Chapter 20. Reactive Arthritis

 Reactive arthritis (ReA) is an inflammatory syndrome 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 ambiguity in the literature in terms of the nomenclature of this condition for many terms and eponyms have been utilized. In 1942 two Harvard researchers, Bauer 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 officer who developed the clinical triad of arthritis, nongonococcal 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 symptoms.3 Further, many common features of ReA are not included in this “classic triad” including involvement 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 nonpathogenic strain of Treponema, some of his later experimentation during World War II was deplorable. Reiter played an active role in the design of a study that inoculated concentration camp victims at Buchenwald with an experimental typhus vaccine, 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.5

 It turns out that Reiter was not the first to describe ReA. In reality, it had been described by many physicians in different parts of the world many years before Reiter's case in 1916. Several others have described similar cases in the literature including Pierre van Forest's description of a case of “secondary arthritis and urethritis” in 1507,6 Thomas Sydenham's association of arthritis with diarrhea in 1686,7 Stoll's documentation of arthritis following dysentery in 1776,8 and Yvan's description of a French captain who developed “ophthalmia” and inflammatory 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 five patients with rather classic ReA in his treatise Pathological and Surgical Observations on the Diseases of the Joints.10 Importantly, he recognized the similar “train of symptoms” that all five patients experienced, and clearly noted the relapsing course in the few who developed chronic disease. Interestingly, 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 effort to standardize the disease terminology for this condition. Because Hans Reiter was not the first 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 process regardless of whether their symptoms involve the three classic organ systems.

 In a similar fashion to the ambiguity that previously involved the proper disease terminology, so too there has been no definitive 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 populations and, as might be expected, the incidence and prevalence of ReA varies widely in studies. Because ReA has a definitive 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 organisms. Finally, many cases diagnosed as seronegative oligoarthritis or undifferentiated oligoarthritis may actually be ReA, thereby resulting in an underestimate of disease prevalence or incidence.

 The postdysentery form of ReA affects 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 approximately 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 estimated 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 identified, 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 undifferentiated 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 rheumatoid arthritis.20 However, the number of patients diagnosed 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 significantly underrecognized.

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Triggering Organisms

Bacteria that commonly cause ReA are Salmonella, Shigella, Campylobacter, Yersinia, and Chlamydia trachomatis. Indeed, these organisms represent the definitive triggers of ReA; however many other infectious agents have been implicated as potential causes (Box 20-1). Chlamydia trachomatis (Ct) is the most common etiologic agent causing ReA in the United States.14,22 Despite the obvious difference of initial route of infection (i.e., gastrointestinal vs. genitourinary), another distinction exists. The postdysentery form of ReA is always preceded by a symptomatic infection, and recent data suggest the more severe the initial gastrointestinal infection, the more likely ReA develops.23–25 However, an initial Ct infection is often asymptomatic.26–28 Recent data suggest that an initial asymptomatic Ct infection is a common cause of ReA.29 In this study, the majority of patients diagnosed with uSpA, because of no known preceding infection prior to the onset of their arthritis, were found to be polymerase chain reaction (PCR) positive for Chlamydiae on synovial tissue analysis. This is in keeping with previous data suggesting that 78% of subjects who develop ReA after a venereal infection had an asymptomatic infection.30 A number of published studies also indicate that Chlamydophila (Chlamydia) pneumonaie (Cpn), a related respiratory pathogen, is another causative agent in ReA, albeit at a lower frequency.31–33

Chlamydiae are Gram-negative, obligate intracellular organisms. The attack rate of ReA after a Ct infection is approximately 5%.30 Synovial tissue analyses from patients affected with postchlamydial ReA have shown that these organisms traffic from the initial site of infection to the synovium. These synovium-based Chlamydiae exist in a morphologically aberrant but metabolically active viable state termed chlamydial persistence.34,35 The pattern of gene expression is attenuated and significantly different than that seen during normal active infection. For example, during persistence of Ct expression of the major outer membrane protein (omp1) gene and several genes required for the cell division process are severely downregulated. This is coupled with differential regulations of the three paralog genes specifying Chlamydia trachomatis heat shock proteins (HSP)-60 [(1) Ct110, (2) Ct604, and (3) Ct755].36 The exact role that these synovium-based persistent Chlamydiae play in terms of disease pathogenesis or disease propagation is not completely understood. Of note, it has been demonstrated that these same persistent Chlamydiae traffic to other end organs, specifically the skin in patients with suspect keratoderma blenorrhagicum.37

