Reactive Arthritis

Etiology

Reactive arthritis is known to be triggered by a bacterial infection, particularly of the genitourinary (Chlamydia trachomatis, Neisseria gonorrhea, Mycoplasma hominis, and Ureaplasma urealyticum) or gastrointestinal (GI) tract (Salmonella enteritidis, Shigella flexneri, and S. disenteriae, 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 and 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.[4][5] Rare cases have been reported after administering the Bacillus Calmette Guerin vaccine treatment for bladder cancer.[6]

Epidemiology

Reactive arthritis is relatively rare, and the incidence in population-based studies is reported to be 0.6 to 27 per 100,000. It is more common in adult males in the second and third decades of life.[7] About 1-3% of patients with nonspecific urethritis develop an arthritis episode. Overall, higher disease activity and worse functional capacity are seen in the lower socioeconomic populations.

Pathophysiology

Reactive arthritis is an immune-mediated syndrome triggered by a recent infection. It is hypothesized that T lymphocytes are induced by bacterial fragments such as lipopolysaccharide and nucleic acids when invasive bacteria reach the systemic circulation. These activated cytotoxic-T cells attack the synovium and other self-antigens through molecular mimicry. The evidence of Chlamydia trachomatis and C pneumoniae ribosomal RNA transcripts, enteric bacterial DNA, and bacterial degradation products in the synovial tissue and fluid supports this. It is believed that anti-bacterial cytokine response is also impaired in reactive arthritis, resulting in decreased bacteria elimination. 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 diagnosing acute ReA. The presence of HLA-B27 is believed to potentiate reactive arthritis by presenting bacterial antigens to T cells, altering the self-tolerance of the host immune system, increasing tumor necrosis factor-alpha production, promoting the invasion of microbes in the gut, and delaying clearance of causative organisms.[8]

Histopathology

Initially, the dermal histopathological features of reactive arthritis are similar to psoriasis. Examination of the synovial fluid reveals large macrophages, reiter cells with phagocytosed neutrophils, lymphocytes, and plasma cells. Extensive pannus formation is very rare.

History and Physical

These symptoms manifest several days to weeks after the initial infection. Diarrhea or other symptoms caused by the offending agents are usually resolved when the patient develops arthritis. A detailed history and physical examination should be performed to investigate recent illnesses such as urethritis, diarrhea, etc. 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. For sexually acquired reactive arthritis, there is a history of sexual intercourse, usually with a new partner, within 3 months of arthritis symptoms. Genital symptoms precede arthritis by about 2 weeks on average. It may include dysuria, discharge, testicular pain in men, intermenstrual or postcoital bleeding, or deep pelvic pain apart from vaginal discharge in women.[9] Reactive arthritis is very common in HIV individuals, and hence, patients with the 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.

Physical Exam

• Sausage-shaped finger, toe, or heel pain
• Asymmetric oligoarthritis- usually of the lower extremities
• Conjunctivitis or iritis
• Acute diarrhea or cervicitis within 4 weeks of the onset of arthritis
• Urethritis or genital ulcers

Two or more of the above features plus involvement of the skeletal system establishes the diagnosis.

Joint and entheses

Patients typically present with acute onset oligo-arthritis, mainly involving the lower extremities, sacroiliac joint, and the lumbar spine. Not more than 6 large joints are affected at a time, and the knee and ankle are the most commonly affected. Joint pain is classically nocturnal with early morning stiffness. 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. About 30% of patients suffer from associated enthesitis in the form of plantar fasciitis or Achilles tendinitis.[10]

Extra-articular manifestations 

Extra-articular manifestations may involve 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. Skin and mucocutaneous changes are common and may include hyperkeratotic skin and erythematous dermatitis. Nail dystrophy is common. Other involvements include pustular psoriasis on the sole (keratoderma menorrhagia), geographic tongue, circinate balanitis, or oral ulceration. Eye involvement is common and may include conjunctivitis (30%) or uveitis. In patients with visual symptoms, recognizing uveitis is paramount as it can rapidly lead to visual loss. Rare cases can involve the cardiovascular system, causing conduction abnormalities in early-stage and aortic regurgitation when advanced. Myelopathy, as well as non-specific gastrointestinal features of diarrhea and colitis, can also persist.[11]

Evaluation

Reactive Arthritis falls within the subclass of seronegative spondyloarthropathies that affect the axial skeleton. Other members of that group are Ankylosing spondylitis and Psoriatic arthritis. Joint involvement is oligoarticular and asymmetrical. 

