eMedicine Specialties > Ophthalmology > Connective Tissue Disorders

Reactive Arthritis

Author: Mounir Bashour, MD, CM, FRCS(C), PhD, FACS, Assistant Professor of Ophthalmology, McGill University; Clinical Assistant Professor of Ophthalmology, Sherbrooke University; Medical Director, Cornea Laser and Lasik MD
Contributor Information and Disclosures

Updated: Jun 8, 2009

Introduction

Background

Reactive arthritis (also referred to as Reiter syndrome) identifies a constellation of clinical findings classically described as the triad of noninfectious urethritis, arthritis, and conjunctivitis, but, perhaps, this syndrome is better described as a triad of arthritis, conjunctivitis or iridocyclitis, and nonbacterial urethritis or cervicitis.

Reactive arthritis is classified as a seronegative spondyloarthropathy. Seronegative spondyloarthropathies are a group of diseases with a negative rheumatoid factor. Diseases include ankylosing spondylitis, reactive arthritis, inflammatory bowel disease, and psoriatic arthritis. These disorders are characterized by spondylitis or sacroiliitis; peripheral joint disease; and, commonly, an increased incidence of the histocompatibility locus antigen B27 (HLA-B27). They also have a high incidence of associated ocular inflammatory disease.

Pathophysiology

Reactive arthritis exists in 2 forms: epidemic and endemic.

Epidemic reactive arthritis occurs after an infectious gram-negative gastroenteritis, dysentery, or nongonococcal urethritis. The ensuing sterile arthritis occurs after the gastroenteritis has resolved. The associated nongonococcal urethritis organisms include Chlamydia trachomatis and Ureaplasma urealyticum.

In a recent study looking at 2299 participants after a mean follow-up of 4.5 years after an outbreak of Escherichia coli O157:H7 and Campylobacter species within a regional drinking water supply, "arthritis was reported in 15.7% of participants who had been asymptomatic during the outbreak, and in 17.6% and 21.6% of those who had moderate and severe symptoms of acute gastroenteritis, respectively (P-value for trend = 0.009). Compared with the asymptomatic participants, those with moderate and severe symptoms of gastroenteritis had an adjusted relative risk of arthritis of 1.19 (95% confidence interval [CI] 0.99-1.43) and 1.33 (95% CI 1.07-1.66), respectively."1 So, the risk of reactive arthritis appears to be correlated to the severity of symptoms during the initiating episode.

While a triggering agent can be identified for epidemic reactive arthritis, none has been identified for endemic reactive arthritis. Although differentiation between the 2 types may be difficult in some cases, it is not essential to either the diagnosis or the treatment. Because patients with reactive arthritis often develop urethritis and present to venereal disease clinics, endemic reactive arthritis was initially believed to be due to a venereal disease. The agent most often linked to endemic reactive arthritis was Chlamydia; however, careful studies have not demonstrated a higher prevalence of chlamydial infection in patients with reactive arthritis compared with controls.

Frequency

United States

The incidence reported in US Navy personnel over a 10-year period was 4 cases per 100,000 men per year. Of patients with nongonococcal urethritis, 1-3% develop reactive arthritides, and probably 20-25% of patients with HLA-B27 also develop reactive arthritides. Reactive arthritis may occur in 1.5% of Shigella enterocolitis cases and 25% of HLA-B27–positive Shigella cases.

International

Frequency is probably similar to that seen in the United States.

Race

No known racial difference in either the incidence or the severity of the disease exists.

Sex

This condition is more commonly identified in males, but it may occur more frequently in females than previously believed.

Age

• Onset of the clinical disease occurs in young adults aged 16-40 years.
• Reactive arthritis is infrequent in children.

Clinical

History

• Presenting signs and symptoms (in order of frequency) include polyarthritis, urethritis or cervicitis, pain in the back or the heel, eye disease, stomatitis, keratoderma blenorrhagica, balanitis, and diarrhea.
• Typically, a latent interval period occurs from the onset of urethritis or diarrhea to the development of rheumatic disease.
• While eliciting the history, ask the patient for symptoms associated with arthritis, conjunctivitis, iridocyclitis, nonbacterial urethritis or cervicitis, dysentery, mucocutaneous disease with circinate balanitis, painless oral ulceration, and keratodermia blennorrhagica.
• Dystrophic nail lesions may also be present. These lesions most commonly manifest as nail pitting, but they may progress to excoriative dystrophic changes.
• The diagnosis is sometimes hard to establish because urethritis or cervicitis may have been forgotten or suppressed and because enteritis and other symptoms may have been mild.
• Pain in the lower back due to insertional tendinitis and sacroiliitis is common.
• The associated arthritis is a migratory, asymmetric, and episodic oligoarthritis, primarily affecting the weightbearing large joints of the lower extremities, especially the knees and the ankles.
• The arthritis often produces swelling and pain in the hindfoot, plantar fasciitis, and Achilles tendinitis. These arthritic manifestations may be acute and short-lived but are often recurrent or chronic. Pedal arthritic changes may be mistaken for chronic injury, occasionally leading to inappropriate surgery.
• Secondary ankylosing spondylitis is not uncommon.
• Other articular features include "sausage digits" due to interphalangeal arthritis of the toes and/or the fingers.
• Systemic symptoms, including fever and weight loss, may occur.
• The disease tends to follow an episodic and relapsing course.

