Epidemiologic approaches to infection and immunity: the case of reactive arthritis

Sherry Rohekar and Janet Pope

Department of Rheumatology, St Josephs Healthcare, London, Ontario, Canada Correspondence to Dr Sherry Rohekar, Department of Rheumatology, St Josephs Healthcare, 268 Grosvenor Street, London, ON N6A 4V2, Canada Tel: +1 519 646 6242; fax: +1 519 646 6348; e-mail: sherry.rohekar@sjhc.london.on.ca Current Opinion in Rheumatology 2009, 21:386390

Purpose of review There is signicant evidence that infection and arthritis are linked, but the nature of this association is unclear. The goal of this review is to examine the case of reactive arthritis (ReA), an inammatory arthritis with a clear infectious trigger. We will rst examine the current state of knowledge of ReA epidemiology and follow it with a discussion of the epidemiologic challenges that ReA studies face. Recent ndings Recent studies have examined outbreaks of gastroenteritis to try and elucidate the epidemiology of ReA. Some have found higher levels of self-reported arthritis than previously thought, and others have implicated organisms such as Escherichia coli O157:H7 that were not traditionally associated with ReA. There is also evidence that the severity of initial infection may be associated with a higher relative risk of developing ReA. New population-based studies have further claried the natural history of infection and subsequent ReA, demonstrating the power of community surveillance. Despite these ndings, several methodological issues complicate the study of ReA. Problems include lack of standard diagnostic criteria, varying culture methods, selection bias and difculties in establishing a control population. Summary Recent studies have continued to increase our knowledge of the epidemiology of ReA. Addressing the multiple challenges that face the study of infection and arthritis will be very useful for future study. Keywords arthritis, epidemiology, infection, methodology, reactive arthritis
Curr Opin Rheumatol 21:386390 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-8711

Introduction
Epidemiologists strive to understand the factors and determinants of health events in large populations, with the goal of applying this knowledge toward the reduction of disease burden. Many practical barriers prevent the study of the epidemiology of infection as it relates to arthritis, such as heterogeneity in populations and arthritis types. Studies are often not directly comparable to each other due to differences in methodology. Despite these barriers, much can still be learned about the relationship between infection, autoimmune response and arthritis.

or genitourinary tract. The most common triggers are Yersinia, Salmonella, Shigella and Campylobacter [1]. ReA is usually grouped with the seronegative spondyloarthropathies (SpA) due to similarities in clinical presentation [13]. Patients typically present with an asymmetric monoarthritis or oligoarthritis of the lower extremities [13]. They may also have sacroiliitis, back pain and extraarticular features such as enthesitis, rash and ocular inammation [13]. Some patients will completely resolve their arthritic symptoms; a proportion will progress to chronic disease [13]. Table 1 [4] summarizes the common clinical features of ReA. There is signicant evidence that the inciting infection and the arthritis are indeed linked. Microbial DNA and RNA of the triggering organism can be retrieved from the sites of inammation, including synovial uid [2,3,5,6]. There is also evidence that host factors, particularly the presence of HLA-B27, play an important role in the pathogenesis of ReA [24,6]. However, these simple factors of antecedent infection in a genetically predisDOI:10.1097/BOR.0b013e32832aac66

Background
The complex path from infection to autoimmune arthritis can be studied by examining reactive arthritis (ReA), an inammatory arthritis with a clear infectious trigger. ReA is typically dened as a sterile synovitis that occurs after an infection at a distant site, usually the gastrointestinal
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Epidemiologic approaches to infection and immunity Rohekar and Pope 387

Table 1 Common clinical manifestations of reactive arthritis System Musculoskeletal Manifestation Arthralgia Arthritis Enthesitis Dactylitis Osteitis/hyperostosis Keratoderma blennorrhagica Psoriasiform Oral ulcers Nail dystrophy Erythema nodosum Conjunctivitis Uveitis Episcleritis Corneal ulcers Circinate balanitis Sterile urethritis Prostatitis Cystitis Cervivitis Salpingo-oophoritis