Other recent data relating to Chlamydia-induced ReA force us to reconsider our traditional paradigms. Because these pathogens are responsible for genital infections, it was logical to assume that the genital strains of C. trachomatis were responsible for triggering ReA. However, there are several serovars of C. trachomatis, specifically serovars A through K. Serovars A, B, and C are ocular (trachoma) serovars and the remainders (serovars D through K) are genital. Remarkably, a recent study analyzing the chlamydial serovars of 36 subjects with known C. trachomatis-induced ReA demonstrated that all 36 synovial tissue samples were positive for the ocular serovars, not the genital serovars.38 It is known that genital infection with the ocular strains do occur, but are rare.39,40 The infrequent rate of genital infections with the ocular strain might explain the low attack rate of ReA in patients with acute chlamydial infections.

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Host Factors

Reactive arthritis represents the classic interplay of host and environment. The environmental triggers outlined above play and undeniable role in disease genesis; the concept of bacterial persistence lends speculative support that these pathogens might also play a role in disease propagation. Certain bacterial serovars or species might be particularly arthritogenic or more prone to dissemination. However, genetic susceptibility also clearly plays a role. Because ReA is one of the spondyloarthritides, much of the focus on host genetics has centered on HLA-B27. There are also data indicating that patients with HIV are at increased risk for ReA and the symptoms can improve with antiretroviral HIV therapy.57

The prevalence of HLA-B27 and reactive arthritis varies around the world.58 In Caucasian populations, HLAB27 is present in 7%–9% of individuals. Older literature suggested that as many as 70%–80% of patients with ReA were HLA-B27 positive.59,60 However, several large epidemiological studies of ReA now dictate that, in reality, about 30%–50% of ReA patients are positive for this antigen.45,61–67 More recent data even suggest there might be no association with HLA-B27 and ReA.25,47,64 The vast majority of data regarding the prevalence of HLA-B27 in ReA comes from epidemiological studies of postenteric ReA after outbreaks with certain enteric pathogens. Therefore, the true prevalence of HLA-B27 in postchlamydial ReA is less well defined.

The possibility exists that HLA-B27 plays more of a role with phenotypic disease expression rather than a true genetic susceptibility locus. Several large ReA studies demonstrate that HLA-B27 positive patients have more severe symptoms, thereby making the condition more clinically apparent.23 This haplotype might also increase one's risk for developing the complete triad of symptoms.68 It should also be noted that the variation in the prevalence of HLA-B27 in various studies described above could, at least in part, be explained by the potential role that HLA-B27 plays on phenotypic expression. The studies cited above suggesting that HLA-B27 has little to no role in disease susceptibility include patients with milder symptoms, whereas the previous studies demonstrating a higher HLA-B27 prevalence only include patients with more fulminate symptoms sometimes requiring the complete triad of symptoms.

Whether HLA-B27 is more important in disease susceptibility or clinical expression, it clearly plays a role in ReA. Many theories exist regarding its pathophysiologic role, but none are proven. Since HLA-B27 is a Class I histocompatability antigen, it has been postulated that HLA-B27 presents arthritogenic microbial peptides to T cells stimulating an autoimmune response, so called molecular mimicry.69 Conversely, B27 itself may serve as the autoantigen that is targeted by the immune system.70 It is also possible that exposure to the triggering bacteria may subvert self-tolerance to the B27 antigen.71 Another theory suggests that the role of HLA-B27 may be to enhance invasion of the causative organisms into human intestinal epithelial cells in patients with postenteric ReA.72 Vast data demonstrate that misfolding of HLA-B27 can lead to the unfolded protein response enhancing the production of interleukin-23;73 however this unfolded protein response has not been definitively linked to ReA. HLA-B27 has multiple alleles that could influence host response and disease susceptibility. One study suggests that although HLA-B*2705 is the most common allele observed in B27-positive ReA patients, this allele is seen less frequently than in the other SpA's and in B27 healthy controls.74

While HLA-B27 is important to pathogenesis in ReA, it is not the sole determinant. Clearly patients who are HLA-B27 negative can develop ReA. It has been suggested that HLA-B*5703 increases the risk for the classic triad of symptoms in patients who develop ReA.75 Gene expression analyses suggest that proangiogenic factors account for genetic susceptibility of ReA.76 Much remains to be learned about other HLA loci or even non-HLA genes that might be important in the pathophysiology of ReA.

