Copyright McGraw-Hill Companies, Inc. All rights reserved.Chapter 20Reactive ArthritisJohn D. CarterHISTORICAL BACKGROUNDReactive arthritis (ReA) is an infammatory syn-drome that results after certain genitourinary or gastrointestinal symptoms. The most common inciting infections include Chlamydia trachomatis, Salmonella, Shigella, Campylobacter, and Yersinia. The term reactive arthritis was introduced in 1973 to describe this type of arthritis that occurs after a triggering infection.1 There is considerable ambigu-ity in the literature in terms of the nomenclature of this condition for many terms and eponyms have been utilized. In 1942 two Harvard researchers, Bau-er and Engelmann, recognized a case of ReA and upon their review of the literature they discovered that Hans Reiter had described this same syndrome in 1916.2 Reiter had described a German ofcer who developed the clinical triad of arthritis, nongono-coccal urethritis, and conjunctivitis after an episode of acute dysentery. It was at that point that Bauer and Engelmann coined the term Reiter syndrome and this eponym was often used to describe the condition.In recent years, the eponym Reiter syndrome became problematic for several reasons. First, most clinicians often demanded that a patient have the classic triad of symptoms involving the synovium, urethra, and conjunctiva before the diagnosis would be made. It is now known that most patients with ReA do not have the complete triad of symp-toms.3 Further, many common features of ReA are not included in this classic triad including involve-ment of the skin and mucous membranes as well as other parts of the eye, namely the anterior uveal tract. More troubling is the acts of the man from which the eponym was coined. Although Hans Reiter was an erudite intellectual and a brilliant investigator who performed many useful studies early in his career including the discovery of the spirochete that causes leptospirosis and a non-pathogenic strain of Treponema, some of his later experimentation during World War II was deplor-able. Reiter played an active role in the design of a study that inoculated concentration camp victims at Buchenwald with an experimental typhus vac-cine, which directly resulted in hundreds of deaths.4 Reiter was arrested after World War II; he was tried and convicted at Nuremberg for these war crimes. Because of this, some have correctly argued that the term Reiter syndrome should be abandoned and should only be used in historical context.5It turns out that Reiter was not the frst to describe ReA. In reality, it had been described by many phy-sicians in diferent parts of the world many years before Reiters case in 1916. Several others have described similar cases in the literature including Pierre van Forests description of a case of second-ary arthritis and urethritis in 1507,6 Thomas Syden-hams association of arthritis with diarrhea in 1686,7 Stolls documentation of arthritis following dysen-tery in 1776,8 and Yvans description of a French captain who developed ophthalmia and infamma-tory arthritis primarily of the lower extremities 15 days after a venereal infection.9 Sir Benjamin Brodie was an English physiologist and surgeon who pioneered research in joint disease. He described fve patients with rather classic ReA in his trea-tise Pathological and Surgical Observations on the Diseases of the Joints.10 Importantly, he recognized the similar train of symptoms that all fve patients experienced, and clearly noted the relapsing course in the few who developed chronic disease. Interest-ingly, in 1897 Launois clearly made the distinction of septic from aseptic arthritis and demonstrated that patients with the latter occasionally develop cutaneous lesions on the plantar surface of the feet (keratoderma blenorrhagicum).11 Finally, two French physicians, Fiessinger and Leroy, described this same syndrome in the exact same year as Reiter, i.e., 1916.12 Therefore, the term Fiessinger Leroy syndrome has occasionally been used in the past, especially in the French literature.In light of the above issues, the more recent literature has made a concerted efort to standard-ize the disease terminology for this condition. Because Hans Reiter was not the frst to describe the syndrome, and the fact that many clinicians are reluctant to diagnose this condition in those who do not display the complete triad of symptoms thereby missing the majority of cases, and ReA is a more descriptive term, the term ReA has become the appropriate terminology for this disease pro-cess regardless of whether their symptoms involve the three classic organ systems.30 Chapter 20: Reactive ArthritisCopyright McGraw-Hill Companies, Inc. All rights reserved.EPIDEMIOLOGYIn a similar fashion to the ambiguity that previ-ously involved the proper disease terminology, so too there has been no defnitive set of diagnostic criteria. This can result in nonhomogenous patient populations in various studies. This coupled with the fact that the disease can often be mild, there has been a traditional overreliance on the complete clinical triad of symptoms, and the incidence of the trigger infections can vary over time, makes epidemiological studies problematic. There is a link between ReA and the human leukocyte antigen (HLA)-B27, but the role this antigen plays in ReA disease susceptibility might be overstated although this HLA antigen plays a role in those individuals who develop chronic disease.13 Nevertheless, the prevalence of HLA-B27 varies between popula-tions and, as might be expected, the incidence and prevalence of ReA varies widely in studies. Because ReA has a defnitive trigger as an etiologic agent, but not all patients exposed to these causative organisms develop ReA, the concept of attack rate is extremely important in ReA. The attack rate represents the percentage of patients