouricaemic treatment, reduction in uric acid levels as part of the acute phase response), and local increase in cytokines that encourage inflammatory responses to crystals and facilitate crystal escape via alterations in cartilage matrix (intercur- rent illness, surgery). Although some triggers (alcohol, dietary ex- cess) increase local urate levels, acute crystallization is considered unlikely. Atypical attacks Acute attacks may manifest as tenosynovitis, bursitis, or cellu- litis. Many patients describe mild episodes of discomfort without swelling lasting a day or so (petite attacks). Ten per cent (10%) of all typical attacks involve more than one joint. Sometimes acute gout, by triggering the acute phase response, provokes migratory attacks in other joints over subsequent days (cluster attacks). Polyarticular attacks are rare, usually occurring after a long history of recurrent attacks: marked systemic upset, fever, and confusion may dominate the clinical picture. Intercritical periods Following the resolution of the first attack, a variable time period elapses before the next attack occurs. The asymptomatic interval be- tween attacks is called the intercritical period. Some patients never have a second attack; in others the next episode occurs after many years; in most, however, a second attack occurs within one year. With time, the frequency and severity of attacks and number of sites in- volved increases, and attacks are more often pauci-​ or polyarticular. Eventually, recurrent attacks and continuing monosodium urate de- position cause joint damage and chronic pain. The interval between the first attack and development of chronic symptoms is variable, but averages about 10 years. The principal determinant is the serum uric acid; the higher it is, the earlier and more extensive the develop- ment of joint damage and tophaceous deposits. Chronic tophaceous gout Large crystal deposits (tophi) produce irregular firm nodules, principally around extensor surfaces of fingers, hands, the ulnar surface of the forearms, olecranon bursae, Achilles tendons, first metatarsophalangeal joints, and the cartilaginous helix of the ear. Marked asymmetry, both locally and between sides, is particu- larly characteristic (Fig. 19.10.3). Monosodium urate crystals be- neath the skin may show a white-​yellow ‘chalky’ discolouration (Fig. 19.10.4). If untreated, tophi can enlarge into gross knobbly swellings that may ulcerate, discharging white and gritty material that causes local inflammation (erythema, pus) even in the absence of secondary infection. If extensive, tophi may rarely involve the eyelids, tongue, larynx, or heart (causing conduction defects and valvular dysfunction). Joints most commonly involved with signs of damage (restricted movement, crepitus, deformity) and varying degrees of synovitis are the first metatarsophalangeal joints, midfoot, small finger joints, and wrists. As with tophi, joint involvement is usually asymmetrical. Occasionally gross destruction may occur in feet and hands, and less commonly other sites. Acute attacks may become less of a feature as chronic symptoms become established. If untreated, the combin- ation of extensive joint destruction and large tophi may cause gro- tesque deformities, particularly of hands and feet. Ankylosis is a rare late event. Although axial involvement is rare, even in late stages, gouty involvement of hips, shoulders, spine and sacroiliac joints, and spinal cord compression by tophi, are all reported. Classification Gout is traditionally classified into primary and secondary, with dif- ferent clinical patterns and separate risk factors and associations de- scribed for each (Tables 19.10.1 and 19.10.2). Primary gout characteristically affects men, with an age of onset between 30 and 60 years of age, and a predeliction for the legs, par- ticularly the first metatarsophalangeal joint. Presentation is with acute attacks, and untreated disease progresses to chronic tophaceous Fig. 19.10.3  Chronic tophaceous gout affecting the hands. Note the eccentric nature of the tophi and the asymmetry between sides. Fig. 19.10.4  Diuretic-​induced gout in an elderly woman, showing tophaceous deposition on pre-​existing nodal osteoarthritis; the white monosodium urate crystals are clearly visible beneath the skin.

section 19  Rheumatological disorders 4486 gout. Over 75% of patients with primary gout are underexcretors of uric acid. A family history of gout is common due to an inherited isolated renal lesion that reduces fractional urate clearance. Fewer than 10% are overproducers of uric acid. The cause usually remains unclear, although a very few have an inherited purine enzyme defect (see Chapter 12.4). Genome-​wide association studies have identi- fied 28 loci influencing serum urate levels, most of which exert their effect via genes either coding for renal urate transporters or those influencing glycolysis. Secondary gout, by contrast, mainly presents in older individuals (>65 years) and shows a more equal gender distribution and equal involvement of the arm and leg peripheral joints. Acute attacks are said to be less frequent and tophi may be the initial manifestation. Primary gout Primary gout associates strongly with metabolic syndrome and obesity, type IV hyperlipidaemia, hypertension, and insulin resist- ance. Hypertension and obesity are independent risk factors for the development of gout; hypertensive microvascular renal damage leads to hyperuricaemia and, in obese patients, insulin resistance and hyperinsulinaemia impair renal urate excretion. The association of primary gout with these common cardiovascular risk factors not surprisingly translates into an important association between pri- mary gout and cardiovascular disease. Excessive consumption of al- cohol, purine-​rich foods, sugar-​sweetened soft drinks and fructose are also independent risk factors for primary gout. Beer drinking confers the greatest risk, attributable in part to its high guanosine content, followed by spirits, with wine conferring only slight risk. The 19th century association with port is partly explained by storage of wines in lead-​lined casks and the addition of lead to sweeten the port: lead inhibits uric acid excretion and also promotes nucleation of monosodium urate. Saturnine gout still occurs in individuals who drink alcohol distilled or stored in lead-​contaminated containers (‘moonshine’). Purine-​rich foods (e.g. meat and seafood), and soft drinks rich in fructose are associated with increased risk of gout, whereas consumption of dairy products, coffee, and vitamin C are protective. Secondary gout The most important risk factors for secondary gout are diuretic therapy and chronic renal impairment. Diuretics are an inde- pendent risk factor for the development of gout, even after adjust- ment for hypertension. Renal tubular organic anion transporters have recently been identified, through which diuretics exert their hyperuricaemic effect. Other drugs may predispose to gout, such as β-​blockers, ACE