Reactive Arthritis 

Updated: Dec 06, 2018
Author: Carlos J Lozada, MD; Chief Editor: Herbert S Diamond, MD 

Overview

Practice Essentials

Reactive arthritis (ReA), formerly termed Reiter syndrome, is an autoimmune condition that develops in response to an infection. It has been associated with gastrointestinal (GI) infections with Shigella, Salmonella, Campylobacter, and other organisms, as well as with genitourinary (GU) infections (especially with Chlamydia trachomatis). See the image below.

Painful erosions on fingers in patient with reacti Painful erosions on fingers in patient with reactive arthritis.

Signs and symptoms

The classic triad of ReA symptoms (found in only one third of patients) consists of the following:

  • Noninfectious urethritis

  • Arthritis

  • Conjunctivitis

In postenteric ReA, diarrhea and dysenteric syndrome (usually mild) is commonly followed by the clinical triad in 1-4 weeks. Some add a fourth component (mucocutaneous findings) to make up a diagnostic tetrad.

The following may be noted:

  • Acute onset of ReA, with malaise, fatigue, and fever

  • Asymmetrical, predominantly lower-extremity, oligoarthritis as the major presenting symptom, sometimes with early myalgias

  • Initial nongonococcal urethritis, with frequency, dysuria, urgency, and urethral discharge

  • In addition to conjunctivitis, ophthalmologic symptoms that include erythema, burning, tearing, photophobia, pain, and decreased vision (rare)

  • Mild recurrent abdominal complaints after a precipitating episode of diarrhea

  • In HIV-positive patients, severe psoriasiform dermatitis, commonly involving the flexures, scalp, palms, and soles

Physical findings in ReA may include the following:

  • Musculoskeletal system - Asymmetric oligoarthritis affecting the weight-bearing joints, predominantly of the lower extremities; sausage-shaped finger (dactylitis); enthesopathy; sacroiliitis

  • Skin and nails - Keratoderma blennorrhagicum; erythema nodosum (uncommon); onychodystrophy

  • Eyes - Conjunctivitis; anterior uveitis; keratitis; scleritis; episcleritis; cataracts; hypotony; glaucoma; corneal ulceration; disc or retinal edema; retinal vasculitis; optic neuritis; dacryoadenitis

  • GU tract - Meatal edema and erythema and clear mucoid discharge; prostatitis; vulvovaginitis; circinate balanitis (balanitis circinata); cervicitis; cystitis; salpingo-oophoritis; pyelonephritis; bartholinitis

  • GI tract - Diarrhea; abdominal pain; lesions resembling inflammatory bowel disease on ileocolonoscopy

  • Other systems - Cardiac (aortitis, aortic regurgitation, transient conduction abnormalities, myocarditis, pericarditis); renal (proteinuria, microhematuria, amyloid deposits, immunoglobulin A [IgA] nephropathy)

See Presentation for more detail.

Diagnosis

The diagnosis of ReA is clinical, based on the history and physical examination. No laboratory study or imaging finding is diagnostic.

The following laboratory studies may be helpful:

  • White blood cell (WBC) and red blood cell (RBC) counts

  • Erythrocyte sedimentation rate (ESR)

  • C-reactive protein (CRP) and other acute-phase reactants

  • IgA antibodies to specific bacterial antigens

  • Serology and cultures (blood, urine, stool, cervix, urethra), particularly for Chlamydia

  • Human leukocyte antigen (HLA)–B27

  • Tuberculin skin test

  • HIV

  • Urinalysis

Imaging modalities that may be considered include the following:

  • Plain radiography (reveals findings in only 40-70% of cases)

  • Whole-body scintigraphy

  • Positron emission tomography

  • Magnetic resonance imaging (MRI), especially of the sacroiliac joints

  • Computed tomography (CT)

  • Ultrasonography or echocardiography

Other studies to be considered include the following:

  • Arthrocentesis, synovial fluid analysis, and synovial biopsy (often needed to rule out an infectious process, especially in monoarticular arthritis with constitutional symptoms)

  • Antistreptolysin O (ASO) or anti-DNase B testing (if poststreptococcal infection is suspected)

  • Electrocardiography (ECG; in patients with a prolonged course of ReA)

See Workup for more detail.

Management

No curative treatment exists; instead, treatment aims at relieving symptoms and is based on symptom severity. Almost two thirds of patients have a self-limited course; as many as 30% develop chronic symptoms, posing a therapeutic challenge.

Pharmacologic agents that may be used in treating ReA include the following:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) - These are the mainstays of therapy

  • Corticosteroids (topical, intra-articular, and systemic)

  • Antibiotics (for Chlamydia-related ReA in particular) - Tetracyclines are commonly given

  • Disease-modifying antirheumatic drugs (DMARDs) - Typically given when NSAIDs are ineffective or contraindicated, these include sulfasalazine, methotrexate, and anti−tumor necrosis factor (TNF) medications, such as etanercept and infliximab

No specific surgical treatment is indicated, though ophthalmologic surgery may be warranted to treat certain ocular manifestations of disease.

Physical therapy may be instituted to avoid muscle wasting and to reduce pain.

See Treatment and Medication for more detail.

Background

Reactive arthritis (ReA) is an autoimmune condition that develops in response to an infection.[1, 2] ReA has been associated with gastrointestinal (GI) infections with Shigella, Salmonella, Campylobacter, and other organisms, as well as with genitourinary (GU) infections (especially with Chlamydia trachomatis).

ReA was described by the German physician Hans Reiter in 1916,[3]  and for a time the disorder was known as Reiter syndrome. This eponym is no longer used, because of Reiter’s activities as a Nazi war criminal, and also because his was not the first description of ReA, and it mischaracterized the pathogenesis.[4, 5]

As currently understood, the term ReA encompasses the older concepts of complete and incomplete reactive arthritis and a clinical syndrome of arthritis with or without extra-articular features that develop within 1 month of infectious diarrhea or GU infection. The classic triad associated with this condition comprises noninfectious urethritis, arthritis, and conjunctivitis (though this triad is not found in all cases).

ReA is frequently associated with the human leukocyte antigen (HLA)–B27 (HLA-B27) haplotype and is classified in the category of seronegative spondyloarthropathies, which includes ankylosing spondylitis, psoriatic arthritis, the arthropathy of associated inflammatory bowel disease, juvenile-onset ankylosing spondylitis, juvenile chronic arthritis, and undifferentiated spondyloarthritis.[6]

A study by Kaarela et al reported that ReA and ankylosing spondylitis appear to be identical.[7] When assessing long-term outcomes of reactive arthritis and ankylosing spondylitis to identify similarities in manifestations of disease, the investigators found a number of similarities. Among these was the determination that sacroiliitis, peripheral arthritis, and iritis developed most often in both chronic ReA and ankylosing spondylitis.

Most ReA patients are young men. Young children tend to have the postdysenteric form, whereas adolescents and young men are most likely to develop ReA after a genitourinary infection. Some authors, interpreting the mucocutaneous findings as pustular psoriasis and the seronegative arthritis as psoriatic arthritis, believe that ReA is best classified as a type of psoriasis.[8]

Defining criteria

The classic triad of ReA—namely, arthritis, conjunctivitis, and noninfectious urethritis—occurs in only about one third of patients at onset. Less stringent diagnostic criteria from the American College of Rheumatology have specified a 1-month duration of arthritis in association with urethritis, cervicitis, or both.

It has been suggested, however, that the syndrome is better described as a triad consisting of arthritis, conjunctivitis or iridocyclitis, and nonbacterial urethritis or cervicitis. Some prefer to describe it as a tetrad, adding the mucocutaneous findings of balanitis circinata and keratoderma blennorrhagicum to the classic triad. In this view, the complete and incomplete forms of ReA can be identified by the presence or absence of the mucocutaneous involvement.

Pathophysiology

ReA is usually triggered by a GU or GI infection (see Etiology). Evidence indicates that a preceding Chlamydia respiratory infection may also trigger ReA.[9] The frequency of ReA after enteric infection averages 1-4% but varies greatly, even among outbreaks of the same organism. Although severely symptomatic GI infections are associated with an increased risk of ReA,[10, 11] asymptomatic venereal infections more frequently cause this disease.[10] About 10% of patients have no preceding symptomatic infection.

ReA is associated with histocompatibility leukocyte antigen B-27 (HLA-B27), a major histocompatibility complex (MHC) class I molecule involved in T-cell antigen presentation. Results for HLA-B27 are positive in 65-96% of patients (average, 75%) with ReA.[12] Patients with HLA-B27, as well as those with a strong family clustering of the disease, tend to develop more severe and long-term disease.[7]

Sun et al reported that susceptibility to ReA arthritis is affected by the levels of certain killer cell immunoglobulin-like receptors (KIRs), which correspond with specific HLA-C ligand genotypes. In individuals with high levels of activating and low levels of inhibitory KIR signals, pathogens can more easily trigger natural killer cell and T cell innate and adaptive immune responses, resulting in the overproduction of cytokines that contribute to the pathogenesis of ReA.[13]

Their study of 138 patients with ReA found that KIR2DS1, which is activating, is associated with susceptibility to ReA, when present alone or in combination with the HLA-C1C1 genotype. KIR2DL2, which is inhibitory, in combination with the HLA-C1 ligand is associated with protection against ReA. Patients with ReA had significantly lower frequencies of KIR2DL2 and KIR2DL5 than did controls. The presence of more than seven inhibitory KIR genes was protective.[13]

The mechanism by which the interaction of the inciting organism with the host leads to the development of ReA is not known. It is possible that microbial antigens cross-react with self-proteins, stimulating and perpetuating an autoimmune response mediated by type 2 T helper (Th2) cells. Chronicity and joint damage have been associated with a Th2 cytokine profile that leads to decreased bacterial clearance.[10]

Synovial fluid cultures are negative for enteric organisms or Chlamydia species. However, a systemic and intrasynovial immune response to the organisms has been found with intra-articular antibody and bacterial reactive T cells. Furthermore, bacterial antigen has been found in the joints. Thus, the elements for an immune-mediated synovitis are present.

