About Reiter's Syndrome

What is Reiter's Syndrome?

The term Reiter's syndrome has fallen into disfavor.  Reiter's syndrome in recent medical literature is simply referred to as reactive arthritis which may or may not be accompanied by extraintestinal manifestations.

Salmonella has been the most frequently studied bacteria associated with reactive arthritis. Overall, studies have found rates of Salmonella-associated reactive arthritis to vary between 6 and 30% (Hill Gaston & Lillicrap, 2003). The frequency of postinfectious Reiter’s syndrome, however, has not been well described. In a Washington State study of an outbreak of foodborne Salmonella gastroenteritis, while 29% developed arthritis, only 3% developed the triad of symptoms associated with Reiter’s syndrome (Dworkin, et al., 2001). However, the range for the occurrence of new joint pain after enteric infection is reported to be between 1 and 4% in adults with Campylobacter, Salmonella, or Shigella infections (Rees, et al., 2004).  In addition, individuals of Caucasian descent may be more likely than those of Asian descent to develop reactive arthritis (McColl, et al., 2000), and children may be less susceptible than adults to reactive arthritis following infection with Salmonella (Rudwaleit, et al., 2001).

The frequency of acute reactive arthritis from other bacteria varies widely and the frequency of Reiter’s syndrome is not as well studied.  Reactive arthritis has been reported to occur in between 0.6% and 24% of Campylobacter gastroenteritis patients (Pope, et al., 2007).  After Shigella infections, subsequent reactive arthritis has ranged from 1.5% to 7% (Hannu, et al., 2005).

A clear association has been made between reactive arthritis and a genetic factor called the human leukocyte antigen (HLA) B27 genotype. HLA is the major histocompatibility complex in humans; these are proteins present on the surface of all body cells that contain a nucleus, and are in especially high concentrations in white blood cells (leukocytes). It is thought that HLA-B27 may affect the elimination of the infecting bacteria or an individual’s immune response (Hill Gaston & Lillicrap, 2003). HLA-B27 has been shown to be a predisposing factor in one-half to over two-thirds of individuals with reactive arthritis (Barth & Segal, 1999; Hill Gaston & Lillicrap, 2003). While HLA-B27 does not appear to predispose to the initial infection itself, it increases the risk of developing arthritis that is more likely to be severe and prolonged. This risk may be slightly greater for Salmonella and Yersinia-associated arthritis than with Campylobacter, but more research is required to clarify this (Hill Gaston & Lillicrap, 2003).  What are the Symptoms of Reiter’s Syndrome?  The three most common symptoms of Reiter’s syndrome are arthritis, conjunctivitis, and urethritis. The onset of symptoms typically occurs one to four weeks following the initial infection and may present acutely or develop slowly over time. Urethritis, a urinary tract inflammation, is often accompanied by symptoms such as a discharge in males, although it may sometimes present as blood in the urine. Females may present with an inflammation of the cervix. Urethritis in either males or females may also be present without symptoms (Barth & Segal, 1999).

Ophthalmic, or eye, manifestations occur in approximately one-third of individuals with Salmonella-associated arthritis (Barth & Segal, 1999). The involvement of the eye in Reiter’s syndrome is most commonly manifested as conjunctivitis, an inflammation of the mucous membrane that covers the eyeball. Conjunctivitis usually appears within a few weeks of the onset of arthritis and urethritis and the symptoms are usually mild, symmetric, and bilateral (Lee et al., 1986; Ostler et al., 1971). Bacterial cultures are negative and the inflammation typically resolves within 10 days without treatment. Conjunctivitis is present in up to 50% of affected individuals and can develop at any time during the course of the disease, although it is more common in reactive arthritis associated with genitourinary or Shigella infections (Kataria & Brent, 2004). Anterior uveitis, an inflammation of the inner eye, is the second most common ocular symptom of Reiter’s syndrome, occurring in up to 12% of affected persons (Ostler et al., 1971). Uveitis is most often acute, unilateral, and recurrent (Lau et al., 1998; Yu et al., 2001). It is more frequent in those who are HLA-B27 positive and in individuals with sacroiliitis, an inflammation of the sacroiliac (sacrum and ilium) joint or region (Kataria & Brent, 2004). Conjunctivitis and uveitis can cause redness of the eyes, eye pain and irritation, and blurred vision. Other ocular conditions also have been associated with Reiter’s, including scleritis, cataract, glaucoma, keratitis, papillitis, retinal and disc edema, and retinal vasculitis (Kiss et al., 2003).

