The first report in the English literature of the classic triad of this entity associated with a postvenereal prodrome was by Sir Benjamin Brodie in 1818 (5 cases).

In 1916, Hans Reiter reported the case of a young soldier who suffered from an acute febrile illness that included purulent conjunctivitis, nongonococcal urethritis, and severe arthritis following an episode of bloody diarrhea. The first case of a preadolescent with the same symptoms was reported in 1947. In 1969, the term reactive arthritis was proposed because of the frequent association between enteric and venereal infections and the subsequent development of Reiter syndrome (RS).

The classic triad of arthritis, urethritis, and conjunctivitis occurs in approximately one third of patients at onset. The less stringent American College of Rheumatology criteria require a one month duration of arthritis in association with urethritis and/or cervicitis. These criteria have an 84.3% sensitivity and 98.2% specificity in differentiating RS from gonococcal arthritis, seronegative rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis.

Pathophysiology: Although the cause of RS has not been established, the association of RS with some infectious agents in the GI or urinary tract has been documented in many children and adults. Gram-negative GI tract infections are the most commonly reported organisms in children. Most cases in adults, however, are mainly secondary to venereal disease. The commonly reported microorganisms are Salmonella, Shigella, Yersinia, Campylobacter, Chlamydia, Mycoplasma, and Ureaplasma species. HIV infection in association with RS has been reported. However, less than 4% of those infected with the above noted organisms develop the symptom complex of RS.

The simultaneous occurrence of RS in children and their parents suggests that similar etiologic factors are important. Genetic carriage of human leukocyte antigen (HLA)-B27 in RS has been studied and is present in 67-92% in pediatric cases (varies with the frequency of the gene in the population at risk). Although the role of HLA-B27 in disease pathogenesis remains unknown, mechanisms of interplay may exist between the microorganism and the gene. HLA-B27 might affect immune mechanisms other than classical antigen presentation, yet the mechanism by which HLA-B27 confers susceptibility remains unknown. Indeed, RS does not develop in all family members who have diarrhea and carry HLA-B27; conversely, RS may develop in a family without carriage of HLA-B27 antigen, suggesting involvement by other unknown factors in RS pathogenesis. Disease penetrance of less than 50% has been found in studies of monozygotic twins. There is less than a 1% risk of an HLA-B27 positive person actually developing RS.

Frequency:

• In the US: Overall (in adults and children) estimated at between 3.5 and 5 per 100,000 males.

• Internationally: RS is relatively infrequent in children, and its true frequency in childhood is difficult to determine. In a report of 344 cases of postdysenteric RS, only 1% occurred in children. Several possible reasons may explain why childhood RS rarely has been documented, including the following:
  • RS usually is not included in the differential diagnosis of arthritis in children.
  • Diagnosis of dysuria and urethritis in young children is difficult, as is differentiating conjunctivitis from other causes.
  • Most cases are sporadic.
  • The disease may occur over a relatively short period, either in a single family or as multiple cases in geographic proximity.

Mortality/Morbidity: The presence of HLA-B27 is a major determinant of disease severity and a predictor of recurrence. RS in a young child or adolescent carrying HLA-B27 often is associated with a recurrent arthritis and a more severe course of the disease (eg, risk of sacroiliitis, acute iridocyclitis). In many ways, the disease course nearly mirrors juvenile ankylosing spondylitis.

Race: Patients with RS have been described in all ethnic groups; no ethnic predisposition is known.

Sex: RS is most prevalent in boys. The male-to-female ratio is 4:1 compared to the 50:1 ratio in adult venereal forms of RS.

History:

• Most children appear healthy before the disease develops.

• Patients typically have no unusual family history of rheumatic disease.

• Some patients may report a history of diarrhea or sexual intercourse about 1-2 weeks prior to symptom onset. Diarrhea precedes onset of RS in 70% of childhood cases.

• RS typically begins with fever and diarrhea, followed by conjunctivitis and then genitourinary, joint, and skin symptoms. RS symptoms do not develop in a consistent order.

• Initial symptoms may be conjunctivitis, arthritis, and urethritis.

• The full classic triad (eg, arthritis, urethritis, conjunctivitis) occurs initially in only 35% of cases. All 3 major symptoms usually develop within a 1- to 2-week period, but all 3 occasionally manifest after 3 to 4 weeks. RS in children apparently has most of the features seen in adult cases.

Physical: The 4 major system involvements are arthritis and enthesitis, conjunctivitis, urethritis, and skin and mucocutaneous lesions.