Mucocutaneous

Most patients present with an asymmetrical oligoarthritis of the lower extremities, but up to 20% may have an inammatory polyarthritis [10]. Inammatory back pain (40% of patients), enthesitis (20%) and ocular inammation (10%) are also common [10]. Approximately half of those affected will be free of symptoms by 6 months, but 20% may proceed to a chronic course [10]. One large study [12] found objective physical ndings on joint examination of those with ReA 5 years after disease onset. A wide variety of organisms have been implicated in ReA; the most common triggers in the developed world include Chlamydia, Salmonella, Shigella and Yersinia [2,4]. One study [13] found that either Chlamydia trachomatis, Yersinia or Salmonella was identied as the triggering bacterium in about 50% of patients with probable or possible ReA. More recent data from outbreak sources indicate that Campylobacter and possibly Escherichia coli O157:H7 are also signicant triggers of ReA [11,14]. However, a causative organism is detected in only 56% of those diagnosed with ReA, even when sought in those with typical symptoms of a gastrointestinal or genitourinary infection [13]. Even fewer pathogens (47%) are identied in those who present clinically with undifferentiated oligoarthritis that is compatible with ReA but lacks an infectious prodrome [13]. Several recent studies have examined outbreaks to try and elucidate the epidemiology of ReA. A survey of the victims of a large outbreak of Salmonella enteritidis in Canada demonstrated a high rate of self-reported symptoms consistent with ReA (62.5% of respondents, 11.5% of those infected) [15]. In this study, the most commonly reported extraintestinal symptoms of the Salmonella outbreak included joint pain, swelling or stiffness (46.2%), morning stiffness more than 30 min (35.6%) and inammatory eye symptoms (24.0%) [15]. A few (19.2%) patients reported visible joint swelling [15]. Interestingly, the incidence of HLA-B27 was the same in those with ReA compared with those without, though HLA-B27 was present more frequently in those who were infected than in healthy controls [odds ratio (OR) 3.0] [15]. This contrasts with previous outbreak studies, which show a trend toward increased joint damage, a greater number of affected joints and enthesitis in those who were HLA-B27-positive [12]. A further analysis of genetic samples obtained from the participants in the

Ocular

Urogenital

Adapted from [14].

posed individual do not tell the full story of ReA as seen in the rheumatology clinic. In this review, we will rst examine the current state of knowledge of epidemiology of ReA and follow it with a discussion of the epidemiologic challenges that ReA studies face.

Epidemiology of reactive arthritis

The annual incidence of ReA is usually estimated at 30 40 cases per 100 000 people and the prevalence 17% [7,8,9]. ReA occurs 16 weeks after a preceding enteric or urogenital infection [10]. The risk of developing ReA after such an infection is 14%, but is substantially increased to 2025% in those who carry HLA-B27 [10]. HLA-B27 is an important factor in the presentation of ReA, but it varies widely between ethnicities [10]. Recent research has indicated that there may be a dose response effect, with those suffering from more severe initial infection more likely to develop arthritis [11]. Table 2 demonstrates the increased relative risk of selfreported arthritis in those with no, moderate and severe symptoms of gastroenteritis [11]. The accuracy of these prevalence, incidence and risk estimates is questionable due to several practical barriers to research, to be discussed later.

Table 2 Results from a study of an outbreak of Campylobacter and Escherichia coli O157:H7 demonstrating that more severe gastrointestinal symptoms were associated with an increased relative risk of self-reported arthritis Severity of gastroenteritis during outbreak None Moderate Severe Self-reported arthritis (%), age and sex-standardized 15.7 17.6 21.6 Crude RR (95% CI) 1.00 (reference) 1.18 (0.981.43) 1.34 (1.071.66) Age and sex-adjusted RR (95% CI) 1.00 (reference) 1.19 (0.991.43) 1.33 (1.071.66)

CI, condence interval; RR, relative risk. Modied with permission from [11].