inhibitors, angiotensin-​II receptor antagonists (other than losartan), low-​dose aspirin, and ciclosporin, although the urate-​enhancing effect of low-​dose aspirin is not thought to be of clinical significance when compared with its cardiovascular bene- fits in this high-​risk group. More widespread organ transplantation and use of ciclosporin as an immunosuppressant have resulted in transplant-​associated gout becoming a challenging problem in sec- ondary care. In contrast, calcium-​channel antagonists and losartan appear to protect against the development of gout. Secondary gout is also associated with osteoarthritis, with both acute attacks of gout and tophi occurring at Heberden’s and Bouchard’s nodes in elderly women (Fig. 19.10.4). There is a strong negative association between gout and rheuma- toid arthritis. This remains unexplained, but probably reflects impaired nucleation/​growth of monosodium urate crystals rather than masking of monosodium urate crystal-​induced inflammation (e.g. by crystal coating with rheumatoid factors). A less strong nega- tive association is also reported between rheumatoid arthritis and calcium pyrophosphate crystal deposition. Gout and renal disease Urolithiasis Uric acid stones account for 5–​10% of all stones in the United Kingdom and the United States of America, and up to 40% in Israel. A history of renal colic can be obtained in 10–​25% of patients with gout, the important aetiological factors being low urinary pH, low urinary volume, and high urinary uric acid concentration. High urinary concentrations occur in overproducers of uric acid, if renal urate clearance is increased (uricosuric drugs, defects in tubular reabsorption), and in situations of dehydration with lowering of Table 19.10.1  Primary and secondary gout: clinical features Clinical feature Primary gout Secondary gout Sex Males ≫ females Males = females Age Middle-​age Elderly Acute attacks Common May be less common Distribution Lower limb ≫ upper limb Lower limb = upper limb Tophi Develop late Develop early Table 19.10.2  Primary and secondary gout: clinical associations and accompanying screening tests Clinical association Screening test Primary gout Male Family history Metabolic syndrome Hypertension Blood pressure monitoring Hyperlipidaemia Fasting lipids Insulin resistance Fasting plasma glucose Obesity Alcohol MCV, liver function tests Purine-​rich foods Sugar-​sweetened soft drinks and fructose Secondary gout Diuretics β-​blockers, ACE inhibitors,
non​losartan angiotensin-​II receptor antagonists Chronic renal failure Creatinine (eGFR) Lead poisoning (rare) Osteoarthritis Ciclosporin (rare) Myeloproliferative disorders (rare) FBC, ESR eGFR, estimated glomerular filtration rate; ESR, erythrocyte sedimentation rate; FBC, full blood count; MCV, mean cell volume.

19.10  Crystal-related arthropathies 4487 urinary pH (diarrhoea, ileostomy). Gouty patients also have an in- creased incidence of calcium-​containing stones, particularly cal- cium oxalate, with no detectable uric acid nidus. Acute uric acid nephropathy describes rapid precipitation of uric acid crystals in renal collecting ducts with secondary acute ob- structive renal failure. This event correlates with the amount of uric acid excreted rather than the level of hyperuricaemia. Strongly acid urine, which reduces uric acid solubility, potentiates the problem. The condition occurs in ill, dehydrated patients with lymphoma or malignancy subjected to aggressive chemotherapy without adequate prophylactic treatment (with allopurinol and/​or recombinant uricase). It also occurs in gouty patients with markedly accelerated purine synthesis (e.g. following excessive exercise or epileptic seiz- ures), when again the condition is largely avoidable by appropriate hydration, urinary alkalinization, and allopurinol prophylaxis. Chronic urate nephropathy Widespread monosodium urate deposition in the interstitium of the medulla and pyramids results in crystal-​induced inflamma- tion with surrounding giant-​cell reaction and fibrosis, affecting in particular the tubular epithelium of the loop of Henle and juxta- posed interstitial tissues. Subsequent changes include glomerular hyalinization and hypertrophy of the intima and media of arteri- oles. Hypertensive damage, tubular obstruction, and secondary pyelonephritis may all complicate this picture. Albuminuria and inability to concentrate the urine maximally are early clinical mani- festations. Progressive renal disease is an important complica- tion of untreated chronic tophaceous gout, endstage renal failure occurring in up to 25% of cases. Calcium oxalate or phosphate crystals may deposit in the renal parenchyma in advanced renal disease of any cause, but are predom- inantly cortical in location (compared with the medullary site of monosodium urate). The association between parenchymal disease and less severe gout remains controversial, being confounded in men by frequent accompanying obesity, hypertension, and drug therapy. The minor progression of renal insufficiency that occurs in most gouty patients, however, is probably largely age related, and life expectancy is not reduced. Differential diagnosis Acute attacks Sepsis and other crystal-​associated synovitis are the main consid- erations. However, the rapidity of onset of severe symptoms that plateau within 12–​24 h is highly characteristic of crystal inflamma- tion; sepsis presents more slowly and is progressive. Gout and sepsis may coexist, as may monosodium urate and calcium pyrophosphate deposition (particularly in elderly patients). Examination of aspir- ated fluid for both crystals and sepsis (Gram stain, culture) is the only sure way of obtaining the correct diagnosis. A wider search for sepsis may be indicated (e.g. blood and urine cultures), particularly in those who are ill. With less classic attacks, other conditions that may be considered include psoriatic and acute reactive arthropathy, acute sarcoid arthropathy, traumatic arthritis, palindromic rheuma- tism, and exacerbation of osteoarthritis. A search for synovial fluid crystals should be undertaken in all patients with unexplained in- flammatory arthritis. Chronic tophaceous gout Other causes of arthritis and periarticular swellings/​nodules that require differentiation are rheumatoid arthritis, generalized nodal osteoarthritis, xanthomatosis with arthropathy, and multicentric reticulohistiocytosis. Gout is usually less symmetrical in distribu- tion than these conditions and, except for xanthomatosis, acute attacks are not a feature. Nodal osteoarthritis, of course, may coexist with gout. Aspiration (joint fluid, nodules) and plain radiographs readily facilitate correct diagnosis. Clinical investigation The history and signs of classical acute or chronic tophaceous gout are highly characteristic, and with a raised serum urate a strong presumptive diagnosis is readily made. However, definitive con- firmation requires demonstration of monosodium urate crystals by compensated polarized light microscopy of fluid from a gouty