Synovitis in ReA is mediated by proinflammatory cytokines. Native T cells under the influence of transforming growth factor (TGF)-β and other cytokines, such as interleukin (IL)-6, differentiate into Th17 effector cells, which then produce IL-17. IL-17 is one of the major cytokines elevated in the synovial fluid of these patients.[14, 15] Deficiencies in regulatory mechanisms can result in increased proinflammatory cytokine production and worse outcome.[16]

The Toll-like receptors (TLRs) recognize different extracellular antigens as part of the innate immune system.[17] TLR-4 recognizes gram-negative lipopolysaccharide (LPS). Studies in mice and humans showed abnormalities in antigen presentation due to downregulation of TLR-4 costimulatory receptors in patients with ReA. Subsequent studies implicated TLR-2 polymorphism associated with acute ReA; however, its role is still disputed.[10, 18]

Molecular evidence of bacterial DNA (obtained via polymerase chain reaction [PCR] assay) in synovial fluids has been found only in Chlamydia -related ReA, and a single placebo-controlled trial of a tetracycline derivative (ie, lymecycline) has shown a reduction in the duration of acute Chlamydia -related, but not enteric-related, ReA.[19] This suggests that persistent infection may play a role, at least in some cases of chlamydial-associated ReA.

In a subsequent trial, the combination of doxycycline and rifampin was superior to doxycycline alone in reducing morning stiffness and swollen and tender joints in patients with undifferentiated spondyloarthropathy.[20]

The role of HLA-B27 in this scenario remains to be fully defined. The following theories have been proposed:

  • Molecular mimicry - This hypothesis suggests that a similarity exists at the molecular level between the HLA-B27 molecule and the inciting organisms, allowing the triggering of an immune response and the subsequent development of clinical disease[21]

  • HLA-B27 as a receptor for certain bacteria - At present, there is little evidence either to confirm or to refute this hypothesis

  • Defective class I antigen-mediated cellular response - This hypothesis suggests that the HLA-B27 molecule may be a defective molecule associated with an aberrant cytotoxic T-cell response

ReA can occur in patients with HIV infection or AIDS—most likely because both conditions can be sexually acquired, rather than because ReA is triggered by HIV. The course of ReA in these patients tends to be severe, with a generalized rash resembling psoriasis, profound arthritis, and frank AIDS. HLA-B27 frequency is the same as that associated with non–AIDS-related ReA in a similar demographic group. This association points out the likely importance of CD8+ cytotoxic T cells as compared with CD4+ Th cells in the pathogenesis of ReA.

ReA is sometimes divided into epidemic and endemic forms. Whereas a triggering agent can be identified for epidemic ReA, none has been identified for endemic ReA. Differentiation between the 2 types of ReA may be difficult in some cases; however, it is not essential to either diagnosis or treatment.

Etiology

Infectious causes

ReA is usually triggered by a GU or GI infection and thus is sometimes classified as venereal or dysenteric. Such infections are mostly the result of gram-negative, obligate, or facultative intracellular pathogens.[22] Organisms that have been associated with ReA include the following:

  • C trachomatis/C pneumoniae[23]

  • Ureaplasma urealyticum

  • Lymphogranuloma venereum (L2 serotype)[24, 25]

  • Neisseria gonorrhoeae

  • Shigella flexneri

  • Salmonella enterica serovars Typhimurium, Enteritidis,[26] and Hadar[27]

  • Mycoplasma pneumoniae

  • Mycobacterium tuberculosis[28]

  • Cyclospora[29]

  • Yersinia enterocolitica and pseudotuberculosis

  • Campylobacter jejuni[30] and coli

  • Clostridium difficile

  • Beta-hemolytic[16] (eg, group A[31] ) and viridans streptococci

Data suggest that chlamydial ReA is underdiagnosed and that asymptomatic chlamydial infections might be a common cause.[32] An important difference between Chlamydia -induced (postvenereal) ReA and postenteric ReA is the presence of viable but aberrant chlamydial organisms in the synovial fluid[33] (so-called Chlamydia persistence[34] ). PCR assay to detect C trachomatis DNA in synovial samples may be a good method for establishing the diagnosis of Chlamydia -induced arthritis in patients with ReA.[35]

The prevalence of different serotypes of C trachomatis antibodies and the incidence of Chlamydia- induced ReA was studied among patients with early arthritis in a defined population in Finland.[12] Antibodies against C trachomatis were most common in patients with arthritis because cases with Chlamydia -induced ReA are included in this subgroup.

Ureaplasma organisms are known to be capable of causing experimental and clinical nongonococcal urethritis. Synovial mononuclear cells from arthritic joints of patients with ReA react with Ureaplasma antigens; this organism has been isolated from an ReA patient.

The enteric pathogen that most commonly results in ReA is Campylobacter (C jejuni, 90-95%; C coli, 5-10%).[36] ReA patients with arthritic symptoms are more frequently infected with C jejuni strains with sialic acid lipo-oligosaccharide. In addition, sialylation of C jejuni lipo-oligosaccharide is associated with more severe enteric disease.[37]

Group A streptococci are known to be capable of causing poststreptococcal ReA.[38] Patients with this condition demonstrate increase antistreptolysin O (ASO) antibodies and an increased erythrocyte sedimentation rate (ESR).[39] ReA can also be induced by tonsillitis. In one study, 13 of 21 patients were positive for ASO and 12 were positive for group A Streptococcus.[40]

Acute tuberculosis can sometimes cause ReA. The resulting condition is known as Poncet disease, which is a different entity from tuberculous arthritis.[41, 42, 43]

ReA following infection with C difficile has been reported.[44, 45]  Intravesical instillation of bacillus Calmette-Guérin (BCG) for bladder cancer has been associated with ReA.[46, 47, 48]  has also been shown to occur after tetanus and rabies vaccination.[49, 50]

Genetic factors

ReA has an important genetic component; it tends to cluster in certain families and almost exclusively affects males, and HLA-B27 is identified in 70-80% of patients.[12] HLA-B27 may share molecular characteristics with bacterial epitopes, facilitating an autoimmune cross-reaction instrumental in pathogenesis. HLA-B27 contributes to the pathogenesis of the disease and reportedly increases the risk of ReA 50-fold.[51] HLA-B51 and HLA-DRB1 alleles have also been shown to be associated with ReA.[35]

Rihl et al found a high proportion of proangiogenic factors accounting for a genetically determined susceptibility to ReA.[52]  Sun et al reported increased susceptibility to ReA associated with the HLA-C1C1 genotype, which indicates the absence of the HLA ligands for the inhibitory killer cell immunoglobulin-like receptor (KIR) KIR2DL1; Imbalance between activating and inhibitory KIR signals may allow pathogens to trigger cytokine overproduction.[13]

Other factors

ReA triggered by adalimumab and leflunomide in a patient with ankylosing spondyloarthropathy and Crohn disease has been described.[53]

Duration of diarrhea and weight loss are also considered risk factors in the development of ReA after enteric infections.[11]

Epidemiology

United States statistics

Data on the incidence and prevalence of ReA are scarce, partly because of a lack of a disease definition and classification criteria; these factors complicate differentiation of ReA from other arthritides.[54] The frequency is estimated to be 3.5-5 cases per 100,000. The incidence reported in US Navy personnel over a 10-year period was 4 cases per 100,000 men per year. The prevalence of ReA may be relatively high among patients with AIDS, especially men who are seropositive for HLA-B27. ReA develops in almost 75% of HIV-positive men with HLA-B27.

An estimated 1-3% of all patients with a nonspecific urethritis develop an episode of arthritis. The incidence is 1-4% after enteric infection. This number jumps to 20-25% after bacterial enteritis in HLA-B27-positive individuals.[36] Prevalence of asymptomatic chlamydial infections, underdiagnosis, and underreporting may make the incidence even higher.[55] It has been noted that worse functional capacity and higher disease activity are observed in the lower socioeconomic classes.[56]

A population-based study assessed ReA after culture-confirmed infections with bacterial enteric pathogens in Minnesota and Oregon.[57] The estimated incidence after culture-confirmed Campylobacter, Escherichia coli O157, Salmonella, Shigella, and Yersinia infections in Oregon was 0.6-3.1 cases per 100,000 population. ReA may occur in 1.5% of Shigella enterocolitis cases and 25% of HLA-B27–positive Shigella cases. After an outbreak of S enterica serovar Enteritidis, 29% had reactive arthritis.[26]

International statistics

The infections that incite ReA may vary with geographic location. For example, Y enterocolitica is more commonly identified in Europe than in North America and thus is responsible for more cases of ReA in countries such as Finland and Norway.[10] The occurrence of ReA appears to be related to the prevalence of HLA-B27 in a population and to the rate of urethritis/cervicitis and infectious diarrhea.

