Reactive Arthritis

Reactive arthritis is inflammation of the joints due to an abnormal immune response (the body’s defensive response to foreign substances) that occurs after an infection of  the genital tract, such as chlamydial infection, or of the intestinal tract, such as gastroenteritis.

If there is additional inflammation elsewhere in the body, such as in the eyes, the condition is known as Reiter’s syndrome.

Reactive arthritis in detail - technical

Reactive arthritis is a subset of postinfectious arthritis in which infection, usually of the gastrointestinal or genitourinary tracts, leads to inflammatory arthritis. Following infection, organisms or their components find their way to joints, where they provoke inflammatory immune responses. Whether the responses cross-react with self antigens is unclear; arthritis may be maintained by persistent infection. The disease commonly has specific extra-articular features not seen in other forms of postinfectious arthritis, and is genetically and pathologically a form of spondyloarthritis (see: Ankylosing spondylitis, other spondyloarthritides, and related conditions).

Clinical presentation—an acute oligoarthritis of weight-bearing joints is a common finding in secondary care, whereas community cases show mild polyarthritis. In addition to synovitis, enthesopathy is common, and extra-articular features include conjunctivitis, keratoderma, balanitis, and mouth ulcers. Urethritis can be reactive and does not necessarily indicate genitourinary infection.

Diagnosis—this depends on a careful history to determine whether there has been preceding infection, followed by examination for enthesopathy and extra-articular features in addition to joint involvement. Definitive proof requires demonstration of recent infection by a triggering organism, using serological, culture, and nucleic acid amplification techniques. In some cases, when the nature of the triggering infection cannot be established, patients may be classified as having undifferentiated spondyloarthritis (see: Ankylosing spondylitis, other spondyloarthritides, and related conditions).

Management—treatment is with symptomatic measures—nonsteroidal anti-inflammatory drugs, intra-articular steroids, and physiotherapy suffice in most cases. Severe, relapsing, or persistent disease may require methotrexate or sulfasalazine. Little evidence supports prolonged treatment with antibiotics, although chlamydial infection requires conventional short-term treatment.

Introduction and historical perspective

The term ‘reactive arthritis’ was introduced in 1969 by Aho in Finland, where the combination of a high prevalence of HLA B27 and gastrointestinal yersinia infection afforded opportunities for studying the disease. However, the condition was first recognized in the 18th and 19th centuries as an arthritis that followed dysentery or venereal disease, and there were descriptions by Hans Reiter and other contemporaries of the disease among troops affected by dysentery in the trenches of the First World War. The term ‘Reiter’s disease’ has been used extensively since that time, but should now be abandoned for several reasons: Reiter was not the first to describe the disease; he erroneously attributed it to spirochaetal infection; and the triad that makes up Reiter’s disease—arthritis, conjunctivitis, and urethritis/cervicitis—is not a clinically meaningful subgroup within reactive arthritis. The incorrect assumption that a patient with Reiter’s triad has sexually acquired reactive arthritis is particularly unhelpful.

Definition

The term ‘reactive arthritis’ is sometimes used rather loosely to cover any form of arthritis that follows infection, and then includes postviral arthritides, rheumatic fever, Lyme disease, and other forms of arthritis that do not generally share clinical features. This usage is not appropriate, and the term ‘postinfectious arthritis’ is much preferred, with this all-embracing term subdivided into different clinical syndromes, one of which is reactive arthritis (Bullet list 1). Defined in this way, reactive arthritis is seen as one of the seronegative spondyloarthritides (ankylosing spondylitis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, undifferentiated spondyloarthritis), sharing clinical and immunogenetic features with those diseases. Other postinfectious arthropathies lack these common features.

In the absence of agreed and validated diagnostic or classification criteria for reactive arthritis, Bullet list 2 presents a useful working classification of those patients who could reasonably be considered to have reactive arthritis. This takes as its starting point the classical pattern of arthritis and typical extra-articular features (Bullet list 3) that are commonly seen after infection by five organisms—salmonella, yersinia, campylobacter, Shigella flexneri, and Chlamydia trachomatis. The same clinical syndrome (i.e. arthritis and extra-articular signs) is also seen, but more rarely, following various other infections, especially of the gastrointestinal tract, e.g. by Clostridium difficile; but genitourinary infection with ureaplasma and respiratory infection with Chlamydia pneumoniae can probably also act as triggers of reactive arthritis. The other large group of patients is those who have asymmetric oligoarthritis without extra-articular features, but with definite laboratory evidence of preceding infection by one of the five major reactive arthritis-associated bacteria.