• Arthritis and enthesitis

• Joint involvement is the most prominent physical finding and the most prolonged symptom of RS. This is the presenting complaint in 25% of childhood cases.
• Joints commonly are described as tender, warm, swollen, and sometimes red.
• Joint symptoms may present initially or several weeks after onset of other symptoms.
• Although these symptoms usually are asymmetric and involve only a few joints, migratory or symmetric involvement also is reported.
• In childhood RS, the patterns of joint involvement are 69% oligoarticular or pauciarticular arthritis, 27% polyarticular, and 4% monoarticular. Affected joints usually are the large weight-bearing joints of the lower extremities, although the upper extremities may be involved.
• The most commonly involved joints are the knee, ankle, metatarsophalangeal, elbow, metacarpophalangeal, hip, shoulder, and wrist. Involvement of the fingers and toes may take the form of dactylitis ("sausage digits").
• Sacroiliitis frequently occurs in adults who are HLA-B27 positive but appears to occur less often in children.
• At times, symptom severity in involved joints fluctuates.
• Most symptoms are self-limited and persist a few months.
• Arthritis usually is remittent and rarely leads to severe limitation of functional capacity.
• Enthesitis (ie, inflammation of ligament and tendon insertions into bone) is thought to be a characteristic feature of RS and may be the predominant complaint. The most common areas involved are the insertions of (1) the Achilles tendon into the calcaneus, (2) the plantar fascia into the inferior surface of the calcaneus, (3) the patellar ligament into the tibial tuberosity, and (4) the quadriceps and patellar ligament into the patella.

• Conjunctivitis

• Conjunctivitis is the most frequent presenting complaint among children (present in 2/3 of cases at onset). Typical findings are bilateral, mucopurulent conjunctivitis, which often varies from mild to severe inflammation.
• Conjunctivitis may be painless or may cause severe symptoms with blepharospasm and photophobia.
• Conjunctivitis usually resolves within 2 weeks.
• Other eye findings (eg, iritis, keratitis, corneal ulceration, optic neuritis) are reported more frequently in children than in adults.

• Urethritis

• Urethritis is difficult to diagnose in children but is present in 30% of childhood cases at onset.
• Obtaining a history of dysuria in children is difficult, possibly because it is mild or absent.
• In patients with painless discharge, staining of the underpants may be evident.
• The recommended procedure is to conduct a careful historical and clinical evaluation for urethritis, searching for pyuria, meatal inflammation, and small peri-meatal ulcerations.
• Balanitis and labial ulcerations have been reported.

• Skin and mucocutaneous lesions

• Skin and mucocutaneous lesions are among the diagnostic criteria for RS. Carefully search for mucocutaneous lesions in patients for whom RS is suspected, although these lesions occur less often in children.
• Keratoderma blennorrhagicum is the distinctive and classic skin manifestation of RS. The lesion begins as macules and vesicles on the lateral aspects of the palms and soles, progressing to hyperkeratotic papules and plaques with a pustular center. Most lesions usually occur on weight-bearing or pressure areas of the soles and palms, as well as on extensor surfaces of the legs and dorsal aspects of the hands and feet. These findings confirm an RS diagnosis.
• Nonspecific maculopapular erythematous rashes often occur in children with RS.
• Other reported skin findings include erythema nodosa, psoriatic-appearing papules, erythematous hyperkeratotic plaques, and nail changes including onycholysis, subungual debris, periungual pustules, and, rarely, pitting.
• Reported mucosal lesions include palatal erosions, balanitis circinata (ie, shallow, sharply demarcated serpiginous ulcers in uncircumcised men and hyperkeratotic plaques in circumcised men), and circinate vulvitis in women. These lesions rarely occur in children but strongly suggest RS.

• Other systemic features include: Low-grade fever, weight loss, epistaxis, pleuritic pain with pleural effusion, lymphadenopathy, or splenomegaly

Lab Studies:

• RS is diagnosed clinically by proper history and physical examination. No specific tests or markers exist for RS. Indicators of inflammation are usually abnormal. Nonspecific laboratory findings include the following:

• Patients have mild normocytic normochromic anemia, thrombocytosis, and leukocytosis (to 20,000/mm³).
• ESR, total serum hemolytic complement (CH50), and C3 levels are elevated. ESR in the 50-60 mm/h range can remain elevated from weeks to months. C1, C4, and C5 levels are normal. C1 inhibitor functional assay (C1INH) and C2 levels may be elevated.
• HLA-B27 carriage occurs in 67-92% of pediatric cases.
• Pyuria: WBCs, RBCs, and small amounts of protein are found on urinalysis. Urine culture may test positive for Chlamydia or Ureaplasma species, although test results may be negative if obtained several weeks after the onset of symptoms.
• A stool culture obtained soon after the onset of diarrhea may identify enteric pathogens (eg, Salmonella, Shigella, Yersinia species). Positive results are higher in children than in young adults or adolescents.
• Synovial fluid reveals increased leukocytes in a range of 10,000-40,000/mm³, with polymorphonuclear cells (37-98%) predominant. Levels of CH50, C1INH, C4, C5, and C3 in synovial fluid are elevated.

Imaging Studies:

• In patients with advanced RS, radiographic findings have included periarticular demineralization, osteopenia, periostitis, bony erosion of peripheral joints, bony erosion at sites of ligament insertions to the bone, spur formation, syndesmophytes, enthesitis, and sacroiliitis.

