Reactive ArthritisDz

Synonyms: Reiter ’s syndrome, sexually acquired reactive arthritis.

ICD-9 Code: 099.3.

ICD-10 Code: M02

Definition: Reactive arthritis is an acute inflammatory arthritis occurring 1 to 4 weeks after an infection. It is characterized by a postinfectious onset, asymmetric oligoarthritis, and extraarticular sites of inflammation, often in association with HLA-B27. The arthritis is usually self-limited but may be chronic and disabling.

Etiology: HLA-B27 positivity is seen in 75% to 80% of whites with reactive arthritis, but only 50% of African Americans. HLA-B27 is associated with increased disease susceptibility and severity and risk of spinal ankylosis and uveitis. Arthritogenic bacteria have been associated with reactive arthritis, possibly with molecular mimicry between bacterial antigens and HLA-B27. Whereas postdysenteric reactive arthritis may arise in HLA-B27–negative patients, postvenereal onset is often HLA-B27 related.

Pathology: Characteristic findings include inflammatory synovitis, inflammation and erosions at the insertion of ligaments and tendons (entheses), excessive production of heterotopic bone at sites of inflammation, and cutaneous pathology similar to that observed in psoriasis. Subclinical intestinal inflammation of the terminal ileum or colon occurs in 60% of patients and may parallel the clinical status and response to therapy.

Demographics: Reactive arthritis is the most common cause of inflammatory arthritis in young men. In Minnesota, the age-adjusted incidence for males (<50 years) was 3.5 cases per 100,000 men. Recent studies suggest that its frequency is decreasing in the HIV era, possibly because of increased use of condoms. Peak onset is during the third decade, but reactive arthritis may also be seen in children. Male:female ratio is 5:1 or 6:1 or higher. Women may go undiagnosed because of occult genitourinary disease and less severe arthritis. Postvenereal disease is more common in males, yet the postdysenteric syndrome affects men and women equally. With epidemic dysentery owing to arthritogenic strains, 5% of infected individuals and 20% of infected HLA-B27–positive individuals develop reactive arthritis.

Infectious Triggers: The most common pathogens known to induce reactive arthritis are enteric (Shigella, Salmonella, Yersinia, and Campylobacter) or urogenital/postvenereal (Chlamydia, Ureaplasma, HIV) pathogens. With enteric infections, the diarrheal illness resolves before the onset of arthritis (usually 1–4 weeks later). Patients with reactive arthritis who are HLA-B27 negative may have epidemic dysentery. Between 2% and 6% of patients develop Reiter ’s syndrome after epidemic dysentery owing to Shigella (Shigella flexneri) and Salmonella (Salmonella typhimurium). In most instances, no infectious cause can be identified.
—Chlamydia trachomatis: More than 50% of patients with reactive arthritis have antibodies to C. trachomatis. Rheumatic features of Chlamydia infections are similar to those described in classic reactive arthritis, except less than
50% are B27 positive, 15% have no urogenital features, and >50% develop chronic arthritis. Diagnosis is suggested by persistent mono- or oligoarthritis; genitourinary symptoms; positive serologic tests, cultures, or PCR evidence of chlamydial infection; and a response to antibiotic therapy.
—HIV and reactive arthritis: Although reactive arthritis has been described in patients with AIDS, studies have not shown an increased risk of Reiter ’s syndrome in HIV-positive populations matched for other risk factors. Most patients with AIDS with reactive arthritis are HLA-B27 positive and present with incomplete reactive arthritis with either (a) an additive, asymmetric polyarthritis or (b) an intermittent oligoarthritis. Dactylitis, conjunctivitis, urethritis, enthesitis, and fasciitis are common. These patients tend to have severe chronic disease and poor response to NSAIDs. Immunosuppressive drugs (i.e., MTX, azathioprine) should be avoided in such patients.

