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

In 1916, Hans Reiter described the classic triad of arthritis, nongonococcal urethritis, and conjunctivitis.

What used to be known as Reiter syndrome is now referred to as reactive arthritis (ReA). This change has occurred in part because of Hans Reiter's affiliation and activities with the Nazis during WWII.

Reactive arthritis refers to acute nonpurulent arthritis complicating an infection elsewhere in the body.

Reactive arthritis falls under the rheumatic disease category of seronegative spondyloarthropathies, which includes ankylosing spondylitis, psoriatic arthritis, the arthropathy of associated inflammatory bowel disease, juvenile-onset ankylosing spondylitis, and juvenile chronic arthritis.

Pathophysiology

Reactive arthritis is triggered following enteric or urogenital infections. Reactive arthritis is associated with human leukocyte antigen (HLA)–B27, although HLA-B27 is not always present in an affected individual, particularly in the presence of HIV.

Bacteria associated with reactive arthritis are generally enteric or venereal and include the following: Shigella flexneri, Salmonella typhimurium, Salmonella enteritidis, Streptococcus viridans, Mycoplasma pneumonia, Cyclospora, Chlamydia trachomatis, Yersinia enterocolitica, and Yersinia pseudotuberculosis. Bacteria or their components (RNA, DNA) have been identified in synovial fluid cells, synovial biopsy specimens, and circulatory monocytes.

Frequency

United States

Frequency is estimated at 3.5 cases per 100,000. (Because of uncertainty of diagnosis and variations in definitions, epidemiologic features are difficult to calculate.)

An estimated 1-3% of all patients with a nonspecific urethritis develop an episode of arthritis. Prevalence of inapparent chlamydial infections may make incidence even higher.

After outbreak of S enteritidis, 29% had reactive arthritis.

International

In Norway, an annual incidence of chlamydia-induced reactive arthritis of 4.6 cases per 100,000 population and an incidence of enteric bacteria–induced reactive arthritis of 5 cases per 100,000 population were reported in 1988-1990.

Occurrence appears to be related to the prevalence of HLA-B27 in a population and the rate of urethritis/cervicitis and infectious diarrhea.

Mortality/Morbidity

Most patients have severe symptoms lasting weeks to 6 months. Approximately 15-50% have recurrent bouts of arthritis. Chronic arthritis or sacroiliitis occurs in 15-30% of cases.

Race

Reactive arthritis is reported most frequently in whites. When reactive arthritis occurs in black persons, it is frequently B27-negative.

Occurrence appears to be related to HLA-B27 prevalence in the population.

Sex

The male-to-female postvenereal ratio is traditionally 5-10:1. The postenteric ratio is 1:1.

Age

The peak onset is in persons aged 15-35 years; reactive arthritis is rarely seen in children. Cases in children are almost entirely postenteric.

CLINICAL

Section 3 of 10  

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

History

• Symptoms generally appear within 1-3 weeks but can range from 4-35 days from onset of inciting episode of urethritis/cervicitis or diarrhea.
• Constitutional symptoms (usually mild)
• • Fever (usually low grade)
  • Malaise
• Musculoskeletal
• • Myalgias (early)
  • Asymmetric joint stiffness, primarily involving the knees, ankles, and feet (wrist may be early target)
  • Low back pain with radiation to the buttocks or thighs
  • Symptoms worse with rest or inactivity
• Urethritis associated with reactive arthritis may be postdysenteric or postvenereal, with frequency, dysuria, urgency, and urethral discharge. It may be mild or inapparent.
• Ophthalmologic
• • Erythema
  • Burning
  • Tearing
  • Photophobia
  • Pain
  • Decreased vision (rare)
• Patients may have mild recurrent abdominal complaints after precipitating episode of diarrhea.