joint, bursa, or tophus. Synovial fluid in acute attacks is typically turbid with diminished viscosity and greatly elevated cell count (>90% neutrophils). Chronic gouty fluid is more variable, but occasionally appears white owing to the high crystal load. Only a few drops col- lected directly on to a slide are required for crystal identification. Monosodium urate crystals are seen readily as strongly birefringent (negative sign), needle-​shaped crystals, 5–​20 µm in length, within cells or occurring freely in fluid. In tophaceous material they occur as dense, tightly packed sheets. During intercritical periods, aspir- ation of an asymptomatic first metatarsophalangeal joint or knee often permits confirmation of the diagnosis by revealing monoso- dium urate crystals. Measurement of the serum urate level is an important investiga- tion, both to confirm the presence of hyperuricaemia and monitor response to treatment. Urate is a negative acute phase reactant, and hence urate levels are frequently lowered during an acute attack of gout. If the serum urate is found to be within the ‘normal range’ during a suspected acute attack it should be repeated during the intercritical period. In primary gout in a young patient, determination of undersecretion or overproduction of uric acid is best undertaken by measuring total urinary excretion on a low-​purine diet, but a quick guide is given by the uric acid/​creatinine ratio estimated on a single urine sample (normally <0.5). In young overproducers, a purine en- zyme defect becomes more likely and should be sought. Assessment of renal function (creatinine, urea, electrolytes, urine testing) should always be undertaken (Table 19.10.2). Given the association of pri- mary gout with cardiovascular disease and the metabolic syndrome, measurement of fasting lipoprotein concentrations and glucose should be made in all patients with primary gout. An intercritical full blood count and measurement of ESR/​viscosity should detect any underlying chronic myeloproliferative disease. During acute attacks a marked acute phase response (high ESR, neutrophil leucocytosis, thrombocytosis, elevated C-​reactive protein) is usual; modest eleva- tions of ESR may also accompany chronic gout. Radiographs supplement the clinical assessment of structural damage but can also aid diagnosis. In early disease they are usu- ally normal. During acute gout, non​specific soft tissue swelling (rarely juxta-​articular osteopenia) may be evident. After repeated attacks, and in chronic disease, joint space narrowing, scler- osis, cysts, and osteophytes (that is, the changes of osteoarthritis)

section 19  Rheumatological disorders 4488 become more frequent in feet and hands. Gouty ‘erosions’ are a less common but more specific abnormality, occurring as para-​articular ‘punched-​out’ bone defects with well-​demarcated sclerotic mar- gins, overhanging hooks of bone, and retained bone density (Fig. 19.10.5). They are typically asymmetric, eccentric lesions positioned away from the ‘bare area’ of the joint, contrasting with more symmetrical, ill-​defined marginal erosions (with osteopenia) of rheumatoid arthritis. Tophi appear as eccentric soft tissue swellings, occasionally with patchy calcification due to epitaxial growth of apatite. In late disease, severe destructive change with osteopenia may occur, and distinction from rheumatoid arthritis or other conditions becomes more difficult. Ultrasonography and dual-​energy computed tomography have emerging roles in the assessment of gout, providing novel non​invasive opportunities to visualize crystal deposits and differentiate monosodium urate from other crystals (Table 19.10.3). Treatment Acute gout The treatment aim is pain relief by reducing inflammation and intra-​articular hypertension, which can be achieved using non​steroidal anti-​inflammatory drugs (NSAIDs), colchicine, or corticosteroids. For the best results, patients should be instructed to take their medication as soon as possible following the start of their attack. Alteration of uric acid levels is avoided until the attack has resolved, as initiation of hypouricaemic drugs may prolong the attack and important information concerning lifelong treatment is best delivered when the patient has fully recovered from their painful episode. Rapid symptom relief may be obtained with a quick-​acting NSAID, given in full dosage. Indometacin has traditionally been considered the NSAID of choice but—​given its frequent renal, gut, and nervous system side effects—​other NSAIDs are to be pre- ferred (e.g. diclofenac or naproxen). In the presence of risk factors for gastrointestinal toxicity (e.g. old age) a gastroprotective agent (a proton pump inhibitor or misoprostol) should be coadministered with a traditional NSAID, or alternatively a selective inhibitor of cyclooxygenase-​2 (COX-​2), such as etoricoxib, can be given, al- though long-​term use should be cautioned by the adverse cardio- vascular profile of both COX-​2 selective agents and primary gout. Oral colchicine is rapidly effective within a few hours. High-​dose regimes such as 1 mg immediately, followed by 0.5 mg every 2–​3 h until symptoms abate, very frequently cause diarrhoea, nausea, and abdominal cramps, and are best avoided. Low-​dose colchi- cine (e.g. 0.5 mg two or three times daily), is widely used with both symptomatic benefit and less toxicity, and is a useful alternative if NSAIDs are contraindicated. Intravenous colchicine, however, is particularly toxic and should never be used. Although previously used as a ‘diagnostic test’, the efficacy of colchicine is not specific to gout: it also ameliorates other crystal-​associated syndromes. Fig. 19.10.5  Characteristic radiographic changes of established gout in a finger: joint space loss and cystic change at the distal interphalangeal joint, ‘pressure erosions’ with overhanging bony ‘hooks’ at both interphalangeal joints, and eccentric soft tissue swelling at the proximal joint. Table 19.10.3  European League Against Rheumatism proposal for terminology of manifestation of calcium pyrophosphate crystal deposition Existing term New term Definition Calcium pyrophosphate dihydrate crystals Calcium pyrophosphate crystals Simplified name for calcium pyrophosphate dihydrate crystals –​ Calcium pyrophosphate deposition Umbrella term for all instances of calcium pyrophosphate crystal occurrence Chondrocalcinosis Chondrocalcinosis Cartilage calcification, identified by imaging or histological identification. Commonly but not always due to calcium pyrophosphate deposition Clinical presentations associated with calcium pyrophosphate deposition –​ Asymptomatic calcium pyrophosphate deposition Calcium pyrophosphate deposition with no apparent clinical consequence, either isolated chondrocalcinosis or osteoarthritis with calcium pyrophosphate deposition Pyrophosphate arthropathy Osteoarthritis with calcium pyrophosphate deposition Calcium pyrophosphate deposition in a joint which also shows changes of OA, on imaging or histological examination Acute pseudogout Acute calcium pyrophosphate crystal arthritis Acute onset, self-​limiting synovitis with calcium pyrophosphate deposition –​ Chronic calcium pyrophosphate crystal inflammatory arthritis Chronic inflammatory arthritis associated with calcium pyrophosphate deposition

