eMedicine Specialties > Dermatology > Papulosquamous Diseases

Reactive Arthritis

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Jorge Romaní, MD, Assistant Professor, Department of Dermatology, Hospital De Palamós Faculty of Medicine, Spain; Lluís Puig, MD, PhD, Program Director, Assistant Professor, Department of Dermatology, Hospital De La Santa Creu I Sant Pau, Universitat Autónoma De Barcelona

Updated: Jun 12, 2009

Introduction

Background

Reactive arthritis is a systemic disorder of unknown etiology that is defined by the development of psoriatic plaques, balanitis, keratoderma, conjunctivitis, urethritis, arthritis, and spondylitis.¹ This symptom complex usually follows an episode of either dysentery or urethritis.

The American Rheumatism Association criteria subcommittee defined this syndrome as 1 month of peripheral arthritis associated with urethritis, cervicitis, or both. The classic triad of the disease, namely urethritis, arthritis, and conjunctivitis, is present in only one third of the patients.

Stoll originally described this triad in 1776. In 1818, Brodie reported the triad in 5 patients. In 1916, 2 separate reports were published during World War I: Fiessinger and Leroy² detailed the findings in 4 patients (in French), and Reiter³ documented the case of a single patient with this triad of symptoms (in German). In 1942, an article by Bauer and Engelman⁴ described the first known American patient with reactive arthritis; they called this disorder, a "syndrome of unknown etiology characterized by urethritis, conjunctivitis, and arthritis (so-called Reiter's disease)." Their work contained only one reference, Reiter's article, and stated erroneously, "First described by Reiter, it has been most commonly referred to as Reiter's disease." Thus, this eponym remains in use despite its historical inappropriateness and Hans Reiter's later activities as a National Socialist war criminal.^5,6,7,8

Reactive arthritis mostly affects young men. It is frequently associated with the human leukocyte antigen B27 (HLA-B27) haplotype and is classified with the seronegative spondyloarthropathies. Reactive arthritis is preferably viewed as a tetrad, with the addition of the mucocutaneous findings of balanitis and keratoderma blennorrhagicum to the classic triad. The complete and incomplete forms of reactive arthritis can be identified by the presence or absence of the full tetrad.

Young children tend to have the postdysenteric form, whereas adolescents and young men are most likely to acquire reactive arthritis after they have urethritis. Interpreting its mucocutaneous findings as pustular psoriasis and its seronegative arthritis as psoriatic arthritis, some believe that reactive arthritis is best classified as a type of psoriasis.⁹

The eMedicine Ophthalmology article Reactive Arthritis and Rheumatology article Reactive Arthritis may be helpful.

Pathophysiology

The etiology of reactive arthritis remains uncertain. Two forms are recognized: a sexually transmitted form and a dysenteric form. Because the urethritis is a possible primary event, research efforts have focused on the identification of a microorganism that could be responsible for activating this disease. The pathophysiologic mechanism is proposed to be the triggering of an autoimmune reaction by these microorganisms.

Mycoplasma (Ureaplasma) species, Neisseria gonorrhoeae, Chlamydia species, and several viruses are among the suspected causative pathogens. Some findings have indicated that Chlamydia species are the etiologic agents in reactive arthritis.¹⁰ The discovery of Chlamydia trachomatis organisms in an involved joint and the confirmation of an immune response against Chlamydia infection (as indicated by high titers of antichlamydial antibodies in serum) have provided additional support to this hypothesis. In situ hybridization has also been used to identify chlamydial infection in synovial tissue.¹¹ Ureaplasma organisms can cause experimental and clinical nongonococcal urethritis. Synovial mononuclear cells from arthritic joints of patients with reactive arthritis react with Ureaplasma antigens; this organism has been isolated from a patient.

Reactive arthritis is also reported to occur after enteric bacterial infections, primarily those caused by parasites (Ascaris lumbricoides) and Shigella, Salmonella, Yersinia, Clostridium, and Campylobacter organisms. Impairment in the glycosaminoglycan defensive barrier was implicated in the development of reactive arthritis and reactive arthritides¹² ; this impairment may facilitate the penetration of infectious agents that are capable of triggering the autoimmune response.

The prevalence of different serotypes of C trachomatis antibodies and the incidence of C trachomatis –induced reactive arthritis was studied among patients with early arthritis in a defined population in Finland.¹³ Antibodies against C trachomatis were most common in patients with arthritis because cases with Chlamydia -induced reactive arthritis are included in this subgroup. The most accepted theory about the pathophysiology of reactive arthritis involves initial activation by a microbial antigen, followed by an autoimmune reaction that involves the skin, eyes, and joints.