More than 40 subtypes of HLA-B27 are known; those associated with the spondyloarthropathies are HLA-B2702, B2704, and B2705.[22] These subtypes may be somewhat geographically segregated. For example, the subtype B2705 is found predominantly in Latin America, Brazil, Taiwan, and parts of India. It is noteworthy that subtypes HLA-B2706 and B2709—found in native Indonesia and Sardinia, respectively—may be partially protective against ReA.[58]

In Norway, an annual incidence of 4.6 cases per 100,000 population for chlamydial ReA and an incidence of 5 cases per 100,000 population for enteric bacteria–induced ReA were reported in 1988-1990. In Finland, nearly 2% of males were found to have ReA after nongonococcal urethritis; the incidence of HLA-B27 is higher in the Finnish population. In the United Kingdom, the incidence of ReA after urethritis is about 0.8%. In the Czech Republic, the annual incidence of ReA in adults during 2002-2003 was reported at 9.3 cases per 100,000 population.[59]

Age-, sex-, and race-related demographics

ReA is most common in young men, with the peak onset in the third decade of life. It rarely occurs in children; when it does, the enteric form of the disease is predominant. Most pediatric patients present with symptoms after the age of 9 years.[46]

In a study of 100 patients with ReA, Lahu and colleagues found that most patients were between 20 and 40 years old and that the first attack occurred earlier in males than females. Of the 100 patients studied, 66% were male.  Urogenital and nasopharyngeal infections were more common among male patients.[60]

ReA after foodborne enteric infections is equally common in males and females. However, the male-to-female ratio for disease associated with venereally acquired infections has been estimated to range from 5:1 to 10:1. A possible prostatic focus of persistent infection is postulated to explain the male predominance of ReA.

The frequency of ReA appears to be related to the prevalence of HLA-B27 in the population. As with other spondyloarthropathies, HLA-B27 and ReA are more common in white people than in black people. When ReA occurs in black persons, it is frequently B27-negative.

Prognosis

ReA has a variable natural history[55] but typically follows a self-limited course, with resolution of symptoms by 3-12 months, even in patients who are acutely incapacitated. A fatal outcome is seldom reported, but death can occur, and it is usually related to the adverse effects of treatment. Postdysenteric cases are associated with a better prognosis than postvenereal cases. The presence of HLA-B27 may predict a more prolonged course and severe outcome, as may infections triggered by Yersinia, Salmonella, Shigella, or Chlamydia.[61]

ReA has a high tendency to recur (15-50% of cases), particularly in individuals who are HLA-B27–positive. A new infection or other stress factor could cause reactivation of the disease.

Approximately 15-30% of patients with ReA develop a long-term, sometimes destructive, arthritis or enthesitis or spondylitis. A 1994 study analyzed 7 factors as predictors of long-term outcome in spondyloarthropathies.[62] The number of patients with ReA in this study was low, and a valid subgroup analysis was impossible. The presence of hip-joint involvement, an ESR higher than 30, and unresponsiveness to nonsteroidal anti-inflammatory drugs (NSAIDs) probably portend a severe outcome or chronicity in ReA.

Patient Education

Poor health-related quality of life and impaired daily physical functioning are observed in patients with refractory or chronic ReA, and strategies focused on improving or maintaining functional status are important in treatment.[18] Educational measures that may be helpful include the following:

  • Encourage patients to monitor themselves for any changes in symptoms.

  • Help patients to become awareness of the chronic or recurrent nature of this syndrome and to accept the need for long-term medications

  • Inform patients that their condition places them at a higher than usual risk for elective ocular surgery

  • Discourage inactivity and immobilization

  • Encourage stretching exercises and range of motion

  • Provide adolescent patients with information on the prevention of sexually transmitted diseases and the use of condoms

For patient education resources, see the Arthritis Center, the Sexually Transmitted Diseases Center, and the Bacterial and Viral Infections Center, as well as Knee Pain, Chlamydia, and Gonorrhea. The American College of Rheumatology also provides patient information on reactive arthritis.

 

Presentation

History

Reactive arthritis (ReA) usually develops 2-4 weeks after a genitourinary (GU) or gastrointestinal (GI) infection (or, possibly, a chlamydial respiratory infection[9] ). About 10% of patients do not have a preceding symptomatic infection. The classic triad of symptoms—noninfectious urethritis, arthritis, and conjunctivitis—is found in only one third of patients with ReA and has a sensitivity of 50.6% and a specificity of 98.9%.[63] In postenteric ReA, diarrhea and dysenteric syndrome (usually mild) is commonly followed by the clinical triad in 1-4 weeks.

In a large percentage of ReA cases, conjunctivitis or urethritis occurred weeks before the patient seeks medical attention. Patients may fail to mention this unless specifically asked. Musculoskeletal disease is evident in many of these patients.[64] Vague, seemingly unrelated complaints may obscure this diagnosis at times.[65]

The onset of ReA is usually acute and characterized by malaise, fatigue, and fever. An asymmetrical, predominantly lower-extremity, oligoarthritis is the major presenting symptom. Myalgias may be noted early on. Asymmetric arthralgia and joint stiffness, primarily involving the knees, ankles, and feet (the wrists may be an early target), may be noted. Low-back pain occurs in 50% of patients.[63] Heel pain associated with Achilles enthesopathies and plantar fasciitis is also common.

Both postvenereal and postenteric forms of ReA may manifest initially as nongonococcal urethritis, with frequency, dysuria, urgency, and urethral discharge; this urethritis may be mild or inapparent. Urogenital symptoms, whether resulting from GU infection or from GI infection, are found in 90% of patients with ReA.[63]

An estimated 0.5-1% of cases of urethritis evolve into ReA. 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.

In men, chlamydial urethritis is less painful and produces less purulent discharge than acute gonorrhea does, making it difficult to notice. Findings from microscopic examination and cultures can be used to rule out Neisseria gonorrhoeae infection. Coinfection with Chlamydia and Neisseria organisms is 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 previous episode of urethritis.

Lymphogranuloma venereum infection may be asymptomatic; screening should be considered in all men who have sex with men (MSM) presenting with acute arthritis, particularly if they are infected with HIV.[66]

In addition to conjunctivitis, ophthalmologic symptoms of ReA include erythema, burning, tearing, photophobia, pain, and decreased vision (rare).

Patients may have mild recurrent abdominal complaints after a precipitating episode of diarrhea.

Association with HIV infection

ReA is particularly common in the context of HIV infection.[67, 68] Accordingly, patients with new-onset ReA must be evaluated for HIV. The existing immunodepression in patients with AIDS poses special management problems.

HIV-positive ReA 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. The disturbances of immune homeostasis in AIDS could account for this peculiar expression of psoriasis in these patients.

Physical Examination

Physical findings in ReA may involve the musculoskeletal system, the skin and nails, the eyes, the GU tract, the GI tract, and other systems (see below).

A scoring system for diagnostic points in ReA-like spondyloarthropathies exists. In this system, the presence of 2 or more of the following points (1 of which must pertain to the musculoskeletal system) establishes the diagnosis:

  • Asymmetric oligoarthritis, predominantly of the lower extremity[69]

  • Sausage-shaped finger (dactylitis),[63] toe or heel pain, or other enthesitis

  • Cervicitis or acute diarrhea within 1 month of the onset of arthritis

  • Conjunctivitis or iritis

  • Genital ulceration or urethritis

Joints, axial skeleton, and entheses

Articular involvement in ReA is typically asymmetric and usually affects the weight-bearing joints (ie, knees, ankles, and hips), but the shoulders, wrists, and elbows may also be affected. In more chronic and severe cases, the small joints of the hands and feet may be involved as well. Dactylitis (ie, sausage digits) may develop. In children, joint involvement is oligoarticular in 69% of cases, polyarticular in 27%, and monoarticular in 4%.

Joints are commonly described as tender, warm, swollen (see the image below), and, sometimes, red. Symptoms may occur initially or several weeks after onset of other symptoms. Migratory or symmetric involvement is also reported. Periostitis and tendinitis may occur, especially involving the Achilles tendon, which produces pain in the heel. The arthritis is usually remittent and rarely leads to severe limitation of functional capacity. Muscular atrophy can develop in severely symptomatic cases.

Swelling of right knee with effusion caused by art Swelling of right knee with effusion caused by arthritis. Image courtesy of Gun Phongsamart, MD.

Enthesopathy, or enthesitis (ie, inflammation of ligament and tendon insertions into bone), is thought to be a characteristic feature of ReA. The Achilles insertion is the most common site; other sites include the plantar fascial insertion on the calcaneus, ischial tuberosities, iliac crests, tibial tuberosities, and ribs.

Sacroiliitis (see the image below) frequently occurs in adults who are positive for human leukocyte antigen (HLA)–B27 (though it is apparently less common in children). It is typically self-limiting. Whereas 50% of patients with ReA may develop low-back pain, most physical examination findings in patients with acute disease are minimal except for decreased lumbar flexion. Patients with more chronic and severe axial disease may develop physical findings similar to, or even indistinguishable from, those of ankylosing spondylitis.

Remarkable tenderness of left sacroiliac joint cau Remarkable tenderness of left sacroiliac joint caused by sacroiliitis. Image courtesy of Gun Phongsamart, MD.

Skin and nails

Skin and mucocutaneous lesions are commonly observed in ReA. The dermal lesions are typified by keratoderma blennorrhagicum,[63] in which hyperkeratotic skin begins as clear vesicles on erythematous bases and progresses to macules, papules, and nodules—found on the soles of the feet (see the image below), palms, scrotum, trunk, or scalp—and eventually coalescing to form a hyperkeratotic erythematous dermatitis resembling pustular psoriasis.[51]

Plaques on soles of patient with reactive arthriti Plaques on soles of patient with reactive arthritis.

Distal involvement with painful and erosive lesions in the tips of the fingers (see the image below) and toes, with pustules and subungual pustular collections, also occurs.

