Reactive Arthritis

Definition, Etiology, PathogenesisTop

Reactive arthritis (ReA) is an inflammatory arthritis, usually asymmetric, oligoarticular or polyarticular, that mostly affects the lower extremities. While the arthritis itself is sterile, ReA typically follows a preceding infection at a distant site, usually of the gastrointestinal or genitourinary tract (sexually acquired reactive arthritis [SARA]). The most frequent organisms include enteric gram-negative rods of Enterobacteriaceae family (Salmonella spp, Yersinia spp, Campylobacter spp, Shigella spp) and Chlamydia spp (Chlamydia trachomatis, Chlamydia pneumoniae). Less frequent organisms include Clostridioides difficile, Vibrio parahaemolyticus, BCG vaccine strains of Mycobacterium bovis (following intravesical administration in treatment of bladder cancer), and Mycoplasma spp (eg, Ureaplasma urealyticum). The immune response to bacterial antigens plays a key role in the pathogenesis of ReA.

Clinical Features and Natural HistoryTop

The preceding infection can occur up to 6 weeks prior to the onset of arthritis. The patient may not be able to recall the infection if symptoms were mild or absent.

1. Systemic symptoms are usually absent but may include malaise, weakness, and fever.

2. Musculoskeletal manifestations:

1) Acute-onset asymmetric oligoarthritis, often affecting the lower extremities (knees, ankles, feet). About 50% of patients can have upper limb involvement. Some develop polyarthritis of the small joints. A small proportion of patients can have arthritis lasting >6 months (termed chronic reactive arthritis).

2) Enthesitis can occur in 20% to 90% of patients. Common sites include the Achilles insertion and plantar fascia insertion on the calcaneus. Heel pain and difficulty walking are symptoms of Achilles tendonitis/enthesitis and plantar fasciitis.

3) Dactylitis frequency is variable but can affect up to 40% of patients.

4) Lower back pain (sacroiliac region and buttocks) and spinal pain/stiffness are symptoms of sacroiliitis and spondylitis. This can occur in up to 50% of patients.

3. Genitourinary manifestations:

1) Vesicles, erosions, or macules, mainly in the external urethral orifice, on the glans penis (termed circinate balanitis), and on the penile shaft. These lesions are more frequent in patients with SARA (up to 70%). They are painless (unless infected) and do not cause scarring.

2) Urethral discharge and dysuria (in men these may be accompanied by prostatitis, orchitis, epididymitis, and cystitis). Symptoms of urethritis or cystitis are present in ~80% of patients with SARA (especially in the case of Chlamydia trachomatis infection). Reactive urethritis is possible in 10% to 30% of patients with enteric infection.

3) Cervicitis or vaginitis in women with SARA is often asymptomatic.

4. Cutaneous and mucosal manifestations:

1) Vesicular lesions with scaling and hyperkeratosis of the soles, papular inflammatory lesions on palms and soles (keratoderma blennorrhagicum). This occurs in 10% to 30% of patients with SARA or less commonly in intestinal infections.

2) Yellowish or grey discolorations, thickening, furrows, and heaped-up hyperkeratosis (mainly in patients with chronic ReA).

3) Erythema nodosum, mainly in patients with Yersinia spp infection.

4) Painless shiny aphthous ulcers on the palate, tongue, and mucosa of the cheeks and lips.

5. Ocular manifestations:

1) Conjunctivitis, usually mild (erythema, lacrimation, rarely lid edema), is often an early manifestation of ReA. It usually resolves after a week but may persist for several months.

2) Acute anterior uveitis (in 10%-20% of patients with positive HLA-B27) causes unilateral eye pain with erythema, lacrimation, photophobia, and blurred vision. It usually resolves quickly with appropriate therapy.

6. Other signs and symptoms: Cardiac involvement (in <10% of patients, mainly those with chronic ReA) causing conduction disturbances and nonspecific ST and T changes found on electrocardiography (ECG); additional cardiac manifestations may include aortic regurgitation, pericarditis, myocarditis, and aortitis involving the ascending aorta. Other features may involve serositis, microscopic colitis, and meningitis (very rare).

The natural history of ReA is highly variable and probably depends on the infectious organism and the patient’s genetic predisposition. Disease duration is typically 3 to 5 months, with most patients having either complete resolution or minimal disease activity within 6 to 12 months of presentation. However, 5% to 20% of patients may have more chronic persistent arthritis. Some patients with chronic ReA may develop features of another spondyloarthropathy, for instance, psoriatic arthritis, ankylosing spondylitis, or enteropathic arthritis. HLA-B27 has been associated with worse prognosis in some studies. Patients with the triad of postinfectious arthritis, urethritis, and conjunctivitis may also have a poorer prognosis.

DiagnosisTop

Diagnostic Tests

1. Laboratory tests: Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels (common but not in all patients), mild leukocytosis, thrombocythemia, anemia, sterile pyuria (rare), positive HLA-B27 (varies widely; 30%-90% of patients).

2. Microbiologic studies:

1) Gastrointestinal specimens: Stool cultures during acute diarrheal illness to test for Salmonella, Shigella, Campylobacter, and Yersinia. Cultures are usually of little value afterwards, as the diarrhea has usually resolved by the time arthritis develops.

