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AUTHOR AND EDITOR INFORMATION

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Author: Akaluck Thatayatikom, MD, Assistant Professor of Pediatrics, Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Faculty of Medicine, Thammasat University, Rangsit Campus, Thailand

Akaluck Thatayatikom is a member of the following medical societies: American Academy of Allergy Asthma and Immunology

Editors: Barry L Myones, MD, Associate Professor, Departments of Pediatrics and Immunology, Pediatric Rheumatology Section, Baylor College of Medicine; Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David D Sherry, MD, Professor of Pediatrics, Division of Rheumatology, University of Pennsylvania; Director of Clinical Rheumatology, Children's Hospital of Philadelphia; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; Barry L Myones, MD, Associate Professor, Departments of Pediatrics and Immunology, Pediatric Rheumatology Section, Baylor College of Medicine; Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital

Author and Editor Disclosure

Synonyms and related keywords: Reiter disease, Reiter’s disease, reactive arthritis, oculourethrosynovial syndrome, arthritis with conjunctivitis, urethritis, spondyloarthropathy, spondyloarthritis, oligoarthritis, sacroiliitis, enthesitis, mucocutaneous lesions, keratoderma blennorrhagicum, balanitis circinata, venereal disease, sexually transmitted disease, STD

INTRODUCTION

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Background

In 1916, Hans Reiter, a Nazi physician, described a young soldier who experienced an acute febrile illness with purulent conjunctivitis, nongonococcal urethritis, and severe arthritis following an episode of bloody diarrhea. In 1918, Sir Benjamin Brodie was the first to report the classic triad of symptoms associated with a postvenereal prodrome (5 cases) in the English literature.

The first preadolescent case was reported in 1947. In 1969, the term reactive arthritis (RA) was proposed because the development of the arthritis, urethritis, and conjunctivitis was closely associated with enteric and venereal infections.

Recently, the use of the Reiter eponym has been argued against and has declined in the medical literature because Reiter, a war criminal, was involved in deadly human experiments during World War II. Additionally, Reiter incorrectly attributed the syndrome to a spirochetal infection. Other terms for the syndrome (eg, RA; oculouretherosynovial syndrome; arthritis with conjunctivitis, urethritis, diarrhea, and oligoarthritis; spondyloarthropathy; spondyloarthritis) have been advocated until pathophysiologic or other insights provide more accurate nomenclature.

Reiter syndrome (RS), a subclassification of RA, is an inflammatory arthritis associated with synovitis, conjunctivitis, urethritis, onycholysis, and enthesitis. The classic triad of RA includes arthritis, conjunctivitis, and urethritis and occurs in approximately one third of patients at onset. Less stringent criteria from the American College of Rheumatology require a 1-month duration of arthritis in association with urethritis, cervicitis, or both. These criteria are 84.3% sensitive and 98.2% specific 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. However, most cases in adults are mainly secondary to venereal disease. The microorganisms commonly associated with RS include Salmonella, Shigella, Yersinia, Campylobacter, Chlamydia, Mycoplasma, and Ureaplasma species.

These microorganisms are believed to mimic self-peptides and to activate a self-immune response. Recently, similarity between microorganisms and a novel gene that encodes a surface protein of activated natural killer (NK) cells has been reported. This evidence supports the hypothesis; however, the role of NK cells in RS has not been defined.   

CD8 T cells are believed to play a role in RS because individuals with human immunodeficiency virus (HIV) infection have presented with RS, particularly individuals with significant CD4 suppression who are in advanced stages of infection  The simultaneous occurrence of RS in children and their parents suggests that similar etiologic factors are involved. Genetic carriage of HLA-B27  in RS has been studied and is present in 67-92% of pediatric cases, although the rate 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 between the microorganism and the gene may be present. HLA-B27 may affect immune mechanisms other than classic antigen presentation, although 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% in studies of monozygotic twins has been found. The risk of an individual with HLA-B27 actually developing RS is less than 1%.

Frequency

United States

In both adults and children the overall frequency is estimated to be 3.5-5 cases per 100,000 males.

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 is often associated with recurrent arthritis and more severe course of the disease (eg, risk of sacroiliitis and acute iridocyclitis). In many ways, the disease course nearly mirrors juvenile ankylosing spondylitis.

Race

Patients with RS have been described in all racial groups; no racial predisposition is known.