19.10  Crystal-related arthropathies 4489 Joint aspiration often provides immediate relief by reducing intra-​articular hypertension, and in difficult cases joint lavage may terminate an attack. Intra-​articular steroid is useful for large joints such as the knee. When NSAIDs or colchicine are contraindicated or unsuccessful, intra-​articular steroid or oral prednisolone (20 mg/​day) can be effective, and for troublesome polyarticular attacks there is support for the use of parenteral steroid. Application of ice locally to an affected joint also provides symptomatic relief. Long-​term management Once any acute attack has resolved, long-​term strategies need con- sideration. Gout is potentially curable. Treatment may involve both considering and eliminating modifiable factors that cause hyperuricaemia, and utilizing hypouricaemic drugs. Management of gout may therefore require alteration in lifestyle and chronic medication: patient compliance and motivation, which depend on appropriate education and counselling, are essential for success. Modification of provoking factors Lifestyle modification is a key component of the management of primary gout. In particular, obesity, excess alcohol consumption, and a high-​purine diet are independent risk factors that are amen- able to modification. Advice concerning weight loss and restriction of the consumption of alcohol (especially beer) and purine-​rich foods should be offered to all patients with primary gout when appropriate. In diuretic-​induced gout, the diuretic should be discontinued or the dose reduced whenever possible, and this may be all that is re- quired. However, this cannot often be achieved where the indica- tion for the diuretic is cardiac failure rather than hypertension, and pharmacological measures are necessary. Urate-​lowering drug therapy Absolute indications for urate lowering therapy are: • recurrent, troublesome acute attacks, although urate lowering therapy should be considered and discussed with the patient earlier • presence of tophi • bone or cartilage damage on radiographs • coexistent renal disease, uric acid urolithiasis • very high uric acid levels (particularly with overproduction and hyperexcretion) The aim of urate-​lowering therapy is the reduction and maintenance of serum urate well below 360 µmol/​litre (6 mg/​dl), which is below the physiological saturation threshold of urate within the serum (approximately 380 µmol/​litre (6.4 mg/​dl)). The lowering of urate below this level reduces the frequency of acute attacks and crystal load. Allopurinol, a purine non​specific xanthine oxidase inhibitor, is the usual drug of choice, permitting flexible tailoring of dose to reduce urate levels below the solubility limit. Allopurinol is usually started at the relatively low dose of 100 mg daily. The serum urate should then be checked at regular intervals (e.g. monthly) and, if tolerated, the dose of allopurinol increased in 100 mg increments up to a maximum dose of 900 mg daily until the serum urate lies well below 360 µmol/​litre (6 mg/​dl). In patients with renal insuffi- ciency, particularly older people, excretion of the active metabolite oxipurinol is delayed and hence dose escalation should be more cau- tious. Treatment should be lifelong. Febuxostat, a non​purine specific xanthine oxidase inhibitor, can be used when allopurinol is contra- indicated or not tolerated and has been shown to produce greater re- ductions in serum urate levels than allopurinol 300 mg daily at either of its two licensed doses (80 mg or 120 mg daily). The uricosurics probenecid (0.5–​1.0 g twice a day) and sulfinpyrazone (100 mg three or four times daily), which prevent proximal tubular reabsorption of urate, are rarely used. They are alternatives to allopurinol in patients with normal renal function but are contraindicated in those with renal impairment, urolith- iasis, or gross overproduction of uric acid (due to reduced effi- cacy and risk of worsening renal function). Benzbromarone, a potent uricosuric, is now increasingly used in parts of Europe, and is the one uricosuric that can be used in patients with mild to moderate renal impairment. Its availability, however, is limited, owing to reports of occasional severe hepatotoxicity (possibly limited to Japanese patients). Lesinurad is a novel selective uric acid reabsorption inhibitor that has been shown to achieve greater reductions in serum urate levels in combination with a xan- thine oxidase inhibitor than that achieved by a xanthine oxidase inhibitor alone. Losartan, an angiotension-​II receptor antagonist, and fenofibrate have mild uricosuric properties that may prove useful in patients with hypertension and/​or hyperlipidaemia in addition to gout. Losartan is therefore a logical alternative anti-​hypertensive agent in diuretic-​induced gout. Acute attacks may be provoked during the first few months of hypouricaemic treatment, especially if initiation is with higher doses (e.g. 300 mg allopurinol). Prophylactic colchicine (0.5 mg twice a day) or a standard dose of NSAID given for the first two to three months of treatment largely avoids ‘breakthrough’ attacks. With any uricosuric, high fluid intake and urine alkalinization in the early weeks of treatment are recommended to avoid deposition of uric acid within the kidney. Serious side effects are unusual with any hypouricaemic drugs. Rare problems include toxic epidermal necrolysis, interstitial neph- ritis and vasculitis (allopurinol hypersensitivity syndrome), neph- rotic syndrome (probenecid), and hepatitis and marrow suppression (both drugs). Important interactions with allopurinol occur with coumarin anticoagulants (due to hepatic microsomal enzyme in- hibition) and purine analogues (such as azathioprine) that are in- activated by xanthine oxidase. Associated hypertension should be treated, but preferably not with diuretics, which elevate serum urate and may provoke acute attacks. Better understanding of the pathophysiology of hyperuricaemia and gout has led to the development of new approaches to treat- ment. Elucidation of the role of the inflammasome and interleukin-​ 1β in the causation of acute attacks has awakened interest in using interleukin-​1 inhibitors such as anakinra, canakinumab, and rilonacept to both treat acute attacks and prevent attacks when initiating urate-​lowering therapy. Recombinant uricase and pegloticase, which convert uric acid to allantoin, produce significant reductions in serum urate levels in patients with severe gout who are unresponsive to, or intolerant of, other urate-​lowering drugs. Currently, however, such drugs are expensive, restricted to hospital settings, and are not all approved for such use, hence they are re- served for exceptional circumstances.

