Reactive arthritis (ReA) is inflammatory arthritis which manifests after several days to weeks after a gastrointestinal or genitourinary infection. It is also described as a classic triad of arthritis, urethritis and, conjunctivitis. However, a majority of patients do not present with the classic triad. It was previously called "Reiter syndrome", named after Hans Reiter, who first described this syndrome. The name, Reiter syndrome was dismissed because it is believed that Hans Reiter was a member of The National Socialist German Workers' Party or the “Nazis” and the director of the Kaiser Wilhelm Institute of Experimental Therapy under whose leadership the war prisoners were subject to many inhumane experiments. Today, it is believed that the disorder is due to autoimmunity in response to an infection from a gastrointestinal infection caused by Salmonella, Shigella, Campylobacter or chlamydia.
Reactive arthritis is known to be triggered by a bacterial infection, particularly of the genitourinary (Chlamydia trachomatis, Neisseria gonorrhea, and Ureaplasma urealyticum) or gastrointestinal (GI) tract (Salmonella enteritidis, Shigella, Yersinia enterocolitica, Campylobacter jejuni, Clostridium difficile). The incidence is about 2% to 4% after a urogenital infection mainly with chlamydia trachomatis and varies from 0% to 15% after gastrointestinal infections with Salmonella, Shigella, Campylobacter, or Yersinia. This might be affected by the epidemiological, environmental factors, the pathogenicity of the bacteria, and differences in the study designs. The enteric ReA occurs commonly following enteric infections. However, chlamydia associated ReA is endemic, especially in developed countries.
Reactive arthritis is relatively rare, and the incidence in population-based studies is reported to be 0.6 to 27 per 100,000. Reactive arthritis is more common in adult males in the second and third decades of their life.
About 1-3% of patients with nonspecific urethritis will develop an episode of arthritis. Overall, higher disease activity and worse functional capacity are seen in the lower socioeconomic populations.
Reactive arthritis is an immune-mediated syndrome triggered by a recent infection. It is hypothesized that when the invasive bacteria reach the systemic circulation, T lymphocytes are induced by bacterial fragments such as lipopolysaccharide and nucleic acids. These activated cytotoxic-T cells then attack the synovium and other self-antigens through molecular mimicry. This is supported by the evidence of Chlamydia trachomatis and C pneumoniae ribosomal RNA transcripts, enteric bacterial DNA and bacterial degradation products in the synovial tissue and fluid. It is believed that anti-bacterial cytokine response is also impaired in reactive arthritis, resulting in the decreased elimination of the bacteria. It is, however, unclear why such localization of inflammation occurs.
The prevalence of HLA-B27 in reactive arthritis is estimated at 30% to 50% in patients with reactive arthritis, although values range widely. In hospital-based studies with more severely affected patients, frequencies as high as 60% to 80% have been reported. HLA-B27 should not be used as a diagnostic tool for a diagnosis of acute ReA. The presence of HLA-B27 is believed to potentiate reactive arthritis by presenting bacterial antigens to T cells, altering self-tolerance of the host immune system, increased TNF-alpha production, promoting invasion of microbes in the gut, and delayed clearance of causative organisms.
Initially, the dermal histopathological features of reactive arthritis are similar to psoriasis. examination of the synovial fluid will reveal large macrophages, reiter cells that have phagocytosed neutrophils, lymphocytes and plasma cells. Extensive pannus formation is very rare.
Patients typically present with acute onset oligo-arthritis, mainly involving the lower extremities, sacroiliac joint, and the lumbar spine. Other extra-articular manifestations such involving the skeletal system (enthesitis, dactylitis), eye (conjunctivitis, anterior uveitis episcleritis, and keratitis), genitourinary (urethritis, cervicitis, prostatitis, salpingo-oophoritis, cystitis or circinate balanitis), mucosal and skin involvement (mucosal ulcers, keratoderma blennorrhagica and erythema nodosum), cardiac (carditis, aortic, conduction and valvular abnormalities), and nail changes (onycholysis, subungual keratosis, or nail pits) also are seen.
These symptoms manifest several days to weeks after the initial infection. Diarrhea or other symptoms caused by the offending agents are usually resolved by the time the patient develops arthritis. A detailed history and physical examination to investigate any recent illness such as urethritis, diarrhea, etc, should be performed. ReA can be self-limiting, recurrent or continuous and about 20% to 25% of the patients may progress to have chronic articular, ocular and cardiac complications.
Reactive arthritis is very common in HIV individuals and hence patients with new-onset disease must have HIV ruled out. Individuals with HIV who develop reactive arthritis often develop severe psoriasiform dermatitis on the scalp, soles, palms, and flexures.
The physical exam may reveal:
Two or more of the above features plus involvement of the skeletal system establishes the diagnosis.
Joint and entheses
The involvement is asymmetric and affects the weight bearing joint. The joints are often warm, painful and swollen. Tendinitis is a common feature of the disease.
Skin and mucocutaneous changes are also common and may include hyperkeratotic skin and erythematous dermatitis. Nail dystrophy is common.
Eye involvement is common and may include conjunctivitis or uveitis.