Physical

• A scoring system for diagnostic points in Reiterlike spondyloarthropathies exists. Two or more of the following points establishes diagnosis (one of which must pertain to the musculoskeletal system):
• • Asymmetric oligoarthritis, predominantly of the lower extremity
  • Sausage-shaped finger (dactylitis), toe or heel pain, or other enthesitis
  • Cervicitis or acute diarrhea within 1 month of the arthritis
  • Conjunctivitis or iritis
  • Genital ulceration or urethritis
• Musculoskeletal
• • Oligoarthritis affecting mainly lower extremities with low-grade inflammation.
  • Knee may become markedly edematous.
  • Distinctive arthropathy of reactive arthritis includes local enthesopathy, which is inflammation at the tendinous insertion into bone, rather than synovium (common in insertions into calcaneus, talar, and subtalar joints).
  • Sausage finger or toe is caused by uniform inflammation.
• Urogenital
• • Meatal edema and erythema and clear mucoid discharge
  • Prostatic tenderness (up to 80%) and vulvovaginitis
• Dermatologic
• • Balanitis circinata - Shallow painless ulcers at meatus and glans penis; moist on uncircumcised patients; may harden and crust on circumcised patients, causing pain and scarring
  • Keratoderma blennorrhagica - Hyperkeratotic skin, which begins as clear vesicles on erythematous bases and progresses to macules, papules, and nodules (found on soles of feet, toes, palms, scrotum, trunk, and scalp)
  • Nail thickening and ridging and superficial oral ulcers
• Ophthalmologic signs - Conjunctivitis (most common), with mucopurulent discharge, chemosis, lid edema, and iritis
• Occurs in the majority of reactive arthritis because of Shigella infection. Occurs in approximately 35% of postvenereal cases.
• Cardiac signs - Aortic regurgitation caused by inflammation of aortic wall and valve

Causes

• Nongonococcal venereal disease (most often Chlamydia) and infectious diarrhea (Shigella, Salmonella, Yersinia) precipitate reactive arthritis.
• HLA-B27 contributes to the pathogenesis of the disease.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Septic arthritis
Other reactive arthritides and spondyloarthropathies

WORKUP

Section 5 of 10  

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

Lab Studies

• Documentation of specific bacterial infection
• • Cervical or urethral swab may be performed. Look for Chlamydia in every case of reactive arthritis, preferably by direct florescent antibody, enzyme immunoassay, or DNA probe for ribosomal RNA. Culture techniques are unreliable; however, serology is useful in some cases.
  • Obtain stool cultures even when bowel symptoms are inapparent or mild.
  • Arthrocentesis and fluid analysis often are needed to rule out an infectious process, especially in monoarticular arthritis with constitutional symptoms.
• Acute cases
• • Neutrophilic leukocytosis
  • Elevated C-reactive protein or C3 and C4 (nonspecific)
  • Erythrocyte sedimentation rate (ESR) - Usually elevated during acute phase of disease
• Chronic cases - Mild normocytic anemia

Imaging Studies

• Plain radiography - May show no abnormalities early in the disease
• • Asymmetric, oligoarticular, and more common in the lower extremities pattern of joint involvement
  • Juxta-articular osteoporosis in acute episodes of arthritis - Erosions have indistinct margins and are surrounded by periosteal new bone.
  • Spinal pattern - Unilateral or bilateral sacroiliitis, asymmetric paravertebral comma-shaped ossification involving the lower thoracic and upper lumbar vertebrae

Other Tests

• Test results for rheumatoid factor and antinuclear antibody are negative. (Test results usually are not available during the ED evaluation.)
• HLA-B27 may be useful when extra-articular features are not present. The presence of antigen correlates with axial disease, carditis, and uveitis. (Test results usually are not available during the ED evaluation.)
• Consider referral for HIV testing in patients presenting with history, symptoms, or findings suggesting increased risk for the disease.

Procedures

• Synovial fluid: Macrophages with vacuoles filled with nuclear debris and whole leukocytes may be found but are nonspecific.
• Synovial biopsy: Nonspecific inflammatory changes; infectious antigens have been found in synovium; immunohistochemistry, polymerase chain reaction, and molecular hybridization may become more useful. (Procedure usually is not performed during the ED evaluation.)

TREATMENT

Section 6 of 10  

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

Emergency Department Care

• Treatment based on symptoms
• Physical therapy during recovery phase

Consultations

• Consult a rheumatologist to discuss appropriate additional tests and medications for symptomatic relief or microbiologic cure and to ensure follow-up treatment.
• Consider an infectious disease (ID) consultation for consideration of empiric antibiotic therapy as well as for patients with coincident manifestations of coincident AIDS-defining illnesses.