Painful erosions on fingers in patient with reacti Painful erosions on fingers in patient with reactive arthritis.

In some patients, typical keratoderma blennorrhagicum develops 1-2 months after the onset of arthritis, with keratotic papules and plaques that are painful under pressure; sometimes, these can be disabling.

Erythematous macules and plaques, diffuse erythema, erosions, and bleeding can appear on the oral and pharyngeal mucosae in 30-60% of patients.[63] Circinate lesions on the tongue resemble geographic tongue (see the image below).

Plaques and erosions of tongue in patient with rea Plaques and erosions of tongue in patient with reactive arthritis.

Erythema nodosum may develop but is uncommon.

Nail dystrophy is present in 20-30% of patients. The nails can become thickened and ridged and may crumble, in a manner resembling mycotic infection or psoriatic onychodystrophy, but nail pitting is not observed. Nail shedding is common.

Eyes

Conjunctivitis is a component of the original triad and is one of the hallmarks of the disease, reported to appear in 33-100% of patients. It tends to occur early in the disease, especially during the initial attack; it may be missed if patients are seen only during subsequent attacks.

An intense red, velvetlike conjunctival injection characterizes the conjunctivitis. Bilateral involvement is common. Edema and a purulent discharge are not rare. The conjunctivitis may be mild and painless or may cause severe symptoms with blepharospasm and photophobia. It usually resolves spontaneously within 2 weeks.

Anterior uveitis (including iritis, iridocyclitis, or cyclitis) is the second most common ocular finding. Iridocyclitis may be the initial ocular manifestation in some patients. Uveitis may occur in 12-37%[63] (or possibly as many as 50%) of patients with ReA and is more frequently found in patients with HLA-B27 and those with sacroiliitis. At clinical examination, redness, pain, impaired vision, and exudation with hypopyon can suggest iritis. Rarely, an ReA patient may have permanent visual loss from macular infarction or foveal scarring.[70]

A particularly serious ocular manifestation is recurrent nongranulomatous iridocyclitis. Recurrences are usually associated with an acute iridocyclitis that has a rapid onset with conjunctival and episcleral edema and injection. The corneal endothelium has cellular debris and poorly defined, small- to medium-sized keratic precipitates. Heavy flare and cells and a very early tendency toward formation of posterior synechiae are characteristic, more so than in most other forms of acute iridocyclitis.

Even the most aggressive pupil-dilation management is sometimes inadequate to prevent synechiae formation. A peripheral iridectomy may be necessary to prevent iris bombé and angle closure if the synechiae cannot be broken.

Heavy flare is sometimes so plasmoid that cells are immobile, and a fibrinlike clot may be seen in the pupillary opening as the inflammation resolves. An acute hypopyon may occur. Cells and inflammatory debris may be seen in the vitreous, and blurring of the disc margins and macular edema may occur with severe or prolonged episodes. Spillover vitreitis may be more common in patients with reactive arthritis than those with ankylosing spondylitis.

Other ocular findings that may be noted in ReA include the following:

  • Scleritis

  • Episcleritis

  • Keratitis - Rarely (4% of cases), patients may develop a punctate epithelial keratitis that may lead to central loss of the corneal epithelium and subepithelial infiltrates[71]

  • Cataracts - Lens clouding and posterior subcapsular cataracts occur with prolonged or repeated episodes

  • Hypotony - This may occur after a severe or prolonged course and may persist after resolution

  • Glaucoma - Secondary open-angle glaucoma may occur because of the anterior chamber reaction and the trabecular obstruction or trabeculitis; it usually resolves with aggressive anti-inflammatory therapy; with repeated recurrences, damage to the trabecular meshwork may occur, resulting in secondary glaucoma

  • Corneal ulceration

  • Disc or retinal edema

  • Retinal vasculitis

  • Optic neuritis

  • Dacryoadenitis (occurs rarely in the setting of chlamydial urethritis)[72]

Genitourinary tract

Urogenital symptoms may be primary or postdysenteric and may include the following[63] :

  • Meatal edema and erythema and clear mucoid discharge

  • Prostatitis causing tenderness (up to 80%) and vulvovaginitis

  • Circinate balanitis (balanitis circinata)

  • Cervicitis

  • Cystitis

  • Salpingo-oophoritis

Circinate balanitis, consisting of small shallow painless ulcers of the urethral meatus or the glans penis (see the images below), is characteristic. The condition is characterized 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. On an uncircumcised penis, the lesions typically remain moist; on a circumcised penis, they may harden and crust, causing pain and scarring in 50% of patients.[63]

Balanitis circinata (circinate balanitis) in patie Balanitis circinata (circinate balanitis) in patient with reactive arthritis.
Balanitis circinata (circinate balanitis). Image c Balanitis circinata (circinate balanitis). Image courtesy of Gun Phongsamart, MD.

Circinate vulvitis is reported in women. Balanitis and vulvitis are rare in children; when they occur, they are suggestive of ReA.[73]

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.

Urethritis is difficult to diagnose in children but is present in 30% of pediatric patients at onset. Obtaining a history of dysuria from children is difficult, possibly because the urinary abnormality 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.

Gastrointestinal tract

Enteric infections may trigger ReA. Pathogens include Salmonella, Shigella, Yersinia, and Campylobacter species. The frequency of ReA after these enteric infections is about 1%-4%. Other enteric bacteria that have been associated with ReA include C difficile,[74] E coli, and Helicobacter pylori.[14] (See Etiology.)

Some patients with ReA continue with intermittent bouts of diarrhea and abdominal pain. Lesions resembling ulcerative colitis or Crohn disease have been described when ileocolonoscopy is performed in patients with established ReA.[74] Although enteritis is usually a prolonged diarrheal episode with frequent passage of bloody loose stools, it can also manifest as a 24-hour episode of increased bowel activity.

Other findings

Aortic regurgitation caused by inflammation of aortic wall and valve may occur. This proximal aortitis can be found in 1-2% of cases.[51] Aortitis may be accompanied by coronary inflammation, which can be fatal in rare cases. Transient conduction abnormalities may develop but are of little significance; rarely, patients may be affected by myocarditis or pericarditis.[51]

Other manifestations of ReA include mild renal pathology with proteinuria and microhematuria. In severe chronic cases, amyloid deposits and immunoglobulin A (IgA) nephropathy have been reported in association with reactive arthritis.[75] IgA nephropathy is the most common type of primary glomerulonephritis worldwide.

Complications

Complications of ReA include the following:

  • Recurrent arthritis (15-50%)

  • Chronic arthritis or sacroiliitis (15-30%)

  • Ankylosing spondylitis (30-50% of HLA-B27–positive patients)

  • Urethral stricture

  • Aortic root necrosis

  • Secondary glaucoma

  • Cataracts

  • Cystoid macular edema

  • Posterior and anterior synechiae

  • Cyclitic membrane

  • Vitreous opacification

  • Ankylosing spondylitis, psoriatic arthritis, and sacroiliitis

  • Erythroderma (rare)

In severe cases, functional impairment may be severe, and a chronic and prolonged clinical course is followed by sequelae (eg, urethral stenosis, chronic arthritis, or ocular impairment).

 

DDx

Diagnostic Considerations

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. If reactive arthritis (ReA) occurs in a child as a result of a sexually transmitted disease, child protective service evaluation is mandatory.

Rheumatoid arthritis and psoriatic arthritis, as well as ankylosing spondylitis, must be differentiated from ReA. A disease flare of ankylosing spondylitis prompted by a minor diarrheal illness has been described as showing features of ReA.[76]

Septic arthritis and pyogenic arthritis also can mimic ReA. Septic arthritis must be ruled out if suspected before a diagnosis of ReA is made. Oligoarticular and asymmetrical involvement, together with the clinical course, may contribute to the diagnostic suspicion. Failure to treat septic arthritis appropriately in a timely manner could result in joint destruction.

Other seronegative arthritides can be present. The question of how to differentiate these conditions from ReA 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 ReA.

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

Syphilis may mimic ReA, especially secondary syphilis in its so-called malignant form with polymorphic vesicular pustules covered with thick crusts.[77]

Other conditions to be considered include the following:

  • Acute lymphoblastic leukemia

  • Immunotherapy/immunization–related arthropathy

  • Synovitis, acne, pustulosis, hyperostosis, and osteomyelitis (SAPHO) syndrome

  • Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome

  • Systemic autoinflammatory disorders

Differentials

Atopic Dermatitis

Balanitis Circumscripta Plasmacellularis

Balanitis Xerotica Obliterans

Balanoposthitis

Behçet Disease

Campylobacter Infections

Cervicitis

Chlamydia

Colitis

Contact Dermatitis, Irritant

Conjunctivitis

Crohn Disease

Glaucoma, Drug-Induced

Glaucoma, Uveitic

Gout and Pseudogout

HLA-B27 Syndromes

Inflammatory Bowel Disease

Iritis and Uveitis

Juvenile Rheumatoid Arthritis

Kawasaki Disease

Lupus Erythematosus, Acute

Lyme Disease

Mycoplasma Infections

Psoriasis

Psoriasis, Guttate

Psoriasis, Plaque

Psoriasis, Pustular

Red Eye Evaluation

Salmonella Infection

Sarcoidosis

Scleritis

Synechia, Peripheral Anterior

Tendonitis

Tenosynovitis

Tick-Borne Diseases, Lyme

Uveitis, Anterior, Nongranulomatous

Ulcerative Colitis

Yersinia Enterocolitica Infection

 

Workup

Approach Considerations

The diagnosis of reactive arthritis (ReA) is clinical, based on the history and physical examination findings. A high index of suspicion is required. No laboratory study or imaging finding is diagnostic of ReA. No specific tests or markers are indicated. Indicators of inflammation are usually abnormal.