Although reactive arthritis is a clinical diagnosis, laboratory tests to detect the offending pathogens to confirm concomitant or preceding infections are usually performed to support the diagnosis. Nucleic acid amplification tests to detect early morning urine sample or urogenital swab to detect chlamydia trachomatis. Positive evidence of Chlamydia by polymerase chain reaction (PCR) in the joint is probably strongly diagnostic, but the current methods used for the detection of chlamydia in the urine are not validated for diagnostic purposes for synovial samples. Serological testing for Chlamydia trachomatis is of limited importance due to serological cross-reactivity between Chlamydia trachomatis and Chlamydia pneumoniae, inability to distinguish past and present infection by the persistence of antibodies, lower or absent antibody response in lower urinary tract infections. Serological testing is available for Salmonella, Yersinia, and Campylobacter but is not useful in clinical practice. There are also gastrointestinal infections, for example, Shigella, in which no reliable serological methods exist. A stool culture may be helpful to detect enteric pathogens.
Acute phase reactants such as the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) may be elevated. Joint aspiration must be performed when possible to rule out other arthritis. The findings in synovial fluid are nonspecific and are characteristic of inflammatory arthritis, with elevated leukocyte counts (typically 2000 to 4000 WBC per ml), with neutrophil predominance.
HLA B 27 can be measured as it correlates with the severity of the disease but is not diagnostic. In immigrants, the tuberculin skin test should be performed.
Plain radiographs may reveal nonspecific inflammatory joint findings, in the acute phase. Ultrasonography or magnetic resonance imaging (MRI) can be used to diagnose peripheral synovitis, enthesitis, or sacroiliitis. Scintigraphy can reveal early stages of enthesitis.
Aspiration of the joint is often done to rule out septic arthritis and crystalline arthritis.
The goals of therapy in reactive arthritis is to provide symptomatic relief and prevent chronic complications. Non-steroidal anti-inflammatory drugs are the initial treatment of choice in the acute phase. Intra-articular or local glucocorticoids as in case of enthesitis or bursitis can be used if the patient has mono/oligoarthritis. Systemic use of glucocorticoids is limited to severe polyarthritis, cardiac and ocular manifestations. Treatment of the underlying concomitant infection, if present should be initiated without delay. Patients who do not have active infection do not benefit from antibiotic therapy. Disease-modifying antirheumatic drugs (DMARDs), mainly Sulphasalazine have shown to be effective in both acute and chronic ReA. Other agents such as methotrexate and azathioprine have shown to be useful in chronic arthritis. They are indicated in patients who have failed Nonsteroidal anti-inflammatory drug (NSAID) therapy. Biologicals such as tumor necrosis factor (TNF) blocking agents (e.g., and infliximab and etanercept have been suggested in the treatment of reactive arthritis. However, further studies are needed to determine their role in the treatment of ReA.
All patients should be urged to become physically active.
The physician should be able to rule out conditions that present with similar clinical findings.
The most common differential diagnosis should include:
Rheumatoid arthritis usually has a self-limited course and the symptoms resolve within 3- 12 months. Patients who are HLA-B27 positive have a higher risk of recurrence of ReA. 15-30% of patients with ReA can develop long-term arthritis or other joint abnormalities. The presence of hip involvement, unresponsiveness to NSAIDs and ESR greater than 30 portend a worse outcome.
Complications of ReA include:
The patient is advised to have regular follow-ups with his primary physician and orthopedic physician to assess for any level of damage caused by the infection.
Some studies have suggested that appropriate treatment of acute GU infection with a 3-month course of antibiotics can prevent ReA. However, this is highly controversial.
Reactive arthritis is a multiorgan disorder that is best managed by a team of healthcare professionals that includes a rheumatologist, ophthalmologist, gastroenterologist, physical therapist, nurse, and pharmacist.
There is no cure for reactive arthritis and the treatment is supportive. All patients should be encouraged to become physically active and a physical therapy consult should be obtained.
The pharmacist should educate the patient on the types of drugs used, their benefits and side effects. If patients are prescribed steroids, the side effects must be closely monitored and the drugs tapered as soon as the clinical symptoms subside.
A consult with a dermatologist is recommended to assess skin lesions and recommend treatment.
The key feature is patient education to help improve physical conditioning, function, and quality of life. The patient should participate in regular exercises to improve exercise endurance and prevent joint stiffness. In addition, the nurse practitioner should educate the patient about safe sex practices to prevent STDs. Because the disorder can induce anxiety and depression, a mental health nurse should follow these patients and offer counseling.
The progression of reactive arthritis is variable, but in most people, the disorder is self-limited with the resolution of the symptoms occurring by 6-18 months. Mortality is very rare today and is usually due to the treatments. In general, causes related to sexually transmitted infections have a worse outcome than those caused by gastrointestinal infections. Despite a cure, recurrences are known to occur in 25-50% of cases, especially those who are HLA-B27 positive. Reactivation may signal a new infection or stress. About 20% of patients will have a long-term disease that results in enthesitis and destructive arthritis. Elevation of ESR, lack of response to NSAIDs and involvement of the hip joint usually is indicative of poor outcome. (Level V)
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