 These recent data regarding the apparent causality of the ocular serovars raise intriguing questions 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 apparent arthritogenicity of the ocular serovar years ago. In the 1960s and early 1970s, Bedsonia (Chlamydia) recovered from patients with ReA caused arthritis 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 affinity 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 environmental sources. It is the most frequently studied enteric bacterium associated with ReA. The attack rate of Salmonella-induced ReA has ranged between 6% and 30% in different studies.43,44 All four of the species of Shigella (S. flexneri, S. dysenteriae, S. 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-negative 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 arthritogenic. A study in Denmark suggests that it was the most likely organism to cause ReA with an attack rate of 23%.23 Other studies have suggested an attack rate of 12%.48,49 As with Chlamydiae, efforts have been made to detect these enteric pathogens in synovial tissue or fluid of patients with ReA. Bacterial DNA or bacterial degradation products have been detected, but, unlike Chlamydiae, no viable organisms have been demonstrated.50–52 However, one study did suggest viable Yersinia were present in synovial samples of these patients,53 yet other data contradict this finding.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 different than that of the persistently viable Chlamydiae. It is also likely that different species from the same genus of the triggering enteric bacteria vary in their arthritogenic propensity.

 Many other organisms have been implicated as potential causes of ReA. These include Ureaplasma urealyticum, H. pylori, and various intestinal parasites. The majority of these reports exist in the form of single cases or small series. Reports of ReA secondary to E. coli,23–25 C. difficile,55 and intravesicular Bacillus Calmette-Guérin (BCG)56 have garnered recent recognition. A recent study in Denmark suggested that a gastrointestinal infection with E. coli was just as likely to cause ReA as Shigella.23

It is apparent that the causative bacteria of ReA are incorporated intracellularly, either in-part or in-whole, then taken from the site of initial infection and trafficked to the synovium. However, what governs this process is not yet evident. It is also not clear if their presence in the affected organs represents a trigger for an autoimmune response, or if these organisms are the source for the inflammatory process. It appears that this phenomenon of cellular uptake, trafficking, and host tolerance is multifactorial in nature.

Although the causative organisms are intracellular pathogens, the process of cellular uptake is not entirely apparent. Indeed the specific mechanisms for cellular uptake of these microbes are probably different for each organism. In the case of Chlamydiae, the quest to find a specific extracellular ligand has been unsuccessful. Intriguing recent data suggest that there might not be a specific chlamydial ligand, rather these pathogens might utilize a different ligand entirely. Apolipoprotein E (ApoE4) that is adherent to the surface of chlamydial elementary bodies (EB) attaches to the host cell low-density lipoprotein (LDL) receptor family carrying the EB with it.77 However, this only appears to be true of C. pneumoniae, not C. trachomatis. In the case of Salmonella, type 1 fimbriae mediate the attachment of this organism to the cell leading to internalization.78

Toll-like receptors (TLR) are a key component of the innate immune system. Because they are among the first line of defense against microbes and they recognize extracellular pathogens, they could play a role in ReA. All of the definitive triggering organisms are Gram-negative with a lipopolysaccharide (LPS) component to their cell wall, and TLR-4 recognizes LPS. TLR-4 deficient mice exposed to Salmonella demonstrate dramatically increased bacterial growth and demise.79 Other animal data have shown that effective host clearance of Ct depends on appropriate TLR-4 expression by neutrophils.80 However, recent human data suggest that TLR-2, not TLR-4, is important in determining ReA disease susceptibility after a Salmonella infection.81

In terms of cytokine response in ReA, it appears that both Th1 and Th2 are important, but the Th2 pathway predominates. Although ReA patients have higher serum TNF-α (Th1) than normal controls,82 lower levels of TNF-α have been demonstrated in ReA compared to other types of inflammatory arthritis.83–85 Synovial fluid analyses from patients with ReA demonstrate higher levels of IL-10 and lower levels of TNF-α and IFN-γ (favoring a Th2 profile).84,85 Interestingly, in terms of postchlamydial ReA, lower levels of these same two cytokines (TNF-α and IFN-γ) have been associated with increased chlamydial replication and overall bacterial burden in vitro.86–88 The suppression of Th1 cytokines is likely mediated through suppression of IL-12 synthesis.

