Introduction
Background
Reactive arthritis, 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 (ReA) 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 Yersinia gastroenteritis. 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.
Pathophysiology
Reactive arthritis usually develops 2-4 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. 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.4 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.5
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.
Frequency
International
In Finland, the annual incidence of reactive arthritis is approximately 30-40 cases per 100,000 adults, but this varies greatly among different geographic locations.
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.6 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 are 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.
Clinical
History
Reactive arthritis usually develops 2-4 weeks after a genitourinary or gastrointestinal infection. Recent evidence indicates that a preceding respiratory infection with Chlamydia pneumoniae may also trigger the disease.3 About 10% of patients do not have a preceding symptomatic infection.
Both postvenereal and postenteric forms of reactive arthritis may manifest initially as nongonococcal urethritis. Mild dysuria, mucopurulent discharge, prostatitis and epididymitis in men, and vaginal discharge and/or cervicitis in women are other possible manifestations.
The onset of reactive arthritis is usually acute and characterized by malaise, fatigue, and fever. An asymmetrical, predominately lower-extremity, oligoarthritis is the major presenting symptom. Low-back pain occurs in 50% of patients. Heel pain is common because of enthesopathies at the Achilles or plantar aponeurosis insertion on the calcaneus. The complete Reiter triad of urethritis, conjunctivitis, and arthritis may occur.
Physical
- Joints, axial skeleton, entheses
- Peripheral joint involvement associated with reactive arthritis is typically asymmetric and usually affects the weight-bearing joints (ie, knees, ankles, 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 also be involved. As in other spondyloarthropathies, dactylitis (ie, sausage digits) may develop.
- While 50% of patients with reactive arthritis 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 ankylosing spondylitis.
- As with other spondyloarthropathies, the enthesopathy of reactive arthritis may be associated with findings of inflammation (ie, pain, tenderness, swelling) at the Achilles insertion. Other sites include the plantar fascial insertion on the calcaneus, ischial tuberosities, iliac crests, tibial tuberosities, and ribs.
- Skin and nails
- Keratoderma blennorrhagica on the palms and soles is indistinguishable from pustular psoriasis and is highly suggestive of chronic reactive arthritis.
- Erythema nodosum may develop but is uncommon.
- Nails can become thickened and crumble, resembling mycotic infection or psoriatic onychodystrophy, but nail pitting is not observed.
- Circinate balanitis may also develop.
- Other mucosal signs and symptoms: Painless shiny patches in the palate, tongue, and mucosa of the cheeks and lips have been described.
- Ocular findings
- Conjunctivitis is part of the classic triad of Reiter syndrome and can occur before or at the onset of arthritis.
- Other ocular lesions include acute uveitis (20% of patients), episcleritis, keratitis, and corneal ulcerations. The lesions tend to recur.
- Enteric infections
- Enteric infections may trigger reactive arthritis. Pathogens include Salmonella, Shigella, Yersinia, and Campylobacter species. The frequency of reactive arthritis after these enteric infections is about 1-4%.
- Some patients with reactive arthritis 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 reactive arthritis.7
- Other manifestations
- Other manifestations of reactive arthritis include mild renal pathology with proteinuria and microhematuria.
- In severe chronic cases, amyloid deposits and immunoglobulin A (IgA) nephropathy have been reported. Cardiac conduction abnormalities may develop, and aortitis with aortic regurgitation occurs in 1-2% of reactive arthritis cases.
Causes
Reactive arthritis is usually triggered by a genitourinary or gastrointestinal infection.
More on Reactive Arthritis |
 Overview: Reactive Arthritis |
| Differential Diagnoses & Workup: Reactive Arthritis |
| Treatment & Medication: Reactive Arthritis |
| Follow-up: Reactive Arthritis |
| References |
| Next Page » |
References
Reiter H. Ueber cine bisher unbekannte spirochaeten-infektion (spirochaetosis arthritica). Dtsche Med Wschr. 1916;42:1535-6.
Lu DW, Katz KA. Declining use of the eponym "Reiter's syndrome" in the medical literature, 1998-2003. J Am Acad Dermatol. Oct 2005;53(4):720-3. [Medline].
