A clinical update on reactive arthritis associated with enteric and genitourinary bacterial infections

A clinical update on reactive arthritis associated with enteric and genitourinary bacterial infections 1 Abstract: Reactive Arthritis (ReA), former...
Author: Brian Fletcher
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A clinical update on reactive arthritis associated with enteric and genitourinary bacterial infections

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Abstract: Reactive Arthritis (ReA), formerly Reiter’s syndrome, is a member of the spondyloarthritis family, a group of inflammatory joint diseases that develops following a bacterial infection of the gastrointestinal or genitourinary tracts. The classic triad of ReA consists of postinfectious arthritis, nongonococcal urethritis, and conjunctivitis, however this triad does not present in all patients. Reactive arthritis is a relatively uncommon disease, affecting 14% of people days to weeks after being infected by an enteric, urogenital, or upper respiratory infection. Arthritic symptoms may present before the infection is cleared from the body, or up to four weeks after symptoms have resolved. Up to 70% of affected patients are positive for the genetic marker, HLA-B27. The typical rheumatologic complaints include asymmetric oligoarthritis, usually occurring in the lower extremities, especially the knees, ankles, and feet. Polyarthritis in the upper extremities can also occur, and sometimes presents in small joints. Various dermatologic manifestations present as well. There are no specific diagnostic criteria for ReA, making the diagnosis clinical and often complex. Supportive evidence from serology and radiographs can assist in the diagnosis and aid in treatment. Non-steroidal anti-inflammatory drugs are currently the mainstay of pharmacologic treatment along with antibiotic therapy for confirmed infections.

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Clinical Review: Reactive Arthritis Introduction Background of Reactive Arthritis Reactive Arthritis (ReA), formerly Reiter’s syndrome, is a member of the spondyloarthritis family, a group of inflammatory joint diseases that develops following a bacterial infection of the gastrointestinal or genitourinary tracts.i ReA was first discovered in 1942 when Hans Reiter, a German physician, reported a case of arthritis, conjunctivitis, and urethritis in a solider eight days after he presented with bloody diarrhea.1 ReA is defined as “an arthritis which developed soon after or during an infection elsewhere in the body, but in which the microorganisms cannot be recovered from the joint.”1 The classic triad of ReA consists of post-infectious arthritis, nongonococcal urethritis, and conjunctivitis.1 This full triad may not occur in all patients. The definition, clinical presentation, diagnostic criteria, and management of ReA have evolved over the years, however still no universally accepted diagnostic or classification criteria for ReA exist. For this reason, ReA is often an ambiguous clinical finding, and subsequently complicated to treat.ii Reactive arthritis is a relatively uncommon disease, affecting 1-4% of patients that have an enteric, urogenital, or upper respiratory infection.1 Arthritic symptoms may present before the infection is cleared from the body, or up to four weeks after symptoms have resolved.iii Up to 70% of affected patients are positive for the genetic marker, HLAB27, (Human leukocyte antigen B27).2 ReA affects men three times more than women, and men tend to have more severe symptoms. The condition is found worldwide, predominantly in adults 20-40 years old. 2 There are only two population-based studies of arthritis following a bacterial infection that have been conducted in the United States, and both differ significantly regarding the frequency of ReA. One study from California used questionnaires to ask patients with lab-confirmed enteric infections to describe their post-infection symptoms and experiences.3 Out of the 1,276 people who responded to the questionnaire, 0.9%

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complained of arthritis after their infection.3 A limitation in this study is that only half of the surveys were returned. In a separate study, 4,468 people with culture-confirmed bacterial infections caused by Campylobacter, Salmonella, Shigella, Yersinia, or Escherichia coli O157 were asked questions via telephone as to whether or not they experienced any arthritic symptoms eight weeks post-infection. In this study, arthritic symptoms occurred in 7.2% of the study population.3 The most ReA symptoms in both studies occurred in patients following a Campylobacter infection.3 Anatomy and/or Pathophysiology of Reactive Arthritis The most common causative organisms of ReA include Chlamydia trachomatis, Yersinia, Salmonella, Shigella and Campylobacter.1 It is unclear as to how the microbes reach the joint. In a Russian study, more than 60% of patients with ReA had positive joint cultures for Chlamydia trachomatis, however negative joint cultures is the more common clinical finding in patients with ReA.iv Reactive arthritis usually begins after an infection involving the gastrointestinal or genitourinary tracts. Initially symptoms include inflammation, stiffness, pain and arthralgia in the joints of the lower extremities. The onset of this joint pain can occur suddenly and can be accompanied by a fever over 102ºF, weight loss, and inflammatory back pain.5 Etiology and Risk Factors Reactive arthritis occurs because of a cellular immune response involving CD8 Tcells. In some cases, such as Chlamydia trachomatis, it is believed that monocytes carry the microorganism into the joint space, activating the immune response, causing inflammation.6 Reactive arthritis affects immunocompromised patients more than immunocompetent patients, specifically those with advanced human immunodeficiency virus with low CD4 T-cells.6 Clinical Presentation of Reactive Arthritis Patient History:

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The patient history is crucial when compiling a differential diagnosis and confirming reactive arthritis. Since the signs and symptoms of ReA are very diverse, patients may initially consult a variety of health care professionals, the most common being rheumatologists, dermatologists, orthopedists, or family practice providers.1 The most common acute presenting symptoms associated with ReA are diarrhea and urethritis, however various extra-articular symptoms can present, including dysuria, pelvic pain, conjunctivitis, oral ulcers, and skin rashes.1 Psoriasiform cutaneous lesions can develop weeks after an infection in 10% of the patients.7 Keratotic papules, plaques, and pustules most commonly occur on the palms and soles. Painful erosive pustules on the fingers and toes are other common dermatological manifestations of the disease.7 Lesions can also be found on the tounge, oral mucosa, and genitalia.7 Typical rheumatologic complaints include asymmetric oligoarthritis, usually occurring in the lower extremities, especially the knees, ankles, and feet.1 Polyarthritis in the upper extremities can also occur, and sometimes presents in small joints.8 (See Table 1). Arthritis can occur in conjunction with the bacterial infection or present after the infection has cleared. The latent period from infection to the onset of symptoms can be a few days to an average of four weeks.8 Blood, urine, and stool cultures should be collected on any patient that presents with a suspected gastrointestinal or urogenital bacterial infection to confirm the causative organism. Physical Exam: The general patient presentation includes fever, weight loss, malaise and other extra-articular symptoms as described above. If these symptoms occur for more than six months, it is considered chronic ReA. Usually these mild, constitutional symptoms resolve within 2-3 months.2 Enthesitis, swelling at the heels, and swollen “sausage” digits are a common physical exam finding in a patient with ReA.7 Hyperkeratotic skin lesions on the soles and palms can present, along with various skin rashes, such as keratoderma blennorrhagica.8 The musculoskeletal exam will reveal peripheral arthritis and may show inflammation in the cervical, thoracic, and lumbosacral spine, and sacroilitis.2

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ReA is more severe in hospitalized patients, who are HLA-B27 positive. These patients have arthritis in large joints, especially the hips, knees and ankles. People in the outpatient setting usually present with less severe arthritis, a lower erythrocyte sedimentation rate, and respond better to non-steroidal anti-inflammatory medications (NSAIDs). Heel and foot involvement is an indicator of a poor prognosis, including disability.2 Screening/Lab Tests/Diagnostic Studies Diagnosis of ReA is based upon clinical presentation and various diagnostic studies. Since there is not a “gold standard” diagnostic test for ReA, researchers in Germany and Scandinavia, created a clinical algorithm to aide in the diagnosis. The first criterion is that the patient has mono- or oligoarthritis of the lower extremities.2 The clinician must also exclude other diagnoses, including septic or traumatic arthritis, gout, and osteoarthritis. If both these criteria are met, then there is a 40% chance the patient has ReA.9 Next, the health provider must investigate for evidence of a previous bacterial infection. If there is a history of symptomatic Chlamydia trachomatis, then the probability of ReA is 90%.10 If the patient does not have symptoms of Chlamydia trachmoatis, but the bacteria can be detected in the urine, then the likelihood of ReA is 60%.10 If the patient presents with an enteric infection, there is a 70% probability that they have acquired ReA.10 Overall, laboratory confirmed infections are only identified in approximately 50% of patients that are diagnosed with possible ReA.10 Routine laboratory tests to evaluate patients with mono- or oligoarticular arthritis, include erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). An ESR over 30 can be a predictor of more severe ReA.2 Currently there are no standard serologic tests for specific antibody titers that are recommended for diagnostic purposes. Patients with a moderate risk of ReA may be good candidates for HLA-B27 testing. However, the diagnostic value of this test to confirm ReA has not been proven in large-scale studies.10 Stool cultures are recommended, even if gastrointestinal symptoms are not present.9 A urinalysis can detect Chlamydia trachomatis.1 Serologic testing for Yersinia, Salmonella, Campylobacter and Chlamydia are relatively easy to perform and inexpensive.