Cardinal Findings: The triad of arthritis, urethritis, and conjunctivitis defines reactive arthritis. However, <33% manifest the full triad. Most patients present with an acute, additive, lower extremity oligoarthritis. A careful history may reveal antecedent infection or extraarticular features to suggest the diagnosis.
—Onset (within 1–4 weeks of exposure): Onset is heralded by extraarticular features. Genitourinary involvement may manifest as dysuria, urethral discharge, prostatitis, cervicitis, or vaginitis. Fever, anorexia, malaise, fatigue, weight loss, and ocular symptoms (conjunctivitis or uveitis) are also common during onset.
—Arthritis: Typically an acute, asymmetric, additive, and ascending inflammatory oligoarthritis, involvement of the lower extremity (knees, ankles, and toes) is most common. The toes or fingers may be affected by dactylitis, resulting in a sausage digit. RA-like polyarthritis is uncommon.
—Axial disease: Symptomatic inflammatory back pain is present in ~50% of individuals. However, radiographic changes are seen in <20% of affected individuals. Sacroiliitis and spondylitis are seen in those with chronicity.
—Enthesitis: Inflammation at the insertion sites of tendon or ligament onto bone is called enthesitis. These sites are often painful but seldom swollen.

Common sites include the heel (insertion of Achilles tendon and plantar fascia), sausage digits, symphysis pubis, ischium, iliac crest, greater trochanter, and chest wall.
—Mucocutaneous: A sterile urethritis (in <33% of patients) may be transient in men and asymptomatic in women. Genitourinary symptoms are seen in postdysenteric or postvenereal reactive arthritis. Common findings also include circinate balanitis, cervicitis, and painless lingual or palatal oral ulcerations. Circinate balanitis is painless and may present as vesicles, shallow ulcerations, or plaques on the glans or shaft of the penis. Keratoderma blennorrhagica appears as painless, papulosquamous lesions on the soles or palms. Nail changes typically manifest as onycholysis, yellowish discoloration, or subungual hyperkeratosis.
—Ocular: Conjunctivitis, uveitis, or keratitis is seen in most patients. Conjunctivitis tends to be bilateral or unilateral, recurrent, and painful; it lasts days rather than weeks. Acute anterior uveitis often occurs with established disease and may follow a chronic or relapsing course.

Uncommon Findings: Cardiac conduction disturbances, myocarditis, aortitis, aortic regurgitation, amyloidosis, CNS involvement, serositis, and pulmonary infiltrates are rarely seen.

Diagnostic Tests: Most patients exhibit elevated ESR and CRP levels. Thrombocytosis, leukocytosis, hypoproliferative anemia, and elevated hepatic enzymes may also be seen. The synovial fluid is inflammatory (mostly neutrophils).
Culture of arthritogenic organisms is uncommon. Culture or serologic proof of infection is not necessary but may indicate the need for antibiotic therapy in Yersinia- or Chlamydia-induced arthritis. HIV testing is not routinely recommended; it should be reserved for those engaged in high-risk behavior.

HLA-B27 testing is seldom necessary. Very few HLA-B27–positive individuals develop reactive arthritis. Thus, HLA-B27 has a low predictive value. HLA-B27 may prove useful in patients with early incomplete features of reactive arthritis.

Imaging: Radiographs may show soft tissue swelling, joint space narrowing, or erosions in the peripheral and sacroiliac joints. Formation of reactive new bone is characteristic and may result in periostitis, enthesitis, or poorly defined intraarticular erosions. Radiographic changes are often most striking in the foot, ankle, and knee. Poorly defined, inflammatory heel spurs are found at the insertion of the plantar aponeurosis.

Axial involvement most often manifests as sacroiliitis. In chronic reactive arthritis, 40% to 60% have radiographic evidence of bilateral, asymmetric, or unilateral sacroiliitis. Ileal sclerosis and ankylosis are late findings. Asymmetric paravertebral ossification with nonmarginal syndesmophytes (bulky osteophytes) is common. Bone scan, CT, and MRI are sensitive in detecting early occult sacroiliitis but are rarely indicated.