who develop ReA after exposure to one of the causative organ-isms. Finally, many cases diagnosed as seronegative oligoarthritis or undiferentiated oligoarthritis may actually be ReA, thereby resulting in an underesti-mate of disease prevalence or incidence.The postdysentery form of ReA afects males and females with the same frequency, whereas the postvenereal form occurs at a male to female ratio of 9:1.14 Adults are more likely to develop ReA than children.15 In Finland, the annual incidence of ReA has been estimated to be 30/100,000 individuals,16 whereas in Norway the annual incidence is ap-proximately 10/100,000.17 In this latter study, the incidences of postenteric and postchlamydial ReA were essentially equal at 5/100,000 and 4.6/100,000, respectively. In the United States, one study esti-mated the age-adjusted annual incidence of ReA in males younger than age 50 as 3.5/100,000.18 However, in this same study no female cases were identifed, suggesting this represents an overall underestimate. In terms of overall prevalence of ReA, a German study suggested a prevalence of 10/100,000.19 Yet, in this study undiferentiated spondyloarthritis (uSpA) was the second most common type of spondyloarthritis diagnosed (after ankylosing spondylitis) and this same diagnosis was more than twice as common as psoriatic arthritis. Data described below suggests that many cases of uSpA are actually ReA. If true, the prevalence of ReA in this German study would be much greater.An analysis of the expected number of cases of ReA and those actually diagnosed rather strongly argues that ReA is underdiagnosed. Perhaps this is most true with postchlamydial ReA. Because many of the organisms responsible for causing ReA are reportable diseases, the annual incidence of these infections is well described. The expected number of cases of ReA that results from these infections should result in an annual incidence of ReA that greatly exceeds the annual incidence of rheuma-toid arthritis.20 However, the number of patients di-agnosed with rheumatoid arthritis greatly exceeds that diagnosed with ReA. One study demonstrated that 36% of ReA subjects went undiagnosed in the community clinic in spite of a clear antecedent gastrointestinal infection.21 These data suggest that awareness of this condition needs to improve and the burden of ReA on society might be signifcantly underrecognized.BACTERIAL TRIGGERS OF REAThese recent data regarding the apparent causal-ity of the ocular serovars raise intriguing ques-tions about other features of ReA, namely the eye involvement with uveitis and/or conjunctivitis and the propensity of uveitis to recur in these subjects. As it turns out, we might have had clues to the ap-parent arthritogenicity of the ocular serovar years ago. In the 1960s and early 1970s, Bedsonia (Chla-mydia) recovered from patients with ReA caused ar-thritis 100% of the time when injected into rabbits; in addition, intra-articular injection of these same organisms often caused ocular involvement.41,42 This suggests these particular organisms were not only arthritogenic, but had the ability to disseminate with particular afnity for the eye.The four enteric organisms known to cause ReA represent the largest bulk of the cases of ReA as a group. Salmonella is a Gram-negative, rod-shaped, motile bacterium widespread in animals and envi-ronmental sources. It is the most frequently studied enteric bacterium associated with ReA. The attack rate of Salmonella-induced ReA has ranged be-tween 6% and 30% in diferent studies.43,44 All four of the species of Shigella (S. fexneri, S. dysenteriae, S. Chapter 20: Reactive Arthritis31Copyright McGraw-Hill Companies, Inc. All rights reserved.sonnei, and S. boydii) can cause ReA. The attack rate of Shigella-induced ReA was reported to be 7%9% in one study.45 Campylobacter is another Gram-neg-ative motile bacterium; it is a very common cause of enteric infections. C. jejuni is the main cause of bacterial food-borne disease in many developed countries.46 It spite of its frequency it appears to be somewhat less arthritogenic with an attack rate of 1%5%.47 Although Yersinia infections are not as common as some of the other enteric pathogens, some data suggest that Yersinia is particularly arth-ritogenic. A study in Denmark suggests that it was the most likely organism to cause ReA with an at-tack rate of 23%.23 Other studies have suggested an attack rate of 12%.48,49 As with Chlamydiae, eforts have been made to detect these enteric pathogens in synovial tissue or fuid of patients with ReA. Bac-terial DNA or bacterial degradation products have been detected, but, unlike Chlamydiae, no viable organisms have been demonstrated.5052 However, one study did suggest viable Yersinia were present in synovial samples of these patients,53 yet other data contradict this fnding.54 As is the case with Chlamydiae, the role these bacterial products play in the pathophysiology of ReA remains uncertain. However, the fact that these enteric bacteria do not appear to be viable, their role is likely diferent than that of the persistently viable Chlamydiae. It is also likely that diferent species from the same genus of the triggering enteric bacteria vary in their arthrito-genic propensity.Many other organisms have been implicated as potential causes of ReA. These include Ureaplasma urealyticum, H. pylori, and various intestinal para-sites. The majority of these reports exist in the form of single cases or small series. Reports of ReA secondary to E. coli,2325 C. difcile,55 and intravesicu-lar Bacillus Calmette-Gurin (BCG)56 have garnered recent recognition. A recent study in Denmark sug-gested that a gastrointestinal infection with E. coli was just as likely to cause ReA as Shigella.2332 Chapter 20: Reactive ArthritisCopyright McGraw-Hill Companies, Inc. All rights reserved.