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The use of imaging studies, including magnetic resonance imaging (MRI) can be helpful to diagnose enthesitis that is not clinically obvious. Radiographic features of ReA can show periosteal reaction, asymmetric sacroilitis, and discontinuous spondylitis.5 Ultimately, the diagnosis of ReA is clinical, with supportive evidence from serology and radiographs.1 Extra-articular manifestations are essential in supporting the diagnosis of ReA.5 Conjunctivitis is noted in up to 50% of ReA patients, and is more common in patients with Chlamydia of the genitourinary tract, or a Shigella infection.5 Management of Reactive Arthritis Pharmacologic Management The treatment of reactive arthritis is still under investigation. However, nonsteroidal anti-inflammatory drugs (NSAIDs) are currently the mainstay of pharmacologic treatment.13 Limited data shows that joint injections with glucocorticoids, and disease modifying antirheumatic drugs (DMARDs) may be beneficial.13 The effectiveness of antibiotic therapy in chronic ReA triggered by Chlamydia, Yersinia, or Campylobacter was studied in 2003. Forty patients were given lymecycline or a placebo.14 The study concluded that the ReA duration in patients who took 300mg of lymecycline three times a day was shorter than those on the placebo, but only in patients with Chlamydia trachomatis-triggered ReA.14 A follow-up study was conducted involving 23 of the original 40 subjects in the study 10 years after the initial ReA diagnosis. The results concluded that there was no significant difference in ReA patients on lymecycline compared to those on placebo.14 The efficacy of a 10-day doxycycline treatment versus a 4-month course was investigated in patients with Chlamydia trachomatis-reactive arthritis. All patients received 100mg of doxycycline twice a day for 10 days, then some continued to receive the doxycycline, while others were given a placebo for 4 months. Of the 37 patients involved in the study (17 on short term treatment, and 15 on long-term treatment), only two patients from each group went into remission.15 The trial concluded that prolonged treatment with doxycycline is not beneficial in treating patients with chronic ReA due to Chlamydia trachomatis.15

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Although the evidence is relatively weak regarding antibiotics and ReA treatment, the medications should still be used when there is evidence of a bacterial infection causing ReA. 15 Prognosis and/or complications associated with Reactive Arthritis The course of ReA varies substantially based on the patient’s clinical presentation and history of infectious disease. The triggering pathogen, genetic background of the patient, other persisting medical illnesses, and whether or not patients were identified in rheumatology clinics all affect the prognosis.11 The majority of patients clear the disease from their system in 6 months or less.13 A study conducted by the European League Against Rheumatism followed 152 people with ReA, and almost all of the subjects’ symptoms were gone within 24 weeks.13 However, after entering remission, some patients still noted sporadic periods of joint and spine pain. It has not been confirmed who is susceptible to chronic arthritis and what the contributing factors are.13 Patients with chronic ReA have a higher risk of developing other inflammatory diseases, such as inflammatory bowel disease, psoriasis, and ankylosing spondylitis.13

Behavioral, social, educational management Due to the strong correlation of enteric and genitourinary bacterial infections to ReA, researchers recommend that prevention of these infections is the best way to avoid ReA.1 Prompt treatment of acute Chlamydia infections in both patients and all their partners may lower the risk of developing ReA.1 These patients should be treated with antibiotics and require close follow-up.1 Patients with enteric infections also require antibiotics and close follow-up. Patient education is important in all clinical settings. Informing patients regarding the risks of traveling to countries where causative organisms are endemic, and the risks associated with being infected with C.trachomatis, Salmonella, Shigella, and other

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organisms linked to ReA can encourage patients to take extra precautions. Patients should also be informed to stay up to date on their immunizations. Living with ReA can be painful and frustrating. Support groups, such as The Reiter’s Info/Support Group, is an example of an organization offering psychological and emotional support to patients with acute and chronic ReA. Health care providers should spend time teaching their patients about the options available to receive support while living with acute or chronic ReA. Follow-up and referral Referral to a rheumatologist is very important when a patient presents to a general practice clinician, dermatologist, orthopedist, or the emergency department. There are not specific guidelines for follow-up of ReA patients. The goals of treatment are to decrease pain and inflammation, minimize disability, and prevent progression of the diease. 2 If the patient starts to relapse, or the efficacy of the medications decrease, they are encouraged to see their rheumatologist for re-evaluation.1