Sex

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

Age

RS has been reported in individuals of all ages, some as young as 2 years, although most pediatric patients present with symptoms after age 9 years. The peak onset is in the third decade of life. 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.


CLINICAL

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History

Several possible factors may explain why Reiter syndrome (RS) in childhood has been rarely documented, including the following:

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

    Physical

    The 4 major symptoms include arthritis and enthesitis, conjunctivitis, urethritis, and skin and mucocutaneous lesions.

    • Arthritis and enthesitis
      • Joint involvement is the most prominent physical finding and is the most prolonged symptom of RS. This is the presenting symptom in 25% of childhood cases.
      • Joints are commonly described as tender, warm, swollen, and, sometimes, red.
      • Joint symptoms may occur initially or several weeks after onset of other symptoms.
      • Although these symptoms are usually asymmetric and involve only a few joints, migratory or symmetric involvement is also reported.
      • In childhood RS, the patterns of joint involvement include oligoarticular or pauciarticular arthritis (69%), polyarticular (27%), and monoarticular (4%). Affected joints are usually the large weight-bearing joints of the lower extremities, although the upper extremities may be involved.
      • The most commonly involved joints include the knee, ankle, metatarsophalangeal, elbow, metacarpophalangeal, hip, shoulder, and wrist. Involvement of the fingers and toes may take the form of dactylitis (ie, sausage digits).
      • Sacroiliitis frequently occurs in adults who are HLA-B27 positive but is apparently less common in children.
      • At times, symptom severity in involved joints fluctuates.
      • Most symptoms are self-limited and persist a few months.
      • Arthritis is usually 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 symptom. The most common areas involved include 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 common presenting symptom in children and is present in two thirds of patients 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 ocular findings (eg, iritis, keratitis, corneal ulceration, optic neuritis) are more common in children than in adults.
    • Urethritis
      • Urethritis is difficult to diagnose in children but is present in 30% of pediatric patients 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 obtain a detailed history and perform a careful clinical evaluation for urethritis, searching for pyuria, meatal inflammation, and small perimeatal 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 in whom RS is suspected, although these lesions occur less often in children.
      • Keratoderma blennorrhagicum is the distinctive and classic skin manifestation of RS. The lesions begin 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 develop 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 the diagnosis.
      • Nonspecific maculopapular erythematous rashes often develop 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 symptoms: Systemic features include low-grade fever, weight loss, epistaxis, pleuritic pain with pleural effusion, lymphadenopathy, or splenomegaly.

    Causes

    See Pathophysiology.


    DIFFERENTIALS

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    Acute Lymphoblastic Leukemia
    Behcet Syndrome
    Campylobacter Infections
    Cervicitis
    Chlamydial Infections
    Colitis
    Crohn Disease
    Juvenile Rheumatoid Arthritis
    Kawasaki Disease
    Lyme Disease
    Mycoplasma Infections
    Salmonella Infection
    Ulcerative Colitis
    Yersinia Enterocolitica Infection

    Other Problems to be Considered

    Other forms of reactive arthritis (RA)
    Poststreptococcal RA Enthesitis-related juvenile idiopathic arthritis
    Oligoarticular juvenile idiopathic arthritis
    Polyarticular juvenile idiopathic arthritis
    Juvenile psoriatic arthritis
    Gonococcal arthritis
    Immunotherapy/Immunization–related arthropathy
    Synovitis, acne, pustulosis, hyperostosis, and osteomyelitis (SAPHO) syndrome
    Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome
    Systemic autoinflammatory disorders
    Acute rheumatic fever


    WORKUP

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    Lab Studies

    • Reiter syndrome (RS) is clinically diagnosed based on history and physical examination findings.
    • 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 (up to 20,000/mL).
      • Erythrocyte sedimentation rate (ESR), total serum hemolytic complement (CH50), and C3 levels are elevated. ESR in the 50- to 60-mm/h range can remain elevated from weeks to months. C1, C4, and C5 levels are within the reference range. C1 inhibitor functional assay (C1INH) and C2 levels may be elevated.
      • HLA-B27 carriage occurs in 67-92% of pediatric cases. Patients with HLA-B27 have more severe articular involvement and more extra-articular disease.
      • WBCs, RBCs, and small amounts of protein are present in urinalysis findings, indicating pyuria. Urine culture findings may be 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). Positive results are more common in children than in young adults or adolescents.
      • Synovial fluid reveals increased leukocytes in a range of 10,000-40,000/mL, with polymorphonuclear cells (37-98%) predominant. CH50, C1INH, C4, C5, and C3 levels in synovial fluid are elevated.