section 19  Rheumatological disorders 4490 Calcium pyrophosphate crystal deposition Deposition of calcium pyrophosphate crystals (Ca2P2O7.2H2O) in articular cartilage is a common age-​related phenomenon. Calcium pyrophosphate crystals preferentially deposit within fibrocartilage and are the most common cause of cartilage calcifica- tion (chondrocalcinosis). Calcium pyrophosphate deposition may occur in otherwise normal cartilage or associate with structural change and clinical arthropathy—​‘arthropathy’. A causal role for calcium pyrophos- phate crystals in acute inflammation is accepted, but their role in chronic arthropathy is unclear. The strong association/​overlap with osteoarthritis led some to consider the historical term ‘pyro- phosphate arthropathy’ not as a crystal deposition disease but as a subset of osteoarthritis, with calcium pyrophosphate a ‘process’ marker associating with a hypertrophic bone response. In 2011, the European League Against Rheumatism proposed a new ter- minology for the manifestations of calcium pyrophosphate crystal deposition (Table 19.10.3). Radiographic chondrocalcinosis has an age-​adjusted standard- ized prevalence of 4.5% in adults over age 40, its prevalence at the knee rising to about 20% in those over age 80. There is an equal sex distribution. Community studies have confirmed an association with osteoarthritis at the knee (age, sex-​adjusted odds ratio 2.0). The age-​standardized prevalence of osteoarthritis with calcium pyro- phosphate deposition in the United Kingdom in people older than 40 is 2.40%. Clinical features Common presentations are acute calcium pyrophosphate crystal arthritis (acute pseudogout), osteoarthritis with calcium pyrophos- phate deposition, or as an asymptomatic incidental radiographic finding (chondrocalcinosis). Other presentations are rare. Acute calcium pyrophosphate crystal arthritis This is one of the commonest causes of acute monoarthritis in older people. Attacks may occur as isolated events or be superimposed upon a background of chronic joint symptoms. Most attacks occur spontaneously, but provoking factors include intercurrent illness, surgery, and local trauma. Although any joint may be involved, the knee is by far the commonest site, followed by the wrist, shoulder, and ankle. Concurrent attacks in several joints are uncommon and polyarticular attacks rare. The typical attack develops rapidly with severe pain, stiffness, and swelling, becoming maximal within just 6 to 24 h of onset. Examination reveals a very tender joint with signs of florid synovitis (increased warmth, tense effusion, restricted movement with stress pain) and often overlying erythema. Fever is common, and elderly patients may appear unwell or mildly confused, especially when more than one joint is involved. Attacks are self-​limiting, usually re- solving within 1 to 3 weeks. The identical clinical presentation of such attacks to gout is the reason for the historical term ‘pseudogout’. Osteoarthritis with calcium pyrophosphate deposition This common condition affects mainly elderly women and targets the same large and medium-​sized joints as acute calcium pyrophos- phate crystal arthritis. Knees are the usual and most severely affected joint. Presentation is with chronic pain, stiffness, and functional im- pairment, with or without superimposed acute attacks. Symptoms usually relate to just a few joints, although examination often re- veals more widespread joint involvement. Affected joints show signs of osteoarthritis (crepitus, bony swelling, restricted movement) with varying degrees of synovitis (often most marked at the knee, radiocarpal, or glenohumeral joint). Knees typically show abnor- mality of two or three compartments; valgus or varus deformity may occur. Although symptoms and signs are those of osteoarthritis, co-​ occurrence with calcium pyrophosphate deposition (osteoarthritis with calcium pyrophosphate deposition) may often be distinguished from uncomplicated osteoarthritis by: • the joint distribution—​in osteoarthritis wrist, glenohumeral, ankle, elbow, and midtarsal involvement is less common • the often marked inflammatory component • superimposition of acute attacks The outcome for osteoarthritis with calcium pyrophosphate deposition is generally good, most patients running a relatively benign course, particularly with respect to small and medium-​ sized joints. If progression occurs, it is usually slow and related to knees, hips, or shoulders. Severe, rapidly progressive, destructive arthropathy occasionally develops at these sites. This is virtually confined to very elderly women and is associated with severe pain, recurrent haemarthrosis (shoulder, knee), and occasional joint leakage. Incidental finding As with uncomplicated osteoarthritis, clinical or radiographic evi- dence of calcium pyrophosphate deposition and chondrocalcinosis are not uncommon incidental findings in older people, and may confound the cause of regional pain if a thorough history and exam- ination are not undertaken. Uncommon presentations Acute tendinitis (triceps, Achilles), tenosynovitis (hand flexors, extensors), and bursitis (olecranon, infrapatellar, retrocalcaneal) occur uncommonly, usually in patients with widespread calcium pyrophosphate crystals. Median and ulnar nerve compression at the wrist may accompany flexor tenosynovitis. Rare tophaceous deposits of calcium pyrophosphate usually present as solitary le- sions in areas of chondroid metaplasia (usually benign cartilage tumours). Classification and associations Calcium pyrophosphate deposition is traditionally classified as: being hereditary; associated with metabolic disease; or sporadic/​ idiopathic (by far the commonest, associated with osteoarthritis). Familial predisposition This is reported from many countries and different ethnic groups. Two clinical phenotypes occur:  early onset (third to fourth decade) florid polyarticular chondrocalcinosis with variable se- verity of accompanying arthropathy; and late onset (sixth to sev- enth decade) oligoarticular chondrocalcinosis (mainly knee) with arthritis resembling sporadic disease. The pattern of inheritance

