10.3 Crystal arthropathies

A number of crystals are associated with acute and chronic arthritis as well as periarticular syndromes and other soft tissue syndromes (Table 10.3.1). The most important of these are:

Gout is one of the oldest known forms of arthritis but the link with hyperuricaemia was only established in the nineteenth century. The fact that gout occurs exclusively in humans can be traced back to defunctioning mutations in the uricase gene. In other animals the accumulation of uric acid, a natural breakdown product of purine metabolism, is prevented by the action of this enzyme. The acute episodes of joint inflammation that characterize gout are said to be the most excruciating form of arthritis known. Acute gout is triggered by activation of the innate immune system through mechanisms that include the NALP3 inflammasome, activation of interleukin (IL)-1 and toll-like receptors. High levels of IL-1 provoke fever and neutrophilia; activated macrophages produce large amounts of tumour necrosis factor (TNF), and there is massive infiltration of the synovial compartment by neutrophils. As the attack continues and ultimately resolves there is a change in the cytokines produced by the macrophage population to a more anti-inflammatory profile with transforming growth factor (TGF)β and IL-10 supplanting TNF. The clinical features of gout are highly variable and include:

Gout is the most common inflammatory arthritis in adult men. Genetic, hormonal, and environmental factors are involved and the prevalence rises with increasing age and serum urate levels. The annual incidence of gout is approximately 0.3 per 1000, and its prevalence in males in the United Kingdom is 3–6 per 1000 adults. The male:female ratio is 8:1 and gout is rare in prepubertal boys and premenopausal women.

In addition to male gender, other risk factors include obesity, alcohol consumption, hypertension, renal failure, diuretics, social class, high protein intake, and a family history of gout. All these risk factors act through increasing serum urate concentrations. Hyperuricaemia is arbitrarily defined as a serum uric acid level two standard deviations above the mean (above 420µmol/L in adult males and 360µmol/L in adult females). Serum urate levels in boys rise at puberty while in women the pubertal rise is smaller and the level only approaches male values after the menopause. There are variations in serum urate levels between ethnic groups.

Several inherited enzyme defects can lead to the overproduction of uric acid. These are inherited as distinct Mendelian traits; X-linked (hypoxanthine-guanine phosphoribosyltransferase deficiency and phosphoribosylpyrophosphate synthetase overactivity), autosomal recessive (glucose-6-phosphatase deficiency), and autosomal dominant (familial urate nephropathy) patterns are recognized. Gout occurring before puberty, in premenopausal females, or where there is strong family history should prompt suspicion of an underlying enzyme defect.

Only 10–30% of hyperuricaemic subjects develop gout. Uric acid is derived from the purines of nucleoproteins through the intermediate metabolites xanthine, hypoxanthine, and guanine predominantly in the liver by the action of xanthine oxidase. Purines themselves are derived either from the diet or by de novo synthesis. Two-thirds of uric acid is renally excreted while the rest is degraded in the gut by bacteria. Lack of functional uricase which oxidizes uric acid to the more soluble allantoin is critical to the human predisposition to gout but other influences are also involved, notably diet and renal handling.

Hyperuricaemia results from overproduction or underexcretion of uric acid (Table 10.3.2). The majority of patients (90%) with primary gout are underexcretors of uric acid with an inability to increase uric acid excretion in response to a purine load. Fewer than 10% are overproducers of uric acid. A minority have underlying disorders of cell proliferation, including malignancy.

The first presentation of gout is usually acute monoarthritis although 10% of initial attacks are polyarticular. The first metata rsophalangeal joint is affected in 50% of initial attacks (podagra) and will be involved in 75% of goutees at some stage (Figure 10.3.1). Lower-limb joint involvement predominates (toes, ankle, knee, small joints of the hands and feet, wrist, elbow, and acromioclavicular joints in order of diminishing frequency). During the asymptomatic hyperuricaemic phase, up to 20% of patients have a history of renal colic from uric acid stones. Gouty arthritis and tophi have a predilection for cooler sites, such as the lower extremities and ears, because this reduces the solubility of monosodium urate.

Typical attacks have a rapid onset, often overnight, with the joint becoming swollen, hot, red, shiny, and extremely painful within a few hours (Figure 10.3.2). Inflammation is at a peak by 24h and can be associated with fever and malaise. Untreated attacks typically take 1–2 weeks to resolve spontaneously. Acute attacks may be triggered by dietary or alcohol excess, starvation, trauma (including surgery), haemorrhage, physical exercise, and severe systemic illness. Acute episodes may also be precipitated by sudden falls in serum urate after starting allopurinol or uricosuric drugs.