Laboratory Studies

Blood tests and urinalysis

The values of acute-phase reactants, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are usually elevated markedly (eg, ESR of 50-60 mm/hr) but later return to the reference range when the inflammation subsides. C1, C4, and C5 levels are within the reference range. C1 inhibitor functional assay (C1INH) and C2 levels may be elevated.

Other laboratory findings include a normocytic normochromic anemia along with mild leukocytosis (up to 20,000/µL) and thrombocytosis during the acute phase. Immunoglobulin A (IgA) antibodies to specific bacterial antigens have been reported. Test results for rheumatoid factor and antinuclear antibodies are negative.

Referral for HIV should be considered in patients presenting with history, symptoms, or findings suggesting increased risk for the disease; certain therapies are contraindicated in these patients.[58] The incidence of ReA is high among patients with AIDS, and HIV testing is mandatory in patients in whom ReA is newly diagnosed, even if they do not have the risk factors.

White blood cells (WBCs), red blood cells (RBCs), and small amounts of protein are present in urinalysis findings, indicating pyuria. Urine culture findings may be positive for Chlamydia or Ureaplasma, though test results may be negative if obtained several weeks after the onset of symptoms.

Serology and cultures

Chlamydia should be sought in every case of ReA. Serology is useful in some cases; however, culture techniques may not be reliable, causative agents are only identified in only 58% of cases with genitourinary (GU) symptoms, and there is a high positive rate in control populations (people without ReA).[12]

If urethritis or cervicitis is present, cervical or urethral cultures should be obtained. Smears of urethral discharge may be sent for antichlamydial staining by direct fluorescent antibody (DFA) testing, enzyme immunoassay (EIA), culture, or nucleic acid probe. Polymerase chain reaction (PCR) assay may be considered.[78] A Giemsa stain or a Wright stain may reveal the classic gram-negative intracellular diplococci associated with gonorrhea. Many patients may experience simultaneous sexually transmitted diseases, particularly chlamydia and gonorrhea.

Results of routine urine cultures are negative. Stool cultures can be helpful for enteric pathogens (eg, Salmonella, Shigella, and Yersinia). Obtaining stool cultures even when bowel symptoms are inapparent or mild may help direct treatment; however, cultures are often negative by the time of presentation.[55]

The US Preventive Services Task Force (USPSTF) guidelines for screening for chlamydial infections and gonorrhea were updated in 2014. The USPSTF recommends screening in sexually active women age 24 years and younger and in older women who are at increased risk for infection. Evidence was insufficient to assess the balance of benefits and harms of screening for chlamydia and gonorrhea in men.[79]

HLA-B27 test

The presence of human leukocyte antigen (HLA)-B27 correlates with axial disease, carditis, and uveitis. HLA-B27 test results are positive in 65%-96% of ReA cases (67-92% of pediatric cases). HLA-B27 testing is not diagnostic of ReA and thus not required; however, it may be helpful for certain purposes (eg, supporting the diagnosis of ReA in patients with joint-restricted symptoms). The HLA-B27 test is moderately expensive and should not be ordered indiscriminately as a screen.

In a report by Shimamoto et al, a Japanese man with ReA was negative for HLA-B27 and other HLA-B27 cross-reactive major histocompatibility complex (MHC) class I antigens but was positive for HLA-B51.[80] Laboratory examination showed significant elevation of serum levels of IgA and IgG antichlamydial antibodies. The authors suggested that a combination of Chlamydia infection and HLA-B51 presence might play a role in the pathogenesis of ReA in this patient.

Tuberculin skin test

A tuberculin skin test may be appropriate in certain individuals, particularly those with demographics strongly suggestive of infectious tuberculosis (TB). TB is far more likely to occur in immigrants from Southeast Asia, Africa, and other endemic regions. Caution must be taken not to interpret a positive skin test as diagnostic of tuberculosis, particularly in individuals who have been given the bacille Calmette-Guérin (BCG) vaccine.

Radiography

Radiologic examination may demonstrate various arthritic changes. These changes tend to be asymmetric and oligoarticular and are more common in the lower extremities. However, radiologic signs are present in only 40-70% of cases, and they may be completely absent even in instances of severe disease. Early in the disease process, radiography often reveals no abnormalities at all.

In more advanced or long-term ReA, periosteal reaction and proliferation at sites of tendon insertion are visible. Exuberant plantar spurs are a common sign in long-term ReA. Changes consistent with chronic plantar fasciitis or Achilles tendinitis may be seen. In the hands and feet, marginal erosions with adjacent bone proliferation occur. The erosions typically have indistinct margins and are surrounded by periosteal new bone and periostitis (see the images below).

Radiograph of feet of 27-year-old man shows erosio Radiograph of feet of 27-year-old man shows erosions in all left metatarsophalangeal (MTP) joints with subluxation and valgus deformity of most toes. Smaller erosions are also visible in fourth and fifth MTP joints of right foot.
Lateral radiograph of foot reveals calcaneal spur Lateral radiograph of foot reveals calcaneal spur and enthesitis.
Radiograph of both hands shows small erosive chang Radiograph of both hands shows small erosive changes in both first metacarpal heads associated with minimal subluxation. Bone density is normal.

Spinal radiographic findings include sacroiliitis and syndesmophytes. Sacroiliitis (unilateral or bilateral) occurs in fewer than 10% of acute cases but develops in half of patients with chronic severe disease (see the image below). Specifically ordering a radiograph of the sacroiliac joint is advisable. Such a film provides a more sensitive tunnel view than a routine film of the lumbosacral spine does.

Radiography of pelvis reveals bilateral asymmetric Radiography of pelvis reveals bilateral asymmetric sacroiliitis.

Syndesmophytes are asymmetric, paravertebral, bulky, discontinuous, comma-shaped ossifications that most commonly involve the lower thoracic and upper lumbar vertebrae (see the image below).

Radiograph in 40-year-old man shows nonmarginal sy Radiograph in 40-year-old man shows nonmarginal syndesmophytes predominantly in lower thoracic and upper lumbar spine.

Severe ankylosing spondylitis occurs in fewer than 5% of cases.

Other Imaging Modalities

Whole-body scintigraphy is a sensible diagnostic tool for use in screening for enthesopathy and arthropathy.[81]

Positron emission tomography has been found to allow recognition of enthesitis in the early stage of ReA, before other modalities would be able to detect it.[82]

Magnetic resonance imaging (MRI) of the sacroiliac joints may reveal disease earlier than conventional radiography would. MRI is more sensitive than computed tomography (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.

Ultrasonography may reveal enthesitis (as periosteal reaction and tendinosis) more accurately that physical examination would.[51, 47] Echocardiography may reveal carditis or valvular dysfunction in patients with poststreptococcal ReA.[83, 84]

Arthrocentesis, Synovial Fluid Analysis, and Synovial Biopsy

Arthrocentesis and fluid analysis are often needed to rule out an infectious process, especially in monoarticular arthritis with constitutional symptoms. Synovial fluid analysis reveals a high WBC count (10,000-40,000/µL), most often with polymorphonuclear leukocytes (PMNs) predominating. CH50, C1INH, C4, C5, and C3 levels are elevated. Gram stain and culture results are negative and are necessary to exclude septic arthritis. Microbial components and antigens have been identified in joint fluid using sophisticated laboratory techniques.

PCR assay has been used to detect Chlamydia and Yersinia antigenic DNA in synovial fluid, but these organisms are highly prevalent in the control population, and results have varied considerably from one institution to another.[36] Synovial fluid PCR has led to the detection of bacterial antigenic material in as many as 50% of patients previously diagnosed with undifferentiated spondyloarthropathy.[85]

Synovial biopsy typically yields nonspecific inflammatory changes; infectious antigens have been found in the synovium. Immunohistochemistry (IHC), PCR assay, and molecular hybridization may become more useful.

Other Studies

Antistreptolysin O (ASO) or anti-DNase B testing may be considered if poststreptococcal infection is suspected.[83, 84]

Electrocardiography (ECG) should be performed in patients with a prolonged course of ReA to evaluate for conduction disturbances.

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, PMNs, and, rarely, plasma cells may be observed in synovial fluid. Such cells account for less than 1% of the synovial fluid WBCs. These cells are found in the synovium; however, extensive pannus formation is rare.

 

Treatment

Approach Considerations

No curative treatment for reactive arthritis (ReA) exists. Instead, treatment aims at relieving symptoms and is based on symptom severity. Almost two thirds of patients have a self-limited course and need no treatment other than symptomatic and supportive care. As many as 30% of patients develop chronic symptoms, posing a therapeutic challenge.[86]

Physical therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), and intralesional corticosteroids may be helpful for joint, tendon, and fascial inflammation. Low-dose prednisone may be prescribed, but prolonged treatment is not advisable. Antibiotics may be given to treat underlying infection. Disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine and methotrexate may be used safely and are often beneficial. No specific surgical treatment is indicated.

Hospitalization of a patient with uncomplicated ReA is not usually indicated. Inpatient care may be considered for patients who are unable to tolerate oral administration of medications, who are unable to ambulate because of significant joint involvement, who have intractable pain, or who have concomitant disease necessitating admission.