MEDICATION

Section 7 of 10  

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

Mainstays of therapy for joint symptoms are nonsteroidal anti-inflammatory drugs (NSAIDs).

Sulfasalazine may be used for patients who do not experience relief with NSAIDs or who have contraindications to NSAIDs.

No published data are available on the effectiveness of selective COX-2 inhibitors; however, COX-2 inhibitors may be tried in patients who do not tolerate NSAIDs.

Extra-articular manifestations are treated individually. Second-line therapies for reactive arthritis, such as systemic or intra-articular steroids, are left to the discretion of the consulting rheumatologist. Antibiotic treatment is indicated for cervicitis or urethritis but not generally for postdysenteric cases.

Cytotoxic therapy, such as methotrexate or azathioprine, is reserved for severe cases and should not be started in the ED. HIV testing must be completed first.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)

Although most NSAIDs are used primarily for their anti-inflammatory effects, they are effective analgesics and are useful for relief of mild to moderate pain. To relieve joint symptomatology, a month's treatment at maximum dose is needed before full effectiveness can be evaluated.

Drug Category: Topical corticosteroids

These agents are used for dermatologic manifestations, such as keratoderma blennorrhagica and circinate balanitis.

Drug Category: Antibiotics

Empiric antimicrobial should cover all likely pathogens in the context of the clinical setting.

Drug Name	Doxycycline (Doryx, Vibramycin, Vibra-Tabs)
Description	Interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity against susceptible bacteria.
Adult Dose	100 mg PO bid for 3 mo
Pediatric Dose	<8 years: Not recommended >8 years: 2-5 mg/kg/d PO once or divided bid; not to exceed 200 mg/d
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate may decrease doxycycline bioavailability; tetracyclines may increase the hypoprothrombinemic effects of anticoagulants; prothrombin activity should be monitored in patients taking both of these types of medications concurrently; coadministration of tetracyclines may decrease pharmacologic effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Unsafe in pregnancy
Precautions	Avoid prolonged exposure to sunlight or tanning equipment because a photosensitivity reaction may occur; use lower than usual doses in patients with renal impairment; if therapy is prolonged, drug serum level determinations may be advisable; use of tetracyclines during tooth development (last one half of pregnancy through 8 y) may cause permanent discoloration of teeth; never administer outdated tetracyclines; degradation products of tetracyclines are highly nephrotoxic and have, on occasion, produced a Fanconilike syndrome

Drug Name	Ciprofloxacin (Cipro)
Description	DOC for improvement in clinical parameters, except joint involvement, in enterogenic reactive arthritis. Ciprofloxacin is a bactericidal antibiotic that inhibits bacterial DNA synthesis and, consequently, growth by inhibiting DNA-gyrase in susceptible organisms.
Adult Dose	250-500 mg PO bid
Pediatric Dose	<18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may interfere with GI absorption of fluoroquinolones, resulting in decreased serum levels (administer antacids 2-4 h before or after taking fluoroquinolones) Cimetidine may interfere with metabolism of fluoroquinolones; ciprofloxacin may reduce therapeutic effects of phenytoin; probenecid may reduce ciprofloxacin renal clearance by 50% and increase serum concentration by 50%; ciprofloxacin may increase theophylline and caffeine concentrations and prolong their duration of action; ciprofloxacin may increase nephrotoxic effect of cyclosporine; digoxin serum levels may be increased when used concurrently with ciprofloxacin; digoxin levels should be monitored; ciprofloxacin may increase effects of anticoagulants; prothrombin time should be monitored
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	In prolonged therapy, perform periodic evaluations of organ system functions, including renal, hepatic, and hematopoietic; patients with renal function impairment may require a dose adjustment; prolonged or repeated antibiotic therapy may result in bacterial or fungal overgrowth of nonsusceptible organisms; such overgrowth may lead to a secondary infection; take appropriate measures if superinfection occurs

Drug Category: Anti-inflammatory agents

These agents are used when NSAIDs do not control arthritis and for inflammatory lesions of intestinal mucosa.

FOLLOW-UP

Section 8 of 10  

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

Further Inpatient Care

• Inpatient care may be considered with patients who are unable to tolerate PO administration of medications, who are unable to ambulate because of significant joint involvement, who have intractable pain, or who have concomitant disease requiring admission.