The course of gout is highly variable; some patients only ever have a single attack while others may rapidly develop polyarticular disease. A gradual evolution through several stages of disease is recognized (acute, episodic, interval, and chronic tophaceous gout). Joint involvement is usually asymmetric and monarticular initially; discrete episodes of inflammation with complete resolution occur in ‘interval gout’ while in the ‘chronic gout’ phase resolution is incomplete and there is always ongoing inflammation at one or more sites, causing progressive cartilage and bone erosion. Tophi may be present at any stage of the disease but are more typical of the late chronic phase. However, some individuals (particularly elderly women treated with thiazide diuretics) may develop massive tophi in the absence of any joint disease. Early diagnosis is important if one is to prevent potentially irreversible destructive arthritis in goutees destined for the more severe forms of the condition.

Septic arthritis can present in a very similar fashion to gout and must be formally excluded. Ideally the diagnosis of gout should be established by aspiration of synovial fluid from the affected joint during an acute attack. It is confirmed by demonstrating intracellular ‘needle-shaped’ monosodium urate crystals that are negatively birefringent under compensated polarized light microscopy (Figure 10.3.3). Joint fluid for examination can be stored at 4°C overnight (or sometimes longer) since urate crystals are generally robust to storage. The fluid itself will be turbid from a high neutrophil count and will exhibit a negative ‘string sign’ characteristic of inflammatory synovitis due to the break down of high molecular weight aggrecan.

Hyperuricaemia (above 420µmol/L in adult males and 360µmol/L in adult females) is confirmed with serum uric acid levels, but raised levels alone do not confirm a diagnosis of gout. During acute attacks uric acid levels are often (approximately 15%) in the normal range, returning to the more typical steady state levels after 6 weeks or so. If the diagnosis of gout is seriously entertained it may be appropriate to obtain a series of measurements of morning (not fasting) serum urates once the acute episode has settled. During acute attacks there is often a neutrophil leucocytosis as high as 20–25 × 10⁹/L. The sedimentation rate and C-reactive protein are typically markedly elevated.

Joint radiographs are rarely useful in establishing an early diagnosis of gout since they are usually normal until the disease becomes established. However, after repeated attacks erosions and secondary osteoarthritic changes may develop. Gouty erosions are classically seen as punched-out cortical lesions with sclerotic margins and overhanging hooks of bone, sometimes well away from the joint (Figure 10.3.4). Bone density is preserved. As uric acid crystals are radiolucent, tophi appear as eccentric soft tissue swellings with patchy calcification due to hydroxyapatite. Chondrocalcinosis may also occur.

The aim of treatment is to relieve pain and reduce inflammation. High doses of short-acting non-steroidal anti-inflammatory drugs (NSAIDs) given early in the attacks are usually effective but cannot be tolerated by some patients. They are contraindicated in renal failure because they decrease the glomerular filtration rate by one-third, cause fluid retention, and can be nephrotoxic.

Oral colchicine is a useful, rapidly effective alternative where NSAIDs cannot be used. The traditional dose schedules employed (1mg immediately followed by 0.5mg every 2h until symptoms improve) were associated for many with unacceptable side effects, such as abdominal cramps, nausea, and diarrhoea. It is now recognized that lower-dose schedules (500µg 2–4 times daily) are very effective while reducing the incidence of side effects very significantly.

Joint aspiration may relieve pain by reducing intra-articular tension and intra-articular corticosteroid injection is very effective in the acute stage. Oral or systemic corticosteroids may be useful in some patients for short periods, particularly in those with polyarticular problems. They may also be useful in some patients with ulcer disease because they are less gastrotoxic than NSAIDs.

Gout is a potentially curable disease but treatment may require an alteration of lifestyle as well as long-term medication. It is sensible to make dietary alterations to achieve gradual weight of possible loss and a reduction in purine intake, to reduce alcohol intake, and if possible to avoid drugs that inhibit renal clearance of urate (e.g. diuretics). Aspirin in standard analgesic doses (600–2400mg/day reduces renal urate clearance but doses used in cardiovascular prophylaxis (75–150mg daily) have no significant effect on urate levels. Such measures may be enough to prevent further attacks but more commonly hypouricaemic agents will be required.

Hypouricaemic drugs are effective in lowering plasma urate levels, reducing the frequency of acute attacks, and decreasing the size of tophi. They are indicated in patients with the following:

Allopurinol lowers uric acid levels by inhibiting xanthine oxidase and hence the final conversion of xanthine and hypoxanthine to uric acid. It should only be started once the acute attack of gout has settled for 2 weeks. Maintenance treatment with low-dose NSDAIDs or colchicine (500mcg once or twice daily) should be used for the first 3 months of any hypouricaemic therapy because of increased risk of acute attacks of gout until lowered levels of urate are established. It should be used with care and in lower doses in the elderly, in patients with renal failure and those on azathioprine. Febuxostat is another xanthine oxidase inhibitor recently introduced for gout which may be useful in cases where allopurinol has been poorly tolerated.

