- Pyrophosphate arthropathy
- Other crystal-related disorders
- Further reading
Crystal-related arthropathy is a class of joint disorder ( or arthropathy) that is characterized by accumulation of tiny crystals in one or more joints. Polarizing microscopy and application of other crystallographic techniques have improved identification of different microcrystals including monosodium urate monohydrate (gout), calcium-pyrophosphate dihydrate (pseudogout), calcium hydroxyapatite, and calcium oxalate.
There are numerous crystals that are linked with arthropathies or periarticular syndromes, but only a few are common. These are monosodium urate monohydrate (gout), calcium pyrophosphate dehydrate (pseudogout, chondrocalcinosis), and basic calcium phosphates (mainly hydroxyapatite).
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 mechanical properties. In general, smaller particle size, marked surface irregularity, and high negative surface charge correlate with inflammatory potential.
Aetiology and pathogenesis—gout is caused by the formation of monosodium urate crystals, and the primary risk factor for its development is hyperuricaemia. It is common (prevalence 0.5–1.4%, rising with age). Risk factors for primary gout include being male, hypertension, obesity, insulin resistance, metabolic syndrome, excess alcohol consumption (especially beer), and a diet rich in purines. These 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 increases 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 variable time period before the second, but this usually occurs within 1 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 monosodium 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 frequently 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 inflammation: options include nonsteroidal anti-inflammatory drugs, low-dose colchicine, joint aspiration, intra-articular (occasionally 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 consumption 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. The uricosurics probenecid and sulfinpyrazone are rarely used, but benzbromarone, a potent uricosuric, is now increasingly used in parts of Europe.
Deposition of calcium pyrophosphate dihydrate 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, associated with osteoarthritis), but can be associated with metabolic disease (hyperparathyroidism, haemochromatosis, hypophosphatasia, hypomagnesaemia) or be hereditary.
Clinical features, diagnosis and management—the following are common presentations. (1) Acute synovitis (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 polarized 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) Chronic pyrophosphate arthropathy—a common condition that affects mainly elderly women and targets the same large and medium-sized joints as pseudogout. Presentation is with chronic pain, stiffness, and functional impairment, with or without superimposed acute attacks. Affected joints show signs of osteoarthritis with varying degrees of synovitis. There is no specific therapy and treatment of any underlying metabolic disease does not influence outcome, which is generally good. (3) Asymptomatic incidental radiographic finding.
Apatites, or basic calcium phosphates, are the usual minerals deposited in extraskeletal tissues, e.g. in arterial walls or tuberculous lesions. Apatite deposition in the supraspinatus tendon is a not uncommon incidental finding, occasionally resulting in severe acute inflammation (acute calcific periarthritis).
Diversity and terminology
Many crystals have been associated with acute synovitis, chronic arthropathy, or periarticular syndromes (Bullet list 1). In practice only monosodium urate monohydrate, calcium pyrophosphate dihydrate, 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, historical extrapolation from gout to other crystal-related conditions, and multiple terms for the same clinical syndrome.
A ‘crystal deposition disease’ is defined as a pathological condition associated with mineral deposits that contribute directly to the pathology. This is probably the situation for all manifestations of gout, for acute syndromes associated with calcium pyrophosphate dihydrate, 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).
Bullet list 1 Crystalline particles associated with joint disease
- Monosodium urate monohydrate
- Calcium pyrophosphate dihydrate (monoclinic, triclinic)
- Basic—hydroxyapatite, octacalcium phosphate, tricalcium phosphate
- Acidic—brushite, monetite
- Calcium oxalate
- Lipid liquid crystals
- Charcot–Leyden (phospholipase) crystals
- Xanthine, hypoxanthine
- Protein precipitates (e.g. cryoglobulins)
- Synthetic corticosteroids
- Plant thorns (semicrystalloid cellulose), especially blackthorn, rose, dried palm fronds
- Sea urchin spines (crystalline calcium carbonate)
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 pyrophosphate arthritis of the knee).
Crystal deposition and clearance
Many factors determine crystal formation and dissolution. 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
- the frequency of mixed crystal deposition (via epitaxial nucleation and growth of one crystal on another)
- nonspecific 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 formation, 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 products 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 monohydrate is the most inflammatory, followed by calcium pyrophosphate dihydrate, then apatite and the less common crystals. In general, smaller particle size, marked surface irregularity, and high negative surface charge correlate with inflammatory potential. Some surface effects result from direct crystal contact, but others are mediated via adsorbed protein, particularly immunoglobulin. Although adsorbed IgG may enhance inflammation, most other protein binding is inhibitory.