19.10  Crystal-related arthropathies 4491 varies, although autosomal dominance is usual. Two chromo- somal locations have been identified in kindreds with young-​onset chondrocalcinosis: CCAL1 on chromosome 8 (associating with se- vere structural arthritis), and CCAL2 on chromosome 5 (mainly associating with isolated polyarticular chondrocalcinosis). The re- sponsible gene at CCAL2 encodes the multipass transmembrane transporter protein ANKH (ankylosis human) that regulates passage of intracellular inorganic pyrophosphate to the extracelluler space. Mutations in ANKH in British, French, and American kindreds re- sult in greatly increased exit of pyrophosphate from chondrocytes, sufficient to exceed the saturation point for calcium pyrophosphate crystal formation. Other mechanisms may operate in other families. For example, histological studies in Japanese and Swedish families suggest a primary abnormality in cartilage matrix that promotes calcium pyrophosphate crystal nucleation and growth. Metabolic disease associations Inorganic pyrophosphate is a by-​product of many biosynthetic reactions, with a turnover of several kilograms per day. Most extracellular inorganic pyrophosphate derives from breakdown of extracellular ATP via the action of the NTP pyrophosphatase plasma cell membrane glycoprotein-​1 (PC-​1). Normally this extra- cellular pyrophosphate is rapidly converted to orthophosphate by pyrophosphatases (particularly alkaline phosphatase) (Fig. 19.10.6). Several metabolic diseases associate with deposition of calcium pyrophosphate (Table 19.10.4), their association being rationalized through putative effects on metabolism of inorganic pyrophos- phate. Suggested mechanisms include: • reduced breakdown of inorganic pyrophosphate by alkaline phos- phatase, owing to (1) reduced levels, (2) inhibitory ions (calcium, iron, copper), or (3) impaired complexing with magnesium • enhanced nucleation by iron or copper • increased calcium concentration Osteoarthritis and joint insult Several observations support a relationship between osteoarthritis and deposition of calcium pyrophosphate crystals, the latter often following rather than preceding joint damage. However, there is a negative association between deposition of calcium pyrophosphate and rheumatoid arthritis, with atypical radiographic features in coexistent disease (retained bone density; marked osteophyte, cyst, and bone remodelling) suggesting that the primary association of calcium pyrophosphate is with hypertrophic tissue response/​osteo- arthritis and not joint damage per se. The explanation for this associ- ation probably relates to changes both in pyrophosphate metabolism and in tissue factors that encourage crystal formation. Levels of PPi cell Pi ATP ANKH Ca++ CPPD crystals Mg++ 1 2 3 nucleation AlkP cell PC1 PPi Fig. 19.10.6  Simplified scheme of extracellular pyrophosphate metabolism, showing putative sites of interaction by metabolic diseases. Hyperparathyroidism, 1,2; haemochromatosis, 1,3; hypophosphatasia, 1; Wilson’s disease, 1,3; and hypomagnesaemia, 1. Alk P, alkaline phosphatize; ANKH, ankylosis human protein; ATP, adenosine triphosphate; CPPD, calcium pyrophosphate dehydrate; Mg++, magnesium; PC1, plasma cell glycoprotein-​1; PPi, pyrophosphate. Table 19.10.4  Metabolic diseases associated with calcium pyrophosphate dihydrate (CPPD) crystal deposition Chondrocalcinosis Acute calcium pyrophosphate
crystal arthritis Osteoarthritis with calcium pyrophosphate deposition Definite associations Hyperparathyroidism + + –​ Haemochromatosis + + + Hypophosphatasia + + –​ Hypomagnesaemia + + –​ Possible associations Hypothyroidism + –​ –​ Gout + + –​ X-​linked hypophosphataemic rickets + + + Familial hypocalciuric hypercalcaemia + –​ –​ Wilson’s disease + –​ –​ Ochronosis + –​ –​ Acromegaly + –​ –​

section 19  Rheumatological disorders 4492 inorganic pyrophosphate in synovial fluid are increased in calcium pyrophosphate deposition, osteoarthritis, and in metabolic diseases that predispose to chondrocalcinosis, but are lower than normal in rheumatoid arthritis. Calcium pyrophosphate crystals form in pericellular sites and associate with lipid, proteoglycan depletion, and adjacent hypertrophic chondrocytes containing lipid granules. It is therefore possible that reduction of inhibitors (such as proteo- glycan) and increase in promotors (such as lipid) may combine to copromote calcium pyrophosphate formation in metabolically ac- tive osteoarthritic tissue that associates with high levels of extracel- lular pyrophosphate. Investigations and diagnosis Critical investigations are synovial fluid analysis and plain radio- graphs. In acute calcium pyrophosphate crystal arthritis, aspirated fluid is often turbid or bloodstained with an elevated cell count (>90% neutrophils). Compensated polarized microscopy reveals calcium pyrophosphate crystals as weakly birefringent (positive sign) rhomboids or rods, about 2 to 10 µm long. Calcium pyrophos- phate crystals are less readily identified and often less numerous than those of monosodium urate; examination of a spun deposit may increase detection. Radiographic aspects relate both to calcification and arthropathy. Chondrocalcinosis signifies extensive deposition and is not always evident: it mainly affects fibrocartilage (particularly knee menisci, wrist triangular cartilage, symphysis pubis), and less commonly hya- line cartilage (Fig. 19.10.7). Although occasionally monoarticular, it usually affects several sites. Calcification of capsule, synovium, and tendons is less common. Chondrocalcinosis and calcification may increase or decrease with time, diminishing chondrocalcinosis often accompanying crystal shedding or cartilage loss. Changes of arthropathy are those of osteoarthritis:  cartilage loss, sclerosis, cysts, and osteophytes. However, characteristics that suggest pyrophosphate include: • distribution between and within joints that is atypical of osteo- arthritis (e. g. glenohumeral disease; isolated or predominant patellofemoral or radiocarpal involvement) • prominence of osteophytes and  cysts • prominent osteochondral  bodies Such combined features may present a distinctive ‘hypertrophic’ appearance even in the absence of chondrocalcinosis (Fig. 19.10.8). Marked cartilage and bone attrition with fragmentation and loose osseous bodies may resemble a Charcot joint in destructive arthropathy. Metabolic predisposition is rare and routine screening of all pa- tients is unrewarding. Nevertheless, arthritis associated with cal- cium pyrophosphate crystals may be the presenting feature of metabolic or familial disease, and a search is warranted in early onset chondrocalcinosis or acute calcium pyrophosphate crystal arthritis (<55 years), florid polyarticular chondrocalcinosis, or presence of additional clinical or radiographic clues. A reasonable screen would include serum calcium, alkaline phosphatase, magnesium, ferritin, and liver function. Differential diagnosis The principal differential diagnosis for acute calcium pyrophosphate crystal arthritis is sepsis or gout, both of which may coexist with calcium pyrophosphate deposition. Gram stain and culture of joint fluid should be undertaken even when calcium pyrophosphate (and/​ or monosodium urate) crystals are identified. Marked bloodstaining may lead to consideration of other causes of haemarthrosis, espe- cially a bleeding disorder or subchondral fracture. Fig. 19.10.7  Radiographic chondrocalcinosis of the knee affecting meniscal fibrocartilage (central, triangular) and hyaline cartilage (linear, parallel to bone). Fig. 19.10.8  Lateral knee radiograph showing predominant patellofemoral involvement by ‘hypertrophic’ osteoarthritis characteristic of osteoarthritis with calcium pyrophosphate deposition.