In/Out Patient Meds

• Nonsteroidal anti-inflammatory agents may control painful arthralgias. Patients must be instructed on compliance and possible need for adjustment to dose or to another agent.
• Empiric antibiotics may be considered after appropriate cultures have been taken. Treat urethritis or cervicitis but generally not diarrhea.

Complications

• Recurrent arthritis (15-50%)
• Chronic arthritis or sacroiliitis (15-30%)
• Ankylosing spondylitis (30-50% of HLA-B27–positive patients)
• Urethral stricture
• Cataracts
• Aortic root necrosis

Prognosis

• Signs and symptoms usually remit within 6 months. However, a significant percentage of patients have recurrent episodes of arthritis (15-50%), and some patients develop chronic arthritis (15-30%).
• Postdysenteric cases are associated with a better prognosis than postchlamydial cases.
• Poor prognosis is associated with hip arthritis, sedimentation rate higher than 30, poor efficacy of NSAIDs, oligoarthritis, onset when patients are younger than 16 years, and sausage finger or toe.

Patient Education

• 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

• Septic arthritis must be ruled out if suspected.
• HIV should be considered, particularly before institution of immunosuppressive therapy.

Special Concerns

• Some pediatric cases involving ocular chlamydial infection have been reported.
• Reactive arthritis was the first rheumatologic disease noted in association with HIV.

REFERENCES

Section 10 of 10

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

• Amor B. Reiter's syndrome. Diagnosis and clinical features. Rheum Dis Clin North Am. Nov 1998;24(4):677-95, vii. [Medline].
• Bauman C, Cron RQ, Sherry DD, Francis JS. Reiter syndrome initially misdiagnosed as Kawasaki disease. J Pediatr. Mar 1996;128(3):366-9. [Medline].
• Connor BA, Johnson EJ, Soave R. Reiter syndrome following protracted symptoms of Cyclospora infection. Emerg Infect Dis. May-Jun 2001;7(3):453-4. [Medline].
• Cuttica RJ, Scheines EJ, Garay SM, et al. Juvenile onset Reiter's syndrome. A retrospective study of 26 patients. Clin Exp Rheumatol. May-Jun 1992;10(3):285-8. [Medline].
• Dworkin MS, Shoemaker PC, Goldoft MJ, Kobayashi JM. Reactive arthritis and Reiter's syndrome following an outbreak of gastroenteritis caused by Salmonella enteritidis. Clin Infect Dis. Oct 1 2001;33(7):1010-4. [Medline].
• Fan PT, Yu DTY. Reiters syndrome. In: Ruddy S, Harris ED Jr, Sledge CB, eds. Kelley's Textbook of Rheumatology. 6th ed. Philadelphia, PA:. WB Saunders;2001:1039-1067.
• Hoogland YT, Alexander EP, Patterson RH, Nashel DJ. Coronary artery stenosis in Reiter's syndrome: a complication of aortitis. J Rheumatol. Apr 1994;21(4):757-9. [Medline].
• Hughes RA, Keat AC. Reiter's syndrome and reactive arthritis: a current view. Semin Arthritis Rheum. Dec 1994;24(3):190-210. [Medline].
• Kasper DL, ed. Reactive arthritis. In: Harrison's Online. Part 13. Section 2. Chap 305. McGraw Hill;2004.
• Kataria RK, Brent LH. Spondyloarthropathies. Am Fam Physician. Jun 15 2004;69(12):2853-60. [Medline].
• Lu DW, Katz KA. Declining use of the eponym "Reiter''s syndrome" in the medical literature, 1998-2003. J Am Acad Dermatol. Oct 2005;53(4):720-3.
• Natarajan UR, Tan TL, Lau R. Reiter's disease following Mycoplasma pneumoniae infection. Int J STD AIDS. May 2001;12(5):349-50. [Medline].
• Petersel DL, Sigal LH. Reactive arthritis. Infect Dis Clin North Am. Dec 2005;19(4):863-83.
• Rihl M, Klos A, Kohler L, Kuipers JG. Infection and musculoskeletal conditions: Reactive arthritis. Best Pract Res Clin Rheumatol. Dec 2006;20(6):1119-37. [Medline].

Article Last Updated: Feb 15, 2007