Reactive arthritis has an important genetic component; it tends to cluster in certain families and almost exclusively affects males, with HLA-B27 identified in 70-80% of patients with reactive arthritis.¹³ HLA-B27 may share molecular characteristics with bacterial epitopes, facilitating an autoimmune cross-reaction instrumental in pathogenesis.

Frequency

United States

Reactive arthritis is a rare entity. Its frequency in the general population is difficult to assess. Its prevalence may be relatively high among patients with AIDS, especially men who are HLA-B27 seropositive. Reactive arthritis develops in almost 75% of HIV-positive men with HLA-B27.

A population-based study assessed reactive arthritis following culture-confirmed infections with bacterial enteric pathogens in Minnesota and Oregon.¹⁴ The estimated incidence following culture-confirmed Campylobacter, Escherichia coli O157, Salmonella, Shigella, and Yersinia infections in Oregon was 0.6-3.1 cases per 100,000 population.

International

In the United Kingdom, the incidence of reactive arthritis after urethritis is about 0.8%. Nearly 2% of Finnish males had reactive arthritis after nongonococcal urethritis; the incidence of HLA-B27 is higher among the Finnish population. Reactive arthritis develops in almost 75% of HIV-positive men with HLA-B27. Its incidence is high among patients with AIDS, and HIV testing is mandatory in patients in whom reactive arthritis is newly diagnosed, even if they do not have risk factors.

Mortality/Morbidity

Reactive arthritis can dramatically alter the patient's life because arthritis and other findings may produce considerable morbidity.

Race

Reactive arthritis affects persons of all races.

Sex

• Reactive arthritis usually affects young men.
• Reactive arthritis is uncommon in women, who represent 2-10% of patients in published series.
• A possible prostatic focus of persistent infection is postulated to explain the male predominance of reactive arthritis.

Age

• Reactive arthritis is most common in young men.
• Reactive arthritis is uncommon in children. When it occurs in children, the enteric form of the disease is predominant.

Clinical

History

A vast majority of cases of reactive arthritis are oligosymptomatic, and conjunctivitis or urethritis are present weeks before the patient's first visit, so they must be found by means of a correct anamnesis.

• Urethritis
  • An estimated 0.5-1% of cases of urethritis evolve into reactive arthritis. Urethritis develops acutely 1-2 weeks after infection through sexual contact, and is similar to gonococcal urethritis. A purulent or hemopurulent exudate appears, and the patient complains of dysuria.
  • Balanitis and vulvitis are rare in children; when they occur, they are suggestive of reactive arthritis.¹⁵
  • In men, urethritis is less painful and produces less purulent discharge than acute gonorrhea, and can go unnoticed. Findings from microscopic examination and cultures can be used to rule out N gonorrhoeae infection. Co-infection with both Chlamydia and Neisseria organisms is possible and common in some areas.
  • In women, urethritis and cervicitis may be mild, with dysuria or slight vaginal discharge, or asymptomatic, which makes diagnosis difficult.
  • Often, the initial urethritis is treated with antibiotics (especially wide-spectrum tetracyclines or macrolides) when findings suggest gonorrhea.
  • Despite an apparent early cure, the manifestations of the disease appear several weeks later, and the patient may not relate them to a prior episode of urethritis.
• Diarrhea: In enteric cases, diarrhea and dysenteric syndrome (usually mild) is followed by the clinical triad, which includes urethritis, in 1-4 weeks.
• General involvement
  • A syndrome, with malaise, low-grade fever, and generalized myalgia or headache can be present.
  • Pericarditis, aortic disease with aortic incompetence, auriculoventricular blockade, optical neuritis, pleuritis, pulmonary infiltrates, thrombophlebitis, and amyloidosis are rarely described in reactive arthritis.

Physical

• Immunoglobulin A (IgA) nephropathy: This is the most common type of primary glomerulonephritis worldwide and is reported in association with reactive arthritis.¹⁶
• Manifestations of the urogenital system
  • Circinate balanitis (see Media File 1) is characteristic. Circinate balanitis is defined by circinate or gyrate white plaques that grow centrifugally and eventually cover the entire surface of the glans penis. The penile shaft and scrotum can be involved. The lesions become rapidly keratotic in a circumcised penis.

Circinate balanitis in a patient with reactive arthritis.