19.10  Crystal-related arthropathies 4493 Chronic calcium pyrophosphate crystal inflammatory arthritis is usually readily distinguished from rheumatoid arthritis by the syn- ovial fluid and radiographic findings, the infrequency of severe sys- temic upset, absence of extra-​articular features, and an acute phase response that is only modest. Proximal stiffness due to glenohumeral involvement may suggest polymyalgia rheumatica, although clinical examination and near normal ESR should exclude the diagnosis. Destructive osteoarthritis with calcium pyrophosphate deposition may simulate a neuropathic joint, although such joints are severely symptomatic and neurological abnormality is absent. Treatment Acute calcium pyrophosphate crystal arthritis As acute calcium pyrophosphate crystal arthritis usually affects only one or a few joints in elderly patients, local therapy is preferred. Aspiration alone often relieves symptoms, but should be combined with intra-​articular steroid in florid cases. Local ice packs are safe and often helpful. With respect to systemic treatments, opioids and oral NSAIDs should be used with caution in the older people (coprescription of a proton pump inhibitor or misoprostol with an NSAID is indicated in those over 65; alternatively, the short-​term use of a selective COX-​2 inhibitor may be considered). Joint lavage is reserved for troublesome steroid-​resistant cases. Colchicine is ef- fective but rarely warranted. Triggering illness (e.g. chest infection) will require appropriate treatment. Rapid mobilization should be in- stituted once the synovitis is settling. Osteoarthritis with calcium pyrophosphate deposition Unlike gout, there is no specific therapy, and treatment of any underlying metabolic disease does not influence outcome. Treatment aims are to reduce symptoms and maintain or improve function. This may include education of the patient in appropriate use of the affected joints, reduction in obesity, improvement of muscle strength, use of a stick or other walking aid, and surgery for severe disease. Chronic synovitis may be improved by intermittent steroid injection or intra-​articular radiocolloid (yttrium-​90). As with acute calcium pyrophosphate crystal arthritis, symptomatic drugs are to be used with caution in older patients; simple analgesics are gener- ally preferable to NSAIDs. Other crystal-​related disorders Apatite-​associated syndromes Hydroxyapatite is the principal bone mineral. Apatites or basic cal- cium phosphates (partially carbonate-​substituted hydroxyapatite, octacalcium phosphate, tricalcium phosphate (rarely)) are the usual minerals to deposit in extraskeletal tissues (e.g. tuberculous lesions, arteries). The [calcium × phosphate] product must be kept high to main- tain skeletal integrity. Specific cellular mechanisms activate calcifi- cation where appropriate (e.g. matrix vesicles in growing cartilage), whereas other mechanisms (such as pyrophosphate and aggregated proteoglycan) inhibit calcification elsewhere. In general, abnormal calcification results from: • elevation of the [calcium × phosphate] product, causing wide- spread metastatic calcification • alteration in the balance between inhibitory and promoting tissue factors, resulting in local dystrophic calcification. In rheumatic diseases, abnormal deposition of basic calcium phos- phates may occur in periarticular tissues (particularly tendon), hya- line cartilage, in association with osteoarthritis, or subcutaneous tissues and muscle, principally in connective tissue diseases. Apatite crystals are too small (5–​500 nm) to be seen by light mi- croscopy, but particles may aggregate to form spherulites that are visible on microscopy. Confirmation of basic calcium phosphates requires sophisticated analytical techniques, and most clinical diagnoses are presumptive, based on radiographic calcification, or non​specific staining of joint fluid or histological material. Acute calcific periarthritis Apatite deposition in the supraspinatus tendon (Fig. 19.10.9) is a relatively common incidental finding (about 7% of adults). It oc- casionally results in severe acute inflammation of the subacromial bursa, periarticular tissues, or joint itself. Periarticular sites around the greater hip trochanter, the foot, or the hand are less commonly affected. Acute episodes may follow local trauma or occur spontaneously. Within a few hours pain and tenderness are often extreme and the area appears swollen, hot, and red. Modest systemic upset and fever are common. Sepsis is usually considered first, but the diagnosis is made following demonstration of radiographic calcification. If the lesion is aspirated, thick white fluid containing many apatite aggregates may be obtained. The condition usually resolves spon- taneously over 1 to 3 weeks, often accompanied by radiographic dis- persal of modestly sized calcifications (crystal shedding). NSAIDs ameliorate symptoms, and the attack can be abbreviated by aspir- ation and injection of steroid. Large deposits may cause mechanical impingement and blocking of movement and require surgical re- moval. Calcific periarthritis rarely results from metabolic abnor- mality (renal failure, hyperparathyroidism, hypophosphatasia) and measurements of serum calcium, alkaline phosphatase, and cre- atinine are usually normal. Rare families are predisposed to calcific Fig. 19.10.9  Shoulder radiograph showing florid supraspinatus tendon calcification (calcific periarthritis).