Bullet list 1 Postinfectious arthritis

  • Postviral arthritis, e.g. parvovirus
  • Poststreptococcal arthritis
  • Rheumatic fever
    • • Arthritis alone
    • • Post-neisseria arthritis
  • Lyme disease
  • Whipple’s disease
  • Reactive arthritis

Laboratory diagnosis of infection is given priority over symptoms as a classification criterion because infection may be clinically silent. Chlamydia is notorious for this, particularly in women, whilst in yersinia infection arthritis is inversely correlated with the severity of gastrointestinal symptoms. Positively identifying the triggering infection often poses practical problems. Patients in whom arthritis develops (with or without extra-articular signs) after symptomatic episodes of gastrointestinal or genitourinary infection are therefore usually regarded as having reactive arthritis, even when no triggering organism can be identified, although the diagnosis is inevitably less secure in these cases. Improvement in methods for diagnosing preceding infection should decrease the size of this group, and may show reactive arthritis to be the commonest cause of acute inflammatory oligo- or monoarthritis in young adults.

Bullet list 2 Working definition of reactive arthritis

  • Classical clinical features:
    • • Asymmetric oligoarthritis, legs predominate
    • • Enthesitis
    • • Extra-articular signs
    • • and proven infection by salmonella, campylobacter, yersinia, shigella, or Chlamydia trachomatis (whether symptomatic or not)
  • Classical clinical features and proven infection by other organisms (e.g. Clostridium difficile, Mycobacterium bovis BCG)
  • Any acute inflammatory arthritis (including monoarthritis) and proven infection by reactive arthritis-associated bacteria
  • Classical clinical features and preceding diarrhoea or urethritis/cervicitis, infection not proven

Bullet list 3 Extra-articular features and their occurrence in other forms of spondyloarthritis

  • Eyes
    • • Conjunctivitis
    • • Uveitis (ankylosing spondylitis and inflammatory bowel disease)
  • Skin and mucous membranes
    • • Oral ulceration
    • • Circinate balanitis
    • • Keratoderma blennorrhagica (psoriasis)
    • • Nail dystrophy (psoriasis)
    • • Erythema nodosum (inflammatory bowel disease)
  • Cardiac
    • • Aortitis (ankylosing spondylitis)
    • • Conduction defects (ankylosing spondylitis)

Epidemiology

Community studies in Scandinavia, where HLA B27 is present in around 12% of the population (compared with 6–7% elsewhere in Europe), have suggested an incidence of 40 to 50 cases/million for each of the endemic organisms (chlamydia, campylobacter). The lower figure of 1.3/million for shigella probably represents a similar incidence to other organisms, as almost all cases were acquired by travellers. Incidence has also been studied in single outbreaks of food poisoning, in which the proportion of infected patients developing arthritis can be accurately assessed. However, in such studies the proportion who develop reactive arthritis varies widely (0–21%). By contrast, careful population studies of campylobacter infection have shown a high incidence (7–16%) of musculoskeletal symptoms not severe enough to require secondary care. The influence of HLA B27 on incidence is important: 60 to 80% of patients with reactive arthritis presenting to rheumatology clinics are positive for HLA B27, whereas among those with mild disease the figure drops to 30% or lower. HLA B27 seems to be associated mainly with the severity and persistence of arthritis, rather than its incidence.

Pathogenesis

There is considerable evidence that organisms reach the joints following infection of the gut or genitourinary tract. They may arrive intact, when they can be detected using the polymerase chain reaction (PCR), or as antigenic material (proteins, lipopolysaccharide) that can be demonstrated in synovial macrophages and polymorphs using organism-specific antibodies. This process can continue for months or even years, suggesting that some of the infections, e.g. yersinia, persist such that antigens/organisms continue to reach the joint. Elevated and persistent titres of IgA antibody to these organisms in reactive arthritis compared with uncomplicated infection also favour the idea of persistence. A clear distinction between septic and postinfectious arthritis is no longer possible, as viable organisms can be detected in the joint in various forms of postinfectious arthritis, including Lyme disease and reactive arthritis. However, an important distinction is that in postinfectious arthritis the organisms in synovium or synovial fluid are noncultivable (although viable), and antibiotics generally do not influence the course of disease (see below).