Data also exist suggesting that these cytokine levels can change over time. ReA patients with a disease duration of greater than 6 months secreted significantly less TNF-α.83 Temporal relationships of these different Th1 and Th2 cytokines might also be important in disease manifestations. Slight changes in the Th1/Th2 balance may explain the relapsing course that is frequently seen chronic ReA. Animal data also suggest that blunting of the initial cytokine response of TNF-α, IFN-γ, and Interleukin-4 (IL-4) to an acute chlamydial infection leads to decreased bacterial clearance.89 Therefore, lower initial responses of these Th1 cytokines may increase the likelihood of developing ReA. These animal data provide an interesting potential correlate to the fact that asymptomatic chlamydial infections in humans can often lead to ReA.

In spite of the fact that ReA has several distinct etiologic agents and the apparent differences in the pathophysiology depending on the triggering microbe, the clinical features of ReA are congruent regardless of the initiating infection. The clinical syndrome that encompasses ReA can involve many different organ systems, although it has a predilection for the synovium, urethra, eye, and the skin (Box 20-2). The symptoms start within 1–4 weeks of the initial infection. However, as stated with Chlamydiae, the inciting infection could be asymptomatic obfuscating the diagnosis. It has traditionally been felt that the vast majority of cases of ReA resolve spontaneously within weeks to months, but more recent data suggest that 30%–50% of cases can become chronic.45,61–67 One series suggested that 63% of patients develop chronic symptoms.18 In general, if a patient experiences symptoms of longer than 6 months duration, then they are felt to have chronic disease (Box 20-3). Typically, patients have more significant symptoms during the acute phase; these can include constitutional symptoms (malaise, fatigue) and fever. If the symptoms persist, then the long-term manifestations tend to be milder. In these chronic cases, it is not unusual for the symptoms to wax and wane.

ReA is often misdiagnosed or underdiagnosed. The reasons are varied, but an overreliance on the “classic” clinical triad of symptoms lends to this underdiagnosis. Some of the earliest descriptions of ReA included patients with this triad of symptoms. For many years, clinicians felt this triad was necessary for the diagnosis. In 1976, the concept of “Incomplete Reiter syndrome” was introduced describing a case series of 13 patients, who were predominately HLA-B27 positive, and presented with oligoarthritis, heel pain, periostitis, dactylitis, and mucocutaneous lesions, but no urethritis or conjunctivitis.90 It is now apparent that the majority of cases do not involve the three classic organ systems.

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Articular

ReA nearly always involves an inflammatory arthritis. It is unclear if some patients with other symptoms of ReA, such as recurrent uveitis or enthesitis without arthritis, might represent cases of ReA as well. Patients with ReA can develop an inflammatory arthritis that involves the axial skeleton and/or the peripheral joints.

The axial arthritis of ReA (Box 20-2) presents as pain and stiffness in the low back and/or buttocks. A classic feature is prolonged pain and stiffness in the morning or after periods of rest or inactivity. These symptoms tend to improve with activity or exercise. The cause of the pain includes inflammation in the synovial portion of the sacroiliac joints and enthesitis of these same joints, pelvis, and lumbar spine. The combination of synovitis and enthesitis of the sacroiliac joints results in one of the classic features of ReA, i.e., sacroiliitis. These symptoms might be more pronounced during the acute phase of the illness. It is important to note that sacroiliitis can often be documented on plain radiographs, but these imaging studies might be of lesser utility in patients with acute symptoms since radiographic evidence of sacroiliitis can take weeks to months to develop. In patients with a high index of suspicion of acute disease and normal plain radiographs, advanced imaging with magnetic resonance imaging (MRI) might prove useful (Fig. 20-1). Such advanced imaging can show evidence of early inflammatory sacroiliitis that might be otherwise missed by conventional radiographs.91 Plain radiographs remain the imaging investigation of choice for patients with chronic disease. ReA patients with radiographic sacroiliitis typically have unilateral or bilateral asymmetric findings.