• MRI is more sensitive than CT or scintigraphy at detecting sacroiliitis and may be necessary for use in children who do not usually exhibit sacroiliac symptoms. MRI is also useful in assessing activity in the tendons and entheses.

Histologic Findings: Histopathologic findings of the early cutaneous lesions are essentially the same as for psoriasis. Early lesions of keratoderma blennorrhagicum and balanitis circinata feature a spongiform pustule in the upper dermis. Later lesions of keratoderma usually no longer contain spongiform pustules but reveal the nonspecific findings of acanthosis, hyperkeratosis, and parakeratosis.

Reiter cells, large macrophages containing engulfed lymphocytes, polymorphonuclear leukocytes, and, rarely, plasma cells, may be seen in synovial fluid. These cells comprise less than 1% of the synovial fluid white blood cells. These cells are found in the synovium, however, extensive pannus formation is rare.

Medical Care:

• No specific therapy for RS is indicated.

• Mild cases of RS may recover spontaneously.

• Antibiotics may be needed to treat infections.

• Maintenance of joint function through physical activity, joint protection, suppression of inflammation.

Consultations:

• Ophthalmology for evaluation of patients with eye involvement

• Rheumatology for followup and medical management.

• Physical and occupational therapy for maintenance of function and gait.

Diet:

• No limitations unless on steroid therapy.

Activity:

• Limited only by the arthropathy.

Arthritis and enthesitis

Aspirin and other short- and long-acting anti-inflammatory drugs (eg, indomethacin, naproxen) improve articular symptoms. In one report, a patient became asymptomatic after 3 months' administration of aspirin at 80 mg/kg/d divided qid; the dosage then was reduced gradually and eventually discontinued. A combination of nonsteroidal anti-inflammatory drugs (NSAIDs) reportedly is effective for severe cases. No published data suggest any nonsteroidal agent is more effective or less toxic than others. (Controlled treatment trials are difficult to conduct with an uncommon disease.)

A short course of antibiotics may be needed, based on the culture results; however, treatment may not affect the course of RS. Administration of longer-term antibiotics to treat joint symptoms provides no established benefits.

Varying success in treating severe cases has been reported from administration of other medications (eg, sulfasalazine, methotrexate, etretinate, ketoconazole, azathioprine, intra-articular steroid injections).

Conjunctivitis

Transient and mild conjunctivitis usually is not treated. Mydriatics and cycloplegics (eg, atropine) with topical corticosteroids may be administered for acute anterior uveitis.

Urethritis and gastroenteritis

Antibiotics may be considered, based upon the cultures used and their sensitivity. In general, treat urethritis with a 7- to 10-day course of erythromycin or tetracycline.

Mucocutaneous lesions

Only local care for mucosal lesions is necessary. Topical steroids may be needed for psoriasiform lesions. Hydrocortisone 2.5% cream is effective for balanitis circinata, and salicylic acid 10% ointment is effective in treating chronic keratoderma blennorrhagicum, although either condition may heal without medical treatment.
Drug Category: Analgesic and antiinflammatory agents -- Aspirin and several NSAIDs are available and have similar effectiveness in treating symptoms.

Drug Category: Antibiotics -- Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the clinical setting. Antibiotic selection should be guided by blood culture sensitivity whenever feasible.

Drug Category: Topical agents -- Topical steroids or salicylic acid may be needed to treat psoriasiform lesions.

Drug Category: Slow-acting antirheumatic disease agents (SAARDs) -- Have shown some efficacy in uncontrolled trials.

Further Outpatient Care:

• Long-term follow-up care is essential to ascertain whether the course of RS is benign.

• Physical and occupational therapy to maintain function and gait.

In/Out Patient Meds:

• Antiinflammatory drugs such as aspirin, naproxen, or indomethacin.

• Antibiotics such as erythromycin or tetracycline.

• Topical agents such as hydrocortisone or salicylic acid ointment.

• Long-acting antiinflammatory/immunomodulatory agents such as sulfasalazine, methotrexate, or azathioprine.

Deterrence/Prevention:

• Education on the prevention of the spread of sexually-transmitted diseases through the use of condoms has been associated with a decrease in the occurrence rate.

Prognosis:

• The natural history of reactive arthritis is extremely variable. RS in most children appears to be a self-limited condition with gradual resolution of symptoms and signs over a period of months. Some patients may experience exacerbations and remissions that can persist from several weeks to several months.
• The clinical course of RS usually is considered benign and self-limited; however, chronic arthritis with sacroiliac abnormalities and corneal scarring has been reported as a result of juvenile RS.
• The presence of HLA-B27 may predict a more prolonged course and severe outcome and should be ascertained in patients with RS.

Patient Education:

• Discourage inactivity and immobilization

• Encourage stretching exercises and range of motion.

• Encourage compliance with medications and activity.

• Provision of information to adolescent patients on the prevention of sexually-transmitted diseases (STDs) and the use of condoms.