Braun J, Laitko S, Treharne J, et al. Chlamydia pneumoniae--a new causative agent of reactive arthritis and undifferentiated oligoarthritis. Ann Rheum Dis. Feb 1994;53(2):100-5. [Medline].
Lauhio A, Leirisalo-Repo M, Lahdevirta J, et al. Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis, with special reference to Chlamydia arthritis. Arthritis Rheum. Jan 1991;34(1):6-14. [Medline].
Carter JD, Valeriano J, Vasey FB. Doxycycline versus doxycycline and rifampin in undifferentiated spondyloarthropathy, with special reference to chlamydia-induced arthritis. A prospective, randomized 9-month comparison. J Rheumatol. Oct 2004;31(10):1973-80. [Medline].
Amor B, Santos RS, Nahal R, et al. Predictive factors for the longterm outcome of spondyloarthropathies. J Rheumatol. Oct 1994;21(10):1883-7. [Medline].
De Vos M, Cuvelier C, Mielants H, et al. Ileocolonoscopy in seronegative spondylarthropathy. Gastroenterology. Feb 1989;96(2 Pt 1):339-44. [Medline].
Maugars Y, Mathis C, Vilon P, et al. Corticosteroid injection of the sacroiliac joint in patients with seronegative spondylarthropathy. Arthritis Rheum. May 1992;35(5):564-8. [Medline].
Clegg DO, Reda DJ, Weisman MH, et al. Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter's syndrome). A Department of Veterans Affairs Cooperative Study. Arthritis Rheum. Dec 1996;39(12):2021-7. [Medline].
Calin A. A placebo controlled, crossover study of azathioprine in Reiter's syndrome. Ann Rheum Dis. Aug 1986;45(8):653-5. [Medline].
Bravo G, Zazueta B, Lavalle C. An acute remission of Reiter's syndrome in male patients treated with bromocriptine. J Rheumatol. May 1992;19(5):747-50. [Medline].
Aho K. Bowel infection predisposing to reactive arthritis. Baillieres Clin Rheumatol. Aug 1989;3(2):303-19. [Medline].
Ahvonen P, Sievers K, Aho K. Arthritis associated with Yersinia enterocolitica infection. Acta Rheumatol Scand. 1969;15(3):232-53. [Medline].
Anandarajah A, Ritchlin CT. Treatment update on spondyloarthropathy. Curr Opin Rheumatol. May 2005;17(3):247-56. [Medline].
Arnett F. Reactive arthritis and enteropathic arthritis. In: Klippel J, Weyand C, Wortmann R, eds. Primer on the Rheumatic Diseases. 11th ed. Atlanta, Ga: National Arthritis Foundation; 1997:184-8.
Arnett FC. Incomplete Reiter's syndrome: clinical comparisons with classical triad. Ann Rheum Dis. 1979;38 Suppl 1:suppl 73-8. [Medline].
Brower A. Arthritis in Black and White. 2nd ed. Philadelphia, Pa: WB Saunders; 1997:252.
Fiessenger N, Leroy E. Contribution a l'etude d'une epidemie de dysenterie dans la Somme. Bull Mem Soc Med Hop Paris. 1916;40:2030-69.
Flagg SD, Meador R, Hsia E, et al. Decreased pain and synovial inflammation after etanercept therapy in patients with reactive and undifferentiated arthritis: an open-label trial. Arthritis Rheum. Aug 15 2005;53(4):613-7. [Medline].
Iliopoulos A, Karras D, Ioakimidis D, et al. Change in the epidemiology of Reiter's syndrome (reactive arthritis) in the post-AIDS era? An analysis of cases appearing in the Greek Army. J Rheumatol. Feb 1995;22(2):252-4. [Medline].
Isomäki H, Raunio J, von Essen R, et al. Incidence of inflammatory rheumatic diseases in Finland. Scand J Rheumatol. 1978;7(3):188-92. [Medline].
Keat A. Reiter's syndrome and reactive arthritis in perspective. N Engl J Med. Dec 29 1983;309(26):1606-15. [Medline].