The axial inflammatory arthritis of ReA involves the thoracic and cervical spine less often than the lumbar spine. If present, symptoms are similar including prolonged pain and stiffness in the morning and improvement with activity. In addition to sacroiliitis, patients can also develop spinal changes on plain radiographs. The most typical finding is nonmarginal syndesmophytes (eFig. 20-1.1). These are thick, bridging, comma-shaped bony growths between vertebral bodies. These are most often seen in patients with chronic disease. Finally, the axial symptoms can include inflammation in cartilaginous joints, such as the symphysis pubis or sternoclavicular joints, with resultant radiographic changes.

The peripheral arthritis of ReA most often is an inflammatory oligoarthritis; there is a predilection for the large joints of the lower extremities. However, patients can also present with a polyarthritis or even monoarthritis. This clinical picture involving one or a few joints, particularly of the lower extremities contrasts with other types of inflammatory arthritis, such as rheumatoid arthritis, that typically present with a symmetrical polyarthritis. As with the axial symptoms, these tend to be more pronounced during the acute stage and can relapse and remit. In patients with more chronic or severe cases the small joints of the hands and feet can be involved. Radiographic features of peripheral joints in patients with chronic disease can include erosive changes, periostitis, and possibly even “pencil-in-cup” deformities most often associated with psoriatic arthritis.

Dactylitis (sausage digit) is a valuable diagnostic clue for potential ReA (Fig. 20-2). Dactylitis represents diffuse inflammation of an entire finger or toe. While not specific to ReA, if present, it is strongly suggestive of a spondyloarthropathy. Besides the spondyloarthropathies, only a few conditions, namely sarcoidosis and gout, cause dactylitis. One series suggested that ReA was the most common diagnosis in patients presenting with dactylitis; 28% of ReA patients had this finding as part of their constellation of symptoms.92

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Enthesitis

Enthesitis, or fibrocatilagenous enthesitis, is inflammation at the transitional zone where collagenous structures such as tendons, ligaments, and joint capsules insert into bone. This is a hallmark feature of ReA (as well as for other types of spondyloarthritis). There are two main phases of enthesitis: (1) subchondral osteitis and (2) reparative ossification. The inflammation starts in the intraosseous portion of the enthesis, eventually destroying the bone and cartilage plate. The defect is rapidly filled with newly formed bone that extends to the terminal part of the tendon producing an enthesophyte (eFig. 20-2.1). Common types of enthesitis in ReA are Achilles tendonitis and plantar fasciitis, but inflammation can occur at any enthesis. Sacroiliitis represents a combination of synovitis and enthesitis.93 A recent report of >6,000 cases of culture-confirmed infections with bacterial enteric pathogens revealed that enthesitis was the most common finding in those individuals who developed ReA.25

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Cutaneous

Dermatologic manifestations of ReA are several. The two most common are keratoderma blenorrhagicum and circinate balanitis. Keratoderma blenorrhagicum is a pustular or plaque-like rash that most often occurs in a palmoplantar distribution (Fig. 20-3). These typically begin as erythematous macules or vesicles. These vesicles are often pustular in nature, but they can also be hemorrhagic; over time they can become thickened or papular forming a horny excrescence. These chronic lesions can become hyperpigmented and may coalesce. Rarely these lesions can occur in a more general distribution involving the entire body94; this is felt to be more likely in the setting of HIV. Interestingly, keratoderma blenorrhagicum is clinically and histologically indistinct from pustular psoriasis.95 Histologic findings include hyperkeratosis and parakeratosis, elongation and hypertrophy of the rete ridges, general epidermal hyperplasia, and extensive neutrophilic infiltration with formation of microabscesses and spongiform pustules. Recently it has been demonstrated that these lesions are PCR positive for Chlamydia trachomatis in patients with suspected Chlamydia-induced ReA.37