Few treatment options exist for HIV-infected patients with severe ReA. Treatment of ReA in the setting of HIV infection poses special problems. However, potentially immunosuppressive therapies (eg, cyclosporine, methotrexate, and psoralen plus ultraviolet A [PUVA]) have been used in some cases, with variable success and relatively few severe complications. A case report from the United Kingdom suggests that antiretroviral therapy may be considered in HIV-infected ReA patients who are unresponsive to standard therapy.[87]

No dietary limitations are necessary unless the patient is receiving steroid therapy. Efforts should be made to maintain joint function with physical activity, joint protection, and suppression of inflammation. Physical therapy may be instituted to avoid muscle wasting and to reduce pain in severe cases. Although no limitations on physical activity need be imposed, symptoms of arthritis will usually limit patients’ activity to some extent.

Pharmacologic Therapy

NSAIDs (eg, indomethacin and naproxen) are the foundation of therapy for ReA.[88] Etretinate/acitretin has been shown to decrease the required dosage of NSAIDs.[63] Sulfasalazine or methotrexate may be used for patients who do not experience relief with NSAIDs after 1 month or who have contraindications to NSAIDs. In addition, sulfasalazine-resistant ReA may be successfully treated with methotrexate.[89]

In a series of 22 pediatric ReA patients from the Republic of China, NSAIDs and sulfasalazine were the mainstays of treatment, with cyclophosphamide used in 14 patients and methotrexate and corticosteroids added in a few.[90] Most achieved full remission within 6 months.

Antibiotic treatment is indicated for cervicitis or urethritis but generally not for postdysenteric ReA. In Chlamydia-induced ReA, some data suggest that prolonged combination antibiotic therapy could be an effective treatment strategy.[34]

Case reports exist that demonstrate the effectiveness of anti−tumor necrosis factor (TNF) medications,[51, 91] such as etanercept and infliximab.[92, 61] No published data are available on the effectiveness of selective cyclooxygenase (COX)–2 inhibitors; however, a COX-2 inhibitor may be tried in patients who do not tolerate NSAIDs and in whom no preexisting contraindication to COX-2 use exists.

Symptom-specific approaches

Arthritis and enthesitis

Joint symptoms are best treated with aspirin or other short-acting and long-acting anti-inflammatory drugs (eg, indomethacin, naproxen). In one report, a patient became asymptomatic after 3 months of aspirin at a dosage of 80 mg/kg/day; the dosage was gradually reduced and eventually discontinued. A combination of NSAIDs is reportedly effective in severe cases. No published data suggest that any NSAID is more effective or less toxic than another (controlled treatment trials are difficult to conduct with an uncommon disease).

Varying success in treating severe cases of ReA with other medications (eg, sulfasalazine, methotrexate, etretinate, ketoconazole, azathioprine, or intra-articular steroid injections) has been reported. In a refractory case or a patient with HIV-associated ReA, the anti−TNF-α agent infliximab may be successful.[93] Depending on the culture results, a short course of antibiotics may be needed; however, treatment may not affect the disease course. Longer-term administration of antibiotics to treat joint symptoms provides no established benefits.

Conjunctivitis and uveitis

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. Patients with recurrent ocular involvement may require systemic corticosteroid therapy and immunomodulators to preserve vision and prevent ocular morbidity.[94]

Urethritis and gastroenteritis

Antibiotics may be considered for urethritis and gastroenteritis, depending on the cultures used and their sensitivity. In general, urethritis may be treated with a 7- to 10-day course of erythromycin or tetracycline. Antibiotic treatment of enteritis is controversial.

Mucocutaneous lesions

Only local care is necessary for mucosal lesions. Topical steroids may be needed for psoriasiform lesions; the use of hydrocortisone or triamcinolone may be beneficial. 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.[73]

Hydrocortisone 2.5% cream and salicylic acid 10% ointment are effective in treating chronic keratoderma blennorrhagicum and circinate balanitis, though either condition may heal without medical treatment. Circinate balanitis usually responds to topical steroids; however, it can be recurrent and create a therapeutic challenge. Balanitis refractory to conventional therapy can be successfully treated with the complementary use of topical 0.1% tacrolimus.[20]

Systemic therapy, if required, consists of the administration of oral acitretin, PUVA, methotrexate, cyclosporine, or some combination thereof.

Nonsteroidal anti-inflammatory drugs

The choice of a specific NSAID depends on the individual response to treatment. Phenylbutazone may work in patients refractive to other NSAIDs. These agents should be used regularly to achieve a good anti-inflammatory effect. Patients must be instructed on compliance and the possible need to adjust the dosage or switch to another agent. Treatment must be continued for 1 month at maximum dosage before effectiveness can be fully evaluated.

NSAIDs may reduce the intensity and the frequency of recurrences of ocular inflammation and allow a decrease in the corticosteroid dosage, which helps decrease the chances of cataract formation and other associated corticosteroid effects.

The decreased awareness of pain sometimes seen with the use of NSAIDs may alter the patient’s recognition of recurrences. Patients should be examined whenever any change in symptoms occurs to evaluate for recurrence of an acute episode of inflammation. Ocular involvement may parallel systemic and joint disease relapses.

Corticosteroids

Corticosteroids may be given either via intra-articular injection or as systemic therapy. For ocular manifestations of ReA, they may also be given topically.

Joint injections can produce long-lasting symptomatic improvement and help avoid the use of systemic therapy. Sacroiliac joints can be injected, usually under fluoroscopic guidance.[95]

Systemic corticosteroids may be particularly useful in patients who do not respond well to NSAIDs or who experience adverse effects related to the use of NSAIDs. The starting dose is guided by a patient’s symptoms and objective evidence of inflammation. Prednisone can be used initially at a dosage of 0.5-1 mg/kg/day, tapered according to response.

Topical corticosteroids and mydriatics should be used early and aggressively to reduce tissue damage. Prolonged topical treatment is necessary for several weeks after the inflammation has cleared; early withdrawal of topical corticosteroids frequently results in the return of inflammatory changes. Keratolytics or topical corticosteroids may improve cutaneous lesions. Topical corticosteroids may be useful for iridocyclitis.

Antibiotics

The current view of the pathogenesis of ReA indicates that an infectious agent is the trigger of the disease, but antibiotic treatment does not change the course of the disease, even when a microorganism is isolated. In these cases, antibiotics are used to treat the underlying infection, but specific treatment guidelines for ReA are lacking.

However, in Chlamydia -induced ReA, studies have suggested that appropriate treatment of the acute genitourinary (GU) infection can prevent ReA and that treatment of acute ReA with a 3-month course of tetracycline reduces the duration of illness. Empiric antibiotics may be considered after appropriate cultures have been taken. Nongonococcal urethritis and other infections can be treated specifically with systemic antibiotics. In the absence of contraindications, treatment of urethritis is recommended, even if improvement is not certain.

Although urethritis and cervicitis are commonly treated with antibiotics, diarrhea generally is not. No evidence indicates that antibiotic therapy benefits enteric-related ReA or chronic ReA of any cause.

Long-term antibiotic therapy may be warranted in cases of poststreptococcal ReA; however, this is currently a controversial topic.[83, 84]

Lymecycline (a tetracycline available outside the United States) was studied in a double-blind placebo-controlled study of patients with chronic ReA for a treatment period of 3 months.[19] The duration of illness was significantly shorter in patients with Chlamydia -induced disease than in those with disease triggered by enteric infections.

Azithromycin was shown to be ineffective in a placebo-controlled trial.[96] Nevertheless, in another study, azithromycin or doxycycline in combination with rifampin for 6 months was reported to be significantly superior to placebo and significantly improved symptoms associated with Chlamydia-induced ReA.[97]

Quinolones have been studied because of their broad coverage, but no clear benefit has been reported.[98] In a randomized, double-blind, placebo-controlled study of 56 patients with recent-onset ReA, 3 months of treatment with a combination of ofloxacin and roxithromycin was not better than placebo in improving outcomes.

More studies are needed before definite recommendations can be made for the role of antibiotics in the management of ReA.[99]

Disease-modifying antirheumatic drugs

In patients who have chronic symptoms or have persistent inflammation despite the use of the agents mentioned above, other second-line drugs may be used. Clinical experience with these DMARDs has been mostly in rheumatoid arthritis and in psoriatic arthritis. However, DMARDs have also been used in ReA, though their disease-modifying effects in this setting are uncertain.

Sulfasalazine has been shown to be beneficial in some patients. The use of this drug in ReA is of interest because of the finding of clinical or subclinical inflammation of the bowel in many patients. Sulfasalazine is more widely used in ankylosing spondylitis. In a 36-week trial of sulfasalazine versus placebo to treat spondyloarthropathies, patients with ReA who were taking sulfasalazine had a 62.3% response rate, compared with a 47.7% rate for the placebo group in peripheral arthritis.[100]

Methotrexate may be used in patients who present with rheumatoidlike disease. Several reports have shown good response, but controlled studies are lacking. Reports also describe the use of azathioprine and bromocriptine in ReA, but again, large studies have not been published.[101, 102] Patients with ReA who have HIV infection or AIDS should not receive methotrexate or other immunosuppressive agents.

Case reports have demonstrated the effectiveness of anti-TNF medications, such as etanercept and infliximab,[51, 91, 93, 103] though there remains a need for randomized, double-blind trials. The high concentrations of TNF-α in the serum and joints of patients with persistent ReA suggest that this cytokine could be targeted in patients who do not respond to NSAIDS and DMARDs. Anti−TNF-α therapy has been demonstrated to be effective treatment for ReA, with a corticosteroid-sparing effect.[104]

However, TNF-α antagonists can increase the risk of serious infection, and it is important to conduct infectious screening and monitoring with a high index of suspicion, as well as preemptive treatment, when such medications are used.[3] Anti-TNF medications can also be associated with severe glomerulonephritis, and it is recommended that renal function be closely monitored in patients treated with these agents.[9]

Interleukin (IL)-6 plays an important role in regulating immune response. Unregulated overproduction of IL-6, however, is pathologically involved in various immune-mediated inflammatory diseases, including ReA. Tocilizumab, a humanized anti–IL-6 receptor antibody, may provide clinical benefit in patients who are refractory to conventional therapy or anti-TNF therapy.[105] However, further clinical studies are required.

