AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Cultures
• • If urethritis or cervicitis is present, cultures should be obtained. Smears of urethral discharge may be sent for antichlamydial staining by direct immunofluorescent antibody, enzyme immunosorbent assay, culture, or nucleic acid probe. A Giemsa stain or a Wright stain may reveal the classic gram-negative intracellular diplococci associated with gonorrhea. Many patients may experience simultaneous sexually transmitted diseases, particularly chlamydia and gonorrhea.
  • Results of routine urine cultures are negative.
  • Stool cultures can be helpful for enteric pathogens.
• Venereal Disease Research Laboratory (VDRL) test and fluorescent treponemal antibody absorption (FTA-ABS) test: Perform serologic testing to rule out syphilis that may be associated with chlamydial infection.
• Synovial fluid aspirates and synovial biopsy samples show a nonspecific mixed inflammatory reaction. Rarely, gonococcus may be recovered.
• The erythrocyte sedimentation rate and the C-reactive protein level may be elevated.
• Rheumatoid factor and antinuclear antibodies are negative.
• HLA-B27
• • HLA-B27 antigen testing is not diagnostic but may be useful.
  • The HLA-B27 test is moderately expensive and should not be ordered indiscriminately as a screen for all patients with uveitis. Instead, this test should be ordered for patients suspected of having ocular disease associated with one of the seronegative spondyloarthropathies.
  • A complete histocompatibility panel, which includes multiple loci and alleles, is not necessary. This test can be exorbitantly expensive, and it is not useful in the workup of patients with uveitis.
• A tuberculin skin test may be appropriate in certain individuals, particularly those with demographics strongly suggestive of infectious tuberculosis (TB). TB is far more likely to occur in immigrants from Southeast Asia, Africa, and other endemic regions. Caution must be taken not to interpret a positive skin test as diagnostic of tuberculous uveitis, particularly in individuals who have been given the bacille Calmette-Guérin (BCG) vaccine.

Imaging Studies

• Radiologic examination demonstrates various arthritic changes.
• • Changes in the sacroiliac joint are present in as many as 32% of patients.
  • Specifically ordering a radiograph of the sacroiliac joint is best. This radiograph provides a more sensitive tunnel view compared to a routine film of the lumbosacral spine.
  • Films of the foot may be useful, revealing changes consistent with chronic plantar fasciitis or Achilles tendonitis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Nongonococcal urethritis and other infections can be treated specifically with systemic antibiotics.
• Physical therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), and intralesional corticosteroids may be helpful for joint, tendon, and fascial inflammation.
• Keratolytics or topical corticosteroids may improve cutaneous lesions.
• Topical corticosteroids may be useful for iridocyclitis.
• Corticosteroids
• • Topical corticosteroids and mydriatics should be used early and aggressively to reduce tissue damage.
  • The use of systemic corticosteroids may be necessary; they should be used for a short period of time with the same precautions noted with other inflammatory diseases.
  • Prolonged topical treatment is necessary for several weeks after the inflammation has cleared; early withdrawal of topical corticosteroids frequently results in the return of inflammatory changes.
• NSAIDs
• • The use of oral nonsteroidal anti-inflammatory agents, such as indomethacin or naproxen, may be helpful. Chronic therapy may be necessary.
  • NSAIDs may reduce the intensity and the frequency of recurrences of the ocular inflammation and allow a decrease in the corticosteroid dosage, which helps to decrease the chances of cataract formation and other associated corticosteroid effects.
  • The decreased awareness of pain sometimes seen with these medications may alter the patient's recognition of recurrences. Patients should be examined whenever any change in symptoms occurs to evaluate for recurrence of an acute episode of inflammation. Ocular involvement may parallel systemic and joint disease relapses.

Surgical Care

• The posterior spillover of inflammatory material in chronic iridocyclitis associated with reactive arthritis may result in persistent vitreous opacification. The cumulative effects of secondary involvement of the vitreous may result in visually disabling vitreous debris and opacification, making these eyes good candidates for vitrectomy. Although vitrectomy should be considered only after prolonged follow-up care and thorough planning, it appears to offer a definitive improvement in vision in certain cases.
• Because of the intense episodes of recurrent inflammation, rendering these eyes as quiet as possible before surgery by using topical, periocular, or systemic corticosteroids is essential. At least 3 months of cell-free slit lamp examinations should be documented prior to elective surgical intervention. This should be extended to 6 months for younger patients and severe cases.
• Preoperative ultrasonography is helpful in determining the degree of vitreous opacification, the thickening of the choroid, and the presence of a cyclitic membrane, which can create significant problems at surgery.
• The major objective of surgery in patients with complicated uveitic cataract and vitreous opacification is to improve vision.
• Vitrectomy may favorably modify the dynamics of the uveitic process, although lensectomy-vitrectomy does not reduce the inflammatory reaction in all cases.
• Cystoid macular edema is the major cause of decreased visual acuity following surgery; however, this is a common and serious complication of chronic uveitis even without surgery. Vitrectomy may actually reduce cystoid macular edema with gradual resolution over a year with an improvement in vision in some patients.