    Imaging Studies

    • Radiography

      • Soft tissue swelling caused by joint effusion, periarticular edema, bursitis, and tendinitis can been observed using radiography. As many as 70% of patients with RS have radiographic abnormalities characterized by asymmetrical involvement of the lower extremity and enthesitis, ill-defined bony erosions with adjacent bony proliferation, and paravertebral ossification.
      • In patients with advanced RS, radiographic findings include 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: MRI is more sensitive than CT or scintigraphy in detecting sacroiliitis and may be necessary 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 in psoriasis. Early lesions of keratoderma blennorrhagicum and balanitis circinata feature a spongiform pustule in the upper dermis. Later lesions of keratoderma usually do not contain spongiform pustules but reveal the nonspecific findings of acanthosis, hyperkeratosis, and parakeratosis. 

    Reiter cells, large macrophages that contain engulfed lymphocytes, polymorphonuclear leukocytes, and, rarely, plasma cells, may be observed in synovial fluid. These cells comprise less than 1% of the synovial fluid WBCs. These cells are found in the synovium; however, extensive pannus formation is rare.


    TREATMENT

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    Medical Care

    • No specific therapy for Reiter syndrome (RS) is indicated.
    • Mild cases of RS may resolve spontaneously.
    • Antibiotics may be needed to treat infection.
    • Maintain joint function with physical activity, joint protection, and suppression of inflammation.

    Consultations

    • Ophthalmologist for evaluation of patients with eye involvement
    • Rheumatologist for follow-up and medical management
    • Physical and occupational therapists for maintenance of function and gait

    Diet

    No dietary limitations are necessary unless the patient is receiving steroid therapy.

    Activity

    Activity is limited only by the arthropathy.


    MEDICATION

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    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 of aspirin administration at 80 mg/kg/d divided 4 times daily; the dosage was gradually reduced and eventually discontinued. A combination of nonsteroidal anti-inflammatory drugs (NSAIDs) is reportedly effective in severe cases. No published data suggest any nonsteroidal agent is more effective or less toxic than another (controlled treatment trials are difficult to conduct with an uncommon disease).

    Infliximab, an anti–tumor necrosis factor (TNF)–a agent, was successfully used to treat patients with post–Yersinia infection reactive arthritis (RA) and HIV-associated Reiter syndrome (RS).

    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 with other medications (eg, sulfasalazine, methotrexate, etretinate, ketoconazole, azathioprine, intra-articular steroid injections) has been reported.

    Conjunctivitis

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

    Urethritis and gastroenteritis

    Antibiotics may be considered, based on 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 anti-inflammatory agents

    Aspirin and several NSAIDs are available and have similar effectiveness in treating symptoms.

    Drug NameAspirin (Anacin, Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin)
    DescriptionShort-acting anti-inflammatory agent with rapid absorption in proximal GI tract. Optimally effective only when stable serum levels of 150-250 mcg/L are achieved after 3-5 d of treatment. Serum aspirin levels can be checked after 5-10 d of treatment. Maximal anti-inflammatory action is generally achieved within 2-4 wk, with some further benefit occurring up to 3 mo.
    Adult Dose325-650 mg PO q4-6h; not to exceed 4 g/d
    Pediatric Dose75-100 mg/kg/d PO divided qid; administer with food to minimize gastritis
    >40 kg: 8-12 tab of 325 mg; not to exceed 4 g/d
    ContraindicationsDocumented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma; administration in children aged <16 y with influenzalike illness because of association of aspirin with Reye syndrome
    InteractionsEffects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs
    PregnancyD - Unsafe in pregnancy
    PrecautionsIncreases risk of abnormal liver enzyme levels, Reye syndrome, and peptic ulcers; may cause transient decrease in renal function and aggravate chronic kidney disease; avoid in patients with severe anemia or history of blood coagulation defects and in those taking anticoagulants; during therapy, regularly question parents and children about eating habits, abdominal pain or diarrhea, tinnitus or subtle hearing loss, behavioral changes, bruising, and epistaxis; family education about potential complications is essential