• Circinate vulvitis is reported in women.
• Prostatitis, cystitis, and pyelonephritis are rare but possible urogenital manifestations of reactive arthritis.
• Bartholinitis can be present in women.
• Proctitis caused by Chlamydia species can occur in both sexes after anal intercourse.
• Conjunctivitis
  • Eye involvement is common.
  • Conjunctivitis appears in approximately 50% of patients with reactive arthritis.
  • Conjunctivitis is often bilateral, and it may be overlooked because of its transitory course.
  • An intense red, velvetlike conjunctival injection characterizes the conjunctivitis.
  • Edema and a purulent discharge are not rare in reactive arthritis–associated conjunctivitis.
• Other ocular manifestations
  • Iritis, iridocyclitis, and uveitis are seldom reported.
  • Iritis is more common in late recurrent episodes, and it only occurs in 3-8% of patients in the first attack.
  • At clinical examination, redness, pain, impaired vision, and exudation with hypopyon can suggest iritis.
  • Recurrent episodes can lead to pupillary synechia and glaucoma.
  • Keratitis rarely is reported.
• Arthritis
  • Articular involvement often is the key symptom of the syndrome. It is common and occurs in approximately 95% of patients.
  • The knee and tarsal joints (which support more weight than other joints) and the sacroiliac region are preferentially involved.
  • Clinically, the articular involvement resembles rheumatoid arthritis, but it is asymmetrical and commonly involves a single joint.
  • Articular swelling; intense pain; and involvement of soft tissue, fascia, and tendons occur.
  • Muscular atrophy can develop in symptomatic cases.
  • Enthesopathy (ie, inflammation at the tendinous insertion into bone) is common in reactive arthritis and in other seronegative arthritides (eg, plantar fasciitis, digital periostitis, Achilles tendinitis).
  • Sacroiliitis is commonly asymptomatic and self-limiting.
  • Early morning pain and stiffness are usually the most common manifestations.
  • Chronic spondylitis indistinguishable from ankylosing spondylitis is described in patients with reactive arthritis.
• Cutaneous involvement
  • Psoriasiform cutaneous lesions can develop weeks after urethritis in 10% of the patients. The palms and soles (see Media File 2) are most commonly involved with keratotic papules, plaques, and pustules that resemble those of pustular psoriasis.

Plaques on the soles of a patient with reactive arthritis.

• In some patients, typical keratoderma blenorrhagica develops 1-2 months after the onset of arthritis, with keratotic papules and plaques that are painful under pressure; sometimes, these can be disabling.
• Distal involvement with painful and erosive lesions in the tips of the fingers (see Media File 3) and toes, with pustules and subungual pustular collections, also occurs.

Painful erosions on the fingers in a patient with reactive arthritis.

• Nail dystrophy is present in 20-30% of patients and often results in nail shedding.
• Erythroderma is described as a rare complication of reactive arthritis.
• Mucosal lesions
  • Erythematous macules and plaques, diffuse erythema, erosions, and bleeding can appear on the oral and pharyngeal mucosae.
  • Circinate lesions on the tongue resemble geographic tongue (see Media File 4).

Plaques and erosions of the tongue in a patient with reactive arthritis.

• Involvement of the enteric mucosa can result in enteritis and diarrhea.
• Reactive arthritis in association with HIV infection^17,18
  • Reactive arthritis is particularly common in the context of HIV infection.
  • Patients who are HIV positive are prone to have severe psoriasiform dermatitis, which commonly involves the flexures, scalp, palms, and soles.
  • Frequently, psoriasiform dermatitis is associated with arthritis that involves the distal joints with a destructive pattern.
  • The disturbances of immune homeostasis in AIDS could account for this peculiar expression of psoriasis in these patients.
  • The existing immunodepression in patients with AIDS poses special management problems.

Causes

The etiology of reactive arthritis remains uncertain. However, 2 forms are recognized: a sexually transmitted form and a dysenteric form.

• Because urethritis is a possible primary event, research efforts have focused on identification of a microorganism that could be responsible for activating this disease.
• The pathophysiologic mechanism is thought to be a triggering of an autoimmune reaction by the microorganisms.
• Mycoplasma (Ureaplasma) species, N gonorrhoeae, Chlamydia species, and several viruses are among the suspected causative pathogens.
• Reactive arthritis triggered by adalimumab (Humira) and leflunomide (Arava) in a patient with ankylosing spondyloarthropathy and Crohn disease has been described.¹⁹
• Detection by polymerase chain reaction of C trachomatis DNA in synovial samples may be a good method to establish the diagnosis of Chlamydia -induced arthritis in patients with reactive arthritis.²⁰

Differential Diagnoses

Other Problems to Be Considered

Gonorrhea and other types of infectious urethritis must be ruled out by means of microbiologic cultures of the urethral exudate.

Gonococcal arthritis does not involve the spine.

Rheumatoid arthritis and psoriatic arthritis, and ankylosing spondylitis must be differentiated from arthritis in reactive arthritis.

Septic arthritis and pyogenic arthritis also can mimic reactive arthritis.

Oligoarticular and asymmetrical involvement, together with the clinical course, may contribute to the diagnostic suspicion.

Other seronegative arthritides can be present. Differentiating these from reactive arthritis is academic because they share a common pathophysiologic pathway and similar treatment.