Within the joint, cellular immune responses to the bacteria responsible for triggering reactive arthritis are readily detected, particularly responses by CD4+ helper T lymphocytes, but also CD8+ T cells. Interestingly, although the association with HLA B27 is often taken to imply that CD8+ T cells are the principal effector cells in the disease, HIV-positive patients with reactive arthritis present during stage I infection, when numbers of CD4+ T cells are less depressed. By contrast, arthritis can be relatively quiescent in full-blown AIDS. Both CD4+ and CD8+ lymphocytes produce proinflammatory cytokines such as interferon-γ and interleukin 17 that can drive joint inflammation by secondary effects on synoviocytes.

How does HLA B27 influence the course of reactive arthritis—particularly its severity and persistence? It has been proposed that infection generates a B27-restricted response by CD8+ T cells to a bacterial peptide that cross-reacts with a component of the joint, i.e. infection triggers autoimmunity by ‘molecular mimicry’. However, no such autoimmune response has yet been demonstrated. Alternatively, HLA B27 may adversely affect the efficiency with which the immune system clears the triggering organism. In this case disease does not require autoimmunity but is primarily driven by persistent bacterial antigens. Lastly, HLA B27 might affect the immune response to the triggering organism qualitatively, e.g. by allowing hyper-responsiveness to particular antigens, or biasing the immune response in favour of the production of proinflammatory cytokines.

Clinical features

Preceding illness

A history of urethritis (dysuria or discharge) and diarrhoea must be sought specifically, as patients do not automatically link these occurrences with their arthritis. The interval between infection and arthritis is variable but not usually more than 3 weeks. By the time a rheumatologist is consulted, many weeks may have passed and the triggering illness forgotten, particularly if symptoms were mild. Note that urethritis may be triggered by gastrointestinal infection: minimally symptomatic gastrointestinal infection and prominent urethritis may cause diagnostic confusion if this possibility is forgotten.

Arthritis

The classical clinical picture in reactive arthritis is an asymmetric oligoarthritis (generally fewer than six joints), predominantly affecting the legs (Bullet list 4). However, any joint can be affected, and some patients have monoarthritis only. Affected joints are often hot and markedly swollen, with septic arthritis and crystal-induced arthritis being the most likely differential diagnoses. Dactylitis, similar to that seen in psoriatic arthritis, also occurs. Many patients describe low back or buttock pain, suggesting involvement of the sacroiliac joint. Arthritis is usually at its worst early in the course of the disease, but new sites can be affected after several months and relapses are not uncommon, even in those in whom disease eventually settles completely. The presence of enthesitis (inflammation of ligamentous and tendinous insertions) in addition to arthritis is helpful diagnostically, with plantar fasciitis and involvement of the Achilles tendon insertion the commonest sites.

Bullet list 4 Pattern of joint involvement in reactive arthritis

  • Oligo- or monoarthritis
    • • Asymmetric
    • • Predominantly legs
  • Coexisting enthesitis or reactive enthesopathy alone
  • Sacroiliac joint involvement
  • Inflammatory back pain
  • Polyarthritis (mild)

The features described above are commonly seen in secondary care, but the milder cases detected in community surveys commonly have polyarthritis, whereas some have only inflammatory back pain or an enthesopathy such as reactive tendonitis.

Extra-articular features

In acute severe disease patients have constitutional symptoms of malaise, fatigue, and fever. More useful diagnostically are the specific extra-articular signs listed in bullet list 3 above. The fact that these extra-articular features are common to other forms of spondyloarthritis greatly strengthens the case for including reactive arthritis in this disease family, and for defining reactive arthritis as a distinct postinfectious syndrome.

