Reactive Arthritis 

  • Author: Carlos J Lozada, MD; Chief Editor: Herbert S Diamond, MD   more...
 
Updated: Jan 5, 2010
 

Background

Reactive arthritis (ReA), also known as Reiter syndrome, is an autoimmune condition that develops in response to an infection. In 1916, Hans Reiter described the triad of nongonococcal urethritis, conjunctivitis, and arthritis in a young German officer with bloody dysentery.[1] In 1916, Fiessinger and Leroy described 4 patients with what they called oculo-urethro-synovial syndrome and associated the syndrome with an outbreak of Shigella dysentery.

Since then, many cases of what is now known as reactive arthritis have been described. The older term Reiter's syndrome, used in the past to describe the same clinical presentations, is being used less frequently. This is because Reiter was a physician leader of the Nazi party in Germany during World War II and authorized medical experiments on prisoners in concentration camps.[2]

Reactive arthritis has been associated with gastrointestinal infections with Shigella,Salmonella, and Campylobacter species and other microorganisms, as well as with genitourinary infections (especially with Chlamydia trachomatis).

Outbreaks of enteric Reiter syndrome have been reported aboard military vessels, cruise ships, and vessels transporting immigrants to the United States. In 1967, the term reactive arthritis was first used in cases associated with Yersiniagastroenteritis. A strong association with human leukocyte antigen (HLA)–B27 was found. This finding helped to confirm the concept of an incomplete Reiter syndrome, in which arthritis can occur in the absence of urethritis and conjunctivitis. Because of the association with HLA-B27 and its clinical overlap with ankylosing spondylitis and psoriatic arthritis, reactive arthritis is classified as a type of seronegative spondyloarthropathy.

In this article, reactive arthritis encompasses the older concepts of complete and incomplete Reiter syndrome and a clinical syndrome of arthritis with or without extra-articular features that develop within one month of infectious diarrhea or genitourinary infection.

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Pathophysiology

Reactive arthritis usually develops 2-6 weeks after a genitourinary or gastrointestinal infection. Recent evidence indicates that a preceding Chlamydia respiratory infection may also trigger reactive arthritis.[3] About 10% of patients do not have a preceding symptomatic infection.

Inflammation of joints, entheses, axial skeleton, skin, mucous membranes, gastrointestinal tract, and eyes may occur. Results for HLA-B27 are positive in 65%-96% of patients (average, 75%) with reactive arthritis. The likelihood of developing reactive arthritis is increased 50-fold in patients who are HLA-B27–positive, but this syndrome can also occur in patients who are HLA-B27 negative.

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. The frequency of reactive arthritis after enteric infection averages 1%-4% but varies greatly, even among outbreaks of the same organism.

The mechanism of the interaction of the inciting organism with the host (often HLA-B27–positive) leading to the development of reactive arthritis is not known. It is unclear if microbial antigens cross-react with self-proteins, stimulating (molecular mimicry) and perpetuating a Th2-cell–mediated autoimmune response. Chronicity and joint damage have been associated with a Th2 cytokine profile that leads to decreased bacterial clearance.[4]

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.

Molecular evidence of bacterial DNA (by polymerase chain reaction [PCR]) in synovial fluids has been found only in Chlamydia -related reactive arthritis, and one placebo-controlled trial of a tetracycline derivative (ie, lymecycline) showed a reduction in the duration of acute Chlamydia -related, but not enteric-related, reactive arthritis.[5] This suggests that persistent infection may play a role, at least in some cases of chlamydial reactive arthritis. In a more recent 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.[6]

The Toll-like receptors (TLRs) recognize different extracellular antigens as part of the innate immune system. TLR-4 recognizes gram-negative lipopolysaccharide (LPS). Studies in mice and humans showed abnormalities in antigen presentation due to down-regulation of TLR-4 costimulatory receptors in patients with reactive arthritis. More recent studies implicated TLR-2 polymorphism associated with acute reactive arthritis; however, its role is still disputed.[4, 7]

The role of HLA-B27 in this scenario remains to be defined but, as discussed elsewhere (Ankylosing Spondylitis and Undifferentiated Spondyloarthropathies), molecular mimicry, presentation of pathogenic peptides, and an altered host response to the bacteria are all possible.

Reactive arthritis, including classic Reiter syndrome, can occur in patients infected with HIV or who have AIDS. This is likely because both conditions can be sexually acquired rather than being triggered by HIV. The course of reactive arthritis in these patients tends to be severe, with a generalized rash that resembles psoriasis, profound arthritis, and frank AIDS. The frequency of HLA-B27 is the same of that associated with non–AIDS-related reactive arthritis in a similar demographic group. This association points out the likely importance of CD8+ cytotoxic T cells compared to CD4+ helper T cells in the pathogenesis of reactive arthritis.

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Epidemiology

Frequency

International

Data on the incidence and prevalence of reactive arthritis are scarce, partly because of a lack of a disease definition and diagnosis criteria; these factors complicate differentiation of reactive arthritis from other arthritides.[8] The reported annual incidence of reactive arthritis is approximately 30-40 cases per 100,000 adults, with a prevalence of 1%-7%, but this varies greatly among different geographic locations.[9] Reports from Latin America, North Africa, India, and Thailand showed low prevalence, with minimal differences between countries.[10, 11]

Mortality/Morbidity

Reactive arthritis typically follows a self-limited course, with resolution of symptoms by 3-12 months, even in patients who are acutely incapacitated. However, reactive arthritis has a high tendency to recur, particularly with ocular and urogenital inflammation. Individuals who are HLA-B27–positive are at a higher risk of recurrence. A new infection or other stress factor could cause reactivation of the disease.

About 15% of patients with reactive arthritis develop a long-term, sometimes destructive, arthritis or enthesitis or spondylitis. In a study by Amor et al (1994), 7 factors were analyzed as predictors of long-term outcome in spondyloarthropathies.[12] The number of patients with reactive arthritis in this study was low, and a valid subgroup analysis was impossible. The presence of hip-joint involvement, an erythrocyte sedimentation rate (ESR) higher than 30, and unresponsiveness to nonsteroidal anti-inflammatory drugs (NSAIDs) probably portend a severe outcome or chronicity in reactive arthritis.

Race

As with other spondyloarthropathies, HLA-B27 and reactive arthritis are more common in white people than in black people.

Sex

Reactive arthritis following foodborne enteric infections is equally common in males and females. The male-to-female ratio of disease associated with venereally acquired infections is 9:1.

Age

Most patients with reactive arthritis are aged 20-40 years.

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Contributor Information and Disclosures
Author

Carlos J Lozada, MD  Director of Rheumatology Fellowship Program, Associate Professor, Department of Medicine, Division of Rheumatology and Immunology, Jackson Memorial Medical Center, University of Miami School of Medicine

Carlos J Lozada, MD is a member of the following medical societies: American College of Physicians and American College of Rheumatology

Disclosure: Nothing to disclose.

Coauthor(s)

Maria F Carpintero, MD  Fellow, Department of Rheumatology, University of Miami, Jackson Memorial Medical Center, Miami Veterans Affairs Medical Center

Maria F Carpintero, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Specialty Editor Board

John Varga, MD  Professor, Department of Internal Medicine, Division of Rheumatology, Northwestern University

John Varga, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, Central Society for Clinical Research, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

Elliot Goldberg, MD  Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology

Disclosure: Nothing to disclose.

Alex J Mechaber, MD, FACP  Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine

Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD  Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa

Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; West Penn Allegheny Health System None Board membership

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