Rheumatic fever and serum sickness are characterized by a course that is more acute than that of reactive arthritis.

Cutaneous lesions of reactive arthritis can mimic the following, but the characteristic clinical picture must raise a suspicion of reactive arthritis: Norwegian scabies, mycosis fungoides, subcorneal pustulosis of Sneddon-Wilkinson, atopic dermatitis, acute exanthematic pustulosis, and other causes of erythroderma.

Workup

Laboratory Studies

• No laboratory or imaging finding is diagnostic of reactive arthritis. The diagnosis is based on clinical data.
• Although a positive HLA-B27 result is not specific of the disease, haplotyping can be used to diagnose reactive arthritis.
• Microbiologic examination of smears, immunofluorescence results, and cultures of the urethral secretion must be considered.
• Microbiologic studies of urine and stool are less helpful; nevertheless, in the dysenteric form, stool culture for enteric pathogens (eg, Salmonella, Shigella, and Yersinia species) should be considered.
• Aspirates of joint fluid usually are sterile.
• A Japanese man with reactive arthritis was negative for HLA-B27 and other HLA-B27 cross-reactive major histocompatibility complex (MHC) class I antigens, but he was positive for human leukocyte antigen B51 (HLA-B51).²¹
  • The laboratory examination findings showed significant elevation of serum levels of immunoglobulin G (IgG) and IgA antichlamydial antibodies.
  • A combination of Chlamydia infection and HLA-B51 presence was suggested to play a role in the pathogenesis of reactive arthritis in this patient. The US Preventive Services Task Force guidelines for screening for chlamydial infections were updated in 2007.²²

Imaging Studies

• Radiologic signs are present in only 40% of the cases. These signs can be completely absent regardless of the severity.
• Whole-body scintigraphy is a sensible diagnostic tool for use in screening for enthesopathy and arthropathy.²³

Other Tests

• The incidence of reactive arthritis is high among patients with AIDS, and HIV testing is mandatory in patients in whom reactive arthritis is newly diagnosed, even if they do not have the risk factors.

Histologic Findings

Histopathologic changes are not different from the histopathologic picture of a psoriasis vulgaris. Acanthosis, with elongation of the rete ridges, psoriasiform hyperplasia, subcorneal abscesses, and spongiform pustules, are observed. The upper dermis shows a mixed inflammatory infiltrate with neutrophils.

Treatment

Medical Care

No curative treatment for reactive arthritis exists. Almost two thirds of patients have a self-limited course and need no treatment other than symptomatic and supportive care. However, reactive arthritis may be associated with chronic recurrent ocular inflammation that mandates systemic therapy (including immunosuppressive treatment) to control the ocular inflammation and to prevent progressive visual loss.²⁴

• Urethritis usually is treated with tetracyclines or macrolides because of the frequency of coexisting infections. The treatment of urethritis has not been shown to modify the course of the disease, but, in the absence of contraindications, treatment is commonly recommended. The antibiotic treatment of enteritis is even more controversial.
• Arthritis in reactive arthritis is amenable to successful treatment with nonsteroidal anti-inflammatory drugs (eg, indomethacin). Occasionally, intra-articular injections of corticosteroids are prescribed. Treatment with methotrexate, azathioprine, gold salts, and penicillamine is proposed in severe cases of reactive arthritis.
• Cutaneous lesions can be treated as those of psoriasis vulgaris. The author recommends beginning with topical 0.1% triamcinolone cream 3 times per day for adults and 2.5% hydrocortisone cream twice per day for children. A topical keratolytic, such as 10% salicylic acid ointment, can be added if needed. Topical salicylic acid and hydrocortisone with oral aspirin has also been suggested.¹⁵
• Systemic therapy, if required, consists of the administration of oral acitretin and/or psoralen plus UVA (PUVA), methotrexate, or cyclosporine.
• The treatment of reactive arthritis in the setting of HIV infection poses special problems. However, potentially immunosuppressive therapies (eg, cyclosporine, methotrexate, PUVA) have been used in some cases, with variable success and a relative scarcity of severe complications.

The clinical trial, New Immunomodulatory Therapy Strategies in Chronic Reactive Arthritis, is currently recruiting and may be of interest.

Medication

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Antibiotics

Antibiotics may be used to treat antibacterial and anti-inflammatory effects, as well for possible coexistent infection.