Surgical Intervention

No surgical therapy for ReA is recommended. However, surgical intervention may be warranted for certain ocular manifestations of the disease.

The posterior spillover of inflammatory material in the chronic iridocyclitis associated with ReA may result in persistent vitreous opacification. The cumulative effects of secondary involvement of the vitreous may result in visually disabling vitreous debris and opacification, making these eyes good candidates for vitrectomy. Although vitrectomy should be considered only after prolonged follow-up care and thorough planning, it appears to offer a definitive improvement in vision in certain cases.

Because of the intense episodes of recurrent inflammation, it is essential to render the eyes as quiet as possible before surgery by using topical, periocular, or systemic corticosteroids. At least 3 months of cell-free slit lamp examinations—6 months for younger patients and severe cases—should be documented before elective surgical intervention.

Preoperative ultrasonography is helpful in determining the degree of vitreous opacification, the thickening of the choroid, and the presence of a cyclitic membrane, which can create significant problems at surgery.

The major objective of surgery in patients with complicated uveitic cataract and vitreous opacification is to improve vision. Vitrectomy may favorably modify the dynamics of the uveitic process, though lensectomy-vitrectomy does not reduce the inflammatory reaction in all cases.

Cystoid macular edema is the major cause of decreased visual acuity after surgery; however, this is a common and serious complication of chronic uveitis even without surgery. Vitrectomy may actually reduce cystoid macular edema with gradual resolution over 1 year and an improvement in vision in some patients.

Prevention

In Chlamydia -induced ReA, studies have suggested that appropriate treatment of the acute GU infection can prevent ReA and that treatment of acute ReA with a 3-month course of antibiotics can reduce the duration of illness. Currently, there is no evidence to indicate that antibiotic therapy is effective for enteric-related ReA or chronic ReA of any cause.

Education on the prevention of the spread of sexually transmitted diseases with condoms has been associated with a decrease in the incidence of postvenereal ReA.

Consultations

Appropriate consultations should be obtained as necessary.

A rheumatologist may be consulted to discuss appropriate additional tests and medications for symptomatic relief and to ensure follow-up treatment. In particular, the consulting rheumatologist may be extremely helpful in suggesting an appropriate oral NSAID or immunosuppressive agent to augment topical and periocular corticosteroid therapy.

Consultation with a urologist may be necessary if particularly prominent genitourinary manifestations develop.

An ophthalmologist may be consulted to confirm the diagnosis and to treat the ophthalmologic manifestations of ReA.

Consultation with a dermatologist is often helpful. For example, dermatologic involvement may occur with several uveitic syndromes; an accurate description of these lesions may help establish the diagnosis in some cases.

Consultation with and treatment by a dentist, an oral surgeon, or a periodontist may be useful for patients with aphthous ulcers.

An internal medicine consultation should be sought when prolonged systemic corticosteroid therapy is anticipated, especially in patients with concomitant diabetes or hypertension.

An infectious disease consultation may be sought when empiric antibiotic therapy is being considered or when the patient has manifestations of coincident AIDS-defining illnesses.

In cases of poststreptococcal ReA, a cardiology consultation is necessary because serial echocardiography and long-term antibiotic therapy may be of benefit to the patient. It should be kept in mind that patients with ReA symptoms who have evidence of preceding streptococcal infection are likely meet the Jones criteria for acute rheumatic fever. Many cardiologists elect to place these patients on long-term penicillin treatment.[83, 84]

It should be noted that current data show no increased risk of valvular heart disease in adult poststreptococcal ReA. On the basis of these findings, routine long-term antibiotic prophylaxis is not recommended in adult poststreptococcal ReA.[31, 49, 39, 38] The above recommendation is valid in pediatric patients with ReA.

Physical and occupational therapists may be consulted for assistance with maintenance of function and gait.

 

Medication

Medication Summary

The goals of pharmacotherapy for reactive arthritis (ReA) are to reduce morbidity, to prevent joint damage, and to alleviate extra-articular disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstays of therapy for joint symptoms. Other types of agents used to treat ReA or its extra-articular manifestations include corticosteroids, antibiotics, and various disease-modifying antirheumatic drugs (DMARDs).

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Class Summary

Several NSAIDs are available for relief of mild to moderate pain in ReA patients. They are similar with respect to effectiveness, though indomethacin may be more effective in the spondyloarthropathies. Cyclooxygenase (COX)-2–specific inhibitors can be used in patients at high risk for GI complications.

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

Aspirin and several NSAIDs are available for use in ReA patients and are comparably effective in treating symptoms.

Aspirin (Ascriptin, Bayer Aspirin, Bayer, Bufferin, Ecotrin Arthritis Strength)

Aspirin is a short-acting anti-inflammatory agent with rapid absorption in the proximal gastrointestinal (GI) tract. It is optimally effective only when stable serum levels of 150-250 µg/L are achieved after 3-5 days of treatment. Serum aspirin levels can be checked after 5-10 days of treatment. Maximal anti-inflammatory action is generally achieved within 2-4 weeks, with some further benefit occurring up to 3 months.

Ibuprofen (Motrin, Advil, NeoProfen, Addaprin)

Ibuprofen inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Indomethacin (Indocin)

Indomethacin is the NSAID of choice in ReA; however, other NSAIDs are often effective as well. It is rapidly absorbed; metabolism occurs in the liver via demethylation, deacetylation, and glucuronide conjugation. Indomethacin inhibits prostaglandin synthesis; it is also a potent COX inhibitor, and this action may decrease local production of arachidonic acid–derived chemotactic factors for eosinophils present in sebum.

Naproxen (Naprosyn, Aleve, Naprelan)

Naproxen is used for relief of mild-to-moderate pain and is available in both short-acting and long-acting forms. It inhibits inflammatory reactions and pain by decreasing the activity of COX, which is responsible for prostaglandin synthesis.

Diclofenac (Voltaren, Cataflam XR, Zipsor, Cambia)

Diclofenac inhibits prostaglandin synthesis by decreasing COX activity, which, in turn, decreases formation of prostaglandin precursors.

Ketoprofen

Ketoprofen is used for relief of mild to moderate pain and inflammation. Small dosages are indicated initially in small patients, elderly patients, and patients with renal or liver disease. Doses higher than 75 mg do not increase the therapeutic effects. Administer high doses with caution, and closely observe the patient's response.

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body’s immune response to diverse stimuli. Topical corticosteroids are used for dermatologic manifestations of ReA, such as keratoderma blennorrhagicum and balanitis circinata (circinate balanitis). For ocular therapy, topical or subtenon injections of steroid have proven effective. Systemic steroids should only be used in cases of macular involvement and only for short periods.

Prednisone (Rayos)

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity the activity of polymorphonuclear leukocytes (PMNs).

Prednisolone acetate 1% (Pred Forte, Pred Mild, Omnipred)

Prednisolone acetate is used mainly for acute iritis. The best approach is to treat aggressively early in the course of the disease, then to gradually taper and discontinue the drug on the basis of the patient's clinical response.

Hydrocortisone valerate (CortAlo, TheraCort, U-Cort, Westcort)

Topical corticosteroids are adrenocorticosteroid derivatives suitable for application to skin or external mucous membranes; they have mineralocorticoid and glucocorticoid effects, resulting in a nonspecific anti-inflammatory activity.

Keratolytic Agents

Class Summary

These agents cause cornified epithelium to swell, soften, macerate, and then desquamate.

Salicylic acid topical (Calicylic, Aliclen, Keralyt, Salkera, Salvax)

Topical salicylic acid, by dissolving intercellular cement substance, produces desquamation of the horny layer of the skin, without affecting the structure of viable epidermis.

Antibiotics

Class Summary

Antibiotics may be used in ReA for antibacterial effects and for treatment of possible coexistent infection. Empiric antimicrobial therapy should cover all likely pathogens in the context of the clinical setting. Whenever feasible, antibiotic selection should be guided by blood culture sensitivity.

Tetracyclines are used to treat urethritis or cervicitis caused by chlamydial organisms. Some evidence shows that tetracycline treatment in chlamydia-induced ReA may reduce the duration, and perhaps the severity, of illness. Collagenase inhibitors have been used to treat early rheumatoid arthritis.

Erythromycin (EryPed 200, E.E.S. 400, Ery-Tab, PCE)

Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It is indicated for treatment of infections caused by susceptible strains of microorganisms (eg, Mycoplasma pneumoniae and Staphylococcus, Streptococcus, and Chlamydia spp) and for prevention of corneal and conjunctival infections.

Erythromycin ophthalmic (Romycin, Ilotycin)

Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It is indicated for the prevention of corneal and conjunctival infections.

Ciprofloxacin (Cipro, Cipro XR)

Ciprofloxacin is the drug of choice for obtaining improvement in clinical parameters (except joint involvement) in postenteric ReA. It is a bactericidal antibiotic that inhibits bacterial DNA synthesis and, consequently, growth by inhibiting DNA gyrase in susceptible organisms.

Tetracycline

Tetracycline is used to treat gram-positive and gram-negative infections, as well as mycoplasmal, chlamydial, and rickettsial infections. It inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunits.

Doxycycline (Adoxa, Doryx, Vibramycin)

Doxycycline is 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. It inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Minocycline (Minocin, Solodyn)

Minocycline is 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. It inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Azithromycin (Zithromax, Zmax)

Azithromycin is used to treat mild-to-moderate microbial infections.