Summary Reactive arthritis is a rare inflammatory disease of the joints that usually occurs after a bacterial infection of the gastrointestinal or genitourinary tracts. Common signs and symptoms associated with ReA include arthritis, conjunctivitis, and urethritis.1 Serology, urine, and stool testing is used to diagnose previous or ongoing infections and sexually transmitted diseases. A joint aspiration is critical if septic arthritis is suspected.1 Testing for HLA-B27 is recommended in patients with suspected ReA. Patients with ReA usually present to a variety of health care providers, but should be referred to a rheumatologist immediately. Since there are not specific diagnostic criteria for ReA, the diagnosis is clinical based on serological and imaging studies. A two-week course of NSAIDs at a dose of at least 500 mg twice daily is the first-line treatment for acute ReA.13 DMARDs can also be used. Intraarticular injections of corticosteroids can be added if oral NSAID treatment is not sufficient in decreasing inflammation. Antibiotic therapy is recommended in patients with an untreated Chlamydia

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trachomatis genitourinary infection.2 Long-term antibiotic therapy in patients with chronic ReA is not recommended.1 The best prevention of ReA is to avoid gastrointestinal and genitourinary bacterial infections, including sexually transmitted diseases. Prompt treatment of these infections is critical in preventing ReA. In most patients ReA spontaneously goes away within six months. However, a minority of patients suffer from chronic ReA with symptoms lasting more than six months.2 The health care provider should counsel these patients on living with ReA, and offer emotional and psychological support.

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References i

Yu D. Reactive Arthritis. Sept. 20, 2009. UpToDate. www.uptodate.com.

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Kim P, Klausmeier T, Orr D. Reactive Arthritis: A Review, Journal of Adolescent Health.

2009;44:309-315. iii

Townes, J. Reactive Arthritis after Enteric Infections in the United States: The Problem of

Definition. Clinical Infectious Disease. 2010: 50: 247-254. 4

Hughes K. Reiter’s syndrome and reactive arthritis: A current view. Seminars in Arthritis and

Rheumatism. 1994;24:190-210. 5

Kataria R, Brent L. Spondyloarthropathies. American Family Physician. 2004:69.2853-2860.

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Eapen B. A new insight into the pathogenesis of Reiter’s syndrome using bioinformatics tools.

International Journal of Dermatology. 2003:42,242-243. 7

Romaní J, Puig L, Baselga E, De Moragas JM. Reiter's syndrome-like pattern in AIDS-

associated psoriasiform dermatitis. Int J Dermatol. Jul 1996;35(7):484. 8

Bas S, Vischer T. Male sex predominance in Chlamydia trachomatis sexually acquired reactive

arthritis: Are women more protected by anti-Chlamydia antibodies? Annals of Rheumatic Diseases. 2001; 60:605-611. 9

Leirialo R. Reactive arthritis. Scandinavia Journal of Rheumatology. 2005; 34:251.

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Fendler L, Sorensen H. Frequency of triggering bacteria in patients with reactive arthritis and

undifferentiated oligoarthritis and the relative importance of the tests used for diagnosis. Annals of Rheumatic Diseases. 2001; 60: 337. 11

Hannu T. Reactive arthritis or post-infectious arthritis? Best Practices and Research Clinical

Rheumatology. 2006; 20:419.

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Kvien T, Gaston, JS. Bardin, T. Three month treatment of reactive arthritis with azithromycin:

a EULAR double blind, placebo controlled study. Annals of Rheumatic Diseases. 2004; 53:1113. 13

Sieper J, Rudwaleit M, Braun J. Diagnosing reactive arthritis: role of clinical setting in the

value of serologic and microbiologic assays. Journal of Arthritis and Rheumatology. 2002; 46:319. 14

Kaasila K, Laasonen L, Leirisalo M. Antibiotic treatment and long term prognosis of reactive

arthritis. Annals of Rheumatic Diseases. 2003; 62:655-658. 15

Putschky, N. Pott, H. Kuipers JG, et al. Comparing 10-day and 4-month doxycycline courses

for treatment of Chlamydia trachomatis-reactive arthritis: a prospective, double-blind trial. Annals of Rheumatic Diseases: 2006; 65:1521-1524. Tables and Figures: Table 1: Comparing Clinical Presentation of Reactive Arthritis with other Spondyloarthropathies Type of arthritis Arthritis Pattern Extra-articular symptoms Asymmetric mono or oligoarthritis Ophthalmologic, musculoskeletal, Reactive arthritis often in lower extremities genitourinary, dermatologic, or cardiovascular signs and symptoms Large joints affected (hip, knee, May cause growth failure and delayed puberty Enteropathic arthritis wrists) Inflammatory, asymmetric Variable presentations possible. Psoriatic arthritis oligoarthritis. Distal joints can be affected Source: Kim P, Klausmeier T, Orr D. Reactive Arthritis: A Review, Journal of Adolescent Health. 2009;44:309315.

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