Minocycline (Dynacin, Minocin)

Used to treat infections caused by susceptible gram-negative and gram-positive organisms, in addition to infections caused by susceptible Chlamydia, Rickettsia, and Mycoplasma organisms. Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Dosing

Adult

50-100 mg PO qd/bid (usually 100 mg bid)

Pediatric

<12 years: Not recommended
>12 years: Administer as in adults

Interactions

Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increasing risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants

Contraindications

Documented hypersensitivity; severe hepatic dysfunction

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity 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 (last half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Doxycycline (Vibramycin, Doryx, Bio-Tab)

Used to treat infections caused by susceptible gram-negative and gram-positive organisms, in addition to infections caused by susceptible Chlamydia, Rickettsia, and Mycoplasma organisms. Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Dosing

Adult

200 mg PO qd

Pediatric

<8 years: Not recommended
>8 years: Administer as in adults

Interactions

Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increasing risk of pregnancy

Contraindications

Documented hypersensitivity; severe hepatic dysfunction

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity 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 (last half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Azithromycin (Zithromax)

Used to treat mild-to-moderate microbial infections.

Dosing

Adult

500 mg PO qd

Pediatric

10-20 mg/kg PO qd

Interactions

May increase toxicity of theophylline, warfarin, and digoxin; effects reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur with coadministered cyclosporine

Contraindications

Documented hypersensitivity; hepatic impairment; do not administer with pimozide

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Site reactions can occur with IV; bacterial or fungal overgrowth may result with prolonged antibiotic use; may increase hepatic enzyme levels and cholestatic jaundice; caution in impaired hepatic function, prolonged QT intervals, or pneumonia; caution in hospitalized, geriatric, or debilitated patients

Cefdinir (Omnicef)

Third-generation cephalosporin indicated for the treatment of susceptible infections.

Dosing

Adult

300 mg PO bid

Pediatric

7 mg/kg PO q12h

Interactions

May increase hypoprothrombinemic effects of anticoagulants; coadministration with potent diuretics and aminoglycosides (eg, loop diuretics) may increase nephrotoxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Reduce dose by one half if CrCl is 10-30 mL/min and by one fourth if <10 mL/min; bacterial or fungal overgrowth of nonsusceptible organisms may occur with prolonged or repeated therapy

Vitamins

These agents are essential for normal DNA synthesis and metabolism of proteins, carbohydrates, and fats.

Calcipotriene (Dovonex)

Synthetic vitamin D-3 analog that regulates skin-cell production and development. Use 0.005% cream, ointment, or solution.

Dosing

Adult

Apply thin film to affected skin bid until response achieved

Pediatric

Apply as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; hypercalcemia; vitamin D toxicity

Precautions

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

Discontinue if skin becomes irritated or if serum calcium level increases beyond the reference range

Nonsteroidal anti-inflammatory drugs

These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclo-oxygenase activity and prostaglandin synthesis. Other mechanisms may include inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.

Indomethacin (Indocin)

Potent inhibitor of cyclo-oxygenase, which may decrease the local production of arachidonic acid–derived chemotactic factors for eosinophils present in sebum.

Dosing

Adult

50 mg PO pc tid; taper as symptoms resolve

Pediatric

<14 years: Not established
>14 years: Administer as in adults

Interactions

Coadministration 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 patient is taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of MTX toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; GI bleeding or renal insufficiency

Precautions

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

Category D in third trimester of pregnancy (may cause closure of ductus arteriosus during the third trimester of pregnancy); may mask signs of infection; may cause fluid retention, peripheral edema, and deterioration of circulatory hemodynamics; can inhibit platelet aggregation and prolong bleeding time; liver and kidney damage may occur (rare)

Antineoplastic agents

These agents have antiproliferative and immunosuppressive effects.

Azathioprine (Imuran)

May be used alone or as a steroid-sparing agent. Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity. Used more commonly for reactive arthritis and psoriasis. Thiopurine methyltransferase levels should be checked prior to the use of azathioprine.

Dosing

Adult

100-200 mg PO qd in combination with prednisone

Pediatric

Not established

Interactions

Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of MTX metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Contraindications

Documented hypersensitivity; thiopurine methyltransferase deficiency; severe bone marrow suppression; severe liver abnormalities

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Adverse effects include teratogenicity, hepatitis, bone marrow suppression, and increased risk of cancer; perform urine analysis, CBC count, and renal and liver function tests and determine serum electrolyte levels before initiating therapy and regularly thereafter; increases risk of neoplasia; caution in liver disease and renal impairment; hematologic toxicities may occur; check serum thiopurine methyltransferase levels prior to therapy

Methotrexate (Folex PFS, Rheumatrex)

Indicated for the symptomatic control of severe, recalcitrant, disabling psoriasis, and severe reactive arthritis. Also used alone or in combination with other anticancer agents in the treatment of advanced mycosis fungoides and cancer of the head, neck, or lung, particularly those of the squamous cell and small cell types.