Extra-articular features are more common in those with severe joint involvement. Conjunctivitis is often transient and no longer present by the time the patient presents. More persistent eye inflammation or painful eyes should raise the question of an acute anterior uveitis rather than a simple conjunctivitis and prompt full ophthalmological assessment. Circinate balanitis is usually asymptomatic and needs to be specifically sought in uncircumcised males. Oral ulceration is usually asymptomatic. Keratoderma blennorrhagica is histologically identical to psoriasis; it is most commonly seen on the soles of the feet, but can also involve the hands or trunk, and psoriaform nail changes are also seen. Erythema nodosum is associated with yersinia infection, but is otherwise uncommon in reactive arthritis. Aortitis and cardiac conduction disorders are rare.

Differential diagnosis

The differential diagnosis of reactive arthritis is summarized in Bullet list 5 below. The principal concerns in acute disease are septic arthritis, crystal arthropathies, and other forms of postinfectious arthritis such as Lyme disease, poststreptococcal arthritis, or gonococcal arthritis. In chronic disease it may be difficult to distinguish reactive arthritis from other forms of spondyloarthritis, especially in those with inflammatory bowel disease, and many patients in whom no infectious trigger can be implicated can be classified as having an undifferentiated spondyloarthritis.

General

The principal aims of investigation are to exclude important differential diagnoses and to identify the triggering organism. Abnormalities in the early stages, when arthritis is most active, are those of a pronounced acute inflammatory response—raised ESR and C-reactive protein, the latter often very marked (>100 mg/litre). Rheumatoid factor and antinuclear antibodies are absent. Positive antineutrophil cytoplasmic antibodies have been described, but the antibodies are not directed against proteinase-3 or myeloperoxidase and the test is not diagnostically useful. Septic arthritis and crystal arthropathies are best excluded by aspiration of synovial fluid followed by culture and microscopy. Blood cultures should be performed and serum urate checked. A chest radiograph may reveal hilar lymphadenopathy, suggesting the diagnosis of sarcoidosis, although yersinia can cause both reactive arthritis and a sarcoid-like illness. Throat swab and antibodies to streptococcal antigens may point to poststreptoccocal arthritis, which does not share extra-articular features with reactive arthritis. In endemic areas, Lyme disease should be considered and antibodies to Borrelia burgdorferi measured.

Microbiological

Stool should be cultured for pathogens associated with reactive arthritis, although cultures are often negative after gastrointestinal symptoms have settled—despite the recent evidence that persistent infection contributes to pathogenesis. Chlamydia infection must be sought in sexually active patients with new partners, particularly when there is no history of gastroenteritis. Formal referral to a department of genitourinary medicine is often helpful. Patients are not infrequently infected with both chlamydia and gonococcus. This can cause confusion, but gonococcal arthritis differs from reactive arthritis with its characteristic rash and absence of classical extra-articular features. Chlamydia can be cultured from urethral or cervical swabs or from urine, and chlamydia antigens can be demonstrated by enzyme-linked immunosorbent assay techniques or by direct immunofluorescence tests. The latter are highly sensitive, in principle able to detect one organism per smear, but require skilled technicians. PCR techniques achieve similar sensitivity and can be applied to urine specimens, which is useful in patients understandably reluctant to undergo urethral and vaginal instrumentation in the investigation of their arthritis.

Bullet list 5 Differential diagnosis of reactive arthritis

  • Septic arthritis
  • Postinfectious arthritis
    • • Lyme disease
    • • Poststreptococcal or neisseria infection
    • • Viral arthritis
  • Crystal arthropathies
  • Other forms of spondyloarthritis
  • Behçet’s
  • Sarcoidosis
  • Trauma, sports injury

Spondyloarthritis in the context of HIV infection also needs to be considered, although this is rare in developed countries. By contrast, many cases of reactive arthritis, often related to dysentery, have recently emerged among the HIV-infected population in sub-Saharan Africa, where the disease was previously unknown. HIV testing should be considered, particularly in patients with unusually severe disease and relevant risk factors.

Immunological

When the triggering organism cannot be demonstrated directly, infection can be inferred on the basis of immune responses. However, this evidence needs to be interpreted cautiously, as in many cases the findings simply imply immunological memory for the organism in question and do not demonstrate a clear relationship between infection and arthritis. For enteric pathogens, specific IgM antibodies may be demonstrated and these, along with IgG, form the basis of the agglutination tests that are widely used. Rising IgG titres may also be helpful. However, when patients present several months into their illness, IgM may no longer be evident and IgG titres stable. In these circumstances high and persistent IgA titres to organisms such as salmonella and yersinia may be useful. Serological diagnosis of chlamydia infection is particularly difficult because of high community levels of infection with Chlamydia pneumoniae, an organism that shares several highly conserved antigens with Chlamydia trachomatis.