Circinate balanitis is a cutaneous manifestation of ReA involving the penis. These are erythematous, pustular, or plaque-like lesions that most often involve the glans of the penis, but they can include the shaft and rarely the scrotum (Fig. 20-4). It has been suggested that these lesions on the glans can exhibit different characteristics depending on whether the patient is circumcised or not. In circumcised males, hyperkeratotic plaques are most typical and in uncircumcised patients they often begin as vesicles or pustules that may coalesce into a circinate pattern (Fig. 20-4).96 Females with ReA can rarely get ulcerative vulvitis that has similar appearance to circinate balanitis.

Patients with ReA may also have nail involvement, which is similar to psoriasis and presents as onycholysis, subungal keratotic debris, transverse ridges, periungual scaly lesions, and nail pitting. These changes occur in about 20%–30% of ReA patients.96 The relationship between distal interphalangeal arthritis and nail involvement is well recognized in psoriatic arthritis,97 the same is also likely to be true for ReA, but there are no definitive data in this regard.

The true prevalence of keratoderma blenorrhagicum and circinate balanitis in patients ReA remains somewhat uncertain. Previous data have suggested that they occur in about 10%98 and 50%99 of patients, respectively and it was felt that they are more common in patients who are HLA-B27 positive.100 However, as is the case with ReA in general, it is not clear if this genetic marker truly increases the occurrence of these cutaneous manifestations or if it has served as a diagnostic bias. More recent data demonstrate that circinate balanitis more strongly correlates with a previous chlamydial infection than previously thought.101 In this same study, there was no apparent association with HLA-B27 and the majority of patients had no other signs or symptoms of ReA. The fact that these lesions are also clinically and histological indistinct from pustular psoriasis can also obfuscate the diagnosis.

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Ocular

(Boxes 20-2 and 20-3)

Although the original “classic triad” of symptoms of ReA included eye involvement, conjunctivitis was specifically mentioned. Not only do patients with ReA develop conjunctivitis, they often develop iritis/anterior uveitis. Although both conditions can occur at any time during the condition, it has traditionally been felt that conjunctivitis most often occurs during the early stage and less frequently becomes chronic whereas iritis/anterior uveitis occurs both as an acute and chronic (intermittent) problem. However, a long-term study of 25 ReA subjects with eye involvement at the time of diagnosis demonstrated that long-term ocular complications included conjunctivitis and anterior uveitis in 96% and 92% of patients, respectively.102 Other long-term complications were seen in this study including posterior uveitis (64%), keratitis (64%), cataract (56%), intermediate uveitis (40%), scleritis (28%), cystoid macular edema (28%), papillitis (16%), and glaucoma (16%). These data suggest that patients with ocular involvement at the time of diagnosis are at increased risk for many long-term ocular complications; perhaps this risk is higher than previously appreciated.

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Mucosal

(Boxes 20-2 and 20-3)

Mucosal involvement of the mouth, oral pharynx, and tongue can occur in patients with ReA, but these are infrequent. If they occur, typical lesions on the oropharnyx include diffuse erythema, macules, and plaques. They are often painless and might go unnoticed by the patient. Such lesions will sometimes present with bleeding. Lesions involving the tongue are most often circinate or annular in appearance. More common mucosal manifestations include intestinal inflammatory lesions that resemble those of inflammatory bowel disease. One study found that 67% of subjects with ReA had histologic evidence of ileocolitis, even in the absence of gastrointestinal symptoms.103 This finding might be higher in patients with postenteric ReA. Finally, it is well described that patients with ReA develop sterile dysuria. Interestingly this occurs with equal frequency in both postvenereal and postenteric ReA. This sterile dysuria can become a chronic intermittent problem for some patients. Prostatitis, cystitis, and pelvic inflammatory disease have also been described.104,105

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Cardiac

(Boxes 20-2 and 20-3)

Cardiac involvement from ReA is rare. There are sparse reports of ReA patients developing pericarditis, aortic regurgitation, or valvular pathologies. When they occur, they are more likely in chronic disease. These manifestations are rare enough in the acute setting that routine echocardiography is not recommended.106 Electrocardiographic abnormalities can occur in the acute setting with significant arrhythmias occurring in approximately 5% of patients.107