Less is known of chronic crystal-induced tissue damage. Postulated effects include persistent synovial inflammation, altered cell metabolism (ingested calcium crystals may stimulate mitogenesis, fibrosis, and calcium-related cellular effects), and deleterious mechanical effects from large deposits. Evidence for activation of inflammatory 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.
Monosodium urate monohydrate crystals are undoubted causal agents in gout, which arises following supersaturation of body tissues with monosodium 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.
The incidence of gout varies in populations from 6.2 to 18.0 per 10 000 patient-years, with an overall prevalence of 5.2 to 14.0 per 1000. Prevalence rises with age and there is strong predominance in men (ranging from 3.6:1 to 8:1), particularly under 65 years of age. Untreated gout evolves slowly through four clinical phases: asymptomatic hyperuricaemia, acute gout, intercritical gout, and chronic tophaceous gout.
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: Disorders of purine and pyrimidine metabolism).
Although hyperuricaemia and gout are strongly linked, they are not synonymous. Around 95% of hyperuricaemic subjects remain asymptomatic throughout life. The risk of developing gout increases with the degree of hyperuricaemia. However, 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. How many hyperuricaemic patients have occult monosodium urate monohydrate deposits is unknown.
Monosodium urate monohydrate 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 asymptomatic phase. Absence of inflammation during this period may relate to low crystal yield, positioning within hypovascular tissues, or inhibitory protein coating.
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 localized irritation and aching. Within just a few hours the joint and surrounding 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 malaise. Examination reveals florid synovitis and swelling, extreme tenderness, and overlying erythema. If left untreated, the attack resolves spontaneously over 5 to 15 days, often with pruritus and desquamation of overlying skin.
Although many attacks occur spontaneously, some situations encourage shedding of preformed monosodium urate monohydrate crystals and triggering of acute attacks. Suggested mechanisms include mechanical 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 (intercurrent illness, surgery). Although some triggers (alcohol, dietary excess) increase local urate levels, acute crystallization is considered unlikely.
Above: Typical acute gout affecting the first metatarsophalngeal joint
Acute attacks may manifest as tenosynovitis, bursitis, or cellulitis. Many patients describe mild episodes of discomfort without swelling lasting a day or so (petite attacks). Ten per cent 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.
Following the resolution of the first attack, a variable time period elapses before the next attack occurs. The asymptomatic interval between 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 1 year. With time, the frequency and severity of attacks and number of sites involved increases, and attacks are more often pauci- or polyarticular. Eventually, recurrent attacks and continuing monosodium urate monohydrate deposition 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 development 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 particularly characteristic. Monosodium urate monohydrate crystals beneath the skin may show a white-yellow ‘chalky’ discolouration. 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 combination of extensive joint destruction and large tophi may cause grotesque 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.
Above: Tophaceous gout affecting the distal inter-phalangeal joint
Gout is traditionally classified into primary and secondary, with different clinical patterns and separate risk factors and associations described for each (Tables 1 and 2). Primary gout characteristically affects men, with an age of onset between 30 and 60 years of age and a predeliction for the legs, particularly the first metatarsophalangeal joint. Presentation is with acute attacks, and untreated disease progresses to chronic tophaceous 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.
|Table 1 Primary and secondary gout: clinical features|
|Clinical feature||Primary gout||Secondary gout|
|Sex||Males >> females||Males = females|
|Acute attacks||Common||May be less common|
|Distribution||Lower limb >> upper limb||Lower limb = upper limb|
|Tophi||Develop late||Develop early|
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 associates strongly with metabolic syndrome and obesity, type IV hyperlipidaemia, hypertension, and insulin resistance. 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 primary gout and cardiovascular disease. Excessive consumption of alcohol and purine-rich foods 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 monohydrate. 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, are associated with increased risk of gout, whereas consumption of dairy products is protective.
|Table 2 Primary and secondary gout: clinical associations and accompanying screening tests|
|Clinical association||Screening test|
|Hypertension||Blood pressure monitoring|
|Insulin resistance||Fasting plasma glucose|
|Alcohol||MCV, liver function tests|
|Chronic renal failure||Creatinine (eGFR)|
|Lead poisoning (rare)|
|Myeloproliferative disorders (rare)||FBC, ESR|
e GFR, estimated glomerular filtration rate; FBC, full blood count; MCV, mean cell volume.
The most important risk factors for secondary gout are diuretic therapy and chronic renal impairment. Diuretics are an independent risk factor for the development of gout, even after adjustment 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 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 benefits 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 secondary care. 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.