Dosing

Adult

7.5 mg as single dose PO qwk or 3 doses of 2.5 mg at 12-h intervals qwk; doses may be adjusted gradually to achieve optimal response, but not ordinarily to exceed a total weekly dose of 20 mg

Pediatric

Not established

Interactions

Oral aminoglycosides may decrease absorption and blood levels of concurrent oral MTX; charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity; folic acid or its derivatives contained in some vitamins may decrease response to MTX; probenecid, NSAIDs, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, can increase plasma levels; may decrease phenytoin plasma levels; may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor CBC counts monthly and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg, dehydration); has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts occur; fatal reactions reported when administered concurrently with NSAIDs

Antimalarials

Derivatives of 4-aminoquinoline are active against a variety of autoimmune disorders. Use with caution because hydroxychloroquine has a known risk of exacerbating psoriasis. These agents should probably be used only in conjunction with rheumatologic evaluation because it is used for the arthritis and not the skin involvement.

Hydroxychloroquine (Plaquenil)

Inhibits chemotaxis of eosinophils, locomotion of neutrophils, and impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate

Dosing

Adult

200 mg PO qd/bid

Pediatric

Not established

Interactions

Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption

Contraindications

Documented hypersensitivity to 4-aminoquinoline derivatives; psoriasis; retinal and visual field changes attributable to 4-aminoquinolines

Precautions

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 liver disease or alcoholism and other drugs known to be hepatotoxic; beware of retinopathy and corneal deposits producing blindness; discontinue medication and reevaluate if any eye changes occur after full ophthalmologic examination including slit lamp, funduscopic and visual acuity, and visual field tests, severe exacerbation of psoriasis is reported

Retinoids

Retinoids decrease the cohesiveness of abnormal hyperproliferative keratinocytes and may reduce the potential for malignant degeneration. They also modulate keratinocyte differentiation.

Isotretinoin (Accutane)

Oral agent used to treat serious dermatologic conditions. Synthetic 13-cis isomer of the naturally occurring tretinoin (trans -retinoic acid). Both agents are structurally related to vitamin A. Alters pattern of keratinization, reduces bacterial flora, and has an anti-inflammatory effect.
A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

Dosing

Adult

0.5-1 mg/kg/d PO

Pediatric

Administer as in adults

Interactions

Toxicity may occur with vitamin A coadministration; pseudotumor cerebri or papilledema may occur when coadministered with tetracyclines; may reduce plasma levels of carbamazepine; microdosed progesterone tablets may be inadequate contraception

Contraindications

Documented hypersensitivity; young children (because of skeletal symptoms); pregnant women or women of childbearing age (unless contraception is accurate), renal or hepatic failure, hypertriglyceridemia, and elevated cholesterol level

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

May decrease night vision; inflammatory bowel disease association with hepatitis, occasional exaggerated healing response of acne lesions (excessive granulation with crusting), and problems with contact lenses may occur; problems in controlling blood sugar in diabetes possible; avoid exposure to UV light or sunlight until tolerance achieved; discontinue treatment if rectal bleeding, abdominal pain, or severe diarrhea occurs; women of childbearing age must simultaneously use 2 effective forms of contraception and sign consent form 1 mo before, during, and after therapy; patients should not donate blood during or 1 mo afterward; patients should avoid skin resurfacing procedures and waxing during therapy and 6 mo afterward; patients should avoid UV or sunlight exposure; may cause depression, psychosis, or even suicidal attempts; musculoskeletal symptoms including skeletal hyperostosis and premature epiphyseal closure reported with prolonged use of high doses (2.24 mg/kg/d), especially in children
Other adverse effects include cheilitis; dry mouth, nose, and skin; epistaxis; flushing; fragility of skin; bruising; pruritus; nail dystrophy; alopecia; pyogenic granuloma; rash; abnormal wound healing; allergic reactions fatigue; dizziness; drowsiness; headaches; malaise; arthralgia; anaphylactic reactions and other allergic reactions; allergic vasculitis; pseudotumor cerebri; calcification of tendons and ligaments; pancreatitis; corneal opacities and decreased night vision; hearing impairment; hypertriglyceridemia; elevation of serum cholesterol levels; alterations in blood sugar levels; anemia; thrombocytopenia; neutropenia; agranulocytosis; elevated CPK levels; hyperuricemia; increased alkaline phosphatase, SGOT, and SGPT levels

Acitretin (Soriatane)

Retinoic acid analog, similar to etretinate and isotretinoin. Etretinate is the main metabolite and has clinical effects similar to those of etretinate. Its mechanism of action is unknown.