The arthritis associated with Reiter’s syndrome generally occurs rapidly, with joints becoming hot and swollen; large effusions, or collections of fluid, can develop in the knee joint (Barth & Segal, 1999; Hill Gaston & Lillicrap, 2003). Wrists, fingers and other joints can be affected, although with less frequency. Joint pain without inflammation may also occur at sites other than those affected by inflammation. A condition called enthesopathy also commonly occurs, in which the tendon that attaches to the bone becomes inflamed (Barth & Segal, 1999; Kataria & Brent, 2004). Enthesopathies occur in 5 to 21% of individuals with Salmonella-associated arthritis (Barth & Segal, 1999). The heel is the most common site with the development of heel pain and Achilles tendonitis, but pain at the insertion of the patellar (kneecap) tendon into the tibia, the larger of the two bones in the lower leg, may also occur. Some individuals with Reiter’s syndrome may develop heel spurs, bony growths that cause chronic foot pain. Arthritis from Reiter’s syndrome can also affect the joints of the back, causing spondylitis, an inflammation of the vertebrae and the attached disks and ligaments in the spinal column, and asymmetric sacroiliitis (Yu et al., 2001).

The duration of reactive arthritis symptoms can vary greatly. The literature suggests that the majority of affected individuals recover within a year although reactive arthritis can become chronic (Kataria & Brent, 2004, Thomson et al., 1995). Up to 50% of those with reactive arthritis may have recurrent bouts of arthritis and 15 to 30% develop chronic arthritis or sacroiliitis (Yu et al., 2001). In one study, 18 (67%) of 27 individuals who developed reactive arthritis after a Salmonella infection continued to have symptoms at five years of follow-up (Thomson et al., 1995). Symptoms were severe enough to force a change in work for four individuals and another four had objective damage to joints radiographically.

Other symptoms of Reiter’s syndrome may include a painless skin rash on the penis in men called circinate balanitis. Skin rashes on the soles of the feet and, less often, on the palms of the hands or elsewhere may also occur; these rashes are called keratoderma blennorrhagicum (or keratosis blennorrhagica) and are similar to psoriasis. They often begin as clear vesicles (blisters) on a red base and progress to macules (flat lesions), papules (raised lesions), and nodules (firm bumps) (Kataria & Brent, 2004). In addition, some people develop mouth ulcers that come and go. In some cases, these ulcers are painless and go unnoticed.

Why Have Some Forms of Reactive Arthritis Been Called Reiter’s Syndrome?

Diagnosis

Diagnosis of reactive arthritis (including the condition formerly called Reiter’s syndrome) is mainly clinical.  There are no diagnostic criteria that have been validated and led to generalized agreement among rheumatologic and other medical authorities.  However, guidance is available for diagnosis (Braun et al, 1999; Hannu et al., 2006; Kingsley & Sieper, 1996; Petersel & Sigal, 2005).  In 1995, the Third International Workshop on Reactive Arthritis established criteria for diagnosing reactive arthritis.  The main criteria involve the pattern of joint involvement and the timing of the onset of the condition (such as soon after an infection).  Diagnosis of Reiter’s syndrome has essentially been replaced with diagnosis of the broader category in which it resides:  reactive arthritis.

The diagnostic criteria of the Third International Workshop on Reactive Arthritis are:

The arthritis should predominantly involve the lower limb, involve few joints (oligoarthritis) and not equally involve both sides of the body (asymmetric).

In addition, there should be evidence of preceding infection.  Although it is ideal to have a culture that is positive for an infectious agent that is recognized to be associated with this condition (such as Salmonella or Chlamydia), if the patient has documented diarrhea or urethritis in the prior 4 weeks, laboratory confirmation is not required.  However, if there is no clear clinical infection, then laboratory confirmation (perhaps with serology or a culture) is essential.  The patient should not have evidence that the joint itself is infected (i.e., septic arthritis).  Also, other causes of monoarthritis (such as gout) or oligoarthritis should not be present.  Interestingly, the above criteria do not require laboratory tests (such as HLA-B27).  Features that have been considered part of Reiter’s syndrome such as conjunctivitis, iritis, skin lesions, noninfectious urethritis, and certain types of cardiac and neurological abnormalities are not required for a diagnosis of reactive arthritis. 