    Drug NameNaproxen
    DescriptionShort-acting (Aleve, Anaprox) and long-acting (Naprosyn, Naprelan) agent for relief of mild-to-moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.
    Adult Dose250-500 mg PO bid; may increase to 1.5 g/d for limited periods (for Naprelan, administer entire calculated dose qd)
    Pediatric Dose10-20 mg/kg/d PO divided bid; not to exceed 1250 mg/d (for Naprelan, administer entire calculated dose qd)
    ContraindicationsDocumented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency
    InteractionsCoadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
    PregnancyB - Usually safe but benefits must outweigh the risks.
    PrecautionsCategory D in third trimester of pregnancy; pseudoporphyria, acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia rarely occurs, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation; hepatic impairment may require dose reduction

    Drug NameIndomethacin (Indochron E-R, Indocin)
    DescriptionRapidly absorbed; metabolism occurs in liver through demethylation, deacetylation, and glucuronide conjugation. Inhibits prostaglandin synthesis.
    Adult Dose25-50 mg PO bid/tid
    75 mg SR PO bid; not to exceed 200 mg/d
    Pediatric Dose1-3 mg/kg/d divided PO tid/qid; not to exceed 4 mg/kg/d or 150-200 mg/d
    ContraindicationsDocumented hypersensitivity; GI bleeding; renal insufficiency
    InteractionsCoadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
    PregnancyB - Usually safe but benefits must outweigh the risks.
    PrecautionsCategory D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; reversible leukopenia may occur (discontinue if leukopenia, granulocytopenia, or thrombocytopenia persists); may cause severe headache in the first few days after initiation of therapy, which usually subsides with continued use; adverse effect sometimes avoided by starting at half dose for 3-4 d with subsequent increase

    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 NameErythromycin (Erythrocin, E.E.S, E-mycin, Eryc)
    DescriptionInhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest; used to treat Mycoplasma pneumoniae and Staphylococcus, Streptococcus, and Chlamydia species infections.
    Adult Dose0.25-1 g PO q6h; not to exceed 4 g/d
    Pediatric Dose30-50 mg/kg/d PO divided tid/qid; not to exceed 2 g/d
    ContraindicationsDocumented hypersensitivity; hepatic impairment
    InteractionsCoadministration may increase toxicity of theophylline, digoxin, carbamazepine, cisapride, valproic acid, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin or simvastatin increases risk of rhabdomyolysis
    PregnancyB - Usually safe but benefits must outweigh the risks.
    PrecautionsCaution in liver disease; estolate formulation may cause cholestatic jaundice; adverse GI effects are common (administer doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

    Drug NameTetracycline (Sumycin, Achromycin)
    DescriptionTreats gram-positive and gram-negative organisms, as well as mycoplasmal, chlamydial, and rickettsial infections. Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s).
    Adult Dose250-500 mg PO q6h
    Pediatric Dose<8 years: Not recommended
    >8 years: 25-50 mg/kg/d PO divided qid; not to exceed 3 g/d
    ContraindicationsDocumented hypersensitivity; severe hepatic dysfunction
    InteractionsBioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants
    PregnancyD - Unsafe in pregnancy
    PrecautionsPhotosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (ie, <8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

    Drug Category: Topical agents

    Topical steroids or salicylic acid may be needed to treat psoriasiform lesions.

    Drug NameHydrocortisone (Cortaid, Dermacort, Westcort, CortaGel)
    DescriptionAn adrenocorticosteroid derivative suitable for application to skin or external mucous membranes. Has mineralocorticoid and glucocorticoid effects resulting in anti-inflammatory activity.
    Adult Dose1-2.5% cream; apply as thin film to affected area 3-4 times per d
    Pediatric DoseApply as in adults
    ContraindicationsDocumented hypersensitivity; viral, fungal, and bacterial skin infections
    InteractionsNone reported
    PregnancyC - Safety for use during pregnancy has not been established.
    PrecautionsProlonged use, application over large surface areas, application of potent steroids, and occlusive dressings may increase systemic absorption of corticosteroids and may cause Cushing syndrome, reversible HPA axis suppression, hyperglycemia, and glycosuria