Dosing

Adult

25-50 mg/d PO given as single dose with main meal; terminate therapy when lesions have resolved

Pediatric

Not established

Interactions

Increases toxicity of MTX (avoid concomitant use); interferes with effects of microdosed progestin minipill; coadministration with alcohol may enhance synthesis of etretinate, which has a much longer half-life (>120 d)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Do not use in severe obesity; women of childbearing age must be capable of complying with effective contraceptive measures; contraception should be continued for at least 3 y after treatment is stopped; etretinate may form from acitretin, which takes about 2-3 y to clear from the body; caution in impaired renal or liver function; perform AST, ALT and LDH tests prior to therapy at 1- to 2-wk intervals until levels are stable and thereafter at intervals as clinically indicated

Follow-up

Further Inpatient Care

• Careful monitoring of this systemic disease is indicated.

Complications

• Erythroderma is described as a rare complication of reactive arthritis.
• In severe cases, functional impairment may be severe, and a chronic and prolonged clinical course is followed by sequelae (eg, urethral stenosis, chronic arthritis, ocular impairment).
• In some patients, arthropathic psoriasis develops.

Prognosis

• The course of reactive arthritis is prolonged. Acute exacerbations and remissions may occur for weeks to months (seldom years), and spontaneous healing may occur with the possibility of recurrences.
• An estimated recurrence rate of 15% per patient-year is reported.
• A fatal outcome is seldom reported, but death can occur, and it is usually related to the adverse effects of treatment.

Patient Education

• Patients should be educated about the many facets of this disorder.
• 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, Chlamydia, Gonorrhea, and Psoriatic Arthritis.

Miscellaneous

Medicolegal Pitfalls

• A patient with new-onset reactive arthritis must be evaluated for HIV. Such patients are at risk for severe psoriasiform dermatitis, which commonly involves the flexures, scalp, palms, and soles. Frequently, psoriasiform dermatitis is associated with arthritis that involves the distal joints in a destructive pattern.

Multimedia

Media file 1: Circinate balanitis in a patient with reactive arthritis.

Media file 2: Plaques on the soles of a patient with reactive arthritis.

Media file 3: Painful erosions on the fingers in a patient with reactive arthritis.

Media file 4: Plaques and erosions of the tongue in a patient with reactive arthritis.

References

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2. Fiessinger N, Leroy E. Contribution a l etude d'une epidemie de dysenterie dans la somme. Bull Soc Med Hop. 1916;40:2030-2069.

3. Reiter H. Spirochateninfektion (Spirochaetosis arthritica). Deutsche Medizinische Wochenschrift. 1916;42:1535-6.

4. Bauer W, Engelman EP. A syndrome of unknown etiology characterized by urethritis, conjunctivitis, and arthritis (so-called Reiter's disease). Trans Assoc Am Physicians. 1942;57:307-313.

5. Panush RS, Wallace DJ, Dorff RE, Engleman EP. Retraction of the suggestion to use the term "Reiter's syndrome" sixty-five years later: the legacy of Reiter, a war criminal, should not be eponymic honor but rather condemnation. Arthritis Rheum. Feb 2007;56(2):693-4. [Medline].

6. Wallace DJ, Weismann M. Should a war criminal be rewarded with eponymous distinction?. J Clin Rheumatol. 2000;6:49-54.

7. Weyers W. The fame and infamy of Hans Reiter. Dermatopathol Pract Concept. 2000;6:340-343.

8. Ackerman AB. Reiter syndrome and Hans Reiter: Neither legitimate!. J Am Acad Dermatol. Mar 2009;60(3):517-8; author reply 518. [Medline].

9. Mahmood A, Ackerman AB. Reiter's syndrome is psoriasis!. Dermatopathol Pract Concept. 2000;6:337-339.

10. Kousa M, Saikku P, Richmond S, Lassus A. Frequent association of chlamydial infection with Reiter's syndrome. Sex Transm Dis. Apr-Jun 1978;5(2):57-61. [Medline].

11. Berlau J, Junker U, Groh A, Straube E. In situ hybridisation and direct fluorescence antibodies for the detection of Chlamydia trachomatis in synovial tissue from patients with reactive arthritis. J Clin Pathol. Nov 1998;51(11):803-6. [Medline].

12. Russell AL. Glycoaminoglycan (GAG) deficiency in protective barrier as an underlying, primary cause of ulcerative colitis, Crohn's disease interstitial cystitis and possibly Reiter's syndrome. Med Hypotheses. Apr 1999;52(4):297-301. [Medline].

13. Savolainen E, Kettunen A, Narvanen A, et al. Prevalence of antibodies against Chlamydia trachomatis and incidence of C. trachomatis-induced reactive arthritis in an early arthritis series in Finland in 2000. Scand J Rheumatol. Mar 18 2009;1-4. [Medline].

14. Townes JM, Deodhar AA, Laine ES, et al. Reactive arthritis following culture-confirmed infections with bacterial enteric pathogens in Minnesota and Oregon: a population-based study. Ann Rheum Dis. Dec 2008;67(12):1689-96. [Medline].