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388 Infectious arthritis and immune dysfunction

most recent study [16] revealed that genetic variants of Toll-like receptor 2 (TLR-2) were signicantly associated with acute ReA. Another Canadian outbreak, this time of Campylobacter jejuni and E. coli O157:H7, was studied prospectively for 4.5 years for participants self-report of chronic arthritis [11]. This study examined both patients with reported gastroenteritis and those who were asymptomatic [11]. Compared with those who were asymptomatic, people with moderate gastrointestinal symptoms had an adjusted relative risk of arthritis of 1.19 [95% condence interval (CI) 0.991.43] [11]. The relative risk was higher in patients who reported severe diarrhea (1.33, 95% CI 1.071.66). Interestingly, rates of prescription medications for arthritis did not seem to associate with gastroenteritis, but those with dysentery may have a relative contraindication to NSAIDs [11]. Some studies rely on follow-up of community-reported disease, rather than sporadic outbreaks. One study [17] retrospectively analyzed a cohort with gastroenteritis in Sweden over a period of 7 years and standardized incidence ratios (SIRs) were calculated by dividing the observed number of cases of ReA by the expected number of cases. Within 1 year, patients with Yersinia infections had an elevated risk of ReA (SIR 47.0, 95% CI 21.589.2). Smaller but still substantial increases in SIR for ReA were found in patients with Salmonella (SIR 18.2, 95% CI 12.026.5) and Campylobacter enteritis (SIR 6.3, 95% CI 3.510.4) [17]. Other musculoskeletal complications of enteric infection included septic arthritis and osteomyelitis [17]. In another population-based study [18], an American telephone interview series was recently conducted on those with culture-conrmed enteric infections (Campylobacter, E. coli O157:H7, Salmonella, Shigella and Yersinia). In this study, 13% of respondents developed symptoms compatible with ReA, with the most common symptoms including new joint pain (56%), new low back pain (44%) and new morning stiffness (32%) [18]. Fifteen percent of those with rheumatic complaints sought healthcare for their new arthritic symptoms; in fact, 6% were formally diagnosed with ReA [18]. The incidence of ReA was highest after infection with Campylobacter (2.1/100 000) and Salmonella (1.4/100 000) [18]. The investigators were able to actually take rheumatologic histories and perform physical examinations on a subset of 82 patients [18]. Of this subset, 66% were conrmed to have ReA by a rheumatologist, with enthesitis being the most common physical nding (88.8%) [18]. A smaller but still substantial proportion of patients were found to have peripheral joint arthritis (19%) [18]. This large population-based study found no association between ReA and HLA-B27, but did nd

that arthritis correlated with increased severity of initial infection [18]. A recent study in Denmark [14] also found a signicant association between the severity of the initial gastroenteritis and the development of ReA. In this study, 14% of individuals affected by gastroenteritis developed symptoms of ReA by survey self-report [14]. A subset of respondents were clinically examined; 21% had objective synovitis, 42% had ndings compatible with ReA and 37% had symptoms not related to ReA [14]. The OR for ReA in an HLA-B27-positive individual was 2.62 (95% CI 1.673.93) [14]. Thus, there appears to be controversy on whether HLA-B27 is associated with community ReA [12,14].

Epidemiologic challenges in reactive arthritis research

The recent studies detailed above are thoughtful approaches to elucidating the epidemiology of ReA. However, ReA is not a clinical entity that is simple to study and its epidemiologic characterization is fraught with problems. In fact, even a standard denition of ReA may be lacking. As one author eloquently wrote, ReA occupies the conceptual ground somewhere between septic arthritis and the classic autoimmune rheumatic diseases such as rheumatoid arthritis [6]. One of the greatest challenges facing researchers is that there is no single dened set of criteria for the clinical diagnosis of ReA. The American College of Rheumatology (ACR) classication criteria for ReA are based on a 1981 study of the percentage sensitivity and specicity of various criteria for typical Reiters syndrome [19,20]. In this framework, a denition of an episode of arthritis of more than 1 month with urethritis and/or cervicitis has a specicity of 98.2% and sensitivity of 84.3% [19]. However, a large proportion of those with gastrointestinal or genitourinary infection can remain completely asymptomatic, with only subclinical disease. Some may not remember the occurrence of mild extraarticular symptoms (recall bias). In these individuals, ReA may present only as a chronic undifferentiated oligoarthritis. Because of these conundrums in classication, studies vary widely in their inclusion and exclusion criteria; furthermore, subsets of those with ReA are likely not included due to lack of classical symptoms. These issues predispose studies of ReA to self-selection bias, wherein more severely affected individuals are more likely to participate. A further challenge to the study of ReA is the lack of a single diagnostic test for the inciting infectious organism. Stool cultures vary between centers and are often negative by the time patients present with their arthritic symptoms. The measure of antibody levels to pathogenic