Diagnostic criteria are broad and rely on clinical symptoms.100,108 Difficulties with these diagnostic criteria have been raised.109 The traditional disease definition also suggests that ReA represents a sterile inflammatory arthritis, but data presented above, specifically pertaining to Chlamydiae, challenge this paradigm. Although not pathognomonic for the condition, the documentation of the DNA presence of one of the causative organisms by PCR in synovial tissue or fluid of patients who fulfill the clinical criteria for ReA represents the most accurate means of diagnosing the condition.110 Unfortunately, such synovial tissue analysis is not readily available for the majority of clinicians. Stool and urogenital sampling for the causative organisms in patients with chronic disease have been analyzed, but many patients test negative limiting the utility of this approach.111,112 Serologic testing for antibodies to the causative organisms is unreliable. Because more than half of affected patients are HLA-B27 negative, this genetic antigen should not be utilized as a diagnostic tool. Therefore, at the current time we are left without a practical diagnostic test. Recognition of an underlying spondyloarthritis and identifying one of the triggering infections remains the most practical means of diagnosis ReA until better diagnostic tests are widely available. A diagnostic algorithm is shown in Figure 20-5.

In the setting of acute or mild ReA, treatment is most often symptomatic and conservative. It is important to remember that many of the symptoms of acute ReA are self-limiting. The initial treatment of choice for the arthritis is nonsteroidal anti-inflammatory (NSAIDs). Not only is there a breadth of clinical experience with NSAIDs demonstrating their efficacy, there are also two randomized trials that have formally evaluated their use in ReA. The first was a double-blind crossover study comparing azapropazone to indomethacin in patients with both psoriatic arthritis and ReA.113 Both medications were efficacious with a trend favoring indomethacin. Neither medication helped with the skin manifestations of either condition. The second was another double-blind crossover study comparing ketoprofen to indomethacin in 50 patients with ReA.114 Both drugs were efficacious in treating the articular symptoms with no significant difference between the two. There were slightly more adverse events with indomethacin in both studies. Corticosteroids are quite helpful in patients with more severe articular symptoms. It has been suggested that systemic corticosteroids might be more efficacious in the treatment of peripheral articular symptoms rather than the axial symptoms.115 Because ReA often involves one or few joints, intra-articular corticosteroids are often a useful treatment strategy.

Initial treatment of many of the extra-articular features of ReA includes topical corticosteroids. These have been utilized to treat iritis/uveitis, keratoderma blenorrhagicum, and circinate balanitis.115 Given the similarities between the cutaneous manifestations of ReA and psoriasis, it is not surprising that other medications used to treat psoriasis have been advocated as potential treatments for keratoderma blenorrhagicum and/or circinate balanitis. Data suggest that topical calcipotriene is a useful treatment modality for keratoderma.116 Emollients, keratolytics, coal tar, and phototherapy have also been advocated for keratoderma blenorrhagicum. In severe cases of keratoderma blenorrhagicum and circinate balanitis methotrexate (low-dose regimen as for psoriasis) and etretinate (0.5 mg/kg body weight) have been found to be beneficial but no formal clinical trials have been performed!

In spite of the fact that ReA often remits, as many as 30%–50% of patients will develop chronic disease. Both the articular and extra-articular features can persist. Because ReA can lead to pathologic sequelae (e.g., joint damage, visual impairment, skin disfigurement) resulting in decreased health-related quality of life, more definitive treatments have been sought. Paralleling the opposing schools of thought regarding the true role bacterial persistence plays in the pathophysiology of the disease, both traditional disease modifying antirheumatic drugs (DMARDs) and antibiotics have been assessed as potential therapeutic options. The latter have been studied in both acute and chronic disease, whereas the former are most often reserved for patients with chronic symptoms.