There is a strong negative association between gout and rheumatoid arthritis. This remains unexplained, but probably reflects impaired nucleation/growth of monosodium urate monohydrate crystals rather than masking of monosodium urate monohydrate crystal-induced inflammation (e.g. by crystal coating with rheumatoid factors). A less strong negative association is also reported between rheumatoid arthritis and calcium pyrophosphate crystal deposition.
Gout and renal disease
Uric acid stones account for 5 to 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 to 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 urinary pH (diarrhoea, ileostomy). Gouty patients also have an increased incidence of calcium-containing stones, particularly calcium 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 obstructive 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 seizures, when again the condition is largely avoidable by appropriate hydration, urinary alkalinization, and allopurinol prophylaxis.
Chronic urate nephropathy
Widespread monosodium urate monohydrate deposition in the interstitium of the medulla and pyramids results in crystal-induced inflammation with surrounding giant-cell reaction and fibrosis, affecting in particular the tubular epithelium of the loop of Henle and juxtaposed interstitial tissues. Subsequent changes include glomerular hyalinization and hypertrophy of the intima and media of arterioles. Hypertensive damage, tubular obstruction, and secondary pyelonephritis may all complicate this picture. Albuminuria and inability to concentrate the urine maximally are early clinical manifestations. Progressive renal disease is an important complication 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 predominantly cortical in location (compared with the medullary site of monosodium urate monohydrate).
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.
Sepsis and other crystal-associated synovitis are the main considerations. However, the rapidity of onset of severe symptoms that plateau within 12 to 24 h is highly characteristic of crystal inflammation; sepsis presents more slowly and is progressive. Gout and sepsis may coexist, as may monosodium urate monohydrate and calcium pyrophosphate dihydrate deposition (particularly in elderly patients). Examination of aspirated 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 Reiter’s arthropathy, acute sarcoid arthropathy, traumatic arthritis, palindromic rheumatism, and exacerbation of osteoarthritis. A search for synovial fluid crystals should be undertaken in all patients with unexplained inflammatory 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 distribution 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.
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 confirmation requires demonstration of monosodium urate monohydrate 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 collected directly on to a slide are required for crystal identification. Monosodium urate monohydrate crystals are seen readily as strongly birefringent (negative sign), needle-shaped crystals, 5 to 20 µm in length, within cells or occurring freely in fluid. In tophaceous material they occur as dense, tightly packed sheets. During intercritical periods, aspiration of an asymptomatic first metatarsophalangeal joint or knee often permits confirmation of the diagnosis by revealing monosodium urate monohydrate crystals.
Measurement of the serum urate level is an important investigation, 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 enzyme defect becomes more likely and should be sought. Assessment of renal function (creatinine, urea, electrolytes, urine testing) should always be undertaken (Table 2). Given the association of primary 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 elevations 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 usually normal. During acute gout, nonspecific soft tissue swelling (rarely juxta-articular osteopenia) may be evident. After repeated attacks, and in chronic disease, joint space narrowing, sclerosis, cysts, and osteophytes (that is, the changes of osteoarthritis) 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 margins, overhanging hooks of bone, and retained bone density. 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.
Above: Characteristic radiographic changes of established gout in a finger
The treatment aim is pain relief by reducing inflammation and intra-articular hypertension. 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 nonsteroidal anti-inflammatory drug (NSAID), given in full dosage. Indometacin has traditionally been considered to be the NSAID of choice but, given its frequent renal, gut, and nervous system side effects, is less preferable to other NSAIDs, 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, although long-term use should be cautioned by the adverse cardiovascular profile of both COX-2 selective agents and primary gout.
Oral colchicine is rapidly effective within a few hours. At the doses described in the British National Formulary (1 mg immediately, followed by 0.5 mg every 2–3 h until symptoms abate), diarrhoea, nausea, and abdominal cramps are very common, causing the patient ‘to run before he can walk’. Low-dose colchicine, 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.
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.
Once any acute attack has resolved, long-term strategies need consideration. 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 amenable 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 where appropriate. In diuretic-induced gout, the diuretic should be discontinued or the dose reduced whenever possible, and this may be all that is required. However, this cannot often be achieved where the indication for the diuretic is cardiac failure rather than hypertension, and pharmacological measures are necessary.
Urate-lowering drug therapy
Indications for urate lowering therapy are:
- recurrent, troublesome acute attacks
- 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 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 insufficiency, particularly older people, excretion of the active metabolite oxipurinol is delayed, and hence dose escalation should be more cautious. Treatment should be lifelong.