Lastly, cellular immune responses to triggering organisms can be demonstrated, particularly in the synovial fluid. Again, these demonstrate only T-cell memory for the organism and do not demonstrate causality—patients with, e.g., rheumatoid arthritis and incidental salmonella infection will have salmonella-specific T cells in their synovial fluid. Such tests are currently used in research rather than diagnostically.

Radiological

Radiological investigations are not diagnostically helpful in the acute stages of disease, with soft tissue swelling and occasionally periarticular osteoporosis at affected joints being the only abnormalities. Radionuclide scintigraphy can demonstrate acute sacroiliitis and may show the full extent of acute synovitis and enthesitis, but is not usually required for clinical management. Radiological changes are confined to the few patients with persistent disease (>1 year duration), with the principal features being erosion of affected joints, including the sacroiliac, and new bone formation manifested as periostitis of metatarsal and metacarpal bones and ‘enthesophytes’, such as plantar spurs. In the spine paravertebral ossification can be seen in the lumbar region: this is asymmetric and differs from the classical changes of ankylosing spondylitis. Erosive changes are also seen at sites of enthesitis such as the calcaneum.

Treatment

Evidence-based therapies for reactive arthritis are lacking, and consensus opinion is the current guide. In the acute phase, affected joints should be rested until they improve substantially. This often needs emphasizing to young, active patients involved in sports, and alternative forms of exercise should be considered. Physiotherapy and advice on exercise is helpful, with quadriceps function needing particular attention in view of the frequent involvement of the knees. Synovial effusions should be aspirated and, when septic arthritis has been excluded, will respond well to injection with long-acting corticosteroids. If chlamydia infection is established or thought likely, patients require conventional treatment with short-term antibiotics, but there is little evidence that this has any effect on the progress of reactive arthritis. Enteric infections do not require antibiotics in their own right, and the arthritis does not respond to antibiotics (see below). Uveitis requires formal ophthalmological assessment and treatment with local steroids.

There are two major unresolved treatment issues in reactive arthritis. Firstly, the place of disease-modifying drugs: sulfasalazine and methotrexate are useful in other forms of spondyloarthritis, and on this basis have been used in reactive arthritis, but without controlled trials confined to this condition (because the disease is often self-limiting, controlled trials of second-line agents are difficult to perform). The second issue is whether long-term antibiotics confer any benefit. In a controlled trial in 1991, a subset of patients with evidence of chlamydia infection benefited from prolonged lymecycline, but subsequent trials using ciprofloxacin and azithromycin have been negative. It may be that organisms in the joint, being in an uncultivable state, are also not susceptible to antibiotics, most of which affect bacterial cell division. A very recent (2009) trial suggests that a combination of rifampicin and doxycycline or azithromycin may be useful in chronic reactive arthritis.

Psychological and quality of life issues

Reactive arthritis commonly affects young fit adults who have not previously experienced any form of prolonged illness or disability. The danger is that the rheumatologist, all too used to the relatively gloomy prognosis of rheumatoid arthritis, may treat reactive arthritis, where there is a high likelihood of complete resolution of disease, too lightly. Patients need to be given a realistic prognosis, i.e. that symptoms may well persist at some level for 6 to 12 months, although in the latter stages these are usually very mild compared with those experienced in the first 4 to 8 weeks. Exacerbations during this time are not uncommon and do not imply that the disease will not eventually resolve. The chances of the patient developing chronic arthritis are less than 10%. Patients benefit from continuing psychological and clinical support throughout the course of their illness, with rapid access to joint aspiration and intra-articular steroid injection when there is recurrent joint swelling.

Areas of uncertainty

Current uncertainties concern classification criteria and management strategies. Both may be resolved by developing more secure diagnostic techniques for identifying the triggering infection. Improved treatment is likely to come from either (1) additional evidence about the importance of persistent infection and how to eliminate it, or (2) discovery of the immune responses responsible for maintaining joint inflammation, whether these are directed against a bacterial antigen or an autoantigen. If a target antigen can be identified, specific immunomodulation strategies would become relevant.