Cefdinir

Cefdinir is a third-generation cephalosporin indicated for treatment of susceptible infections.

Aminosalicylic Acid Derivatives

Class Summary

Aminosalicylic acid derivatives are used to reduce inflammation when NSAIDs do not control arthritis or when inflammatory lesions of the intestinal mucosa are present.

Sulfasalazine (Azulfidine EN-tabs, Sulfazine, Sulfazine EC)

Sulfasalazine is used as a second-line therapy to treat ReA that is not controlled with NSAIDs alone. It is a conjugate of the salicylate 5-aminosalicylic acid (5-ASA) and the sulfonamide sulfapyridine (linked by an azo bond). Sulfasalazine is primarily excreted in the urine unchanged. Most of the 5-ASA remains in the colon and is not absorbed. Sulfasalazine acts locally to decrease the inflammatory response in the joints and systemically inhibits prostaglandin synthesis and folate metabolism.

Vitamins, Fat-Soluble

Class Summary

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

Calcipotriene (Dovonex, Calcetrene, Sorilux)

Calcipotriene is a synthetic vitamin D-3 analogue that regulates skin-cell production and development. It is available as a 0.005% cream, ointment, or solution.

Antineoplastic Agents

Class Summary

Antineoplastic agents have immunosuppressive effects and inhibit cell growth and proliferation. They are used when the disease is aggressive and unremitting.

Azathioprine (Imuran, Azasan)

Azathioprine may be used alone or as a steroid-sparing agent. It antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. Azathioprine may decrease proliferation of immune cells, thereby reducing autoimmune activity. It is used more commonly for ReA and psoriasis. Thiopurine methyltransferase levels should be checked before azathioprine is used.

Methotrexate (Trexall, Rheumatrex)

Methotrexate is an antimetabolite that is indicated for the symptomatic control of severe ReA and severe, recalcitrant, disabling psoriasis. It is 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.

Antimalarials

Class Summary

Derivatives of 4-aminoquinoline are active against a variety of autoimmune disorders. They must be used with caution because hydroxychloroquine is known to be capable of exacerbating psoriasis. Because hydroxychloroquine is used for the joint involvement and not the skin involvement, it should probably be given only in conjunction with rheumatologic evaluation.

Hydroxychloroquine (Plaquenil)

It is not clear how hydroxychloroquine works. It is known to interfere with TLR signaling, inhibit chemotaxis of eosinophils neutrophils, and impair complement-dependent antigen-antibody reactions. A 200-mg quantity of hydroxychloroquine sulfate is equivalent to 155 mg of hydroxychloroquine base and 250 mg of chloroquine phosphate.

Retinoid-like Agents

Class Summary

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

Isotretinoin (Absorica, Claravis, Myorisan, Zenatane)

Oral agent used to treat serious dermatologic conditions. It is a synthetic 13-cis isomer of the naturally occurring tretinoin (trans-retinoic acid), and both agents are structurally related to vitamin A. Isotretinoin alters the pattern of keratinization, reduces bacterial flora, and has an anti-inflammatory effect.

A US Food and Drug Administration (FDA)–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin (see iPLEDGE). This registry aims to achieve further decreases in the risks of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

Acitretin (Soriatane)

Acitretin is a retinoic acid analogue, similar to etretinate and isotretinoin. Etretinate is the main metabolite and has similar clinical effects. Acitretin's mechanism of action is unknown.

Tumor Necrosis Factor Blockers

Class Summary

Anti–tumor necrosis factor (TNF)–α therapy may be considered in refractory cases of ReA.

Infliximab (Remicade)

Infliximab is a chimeric IgG1κ monoclonal antibody that binds specifically to the soluble and transmembrane forms of TNF-α and inhibits the binding of TNF-α to its receptors.

 

Questions & Answers

Overview

What is reactive arthritis (ReA)?

What are the signs and symptoms of reactive arthritis (ReA)?

Which physical findings are characteristic of reactive arthritis (ReA)?

Which lab tests are performed in the workup of reactive arthritis (ReA)?

Which imaging studies are performed in the workup of reactive arthritis (ReA)?

Which studies may be considered in the workup of reactive arthritis (ReA)?

How is reactive arthritis (ReA) treated?

What is the role of surgery in the treatment of reactive arthritis (ReA)?

What is reactive arthritis (ReA)?

What are the diagnostic criteria for reactive arthritis (ReA)?

What is the pathophysiology of reactive arthritis (ReA)?

What is the role of synovitis in the pathophysiology of reactive arthritis (ReA)?

What is the role of HLA-B27 in the pathophysiology of reactive arthritis (ReA)?

What is the role of HIV infection in the pathophysiology of reactive arthritis (ReA)?

What are infectious causes of reactive arthritis (ReA)?

What is the role of genetics in the etiology of reactive arthritis (ReA)?

Which factors increase the risk of reactive arthritis (ReA)?

What is the incidence of reactive arthritis (ReA) in the US?

What is the global incidence of reactive arthritis (ReA)?

Which patient groups have higher incidence of reactive arthritis (ReA)?

What is the prognosis of reactive arthritis (ReA)?

What is included in patient information about reactive arthritis (ReA)?

Presentation

Which clinical history findings are characteristic of reactive arthritis (ReA)?

What are the signs and symptoms of urethritis in patients with reactive arthritis (ReA)?

What are the signs and symptoms of lymphogranuloma venereum infection in patients with reactive arthritis (ReA)?

What are the ophthalmologic symptoms of reactive arthritis (ReA)?

Which symptoms may be present in reactive arthritis (ReA) following an episode of diarrhea?

What is the association of reactive arthritis (ReA) with HIV infection?

What is the scoring system for diagnosing reactive arthritis (ReA)-like spondyloarthropathies?

Which joints, axial skeleton, and entheses findings are characteristic of reactive arthritis (ReA)?

Which skin and nail findings are characteristic of reactive arthritis (ReA)?

Which ocular findings are characteristic of reactive arthritis (ReA)?

Which urogenital findings are characteristic of reactive arthritis (ReA)?

What are findings of circinate balanitis in patients with reactive arthritis (ReA)?

What are findings of circinate vulvitis in patients with reactive arthritis (ReA)?

Which GI findings are characteristic of reactive arthritis (ReA)?

Which cardiac findings suggest reactive arthritis (ReA)?

Which renal findings suggest reactive arthritis (ReA)?

What are the possible complications of reactive arthritis (ReA)?

DDX

How are other types of arthritis differentiated from reactive arthritis (ReA)?

Which conditions should be included in the differential diagnoses of reactive arthritis (ReA)?

Workup

How is reactive arthritis (ReA) diagnosed?

What is the role of blood tests and urinalysis in the workup of reactive arthritis (ReA)?

What is the role of serology and cultures in the workup of reactive arthritis (ReA)?

What is the role of HLA-B27 testing in the workup of reactive arthritis (ReA)?

What is the role of a tuberculin skin test in the workup of reactive arthritis (ReA)?

What is the role of radiography in the workup of reactive arthritis (ReA)?

Which radiographic findings are characteristic of reactive arthritis (ReA)?

What is the role of imaging in the workup of reactive arthritis (ReA)?

What is the role of arthrocentesis, synovial fluid analysis, and synovial biopsy in the workup of reactive arthritis (ReA)?

Which tests are performed in the workup of reactive arthritis (ReA) when poststreptococcal infection is suspected?

What is the role of ECG in the workup of reactive arthritis (ReA)?

Which histologic findings are characteristic of reactive arthritis (ReA)?

Treatment

How is reactive arthritis (ReA) treated?

What is included in the pharmacologic therapy for reactive arthritis (ReA)?

How are the joint symptoms of reactive arthritis (ReA) treated?

How are conjunctivitis and uveitis treated in patients with reactive arthritis (ReA)?

How are urethritis and gastroenteritis treated in patients with reactive arthritis (ReA)?

How are mucocutaneous lesions treated in patients with reactive arthritis (ReA)?

What is the role of NSAIDs in the treatment of reactive arthritis (ReA)?

What is the role of corticosteroids in the treatment of reactive arthritis (ReA)?

What is the role of antibiotics in the treatment of reactive arthritis (ReA)?

What is the role of DMARDs in the treatment of reactive arthritis (ReA)?

What is the role of surgery in the treatment of reactive arthritis (ReA)?

How is reactive arthritis (ReA) prevented?

Which specialist consultations are beneficial to patients with reactive arthritis (ReA)?

Medications

Which medications are used in the treatment of reactive arthritis (ReA)?

Which medications in the drug class Tumor Necrosis Factor Blockers are used in the treatment of Reactive Arthritis?

Which medications in the drug class Retinoid-like Agents are used in the treatment of Reactive Arthritis?

Which medications in the drug class Antimalarials are used in the treatment of Reactive Arthritis?

Which medications in the drug class Antineoplastic Agents are used in the treatment of Reactive Arthritis?

Which medications in the drug class Vitamins, Fat-Soluble are used in the treatment of Reactive Arthritis?

Which medications in the drug class Aminosalicylic Acid Derivatives are used in the treatment of Reactive Arthritis?

Which medications in the drug class Antibiotics are used in the treatment of Reactive Arthritis?

Which medications in the drug class Keratolytic Agents are used in the treatment of Reactive Arthritis?

Which medications in the drug class Corticosteroids are used in the treatment of Reactive Arthritis?

Which medications in the drug class Nonsteroidal Anti-inflammatory Drugs (NSAIDs) are used in the treatment of Reactive Arthritis?