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Epidemiologic approaches to infection and immunity Rohekar and Pope 389

organisms is complicated by high rates of positivity in control populations [21]. Crossreactivity with other species may also occur; some tests for Chlamydia do not differentiate between C. trachomatis and the common C. pneumoniae [3]. Even the results of PCR techniques to identify organisms in the genitourinary tract or directly from synovial uid vary greatly between centers [21]. Diagnostic difculties are amplied when host properties are considered, such as the presence or absence of HLAB27 and its subgroups [21]. Populations vary signicantly in their baseline prevalence of HLA-B27, from 4 to 53% [1]. Additionally, we now have the ability to examine increasingly more specic patient properties, such as the use of genotyping to detect variants in TLRs [16]. Some of these issues in diagnosis have been carefully explored in a review article by Sieper et al. [21], who calculated a series of posttest probabilities for the diagnosis of ReA following a variety of diagnostic tests. Another issue complicating ReA research is that of setting. The prevalence of pathogens varies greatly from country to country, and between communities, and frequently changes with time. For example, gastroenteritis due to Yersinia infection is common in parts of Europe, but rare in North America [21]. This makes direct comparison between studies difcult. Studies conducted in hospitals are prone to selection or referral bias, wherein included patients are more likely to have severe or prolonged disease. Outbreaks afford a unique opportunity to investigators interested in studying ReA. By prospectively studying those affected by point-source infections, investigators can minimize ascertainment bias, in which patients associate prior noninfectious gastrointestinal or genitourinary symptoms with their arthritis [15]. Unfortunately, outbreak studies are often difcult to conduct practically. Due to cost and practicality, it is difcult to have the arthritis assessed by a physician; most studies rely on patients self-report. Again, patients with more severe disease may be more likely to respond. In the case of some recent outbreaks, the possibility of class-action lawsuits against companies with contaminated food products may affect study participation. It is difcult to ascertain the true number of exposed individuals in any outbreak, thus making it difcult to establish a true sampling frame of those affected and controls. Additional problems include accessing patient records in outbreaks (often protected by privacy legislation) and obtaining timely ethics approval to conduct the study [15]. Finally, it is possible that ReA encompasses a constellation of different diseases rather than a unied entity. Arthritis triggered by urinary infections may be clinically signicantly different from those with gastrointestinal

origins. Several studies [3,6,21] have suggested that antibiotics may be effective in genitourinary Chlamydiainduced ReA, but not after a gastroenteritis.

Conclusion
ReA typies the complexities involved in studying disease processes in which the interplay between genetics and environment is critical. ReA, by denition, involves an infectious trigger and an inammatory musculoskeletal outcome, but the intermediate steps of autoimmune reaction remain elusive. Recent studies have continued to increase our knowledge of the epidemiology of ReA. These studies include outbreak research and large population-based cohorts. Many suggest [9,11,12,15,17,18] that ReA may be a fairly common consequence of genitourinary or gastrointestinal infection. Organisms previously overlooked as triggers, such as E. coli H7:O157, are emerging as potential arthritic pathogens [11]. With recent trends to treat undifferentiated arthritis early, ReA is an important clinical consideration for any rheumatologist. There are great challenges that face the study of ReA. The establishment of a clear set of diagnostic criteria would be a great benet and should be the focus of further discussion. Establishing widely accepted diagnostic criteria would allow researchers studying diverse populations to compare their results more directly with those of other centers. This consistency would simplify the goal of fully understanding which determinants of health may be used to reduce the burden of autoimmune inammatory arthritis.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:  of special interest  of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 430). 1 2 3 Hill Gaston JS, Lillicrap MS. Arthritis associated with enteric infection. Best Pract Res Clin Rheumatol 2003; 17:219239. Toivanen A, Toivanen P. Reactive arthritis. Best Pract Res Clin Rheumatol 2004; 18:689703. Colmegna I, Cuchacovich R, Espinoza LR. HLA-B27-associated reactive arthritis: pathogenetic and clinical considerations. Clin Microbiol Rev 2004; 17:348369. Toivanen A, Toivanen P. Reactive arthritis. Curr Opin Rheumatol 2000; 12:300305. Kim TH, Uhm WS, Inman RD. Pathogenesis of ankylosing spondylitis and reactive arthritis. Curr Opin Rheumatol 2005; 17:400405. Inman RD. Mechanisms of disease: infection and spondyloarthritis. Nat Clin Pract Rheumatol 2006; 2:163169. Hochberg MC, Silman AJ, Smolen JS, et al., editors. Rheumatology. 3rd ed. London: Mosby; 2003.