    Drug NameSalicylic acid (Kerasal ointment)
    DescriptionBy dissolving intercellular cement substance, produces desquamation of horny layer of skin, while not affecting structure of viable epidermis.
    Adult Dose10% ointment; apply as thin layer to affected area 1-2 times per d
    Pediatric DoseApply as in adults
    ContraindicationsDocumented hypersensitivity; prolonged use in infants, people with diabetes mellitus, and patients with impaired circulation (not recommended)
    InteractionsNone reported
    PregnancyC - Safety for use during pregnancy has not been established.
    PrecautionsAvoid contact with mucous membranes and eyes; immediately flush with water for 15 min if contact with eyes or mucous membranes occurs; avoid inhaling vapors

    Drug Category: Slow-acting antirheumatic disease agents (SAARDs)

    These agents have shown some efficacy in uncontrolled trials.

    Drug NameSulfasalazine (Azulfidine, EN-tabs)
    DescriptionConjugate of the salicylate 5-aminosalicylic acid and the sulfonamide sulfapyridine (linked by an azo bond). Sulfasalazine is primarily excreted in the urine unchanged. Most of the 5-aminosalicylic acid remains in the colon and is not absorbed. Acts locally to decrease the inflammatory response in the joints and systemically inhibits prostaglandin synthesis and folate metabolism. Two multicenter placebo-controlled trials have indicated tolerability and some efficacy in patients with RS.
    Adult Dose1 g PO tid/qid initially, followed by maintenance dose of 2 g/d PO divided q6-12h
    Pediatric Dose<2 years: Not established
    >2 years: 10-15 mg/kg/d initially, then increase qwk over 4 wk to achieve maintenance dosage of 30-50 mg/kg/d PO divided bid/tid; not to exceed 2 g/d
    ContraindicationsDocumented hypersensitivity; sulfa drugs or any component; GI or GU obstruction
    InteractionsDecreases effects of iron, digoxin, and folic acid; conversely, increases effect of PO anticoagulants, PO hypoglycemic agents, and methotrexate
    PregnancyB - Usually safe but benefits must outweigh the risks.
    PrecautionsCaution in patients with renal or hepatic impairment, blood dyscrasias, or urinary obstruction

    Drug Category: Biological therapies

    Anti–TNF-a therapy may be considered in refractory cases.

    Drug NameInfliximab (Remicade)
    DescriptionChimeric IgG1kmonoclonal antibody binding specifically to the soluble and transmembrance forms of TNF-a and inhibiting the binding of TNF-a with its receptors.
    Adult DoseInduction: 3 mg/kg as a single IV infusion at 0, 2, and 6 wk
    Maintenance: 3 mg/kg/IV q8wk
    If incomplete response or clinically indicated, subsequent doses may be escalated up to 10 mg/kg or administered at 4-wk intervals
    Pediatric DoseNot established; in refractory cases, may consider administering as in adults
    ContraindicationsDocumented hypersensitivity to infliximab or murine proteins; moderate to severe (NYHA Class III/IV) CHF at doses greater than 5 mg/kg
    InteractionsIncreases risk of serious infections and neutropenia with concurrent use of other TNF-a–blocking agents or anakinra
    PregnancyB - Usually safe but benefits must outweigh the risks
    PrecautionsAnti-TNF therapy potentially alters normal immune responses; serious and fatal infections including tuberculosis, invasive fungal infections, and opportunistic infections have been reported; evaluate and monitor for infections before, during, and after treatment; may cause infusion reactions (eg, hypotension or hypertension, flushing), hepatotoxicity, leukopenia, neutropenia, thrombocytopenia, demyelinating disorders, or lymphoma


    FOLLOW-UP

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    Further Outpatient Care

    • Long-term follow-up care is essential to ascertain whether the course of Reiter syndrome (RS) is benign.
    • Physical and occupational therapy is used to maintain function and gait.

    In/Out Patient Meds

    • Anti-inflammatory drugs such as aspirin, naproxen, or indomethacin
    • Antibiotics such as erythromycin or tetracycline
    • Topical agents such as hydrocortisone or salicylic acid ointment
    • Long-acting anti-inflammatory/immunomodulatory agents such as sulfasalazine, methotrexate, or azathioprine

    Deterrence/Prevention

    • Education on the prevention of the spread of sexually transmitted diseases with condoms has been associated with decrease incidence.