American College of Rheumatology developed diagnostic guidelines for Reactive arthritis in 1999. The criteria were divided into 

MAJOR

• Asymmetric oligo or monoarthritis involving lower extremities
• Either enteritis or urethritis symptoms preceding the onset of arthritis by a time interval of 3 days to 6 weeks

MINOR

• The presence of a triggering infection, as evidenced by culture positivity
• The presence of persistent synovial involvement

Genitourinary symptoms, metatarsophalangeal joint involvement, elevated C reactive protein, and positive HLA- B27 render a 69% sensitivity and 93.5% specificity in diagnosing reactive arthritis.[12] 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 from an early morning urine sample or urogenital swab are utilized to detect Chlamydia trachomatis and Neisseria gonorrhea. A nucleic acid amplification test for Mycoplasma genitalium is also available nowadays and is relevant in men with urethritis. Positive evidence of Chlamydia by polymerase chain reaction (PCR) in the joint is probably strongly diagnostic. However, the current methods used to detect 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, such as Shigella, for which no reliable serological methods exist. A stool culture may help detect enteric pathogens.[13][14]

Certain complications, like uveitis, are important to identify. The slit-lamp exam helps diagnose cells in the anterior chamber in acute iritis. Therefore, ocular symptoms in a suspected patient should generate a prompt referral to an ophthalmologist. The usual presentation of uveitis involves acute pain, photophobia, visual impairment, scleral injection, and hypopyon.

Acute phase reactants such as the erythrocyte sedimentation rate (ESR) or C-reactive protein may be elevated. Joint aspiration must be performed when possible to rule out other arthritis. Aspiration of the joint is often done to rule out septic arthritis and crystalline 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. It is also important in the localization of arthritis. Sacroiliitis occurs more commonly in HLA B 27-positive patients [15]. In a patient from an endemic population, the tuberculin skin test should be performed. Plain radiographs may reveal nonspecific inflammatory joint findings in the acute phase. Ultrasonography or magnetic resonance imaging can diagnose peripheral synovitis, enthesitis, or sacroiliitis. Scintigraphy can reveal the early stages of enthesitis.

Treatment / Management

If an infectious agent has been identified as a trigger for reactive arthritis, antimicrobial therapy is recommended, often for 3 to 6 months. It can significantly shorten the time to remission.[16] Treatment of the underlying concomitant infection, if present, should be initiated without delay. Patients who do not have an active infection do not benefit from antibiotic therapy.[17] Vasey et al reported the results of a double-blinded prospective triple placebo trial in which Chlamydia-positive patients by PCR were treated for 6 months with a combination of doxycycline and rifampin or azithromycin and rifampin. The treatment arm achieved statistically significant symptom remission and PCR negativity, although the study was underpowered to identify the preferred combination of antibiotics. (A1)

The goal 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 cases of enthesitis or bursitis, can be used if the patient has mono/oligoarthritis. Mechanical devices like orthotics and insoles can be useful. Systemic use of glucocorticoids is limited to severe polyarthritis and cardiac and ocular manifestations. Disease-modifying antirheumatic drugs, mainly sulphasalazine, are effective in both acute and chronic ReA. Other agents, such as methotrexate and azathioprine, are useful in chronic arthritis. They are indicated in patients who have failed Nonsteroidal anti-inflammatory drug (NSAID) therapy. Biologicals such as tumor necrosis factor blocking agents (eg, infliximab and etanercept have been suggested in treating reactive arthritis. However, further studies are needed to determine their definitive indications.[18][19][20] All patients should be urged to become physically active. Strengthening exercises are a key component of long-term therapy to prevent muscle wasting. (A1)

Differential Diagnosis

The physician should be able to rule out conditions that present with similar clinical findings. The most common differential diagnosis should include:

• Gonococcal arthritis 
• Gouty arthritis 
• Still disease 
• Septic arthritis
• Rheumatic fever 
• Psoriatic arthritis 
• Ankylosing spondylitis
• Rheumatoid arthritis
• Immunotherapy/immunization–related arthropathy
• Secondary syphilis
• Tubercular arthritis 

Prognosis

Reactive arthritis usually has a self-limited course, and the symptoms resolve within 3 to 5 months. Symptoms lasting beyond 6 months indicate a chronic element of the disease. Sacroiliitis is the most common chronic joint involvement. 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

Complications of ReA include:     

• Recurrent arthritis (15 to 50%)    
• Chronic arthritis or sacroiliitis 
• Ankylosing spondylitis (30 to 50% if the patient is also HLA-B27–positive)    
• Urethral stricture
• Aortic root necrosis 
• Cataracts    
• Cystoid macular edema