section 19  Rheumatological disorders 4494 periarthritis at multiple sites despite no evidence of altered calcium phosphate product. Osteoarthritis and apatite-​associated destructive arthritis Modest amounts of basic calcium phosphates are commonly found in synovial fluid from osteoarthritic joints, in isolation or with cal- cium pyrophosphate (mixed crystal deposition). Whether apatite plays any part in inflammatory exacerbations or associates with se- verity or progression of osteoarthritis remains uncertain. The uncommon condition ‘apatite-​associated destructive arthritis’ is often considered a subset of osteoarthritis. It is virtually confined to elderly women and affects the hip, shoulder (Milwaukee shoulder), or knee. It has the general appearance of severe large joint osteo- arthritis but is particularly characterized by: rapid progression, often leading to severe pain and disability within a few months of onset; development of marked instability; large, cool effusions; and an atro- phic radiographic appearance with marked cartilage and bone attri- tion and little osteophyte or bone remodelling. Aspirated fluid has normal viscosity and a low cell count but contains large amounts of apatite aggregates, seen readily on light microscopy following non​specific calcium staining (Alizarin Red, acidic pH). The differential diagnosis may include sepsis (excluded by synovial fluid culture), late avascular necrosis, or neuropathic joint. The pathogenesis of this condition remains unclear. Although apatite particles could contribute to tissue damage by stimulating release of collagenase and other proteolytic enzymes from synovial cells, it is most likely that the apatite is noncontributory and prin- cipally reflects the severity of subchondral bone attrition. The out- come is poor and usually requires surgical intervention. Other apatite syndromes Deposition of very large tophaceous periarticular apatite (tumoural calcinosis) may occur in patients with chronic renal failure managed by dialysis. Apatite has also been incriminated in the occasional ero- sive interphalangeal arthropathy seen in such patients. Other crystals Cholesterol Cholesterol crystals may induce acute synovitis, acute tenosynovitis, and chronic xanthomatous tendinitis in hypercholesterolaemic subjects. Cholesterol and other lipid crystals may also occur as a non​specific finding in chronic synovitis, most commonly due to rheumatoid arthritis. In this situation the lipid probably derives from cellular debris and its pathogenic significance is uncertain. Oxalate Oxalate crystals have been incriminated in acute and chronic ar- ticular and periarticular syndromes occurring in association with either primary familial oxalosis (types I  and II) or secondary oxalosis (Chapter 12.10). Chronic renal failure managed with dia- lysis is the commonest cause of secondary oxalosis, particularly if ascorbic acid supplementation has been given. Acute symmet- rical interphalangeal and metacarpophalangeal arthritis, with or without tenosynovitis, and digital calcific deposits are the usual manifestation. Large joint involvement, chondrocalcinosis, and tophaceous periarticular masses are less common. Calcium oxalate crystals may also cause life-​threatening organ involvement, with peripheral vascular insufficiency and digital necrosis, cardiomy- opathy, peripheral neuropathy, and aplastic anaemia. There is no effective treatment. Extrinsic crystals These rare causes of locomotor problems. Acute flares following intra-​articular injection of corticosteroids are uncommon but may represent iatrogenic crystal-​induced inflammation. Penetrating in- juries involving plant thorns and sea urchin spines may cause acute and chronic inflammatory synovitis, periostitis, or periarticular le- sions that only resolve following surgical removal of the crystalline material. FURTHER READING Abhishek A, Doherty M (2011). Pathophysiology of articular chondrocalcinosis—​role of ANKH. Nat Rev Rheumatol, 7, 96–​104. Choi HK, et al. (2005). Pathogenesis of gout. Ann Intern Med, 143, 499–​516. Edwards NL, So A (2014). Emerging therapies for gout. Rheum Dis Clin N Am, 40, 375–​87. Jordan KM, et al. (2007). British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the manage- ment of gout. Rheumatology (Oxford), 46, 1372–​4. Khanna D, et al. (2012). American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken), 64, 1431–​46. Khanna D, et al. (2012). American College of Rheumatology guide- lines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken), 64, 1447–​61. Petrilli V, Martinon F (2007). The inflammasome, autoinflammatory diseases, and gout. Joint Bone Spine, 74, 571–​6. Richette P, et al. (2009). An update on the epidemiology of calcium pyrophosphate dihydrate crystal deposition disease. Rheumatology (Oxford), 48, 711–​5. Roddy E, Choi HK (2014). Epidemiology of gout. Rheum Dis Clin N Am, 40, 155–​75. Roddy E, et al. (2013). Clinical review: gout. BMJ, 347, f5648. Rosenthal AK, Ryan LM (2014). Nonpharmacologic and pharmaco- logic management of CPP crystal arthritis and BCP arthropathy and periarticular syndromes. Rheum Dis Clin N Am, 40, 343–​56. Zhang W, et  al. (2006). EULAR evidence based recommendations for gout—​part I diagnosis: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis, 65, 1301–​11. Zhang W, et al. (2006). EULAR evidence based recommendations for gout—​part II management: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis, 65, 1312–​24. Zhang W, et al. (2011). European League Against Rheumatism recom- mendations for calcium pyrophosphate deposition. Part I: termin- ology and diagnosis. Ann Rheum Dis, 70, 563–​70. Zhang W, et al. (2011). EULAR recommendations for calcium pyro- phosphate deposition. Part II:  management. Ann Rheum Dis, 70, 571–​5.