Several DMARDs have been advocated as treatments for ReA. These include sulfasalazine, methotrexate, azathioprine, and cyclosporine. Surprisingly, only one of these, sulfasalazine, has been formally evaluated in prospective clinical trials. Sulfasalazine has been studied as a potential treatment for both acute and chronic ReA. In the acute ReA study, there was no significant difference between sulfasalazine and placebo in terms of pain, number of swollen joints, and erythrocyte sedimentation rate (ESR) after 6 months of therapy.117 In addition, there was no apparent efficacy difference in patients regarding the initial triggering infection, HLA-B27 status, or presence/absence of axial arthritis. However, it is important to remember that acute ReA often remits spontaneously, so this potentially confounds these data. Sulfasalazine has also been studied in the setting of chronic ReA.118 In this study, all patients had failed NSAIDs and were followed for 36 weeks’ duration. There was a trend favoring sulfasalazine over placebo in terms of overall response. Sulfasalazine fared significantly better than placebo in some of the secondary endpoints including a longitudinal analysis and ESR.

The tumor necrosis factor (TNF)-α antagonists have demonstrated remarkable success treating several types of inflammatory arthritis including other types of spondyloarthritides, namely ankylosing spondylitis and psoriatic arthritis. Therefore it might seem logical that they would be useful therapeutic agents for ReA. However, several studies suggest that ReA is more of a Th2 driven disease.83–85 Conversely, ReA patients have higher serum TNF-α levels than normal controls.82 Adding to this complexity, it has been suggested that the Th1 versus Th2 predominance depends on the cell analyzed (synovial fluid derived T-cell clones vs. synovial fluid mononuclear cells).82 It should also be noted that, in the case of chlamydial persistence, chlamydial replication is inversely proportional to TNF-α levels.86–88 There are no randomized trials in ReA to accurately assess the efficacy of anti-TNF therapy, but several case reports and a small open label study suggest clinical benefit with these drugs in the treatment of ReA.119–122 It might also be noteworthy that a rare, but defined, adverse event of anti-TNF therapy, in general, includes the onset of de novo psoriasis.123 The similarities of keratoderma blenorrhagicum and pustular psoriasis are well described. The majority of these cases of anti-TNF therapy induced psoriasis occurs on the palms and/or soles and is pustular in nature. Three reported cases have been shown to be PCR positive for Chlamydia trachomatis on lesional skin biopsies.37 The exact pathophysiology of these de novo cases of psoriasiform lesions remains unknown.

The fact that certain bacterial organisms are responsible for the genesis of ReA makes the notion of using antibiotics plausible. Data have demonstrated that the causative bacterial organisms traffic to the synovium and in the case of persistent synovium-based Chlamydiae, specifically, these organisms exist in a viable, albeit aberrant, state. This important difference in postchlamydial and postenteric ReA suggests a potential difference in antimicrobial response.

The first prospective, double-blind trial assessed antibiotics in the setting of acute ReA.124 In this trial, 3 months of therapy with lymecycline significantly decreased the duration of illness in those subjects with postchlamydial ReA, but not those with the postenteric variety. This led to several studies assessing the utility of long-term treatment with various antibiotics, including ciprofloxacin, azithromycin, and doxycycline, in the ensuing years that produced negative results.67,125–128 However, the initial concept that postchlamydial and postenteric ReA might behave differently in terms of therapeutic response was somewhat lost in these follow-up studies. More recently, data have suggested that a prolonged course of combination antibiotics is an efficacious treatment specifically for chronic postchlamydial ReA. Initially, an open-label comparison of doxycycline with rifampin versus doxycycline monotherapy suggested superiority with the former.65 A double-blind, placebo-controlled follow-up study demonstrated that 6-month courses of doxycycline with rifampin and azithromycin with rifampin were significantly better than placebo.129 In this study, all patients had to be PCR positive for Chlamydiae in order to be randomized to treatment. Significantly more patients on combination antimicrobial therapy converted to PCR negative compared to those treated with placebo after 6 months of therapy.

In terms of chronic diseases, ReA is unique in that the etiologic agents are known. This insight into disease initiation has led to significant advances in the understanding of this condition but much remains to be learned regarding its pathophysiology. In an almost ironic fashion, the definitive nature of disease genesis is juxtaposed with convoluted evolution regarding disease terminology and the original overreliance on the “classic triad” of symptoms; these issues have now been clarified. However, there remains ambiguity regarding a definitive therapeutic approach. Ongoing studies will hopefully answer the latter.