15. Arora S, Arora G. Reiter's disease in a six-year-old girl. Indian J Dermatol Venereol Leprol. Jul-Aug 2005;71(4):285-6. [Medline].

16. Satko SG, Iskandar SS, Appel RG. IgA nephropathy and Reiter's syndrome. Report of two cases and review of the literature. Nephron. Feb 2000;84(2):177-82. [Medline].

17. Lin RY. Reiter's syndrome and human immunodeficiency virus infection. Dermatologica. 1988;176(1):39-42. [Medline].

18. Romaní J, Puig L, Baselga E, De Moragas JM. Reiter's syndrome-like pattern in AIDS-associated psoriasiform dermatitis. Int J Dermatol. Jul 1996;35(7):484-8. [Medline].

19. Thielen AM, Barde C, Janer V, Borradori L, Saurat JH. Reiter syndrome triggered by adalimumab (Humira) and leflunomide (Arava) in a patient with ankylosing spondylarthropathy and Crohn disease. Br J Dermatol. Jan 2007;156(1):188-9. [Medline].

20. Siala M, Gdoura R, Younes M, et al. Detection and frequency of Chlamydia trachomatis DNA in synovial samples from Tunisian patients with reactive arthritis and undifferentiated oligoarthritis. FEMS Immunol Med Microbiol. Mar 2009;55(2):178-86. [Medline].

21. Shimamoto Y, Sugiyama H, Hirohata S. Reiter's syndrome associated with HLA-B51. Intern Med. Feb 2000;39(2):182-4. [Medline].

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23. Kim SH, Chung SK, Bahk YW, Park YH, Lee SY, Sohn HS. Whole-body and pinhole bone scintigraphic manifestations of Reiter's syndrome: distribution patterns and early and characteristic signs. Eur J Nucl Med. Feb 1999;26(2):163-70. [Medline].

24. Kiss S, Letko E, Qamruddin S, Baltatzis S, Foster CS. Long-term progression, prognosis, and treatment of patients with recurrent ocular manifestations of Reiter's syndrome. Ophthalmology. Sep 2003;110(9):1764-9. [Medline].

25. Amor B. Reiter's syndrome. Diagnosis and clinical features. Rheum Dis Clin North Am. Nov 1998;24(4):677-95, vii. [Medline].

26. Barth WF, Segal K. Reactive arthritis (Reiter's syndrome). Am Fam Physician. Aug 1999;60(2):499-503, 507. [Medline].

27. Carter JD, Gerard HC, Hudson AP. Psoriasiform lesions induced by tumour necrosis factor antagonists: a skin-deep medical conundrum. Ann Rheum Dis. Aug 2008;67(8):1181-3. [Medline].

28. Goyal NN, Dhurat RS, Jerajani HR. Carbamazepine in Reiter's syndrome. Sex Transm Infect. Jun 2000;76(3):220. [Medline].

29. Kim YA, Bagley MP, Thomas I. Incomplete Reiter's syndrome in a black patient showing HLA B 27. Cutis. Apr 1991;47(4):253-4. [Medline].

30. Reiter H. Vorschlage zur Neugestaltung des Hygieneunterrichts und zur Sicherung des Nachwuchses auf dem Gebiet der Hygiene. Munch Med Wschr. 1938;85:16-19.

31. 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].

Keywords

RS, Reiter disease, Reiter syndrome, Reiter's syndrome, Fiessinger-Leroy-Reiter syndrome, Fiessinger-Leroy syndrome, arthritis urethritica, blennorrheal idiopathic arthritis, reactive arthritis, conjunctivo-urethro-synovial syndrome, polyarthritis enterica, keratoderma blenorrhagica, urethritis

Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Jorge Romaní, MD, Assistant Professor, Department of Dermatology, Hospital De Palamós Faculty of Medicine, Spain
Disclosure: Nothing to disclose.

Lluís Puig, MD, PhD, Program Director, Assistant Professor, Department of Dermatology, Hospital De La Santa Creu I Sant Pau, Universitat Autónoma De Barcelona
Lluís Puig, MD, PhD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, European Academy of Dermatology and Venereology, and International Society of Dermatopathology
Disclosure: Nothing to disclose.

Medical Editor

Robin Travers, MD, Assistant Professor of Medicine (Dermatology), Dartmouth University School of Medicine; Staff Dermatologist, New England Baptist Hospital; Private Practice, SkinCare Physicians
Robin Travers, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Informatics Association, Massachusetts Medical Society, Medical Dermatology Society, and Women's Dermatologic Society
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio
Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, and Texas Dermatological Society
Disclosure: Nothing to disclose.

CME Editor

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital
Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

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