Consultations

• Rheumatology: The consulting rheumatologist may be extremely helpful in suggesting an appropriate oral NSAID or immunosuppressive agent to augment topical and periocular corticosteroid therapy.
• Internal medicine
• • A medical consultation should be sought when prolonged systemic corticosteroid therapy is anticipated, especially in patients with concomitant diabetes or hypertension.
  • Even the most experienced uveitis specialists appreciate assistance in the treatment of patients who may have potentially lethal adverse effects from corticosteroids, potent NSAIDs, or immunosuppressive cytotoxic agents.
• Dermatology
• • Dermatologic involvement may occur with several uveitic syndromes.
  • An accurate description of these lesions may help establish the diagnosis in some cases.
• Dentistry: Consultation and treatment by a dentist, an oral surgeon, or a periodontist may be useful for patients with aphthous ulcers.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Joint symptoms are best treated by NSAIDs.² High and sustained doses often have to be used. For acute arthritis, indomethacin is often effective. Any other NSAID can also be used. Phenylbutazone may work in patients refractive to other NSAIDs. One-month treatment at maximum dosage is needed before effectiveness can be fully evaluated.

Drug Category: Nonsteroidal anti-inflammatory agents (NSAIDs)

Have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known but may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions, may exist.

Drug Category: Anti-inflammatory agents

Systemically interfere with events leading to inflammation.

Drug Category: Cytotoxic agents

Inhibit cell growth and proliferation. Used when the disease is aggressive and unremitting.

Drug Category: Corticosteroids

For ocular therapy, topical or sub-Tenon injections of steroid have proven effective. Systemic steroids should only be used in cases of macular involvement and only for a short period of time.

Drug Name	Prednisolone acetate 1% (Pred Forte)
Description	Mainly for acute iritis; best therapy is to treat aggressively early in the course of the disease. Gradually taper and discontinue based upon clinical response.
Adult Dose	1 gtt qid or greater depending on severity of uveitis
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular infections
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in hypertension; known to cause cataract formation with long-term use; suspect fungal invasion in any persistent corneal ulceration where a corticosteroid has been used or is in use (obtain fungal cultures when appropriate)

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Patients should receive follow-up care as needed.

Complications

• Secondary glaucoma
• Cataracts
• Cystoid macular edema
• Posterior and anterior synechiae
• Cyclitic membrane
• Vitreous opacification
• Ankylosing spondylitis, psoriatic arthritis, and sacroiliitis

Prognosis

• Occasionally, this process becomes chronically active or recurs at frequent intervals, requiring long-term management. This condition is a result of chronic blood-aqueous barrier breakdown and is avoidable in most circumstances by prompt aggressive treatment of each new attack.
• Many patients have chronic, persistent, or recurrent disease, including arthritis, urethritis, uveitis, and skin lesions, for many years.

Patient Education

• Educating patients about the disease is important. Patients should monitor themselves for any changes in symptoms.
• Acceptance of the need for long-term medications and awareness of the chronic or recurrent nature of this syndrome are keys to the cooperation of any patient with reactive arthritis.
• For excellent patient education resources, visit eMedicine's Arthritis Center, Sexually Transmitted Diseases Center, and Bacterial and Viral Infections Center. Also, see eMedicine's patient education articles Knee Pain and Chlamydia.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• No medicolegal pitfalls exist, other than those associated with uveitis treatment, cataract surgery, or vitrectomy. Patients with reactive arthritis must be aware that their condition places them at a higher than usual risk for elective ocular surgery.

Special Concerns

• Few treatment options exist for patients with severe reactive arthritis accompanied by HIV infection.
• Phenylbutazone may be effective when other NSAIDs fail.
• Sulfasalazine may be used safely and is often beneficial. Prednisone at a low dosage may be prescribed, but prolonged treatment is not advisable.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Garg AX, Pope JE, Thiessen-Philbrook H, Clark WF, Ouimet J. Arthritis risk after acute bacterial gastroenteritis. Rheumatology (Oxford). Feb 2008;47(2):200-4. [Medline].
2. Rudwaleit M, Braun J, Sieper J. Treatment of reactive arthritis: a practical guide. BioDrugs. Jan 2000;13(1):21-8. [Medline].
3. Amor B. Reiter's syndrome. Diagnosis and clinical features. Rheum Dis Clin North Am. Nov 1998;24(4):677-95, vii. [Medline].
4. Banares A, Hernandez-Garcia C, Fernandez-Gutierrez B, Jover JA. Eye involvement in the spondyloarthropathies. Rheum Dis Clin North Am. Nov 1998;24(4):771-84, ix. [Medline].
5. Kohnke SJ. Reactive arthritis. A clinical approach. Orthop Nurs. Jul-Aug 2004;23(4):274-80. [Medline].
6. Lee DA, Barker SM, Su WP, Allen GL, Liesegang TJ, Ilstrup DM. The clinical diagnosis of Reiter's syndrome. Ophthalmic and nonophthalmic aspects. Ophthalmology. Mar 1986;93(3):350-6. [Medline].
7. Mahoney BP. Rheumatologic disease and associated ocular manifestations. J Am Optom Assoc. Jun 1993;64(6):403-15. [Medline].
8. Ostler HB. Oculogenital disease. Surv Ophthalmol. Jan-Feb 1976;20(4):233-46. [Medline].

Article Last Updated: Apr 10, 2008