Keys to Diagnosis: An asymmetric, inflammatory oligoarthritis with enthesitis (heel pain), nail, genitourinary, or ocular findings raise suspicion of reactive arthritis.

Diagnostic Criteria: ACR criteria require peripheral arthritis of more than 1- month duration and association with urethritis or cervicitis. These criteria show a sensitivity of 84.3% and a specificity of 98.2%.

Differential Diagnosis: Reactive arthritis should be distinguished from septic (especially gonococcal) arthritis, gout, sarcoidosis, erythema nodosum, seronegative RA, and ARF. Distinction from the other SpA and other reactive arthritides (e.g., Yersinia, Chlamydia) may be difficult. Overlap of reactive arthritis and psoriasis or enteropathic arthritis may occur.

Therapy: Treatment should be aimed at patient education, joint protection, maintenance of function, relief of pain, suppression of inflammation, and, when appropriate, eradication of infection. Inactivity and immobilization should be discouraged, and stretching and range-of-motion exercises should be encouraged.

Treatment with NSAIDs improves symptoms but does not alter the course of chronic inflammatory disease. Indomethacin, sulindac, naproxen, diclofenac, enteric-coated salicylate, and phenylbutazone are approved by the FDA for use in AS and reactive arthritis. Phenylbutazone is no longer available, primarily because of the risk of aplastic anemia. Indomethacin, in anti-inflammatory doses (2–3 mg/kg), is commonly used in the treatment of reactive arthritis. The sustained-release form is effective in the treatment of morning stiffness. Other NSAIDs and COX-2 inhibitors also have been used. Long-term NSAID therapy is indicated as long as clinical evidence of inflammation (arthritis, enthesitis) persists.

Corticosteroids are relatively ineffective in the routine management of reactive arthritis. However, intraarticular or perilesional (tendons or entheses) injections or topical corticosteroids may benefit some patients.

DMARD therapy is indicated in patients with chronic reactive arthritis unresponsive to NSAIDs. Azathioprine, MTX, and sulfasalazine have shown effcacy in uncontrolled trials. In a multicenter, placebo-controlled trial, sulfasalazine (2 g/day) was effective in treating the peripheral arthritis of reactive arthritis. There are anecdotal reports of efficacy with TNF inhibitors in reactive arthritis.

Antibiotic therapy may be indicated in patients with culture-, serology-, or PCR-proven Yersinia- or Chlamydia-induced arthritis. Several reports suggest >3 months of antibiotic therapy (doxycycline or lymecycline) for patients with
Chlamydia-induced arthritis. Recent reports suggest conflicting evidence favoring long-term benefit to antibiotic therapy. Reactive arthritides caused by Salmonella and Shigella do not respond to antibiotic therapy. Patients with idiopathic reactive arthritis will not benefit from antibiotic treatment.

Prognosis: In most patients, the initial episode of arthritis is self-limiting and lasts weeks to months. Many patients experience recurrent attacks, often after prolonged disease-free intervals. Less than 30% of patients exhibit a chronic arthritis. Severe disability occurs in <15% of patients and may be secondary to persistent lower extremity arthritis, aggressive axial involvement, or blindness. Death is rare and is usually from cardiac complications or amyloidosis.

BIBLIOGRAPHY

Cush JJ, Lipsky PE. Reiter’s syndrome and reactive arthritis. In: Koopman WJ, ed. Arthritis and allied conditions:a textbookof rheumatology, 13th ed. Baltimore: Williams & Wilkins,1997:1209–1227.

Flores D, Marquez J, Garza M, et al. Reactive arthritis: newer developments. Rheum Dis Clin North Am 2003;29:37–59. PMID:12635499

Laasila K, Laasonen L, Leirisalo-Repo M. Antibiotic treatment and long term prognosis of reactive arthritis. Ann Rheum Dis 2003;62:655–658. PMID: 12810429

Mease PJ. Disease-modifying antirheumatic drug therapy for spondyloarthropathies: advances in treatment. Curr Opin Rheumatol 2003;15:205–212. PMID: 12707572