Physical

• Musculoskeletal system
  • Reactive arthritis usually involves the large weightbearing joints of the lower extremities. The knees and the ankles are most frequently involved, with redness and diffuse swelling. Multiple joint involvement is usual.
  • Periostitis and tendinitis may occur, especially involving the Achilles tendon, which produces pain in the heel.
• Dermatologic
  • The dermal lesions are typified by keratoderma blenorrhagica, which begins as discrete vesicles that thicken and become hyperkeratotic nodules. This is described as a hyperkeratotic erythematous dermatitis, which resembles pustular psoriasis. It may not be present until the later course of the disease.
  • Lesions of keratoderma blenorrhagica occur most commonly on plantar surfaces and toes but may appear on the palms. Circinate balanitis refers to small shallow painless ulcers of the urethral meatus or the glans penis.
• Gastrointestinal
  • Superficial oral ulcers are frequent.
  • Enteritis is usually a prolonged diarrheal episode with frequent passage of bloody loose stools, but it can manifest as a 24-hour episode of increased bowel activity.
• Cardiovascular: Cardiac arrhythmias and aortic regurgitation may be evident. Aortitis may be accompanied by coronary inflammation, which can be fatal in rare cases.
• Ophthalmic
  • Conjunctivitis
    • Conjunctivitis is one component of the original triad (as described by Reiter) and is one of the hallmarks of the disease. It tends to occur early in the disease, especially during the initial attack. Conjunctivitis may be missed if patients are seen only during subsequent attacks.
    • Conjunctivitis is usually described as mucopurulent and is often sterile. It is included in the differential diagnosis for chronic follicular conjunctivitis.
    • The frequency of conjunctivitis in patients with reactive arthritis is reportedly 33-100%.
    • It may be accompanied by iridocyclitis, episcleritis, or scleritis. Punctate and subepithelial corneal involvement has also been reported.
  • Uveitis
    • The more serious ocular manifestation is recurrent nongranulomatous iridocyclitis. Iridocyclitis may be the initial ocular manifestation in some patients. Uveitis may occur in as many as 50% of patients with reactive arthritis.
    • Recurrences are usually associated with an acute iridocyclitis that has a rapid onset with conjunctival and episcleral edema and injection.
    • The corneal endothelium has cellular debris and poorly defined, small- to medium-sized keratic precipitates.
    • Heavy flare and cells and a very early tendency toward formation of posterior synechiae are characteristic, more so than in most other forms of acute iridocyclitis.
    • Even the most aggressive pupil-dilation management is sometimes not adequate to prevent synechiae formation.
    • A peripheral iridectomy may be necessary to prevent iris bombé and angle closure if the synechiae cannot be broken.
    • Heavy flare is sometimes so plasmoid that cells are immobile, and a fibrinlike clot may be seen in the pupillary opening as the inflammation resolves. An acute hypopyon may occur.
    • Cells and inflammatory debris may be seen in the vitreous, and blurring of the disc margins and macular edema may occur with severe or prolonged episodes. Spillover vitritis may be more common in patients with reactive arthritis than those with ankylosing spondylitis.
• Keratitis: Rarely, patients may develop a punctate epithelial keratitis that may lead to central loss of the corneal epithelium and subepithelial infiltrates.
• Cataracts: Lens clouding and posterior subcapsular cataracts occur with prolonged or repeated episodes.
• Hypotony: This condition can occur following a severe or prolonged course and may persist after resolution.
• Glaucoma
  • Secondary open-angle glaucoma may occur because of the anterior chamber reaction and the trabecular obstruction or trabeculitis. This glaucoma usually resolves with aggressive anti-inflammatory therapy.
  • With repeated recurrences, damage to the trabecular meshwork may occur, resulting in secondary glaucoma.

Causes

• In reactive arthritis, infectious organisms are suggested to be the etiologic agents by reports of clinically indistinguishable acute disease following epidemic dysentery and sexually transmitted nongonococcal urethritis believed to be due to Chlamydia species or, possibly, Mycoplasma species or Ureaplasma urealyticum.
• Large epidemics of dysentery have been linked to multiple occurrences of arthritis, urethritis, and iridocyclitis. Shigella, Campylobacter, Salmonella, and Yersinia have been implicated. The risk of individuals who are HLA-B27–positive developing reactive arthritis following Shigella infection is approximately 25%.
• Although the cause is unknown, the high correlation with the presence of HLA-B27 (75-95%) is clearly recognized. The B27 allele may be closely linked on chromosome 6 to an immune response gene causing uveitis and reactive arthritis.
• The mechanism by which the HLA-B27 gene product predisposes to the disease is unknown, but 3 theories have been proposed. These theories include molecular mimicry, the suggestion that HLA-B27 provides a receptor for the inciting organism, and the possibility that HLA-B27 is associated with a defective class I antigen-mediated cellular response.
  • The molecular mimicry hypothesis suggests that a similarity exists at the molecular level between the HLA-B27 molecule and the inciting organisms, allowing for the triggering of an immune response and the subsequent development of clinical disease.
  • The possibility that the HLA-B27 molecule may act as a receptor for certain types of bacteria that then lead to the arthritis has been proposed, but little evidence exists to either confirm or refute this hypothesis.
  • Another hypothesis suggests that the HLA-B27 molecule may be a defective molecule associated with an aberrant cytotoxic T-cell response. The importance of the cytotoxic T-cell response in the development of reactive arthritis has been underscored by the coexistence of reactive arthritis in patients with acquired immunodeficiency syndrome (AIDS).
  • Yersinia antigens have been detected in the synovial fluid of patients with reactive arthritis after Yersinia infection, suggesting that persistent antigenic stimulation may contribute to the inflammatory response.

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