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, urolithiasis, or gross overproduction of uric acid (due to reduced efficacy 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).
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 antihypertensive 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 2 to 3 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 nephritis and vasculitis (allopurinol hypersensitivity syndrome), nephrotic syndrome (probenecid), and hepatitis and marrow suppression (both drugs). Important interactions with allopurinol occur with coumarin anticoagulants (due to hepatic microsomal enzyme inhibition) and purine analogues (such as azathioprine) that are inactivated by xanthine oxidase. Associated hypertension should be treated, but preferably not with diuretics, which elevate serum urate and may provoke acute attacks.
New urate-lowering agents are in development. Febuxostat, a nonpurine-based xanthine oxidase inhibitor, has been shown to produce greater reductions in serum urate levels than allopurinol 300 mg daily, with apparently less toxicity. Recombinant uricase, currently licensed for the prevention of tumour-lysis syndrome, produces significant reductions in serum urate levels in patients unresponsive to, or intolerant of, allopurinol.
Deposition of calcium pyrophosphate dihydrate crystals (Ca2P2O7.2H2O) in articular cartilage is a common age-related phenomenon. Calcium pyrophosphate dihydrate crystals preferentially deposit within fibrocartilage and are the most common cause of cartilage calcification (chondrocalcinosis).
Calcium pyrophosphate dihydrate deposition may occur in otherwise normal cartilage or associate with structural change and clinical arthropathy—‘arthropathy’. A causal role for calcium pyrophosphate dihydrate crystals in acute inflammation is accepted, but their role in chronic arthropathy is unclear. The strong association/overlap with osteoarthritis has led some to consider pyrophosphate arthropathy not as a crystal deposition disease but as a subset of osteoarthritis, with calcium pyrophosphate dihydrate a ‘process’ marker associating with a hypertrophic bone response.
Radiographic chondrocalcinosis has an age-adjusted standardized 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), but this is largely through an association with osteophyte rather than joint space narrowing. The age-standardized prevalence of osteoarthritis plus chondrocalcinosis (i.e. pyrophosphate arthropathy) in the United Kingdom in people older than 40 is 2.40%.
Common presentations are acute synovitis, chronic arthritis, or as an asymptomatic incidental radiographic finding. Other presentations are rare.
Acute synovitis (pseudogout)
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 resolving within 1 to 3 weeks. The identical clinical presentation of such attacks to gout is the reason for the term ‘pseudogout’.
Chronic pyrophosphate arthropathy
This common condition affects mainly elderly women and targets the same large and medium-sized joints as pseudogout. Knees are the usual and most severely affected joint. Presentation is with chronic pain, stiffness, and functional impairment, with or without superimposed acute attacks. Symptoms usually relate to just a few joints, although examination often reveals 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 abnormality of two or three compartments; valgus or varus deformity may occur.
Although symptoms and signs are those of osteoarthritis, chronic pyrophosphate arthropathy 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 chronic pyrophosphate arthropathy 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.
As with osteoarthritis, clinical or radiographic evidence of pyrophosphate arthropathy and chondrocalcinosis are not uncommon incidental findings in older people, and may confound the cause of regional pain if a thorough history and examination are not undertaken.
Acute tendinitis (triceps, Achilles), tenosynovitis (hand flexors, extensors), and bursitis (olecranon, infrapatellar, retrocalcaneal) occur uncommonly, usually in patients with widespread calcium pyrophosphate dihydrate crystals. Median and ulnar nerve compression at the wrist may accompany flexor tenosynovitis. Rare tophaceous deposits of calcium pyrophosphate dihydrate usually present as solitary lesions in areas of chondroid metaplasia (usually benign cartilage tumours).
Classification and associations
Calcium pyrophosphate dihydrate deposition is traditionally classified as: being hereditary; associated with metabolic disease; or sporadic/idiopathic (by far the commonest, associated with osteoarthritis).
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 severity of accompanying arthropathy; and late onset (sixth to seventh decade) oligoarticular chondrocalcinosis (mainly knee) with arthritis resembling sporadic disease. The pattern of inheritance varies, although autosomal dominance is usual. Two chromosomal locations have been identified in kindreds with young-onset chondrocalcinosis: CCAL1 on chromosome 8 (associating with severe structural arthritis), and CCAL2 on chromosome 5 (mainly associating with isolated polyarticular chondrocalcinosis).