Kingsley G, Panayi G. Antigenic responses in reactive arthritis. Rheum Dis Clin North Am. Feb 1992;18(1):49-66. [Medline].
Kvien TK, Gaston JS, Bardin T, et al. Three month treatment of reactive arthritis with azithromycin: a EULAR double blind, placebo controlled study. Ann Rheum Dis. Sep 2004;63(9):1113-9. [Medline].
Lee AT, Hall RG, Pile KD. Reactive joint symptoms following an outbreak of Salmonella typhimurium phage type 135a. J Rheumatol. Mar 2005;32(3):524-7. [Medline].
Leirisalo M, Skylv G, Kousa M, et al. Followup study on patients with Reiter's disease and reactive arthritis, with special reference to HLA-B27. Arthritis Rheum. Mar 1982;25(3):249-59. [Medline].
Moll JM, Haslock I, Macrae IF, et al. Associations between ankylosing spondylitis, psoriatic arthritis, Reiter's disease, the intestinal arthropathies, and Behcet's syndrome. Medicine (Baltimore). Sep 1974;53(5):343-64. [Medline].
Noer HR. An "experimental" epidemic of Reiter's syndrome. JAMA. Nov 14 1966;198(7):693-8. [Medline].
Petersel DL, Sigal LH. Reactive arthritis. Infect Dis Clin North Am. Dec 2005;19(4):863-83. [Medline].
Reveille JD, Arnett FC. Spondyloarthritis: update on pathogenesis and management. Am J Med. Jun 2005;118(6):592-603. [Medline].
Rohekar S, Tsui FW, Tsui HW, Xi N, Riarh R, Bilotta R, et al. Symptomatic acute reactive arthritis after an outbreak of salmonella. J Rheumatol. Aug 2008;35(8):1599-602. [Medline].
Sieper J, Fendler C, Laitko S, et al. No benefit of long-term ciprofloxacin treatment in patients with reactive arthritis and undifferentiated oligoarthritis: a three-month, multicenter, double-blind, randomized, placebo-controlled study. Arthritis Rheum. Jul 1999;42(7):1386-96. [Medline].
Solitar BM, Lozada CJ, Tseng CE, et al. Reiter's syndrome among Asian shipboard immigrants: the case of The Golden Venture. Semin Arthritis Rheum. Apr 1998;27(5):293-300. [Medline].
Toivanen A, Toivanen P. Aetiopathogenesis of reactive arthritis. Rheumatol Eur. 1995;24(1):5-8.
Toivanen A, Toivanen P. Epidemiologic, clinical, and therapeutic aspects of reactive arthritis and ankylosing spondylitis. Curr Opin Rheumatol. Jul 1995;7(4):279-83. [Medline].
Townes JM, Deodhar AA, Laine ES, Smith K, Krug HE, Barkhuizen A, et al. Reactive arthritis following culture-confirmed infections with bacterial enteric pathogens in Minnesota and Oregon: a population-based study. Ann Rheum Dis. Feb 13 2008;[Medline].
van Bohemen CG, Lionarons RJ, van Bodegom P, et al. Susceptibility and HLA-B27 in post-dysenteric arthropathies. Immunology. Oct 1985;56(2):377-9. [Medline].
Wakefield D, McCluskey P, Verma M, et al. Ciprofloxacin treatment does not influence course or relapse rate of reactive arthritis and anterior uveitis. Arthritis Rheum. Sep 1999;42(9):1894-7. [Medline].
Further Reading
Keywords
reactive arthritis, Reiter syndrome, Reiter's syndrome, RS, ReA, nongonococcal urethritis, conjunctivitis, oculo-urethro-synovial syndrome, Chlamydia reactive arthritis, chlamydial reactive arthritis , Shigella dysentery, gastrointestinal infections, Salmonella, Campylobacter, Chlamydia trachomatis, C trachomatis, Yersinia, ankylosing spondylitis, psoriatic arthritis, seronegative spondyloarthropathy, infectious diarrhea, genitourinary infection