2) Genitourinary specimens: First-catch urine and genital swab (cervical, urethral) testing can detect C trachomatis using nucleic acid amplification techniques.

3) Serologic testing is primarily used in epidemiologic studies and is less useful in clinical practice. In patients with Yersinia and Salmonella infections, serologic studies reveal a ≥4-fold increase in the specific IgG levels within a few weeks of infection.

3. Synovial fluid examination is performed mainly to exclude other causes of arthritis. Findings are nonspecific and characteristic of inflammatory arthritis. Synovial fluid culture is negative as ReA is not septic arthritis.

4. Imaging studies: In acute ReA findings on radiographs are usually limited to joint swelling. In patients with chronic ReA changes similar to other seronegative spondyloarthropathies (erosions, joint space loss, new bone formation) may be seen. In patients with axial disease radiographic sacroiliitis can be seen in some patients. Magnetic resonance imaging (MRI) of the spine (if clinically indicated) may reveal early changes (synovitis, enthesitis, osteitis).

Diagnostic Criteria

The diagnosis of ReA is based on establishing a relationship between the clinical features and a prior infection of the intestinal or genitourinary tract with organisms causing ReA. In patients with SARA a complete workup for sexually transmitted diseases (including gonorrhea) and investigation of the patient’s sexual partners is indicated.

Differential Diagnosis

Other spondyloarthritides, septic arthritis, postinfectious arthritis (Lyme disease, postviral and poststreptococcal arthritis), crystal arthropathy, Behçet disease, sarcoidosis, trauma.

TreatmentTop

Treatment of Arthritis and Enthesitis

1. Limitation of physical activity, particularly of walking in patients with arthritis of the lower extremities.

2. Physiotherapy aimed at reducing symptom severity, maintaining joint motion, and preventing muscle atrophy.

3. Pharmacologic treatment:

1) Nonsteroidal anti-inflammatory drug (NSAIDs) are the mainstay of treatment in early ReA (agents and dosage: see Table 2 in Osteoarthritis).Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and indirectness. Carlin EM, Ziza JM, Keat A, Janier M. 2014 European Guideline on the management of sexually acquired reactive arthritis. Int J STD AIDS. 2014 Nov;25(13):901-12. doi: 10.1177/0956462414540617. Epub 2014 Jun 27. PMID: 24974322.

2) Intra-articular glucocorticoids administered intra-articularly (after septic arthritis has been excluded) or systemically via oral or IM route (as in treatment of rheumatoid arthritis) can provide rapid relief.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and indirectness. Carlin EM, Ziza JM, Keat A, Janier M. 2014 European Guideline on the management of sexually acquired reactive arthritis. Int J STD AIDS. 2014 Nov;25(13):901-12. doi: 10.1177/0956462414540617. Epub 2014 Jun 27. PMID: 24974322.

3) Systemic glucocorticoids (oral or IM) in patients with oligoarthritis or polyarthritis with inadequate response or contraindication to NSAIDs. Low to moderate starting doses, for instance, 20 to 40 mg prednisone (as in treatment of rheumatoid arthritis) can provide a rapid relief, followed by taper.Evidence 3Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and indirectness. Carlin EM, Ziza JM, Keat A, Janier M. 2014 European Guideline on the management of sexually acquired reactive arthritis. Int J STD AIDS. 2014 Nov;25(13):901-12. doi: 10.1177/0956462414540617. Epub 2014 Jun 27. PMID: 24974322.

4) Disease-modifying antirheumatic drugs (DMARDs) (agents, dosage, contraindications, adverse effects: see Table 3 in Rheumatoid Arthritis) are used if NSAIDs and glucocorticoids are ineffective in early disease or if arthritis becomes chronic.

a) Conventional synthetic DMARDs: Sulfasalazine (moderate efficacy in patients with peripheral arthritis, ineffective in patients with axial arthritis or enthesitis).Evidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias. Clegg DO, Reda DJ, Weisman MH, et al. Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter's syndrome). A Department of Veterans Affairs Cooperative Study. Arthritis Rheum. 1996 Dec;39(12):2021-7. PubMed PMID: 8961907. When ineffective, use methotrexate.

b) Biologic DMARDs: Infliximab, etanercept, adalimumab have been used with success in patients with severe ReA.

Treatment of Cutaneous and Mucosal Manifestations

1. Cutaneous lesions: Mild lesions require no treatment. In patients with moderate lesions use keratolytic agents (eg, topical salicylates), topical glucocorticoids, or calcipotriene (INN calcipotriol) cream or ointment. In patients with severe lesions use methotrexate or retinoids.

2. Circinate balanitis: Use weak topical glucocorticoids (eg, hydrocortisone cream).

Treatment of Anterior Uveitis

Glucocorticoids in the form of eye drops (or oral in patients not responding to topical treatment) and mydriatics.

Treatment of Infection

1. Antimicrobial treatment is indicated only in patients with a documented active infection and is mainly used for Chlamydia spp infection. Antimicrobial treatment does not prevent the development of ReA.

2. C trachomatis infection: Early antimicrobial treatment in patients with C trachomatis urethritis (see Urethritis) reduces the risk of recurrence and development of chronic ReA.

3. C pneumoniae infection: see Community-Acquired Pneumonia.

4. C difficile infection: see Clostridioides difficile Infection.