The responsible 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 result 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 dihydrate 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 extracellular pyrophosphate is rapidly converted to orthophosphate by pyrophosphatases (particularly alkaline phosphatase). A number of metabolic diseases associate with deposition of calcium pyrophosphate dihydrate (Table 3), their association being rationalized through putative effects on metabolism of inorganic pyrophosphate. Suggested mechanisms include:
- reduced breakdown of inorganic pyrophosphate by alkaline phosphatase, 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
|Table 3 Metabolic diseases associated with calcium pyrophosphate dihydrate (CPPD) crystal deposition|
|Chondrocalcinosis||Pseudogout||Chronic CPPD arthropathy|
|X-linked hypophosphataemic rickets||+||+||+|
|Familial hypocalciuric hypercalcaemia||+||–||–|
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, a negative association exists between deposition of calcium pyrophosphate dihydrate 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 dihydrate is with hypertrophic tissue response/osteoarthritis and not joint damage per se. The explanation for this association probably relates to changes both in pyrophosphate metabolism and in tissue factors that encourage crystal formation. Levels of inorganic pyrophosphate in synovial fluid are increased in pyrophosphate arthropathy, 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 proteoglycan) and increase in promotors (such as lipid) may combine to copromote calcium pyrophosphate dihydrate formation in metabolically active osteoarthritic tissue that associates with high levels of extracellular pyrophosphate.
Investigations and diagnosis
Critical investigations are synovial fluid analysis and plain radiographs. In pseudogout 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 pyrophosphate 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 hyaline cartilage. 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 osteoarthritis (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. 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 patients is unrewarding. Nevertheless, arthritis associated with calcium pyrophosphate crystals may be the presenting feature of metabolic or familial disease, and a search is warranted in early onset chondrocalcinosis or pseudogout (<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.
The principal differential diagnosis for pseudogout 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, especially a bleeding disorder or subchondral fracture.
Chronic pyrophosphate arthropathy is usually readily distinguished from rheumatoid arthritis by the synovial fluid and radiographic findings, the infrequency of severe systemic 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 pyrophosphate arthropathy may simulate a neuropathic joint, although such joints are severely symptomatic and neurological abnormality is absent.
As pseudogout 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, paracetamol is safe but 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 effective but rarely warranted. Triggering illness (e.g. chest infection) will require appropriate treatment. Rapid mobilization should be instituted once the synovitis is settling.
Chronic pyrophosphate arthropathy
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 pseudogout, symptomatic drugs are to be used with caution in older patients; simple analgesics are generally preferable to NSAIDs.
Other crystal-related disorders
Hydroxyapatite is the principal bone mineral. Apatites or basic calcium 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 maintain skeletal integrity. Specific cellular mechanisms activate calcification 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 widespread 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 phosphates may occur in periarticular tissues (particularly tendon), hyaline 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 microscopy, 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 nonspecific staining of joint fluid or histological material.
Acute calcific periarthritis
Apatite deposition in the supraspinatus tendon is a relatively common incidental finding (about 7% of adults). It occasionally 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 spontaneously over 1 to 3 weeks, often accompanied by radiographic dispersal of modestly sized calcifications (crystal shedding). NSAIDs ameliorate symptoms, and the attack can be abbreviated by aspiration and injection of steroid. Large deposits may cause mechanical impingement and blocking of movement and require surgical removal. Calcific periarthritis rarely results from metabolic abnormality (renal failure, hyperparathyroidism, hypophosphatasia) and measurements of serum calcium, alkaline phosphatase, and creatinine are usually normal. Rare families are predisposed to calcific 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 calcium pyrophosphate dihydrate (mixed crystal deposition). Whether apatite plays any part in inflammatory exacerbations or associates with severity 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 osteoarthritis 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 atrophic radiographic appearance with marked cartilage and bone attrition 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 nonspecific 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 principally reflects the severity of subchondral bone attrition. The outcome 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 erosive interphalangeal arthropathy seen in such patients.
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 nonspecific 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 crystals have been incriminated in acute and chronic articular and periarticular syndromes occurring in association with either primary familial oxalosis (types I and II) or secondary oxalosis. Chronic renal failure managed with dialysis is the commonest cause of secondary oxalosis, particularly if ascorbic acid supplementation has been given. Acute symmetrical 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, cardiomyopathy, peripheral neuropathy, and aplastic anaemia. There is no effective treatment.
These rare causes of locomotor problems. Acute flares following intra-articular injection of corticosteroids are uncommon but may represent iatrogenic crystal-induced inflammation. Penetrating injuries involving plant thorns and sea-urchin spines may cause acute and chronic inflammatory synovitis, periostitis, or periarticular lesions that only resolve following surgical removal of the crystalline material.
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