4 5 6 7

8 Pope JE, Krizova A, Garg AX, et al. Campylobacter reactive arthritis: a  systematic review. Semin Arthritis Rheum 2007; 37:4855. An excellent review of the literature on the epidemiology of Campylobacterassociated ReA.

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390 Infectious arthritis and immune dysfunction

9 Soderlin MK, Borjesson O, Kautiainen H, et al. Annual incidence of inammatory joint diseases in a population based study in southern Sweden. Ann Rheum Dis 2002; 61:911915. 15 Rohekar S, Tsui FW, Tsui HW, et al. Symptomatic acute reactive arthritis after  an outbreak of Salmonella. J Rheumatol 2008; 35:15991602. Outbreak study demonstrating high rates of self-reported ReA after Salmonella infection. 16 Tsui FW, Xi N, Rohekar S, et al. Toll-like receptor 2 variants are associated  with acute reactive arthritis. Arthritis Rheum 2008; 58:34363438. This study showed that genetic variants of TLR-2, but not TLR-4, were associated with acute ReA after infection with Salmonella. 17 Ternhag A, Torner A, Svensson A, et al. Short- and long-term effects of  bacterial gastrointestinal infections. Emerg Infect Dis 2008; 14:143148. Population-based study that calculated SIRs for ReA with Yersinia, Salmonella and Campylobacter infections. 18 Townes JM, Deodhar AA, Laine ES, et al. Reactive arthritis following culture conrmed infections with bacterial enteric pathogens in Minnesota and Oregon: a population-based study. Ann Rheum Dis 2008; 67:16891696. Large population-based study of ReA after Salmonella, Shigella and Yersinia infections in the United States. 19 Willkens RF, Arnett FC, Bitter T, et al. Reiters syndrome: evaluation of preliminary criteria for denite disease. Arthritis Rheum 1981; 24:844849. 20 American College of Rheumatology. 2009. www.rheumatology.org.  Includes the current ACR classication criteria for ReA. 21 Sieper J, Rudwaleit M, Braun J, van der Heijde D. Diagnosing reactive arthritis: role of clinical setting in the value of serologic and microbiologic assays. Arthritis Rheum 2002; 46:319327.

10 Sieper J, Rudwaleit M, Khan MA, Braun J. Concepts and epidemiology of spondyloarthritis. Best Pract Res Clin Rheumatol 2006; 20:401 417. 11 Garg AX, Pope JE, Thiessen-Philbrook H, et al., Walkerton Health Study  Investigators. Arthritis risk after acute bacterial gastroenteritis. Rheumatology (Oxford) 2008; 47:200204. A study of a large community outbreak of E. coli O157:H7 and Campylobacter with 4.5 years of follow-up. Demonstrated that those with more severe diarrheal symptoms had an increased relative risk of arthritis. 12 Thomson GT, DeRubeis DA, Hodge MA, et al. Post-Salmonella reactive arthritis: late clinical sequelae in a point source cohort. Am J Med 1995; 98:1321. 13 Fendler C, Laitko S, Sorensen H, et al. 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 2001; 60:337343. 14 Schiellerup P, Krogfelt KA, Locht H. A comparison of self-reported joint  symptoms following infection with different enteric pathogens: effect of HLA-B27. J Rheumatol 2008; 35:480487. Another study demonstrating severity of ReA was correlated with the severity of gastrointestinal symptoms, as well as an association with HLA-B27.

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