Treatment

Symptomatic treatment with high doses of a nonsteroidal anti-inflammatory drug (NSAID) and steroid injections into affected joints can be helpful (Barth & Segal, 1999). NSAIDs can reduce joint inflammation and are commonly used to treat patients with reactive arthritis. Some traditional NSAIDs, such as aspirin and ibuprofen, are available without a prescription, but others that are more effective for reactive arthritis, such as indomethacin and tolmetin, must be prescribed by a doctor. Less is known about whether a new class of NSAIDs, called COX-2 inhibitors, is effective for reactive arthritis, but they may reduce the risk of gastrointestinal complications associated with traditional NSAIDs (National Institutes of Health, 2004). For people with severe joint inflammation, injections of corticosteroids directly into the affected joint may reduce inflammation. Doctors usually prescribe these injections only after trying unsuccessfully to control arthritis with NSAIDs.

A small percentage of patients with reactive arthritis have severe symptoms that cannot be controlled with any of the above treatments. For these people, medicine that suppresses the immune system, such as sulfasalazine or methotrexate, may be effective (Clegg, et al, 1996; Creemers et al, 1994; National Institutes of Health, 2004).
Topical corticosteroids, which come in a cream or lotion, can be applied directly on the skin lesions associated with reactive arthritis. Topical corticosteroids reduce inflammation and promote healing (National Institutes of Health, 2004).

Antibiotics to eliminate the bacterial infection that triggered the reactive arthritis may be prescribed. The specific antibiotic prescribed depends on the type of bacterial infection present. It is important to follow instructions about how much medicine to take and for how long; otherwise the infection may persist. Typically, an antibiotic is taken for 7 to 10 days or longer (National Institutes of Health, 2004). Currently, however, there is no evidence to suggest that antibiotic treatment is beneficial once reactive arthritis has occurred (Hill Gaston & Lillicrap, 2003).

Several relatively new treatments that suppress tumor necrosis factor (TNF), a protein involved in the body's inflammatory response, may be effective for reactive arthritis and other spondyloarthropathies. They include etanercept and infliximab. These treatments were first used to treat rheumatoid arthritis (National Institutes of Health, 2004).

Exercise, when introduced gradually, may help improve joint function. In particular, strengthening and range-of-motion exercises will maintain or improve joint function. Strengthening exercises builds up the muscles around the joint to better support it. Muscle-tightening exercises that do not move any joints can be done even when a person has inflammation and pain. Range-of-motion exercises improve movement and flexibility and reduce stiffness in the affected joint. For patients with spine pain or inflammation, exercises to stretch and extend the back can be particularly helpful in preventing long-term disability. Aquatic exercise also may be helpful. Before beginning an exercise program, patients should talk to a health professional who can recommend appropriate exercises (National Institutes of Health, 2004). 

Prognosis

Approximately 20% of people with reactive arthritis will have chronic (long-term) arthritis, which usually is mild. Studies show that between 15 and 50% of patients will develop symptoms again sometime after the initial flare has disappeared (Yu et al, 2001; National Institutes of Health, 2004). Back pain and arthritis are the symptoms that most commonly reappear. Up to one-third of affected individuals will have chronic, severe arthritis that is difficult to control with treatment and may cause joint deformity (Kataria & Brent, 2004; Leirisalo-Repo et al., 1997; National Institutes of Health, 2004; Yu et al., 2001). One study found that two-thirds of individuals who developed reactive arthritis after a Salmonella infection continued to have symptoms at five years of follow-up (Thomson et al, 1995). Symptoms were severe enough to force a change in work for four of 18 individuals and another four had objective damage to joints radiographically.

Overall, a relapsing course appears less common in enteric-infection-related disease than in Chlamydia-associated reactive arthritis (of genitourinary origin). HLA-B27 contributes to the development of chronic disease and therefore, the prognosis is less favorable in those who are HLA-positive (Hill Gaston & Lillicrap, 2003; Leirisalo-Repo et al., 1997).

Prevention

Because Reactive Arthritis is the result of a prior infection, no one specific measure can be prescribed for the prevention of Reiter’s syndrome or Reactive Arthritis. 