    Prognosis

    • The natural history of reactive arthritis (RA) widely varies. 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 is usually 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.
    • Provide information to adolescent patients on the prevention of sexually transmitted diseases and the use of condoms. 


    MISCELLANEOUS

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    Medical/Legal Pitfalls

    • Reiter syndrome (RS) is uncommon in children. Some patients may not present with the classic triad of symptoms. Diagnosis of the disease requires a high index of suspicion.
    • RS is a differential diagnosis in patients who present with joint symptoms and other system involvement (eg, skin, eye, urinary tract).
    • If RS occurs in a child as a result of a sexually transmitted disease, child protective service evaluation is mandatory.


    MULTIMEDIA

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    Media file 1:  Swelling of right knee with effusion caused by arthritis. Image courtesy of Gun Phongsamart, MD.
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    Media type:  Photo

    Media file 2:  Remarkable tenderness of left SI joint caused by sacroiliitis. Image courtesy of Gun Phongsamart, MD.
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    Media type:  Photo

    Media file 3:  Balanitis circinata. Image courtesy of Gun Phongsamart, MD.
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    Media type:  Photo

    Media file 4:  Achilles tendinitis and swelling of the retrocalcaneal bursa.
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    Media type:  Photo


    REFERENCES

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    • Bauman C, Cron RQ, Sherry DD, Francis JS. Reiter syndrome initially misdiagnosed as Kawasaki disease. J Pediatr. Mar 1996;128(3):366-9. [Medline].
    • Brodie BC. Pathological and Surgical Observations on Diseases of the Joints. London, England:. Longman, Hurst, Rees, Orme, and Brown;1818.
    • Cush JJ, Lipsky PE. Reiter's Syndrome and Reactive Arthritis. In: Koopman's Textbook of Arthritis and Allied Health Conditions. 14th ed. Philadelphia, Pa:. Lippincott, Williams, & Wilkins;2001:1324-44.
    • 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].
    • Eapen BR. A new insight into the pathogenesis of Reiter's syndrome using bioinformatics tools. Int J Dermatol. Mar 2003;42(3):242-3. [Medline].
    • Gaylis N. Infliximab in the treatment of an HIV positive patient with Reiter's syndrome. J Rheumatol. Feb 2003;30(2):407-11. [Medline].
    • Hughes RA, Keat AC. Reiter's syndrome and reactive arthritis: a current view. Semin Arthritis Rheum. Dec 1994;24(3):190-210. [Medline].
    • Jacobs JC, Berdon WE, Johnston AD. HLA-B27-associated spondyloarthritis and enthesopathy in childhood: clinical, pathologic, and radiographic observations in 58 patients. J Pediatr. Apr 1982;100(4):521-8. [Medline].
    • Keat A. Reiter's syndrome and reactive arthritis in perspective. N Engl J Med. Dec 29 1983;309(26):1606-15. [Medline].
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    • 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.
    • Oili KS, Niinisalo H, Korpilahde T, Virolainen J. Treatment of reactive arthritis with infliximab. Scand J Rheumatol. 2003;32(2):122-4. [Medline].
    • Panush RS, Paraschiv D, Dorff RE. The tainted legacy of Hans Reiter. Semin Arthritis Rheum. Feb 2003;32(4):231-6. [Medline].
    • Reiter H. Ueber eine bisher unerkannte spirochaeteninfektion (Spirochaetosis arthritica). Dtsch Med Wochenschr. 1916;42:1535-6.
    • Rosenberg AM, Petty RE. Reiter's disease in children. Am J Dis Child. Apr 1979;133(4):394-8. [Medline].
    • Singsen BH, Bernstein BH, Koster-King KG, et al. Reiter's syndrome in childhood. Arthritis Rheum. Mar 1977;20(2 Suppl):402-7. [Medline].
    • Willkens RF, Arnett FC, Bitter T, et al. Reiter's syndrome. Evaluation of preliminary criteria for definite disease. Arthritis Rheum. Jun 1981;24(6):844-9. [Medline].
    • Zivony D, Nocton J, Wortmann D, Esterly N. Juvenile Reiter's syndrome: a report of four cases. J Am Acad Dermatol. Jan 1998;38(1):32-7. [Medline].

    Arthritis, Conjunctivitis, Urethritis Syndrome excerpt

    Article Last Updated: Apr 24, 2007