Reactive arthritis differs from other forms of inflammatory arthritis in having a clearly defined onset and being triggered by known infectious agents. Genetic influences that result in a minority of infected individuals developing arthritis are being investigated. These include HLA B27, but it is likely that other genes are also involved. Genome screening now being applied to ankylosing spondylitis may throw up candidates that also play a role in reactive arthritis.

Further reading

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Reviews of pathogenesis

Gaston JSH (2000). Immunological basis of chlamydia induced reactive arthritis. Sex Transm Infect, 76, 156–61.

Sieper J, Braun J (1995). Pathogenesis of spondylarthropathies: persistent bacterial antigen, autoimmunity, or both? Arthritis Rheum, 38, 1547–54.

Incidence following enteric infection

Fendler C, et al. (2001). Frequency of triggering bacteria in patients with reactive arthritis and undifferentiated oligoarthritis and the relative importance of the tests used for diagnosis. Ann Rheum Dis, 60, 337–43.

Gaston JSH (2005). Shigella induced reactive arthritis. Ann Rheum Dis, 64, 517–8.

Hannu T, et al. (2002). Campylobacter-triggered reactive arthritis: a population-based study. Rheumatology (Oxford) 41, 312–8.

Hannu T, et al. (2005). Reactive arthritis attributable to Shigella infection: a clinical and epidemiological nation-wide study. Ann Rheum Dis, 64, 594–8.

Evidence that bacteria or bacterial antigens reach the joint in reactive arthritis

Gaston JSH, Cox C, Granfors K (1999). Clinical and experimental evidence for persistent Yersinia infection in reactive arthritis. Arthritis Rheum, 42, 2239–42.

Gerard HC, et al. (1998). Synovial Chlamydia trachomatis in patients with reactive arthritis/Reiter’s syndrome are viable but show aberrant gene expression. J Rheumatol, 25, 734–42. 

Granfors K, et al. (1989). Yersinia antigens in synovial fluid cells from patients with reactive arthritis. New Engl J Med, 320, 216–21.

Granfors K, et al. (1990). Salmonella lipopolysaccharide in synovial cells from patients with reactive arthritis. Lancet, 335, 685–8.

Immune responses in reactive arthritis

Gaston JSH, et al. (1989). Synovial T lymphocyte recognition of organisms that trigger reactive arthritis. Clin Exp Immunol, 76, 348–53. 

Granfors K, Toivanen A (1986). IgA-anti-yersinia antibodies in yersinia-triggered reactive arthritis. Ann Rheum Dis , 45, 561–5.

Hermann E, et al. (1993). HLA-B27-restricted CD8 T-cells derived from synovial fluids of patients with reactive arthritis and ankylosing spondylitis. Lancet, 342, 646–50.

Reactive arthritis and other spondyloarthritis in HIV infection

Njobvu P, McGill P (2005). Human immunodeficiency virus related reactive arthritis in Zambia. J Rheumatol, 32, 1299–304.

Treatment in reactive arthritis

Dougados M, et al. (1995). Sulfasalazine in the treatment of spondylarthropathy: a randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheum, 38, 618–27.

Kvien TK, Gaston JSH, et al. (2004). Three month treatment of reactive arthritis with azithromycin: a EULAR double blind, placebo controlled study. Ann Rheum Dis, 63, 1113–9.

Lauhio A, et al. (1991). Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis with special reference to chlamydia arthritis. Arthritis Rheum, 34, 6–14.

Sieper J, et al. (1999). No benefit of long-term ciprofloxacin treatment in patients with reactive arthritis and undifferentiated oligoarthritis—a three-month, multicenter, double-blind, randomized, placebo-controlled study. Arthritis Rheum, 42, 1386–96.

Wakefield D, et al. (1999). Ciprofloxacin treatment does not influence course or relapse rate of reactive arthritis and anterior uveitis. Arthritis Rheum, 42, 1894–7.

Yli-Kerttula T, et al. (2000). Effect of a three month course of ciprofloxacin on the outcome of reactive arthritis. Ann Rheum Dis, 59, 565–70.

Yli-Kerttula T, et al. (2003). Effect of a three month course of ciprofloxacin on the late prognosis of reactive arthritis. Ann Rheum Dis, 62, 880–4.