These are useful particularly if allopurinol is not tolerated and in subjects who are under-excretors of urate. They prevent tubular resorption of uric acid, but are ineffective in renal failure (creatinine clearance <50mL/min). They are contraindicated if there is a history of renal stones. Sulfinpyrazone (50mg twice daily to 100mg four times daily) is commonly used. Benzbromarone (50–200mg daily) can be used in patients with moderate renal impairment when other uricosuric drugs are ineffective.

As with allopurinol, the aim of hypouricaemic drugs is to maintain the serum urate level below 300µmol/L. High fluid intake is recommended in the early weeks of treatment to prevent uric acid deposition within the kidney and the formation of uric acid stones.

Human recombinant uricase is now available but has relatively limited applicability to the general treatment of gout. It is expensive, has a relatively short half-life, and requires weekly parenteral administration. It is occasionally used in the management of difficult cases or in the management of tumour lysis syndrome.

The deposition of the calcium pyrophosphate dihydrate (CPPD) in cartilage is often an age-related phenomenon that does not necessarily imply any significant underlying joint problem. It may occur in normal cartilage or in cartilage already damaged by osteoarthritis. CPPD deposition within a joint can result in an acute arthritis.

Chondrocalcinosis is uncommon in adults younger than 50 years old but occurs in up to 10% of the population over 65, increasing to 30% of those older than 85 years. Calcium pyrophosphate disease is more common in women and acute pyrophosphate arthropathy (‘pseudogout’) is the commonest cause of monoarthritis in the elderly (Box 10.3.1). An underlying metabolic abnormality is present in fewer than 10% of patients but should be sought in patients with younger onset disease.

The clinical features can mimic many different forms of arthritis; these include gout or septic arthritis, rheumatoid arthritis, osteoarthritis, Charcot joint, or even ankylosing spondylitis. Attacks of pseudogout often take longer to reach peak intensity than gout but may run a more protracted course. Larger joints, including the knees and wrists, are more frequently affected but virtually any joint may be affected. Chronic forms of pyrophosphate arthropathy have a variable pattern of joint involvement but should be particularly remembered in patients who have an unusual pattern of arthritis (e.g. ankle arthritis in the absence of injury, apparently degenerative arthritis of the metacarpophalangeal joints, or unexplained early onset arthritis).

Acute pseudogout is diagnosed by microscopic examination of synovial fluid under polarized light. Calcium pyrophosphate crystals are rhomboid shaped and weakly positively birefringent. Both septic arthritis and gout can coexist with pseudogout, so the presence of crystals does not rule out these other conditions and fluid should also be sent for Gram stain and culture to rule out infection. Repeated joint aspiration and synovial fluid examination may be necessary to confirm the diagnosis since these crystals are harder to identify than urate crystals and are also less robust if left standing prior to examination.

Radiographs often show chondrocalcinosis as fine linear calcification parallel to the subchondral bone in articular hyaline cartilage (Figure 10.3.5). In fibrocartilage, ligaments, and joint capsules, calcifications appear as diffuse punctate linear densities. However, no more than 50% of individuals with pyrophosphate arthritis exhibit chondrocalcinosis so its absence does not exclude the diagnosis.

In pyrophosphate arthropathy, radiographs often show changes of arthritis at sites not normally seen in osteoarthritis, such as the radiocarpal joint of the wrist, metacarpophalangeal joints, the talonavicular or patellofemoral joint in isolation. Erosions of the femoral cortex superior to the patella and osteonecrosis of the medial femoral condyle also point towards a diagnosis of calcium pyrophosphate disease. In the axial skeleton, intervertebral disc calcification, sacroiliac erosions, and subchondral cysts in the facet joints can occur.

An atypical arthropathy may be the first clue to an underlying metabolic disease. In patients younger than 55 years a metabolic cause should be excluded. As a minimum screen the following tests are recommended: plasma calcium (hyperparathyroidism), ferritin and iron (haemochromatosis), magnesium (hypomagnesaemia) and alkaline phosphatase (hypophosphatasia).

The principles of treatment are similar to gout; aspiration of the affected joint with injection of corticosteroids is the treatment of choice. NSAIDs at full dose, started at the onset of symptoms, are generally effective. Colchicine can also be tried but there is no effective long-term suppressive treatment known. Unfortunately, in cases where the pyrophosphate arthritis is secondary to another metabolic disorder, such as haemochromatosis, correction of the underlying metabolic disturbance (viz venesection to correct iron overload) will not prevent further progression of the arthropathy.

Basic calcium phosphate, hydroxyapatite, is the calcium-containing mineral laid down in bone, dentine, and enamel. Hydroxyapatite and several other calcium-containing minerals may be found in soft tissues, tendon calcifications, and other forms of arthritis. Collectively, these minerals are referred to as basic calcium phosphate which is associated with the following joint disorders: calcific tendinitis, acute calcific periarthritis, and apatite-associated destructive arthropathy (Figure 10.3.6).

Calcium oxalate crystals have a characteristic bipyramidal appearance and occur in effusions from patients with primary oxalosis, a rare recessive disorder, or end-stage renal failure.