Bacteria known to cause Reactive Arthritis are sensitive to heat and other common disinfection procedures, including pasteurization of milk, adequate cooking of meat and poultry, and chlorination or ozonation of water.  The most reliable method to ensure such bacteria as Salmonella, Campylobacter, and Shigella are killed during the cooking process is to use a digital food thermometer. 

References

Barth WF, Segal K.  (1999).  “Reactive arthritis (Reiter's syndrome).”  American Family Physician.  60(2):499-503, 507.

Braun J, Kigsley G, van der Heijde D et al. (2000).  On the difficulties of establishing a consensus on the definition of and diagnostic investigations for reactive arthritis.  Results and discussion of a questionnaire prepared for the 4th International Workshop on Reactive Arthritis, Berlin, Germany, 3-6 July 1999.  Journal of Rheumatology.  27:2185-92.

Dworkin MS, Shoemaker PC, Goldoft MJ, Kobayashi JM.  (2001).  “Reactive arthritis and Reiter's syndrome following an outbreak of gastroenteritis caused by Salmonella enteritidis.  Clin. Infect. Dis.  33(7):1010-1014. 

Hannu T, Inman R, Granfors K, Lerisalo-Repo M. (2006).  Reactive arthritis or post-infectious arthritis?  Best Practices and Research Clinical Rheumatology 2006;20:419-33.

Hannu T, Mattila L, Siitonen A, Leirisalo-Repo.  (2005).  Reactive arthritis attributable to Shigella infection:  a clinical and epidemiological nationwide study.  Annals of Rheumatologic Diseases.  64:594-598.

Hill Gaston JS, Lillicrap MS.  (2003).  Arthritis associated with enteric infection. Best Practices & Research Clinical Rheumatology.  17(2):219-239. 

Kataria RK, Brent LH.  (2004).  Spondyloarthropathies.  American Family Physician 69(12):2853-2860.

Kingsley G, Sieper J. (1996).  Third International Workshop on Reactive Arthritis.  23-26 September 1995, Berlin, Germany.  Annals of Rheumatic Diseases 55:564-84. 

Kiss S, Letko E, Qamruddin S, Baltatzis S, Foster CS.  (2003).  Long-term progression, prognosis, and treatment of patients with recurrent ocular manifestations of Reiter's syndrome.  Ophthalmology.  110(9):1764-1769.

Leirisalo-Repo M, Helenius P, Hannu T, Lehtinen A, Kreula J, Taavitsainen M, Koskimies S.  (1997).  Long-term prognosis of reactive Salmonella arthritis. Annals of Rheumatic Disease.  56(9):516-520.

McColl GJ, Diviney MB, Holdsworth RF, McNair PD, Carnie J, Hart W, McCluskey J.  (2000).  HLA-B27 expression and reactive arthritis susceptibility in two patient cohorts infected with Salmonella Typhimurium.  Australian and New Zealand Journal of Medicine 30(1):28-32.

Panush RS, Paraschiv D,  Dorff RE.  (2003).  The tainted legacy of Hans Reiter.  Seminars in Arthritis and Rheumatology.  32:231-236.

Petersel DL, Sigal LH.  (2005).  Reative arthritis.  Infectious Disease Clinics in North America.  19:863-883.

Pope JE, Krizova A, Garg AX, Thiessen-Philbrook H, Ouimet JM.  (2007).  Campylobacter reactive arthritis:  a systematic review.  Seminars in Arthritis and Rheumatism 2007 (in press as of July 2007).

Rees JR, Pannier MA, McNees A, Shallow S, Angulo FJ, Vugia DJ.  (2004).  Persistent diarrhea, arthritis, and other complications of enteric infections: a pilot survey based on California FoodNet surveillance, 1998-1999. Clin. Infect. Dis.  38(Suppl 3):S311-S317.

Rudwaleit M, Richter S, Braun J, Sieper J.  (2001).  Low incidence of reactive arthritis in children following a Salmonella outbreak. Annals of the Rheumatic Diseases.  60(11):1055-1057.  

Thomson GT, DeRubeis DA, Hodge MA, Rajanayagam C, Inman RD.  (1995).  Post-Salmonella reactive arthritis: late clinical sequelae in a point source cohort.  The American Journal of Medicine.  98(1):13-21.