What is Reactive Arthritis or Reiter’s Syndrome?

Reactive Arthritis refers to a group of arthritic diseases that includes a subset formally know as “Reiter’s Syndrome” The old term Reiter’s syndrome has fallen into disfavor.  In recent medical literature Reiter’s Syndrome is simply referred to as Reactive Arthritis which may or may not be accompanied by extraintestinal manifestations.

Reactive Arthritis is the name used to describe an uncommon, but potentially debilitating group of symptoms that follows a gastrointestinal, genitourinary, or viral infection. The most common gastrointestinal bacteria involved are Salmonella, Campylobacter, Yersinia, Shigella, E. coli, and Vibrio. The most common genitourinary causes are sexually transmitted diseases such as Chlamydia and Gonorrhea. The most common viral causes are the common flu, HIV, and Parvovirus.

The specific triad of arthritis, conjunctivitis, and urethritis was known as Reiter’s Syndrome. In many patients, however, only one or two of these symptoms many be present, such as arthritis and urethritis or arthritis and conjunctivitis. [1] A reactive arthritis may develop after a person eats food that has been tainted with the pathogenic bacteria. Many patients will get severe bloating, abdominal pain, and watery diarrhea. However in some patients, the initial infection may be milder and not easily recognized, but the reactive arthritis may still occur. Reactive arthritis typically involves inflammation of one joint (monoarthritis) or several joints (oligoarthritis), preferentially affecting those of the lower extremities.  The most common joints affected are the knees and ankles. The pattern of joint involvement is usually asymmetric. Inflammation can also be commonly seen at an enthesis (a place where ligaments and tendons attach to bone), especially the front of the knee or the back of the ankle where the Achilles attaches to the calcaneal bone.   This is referred to as an enthesopathy. It causes local swelling and pain with walking or exercise.

Salmonella has been the most frequently studied bacterium associated with reactive arthritis. Overall, studies have found rates of Salmonella-associated reactive arthritis to vary between 6% and 30%. [1] The frequency of post-infectious Reiter’s syndrome specifically, however, has not been well described. In a Washington State study of an outbreak of foodborne Salmonella gastroenteritis, 29% of patients developed arthritis, but only 3% developed the triad of symptoms associated with Reiter’s syndrome. [2] In addition, individuals of Caucasian descent may be more likely than those of Asian descent to develop reactive arthritis, [3] and children may be less susceptible than adults to reactive arthritis following infection with Salmonella. [4]

The frequency of acute reactive arthritis from other bacteria varies widely. The occurrence of new joint pain alone after enteric infection is reported to be between 1 and 4% in adults with Campylobacter or Shigella infections. [5]   In another study, it has been reported to occur in 0.6% to 24% of Campylobacter gastroenteritis patients. [6]   After Shigella infection the percentage of patients who exhibit subsequent reactive arthritis ranges from 1.5% to 7%. [7]

A clear association has been made between reactive arthritis and a genetic marker called the Human Leukocyte Antigen (HLA) B27 genotype. HLA is a 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. [1] HLA-B27 has been shown to be a predisposing factor in one-half to over two-thirds of individuals with reactive arthritis. [8,1] 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. [1]

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

One could also ask, “Why isn’t Reiter’s syndrome called Reiter’s syndrome anymore?”  The answer is that the syndrome, or group of symptoms, is named for Hans Reiter who described a soldier with the triad of urethritis (burning and pain with urination), conjunctivitis (redness and pain of the eye), and arthritis (swelling and pain of the joints) after having bloody diarrhea in 1916.  However, the history of this constellation of signs actually predates his description.  And what is disturbing is that Reiter was a high-ranking Nazi official who was responsible for medical experiments in concentration camps. [9, 10]   As a result, the term Reiter’s syndrome has fallen out of favor and Reactive Arthritis is preferred to describe the post-infectious arthritis which may be accompanied by extra-articular manifestations (such as urethritis and conjunctivitis).

What are the Symptoms of Reactive Arthritis?

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. It can occasionally occur years after the initial infection. In many patients the urethritis and conjunctivitis symptoms are usually mild, symmetric, and bilateral. [11, 12] Bacterial cultures are negative and the inflammation typically resolves within 10 days without treatment.

Urethritis, a urinary tract inflammation, is often accompanied by symptoms such as a penile discharge in males, pain with urination, or blood in the urine. Females may also present with an inflammation of the cervix or pain during intercourse. Urethritis in either males or females may also be present without symptoms but can show up on a urine test with your doctor. [8]

Ophthalmic, or eye, manifestations occur in approximately one-third of individuals with Salmonella-associated arthritis. [8]  The involvement of the eye in reactive arthritis 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. Conjunctivitis and uveitis often presents with redness of the eyes, eye pain and irritation, blurred vision and a yellowish discharge. 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. [13]

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. [12] Uveitis is most often acute, unilateral, and recurrent. [14, 15]  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. [13] Other ocular conditions also have been associated with Reiter’s, including scleritis, cataract, glaucoma, keratitis, papillitis, retinal and disc edema, and retinal vasculitis. [16]

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 or ankle. [1, 8] 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. [8, 13] Enthesopathies occur in 5 to 21% of individuals with Salmonella-associated arthritis. [8] 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 reactive arthritis may develop heel spurs, bony growths that cause chronic foot pain. Arthritis from reactive arthritis 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. [15] Patients will present with pain and morning stiffness in the lower back or neck. Pain will be worse after rest or sleep and better after walking for a while.

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. [13, 17] Up to 50% of those with reactive arthritis may have recurrent bouts of arthritis and 15 to 30% develop chronic arthritis or sacroiliitis. [15] 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. [17] 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 reactive arthritis 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). [13] In addition, some people develop mouth ulcers that come and go. In some cases, these ulcers are painless and go unnoticed.

How is Reactive Arthritis or Reiter’s Syndrome diagnosed?

Diagnosis of reactive arthritis (including the condition formerly called Reiter’s syndrome) is mainly clinical.  There are no validated diagnostic criteria, however some guidance for diagnosis is available. [18, 19, 20, 10]   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 one or only a few joints and not equally involve both sides of the body (asymmetric).
• There should be evidence or a history 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.
• 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 (such as rheumatoid arthritis) should be ruled out.

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.

How is Reiter’s Syndrome treated?

Testing for and treating any underlying infection is often attempted but in many cases the underlying infection is self limited or can no longer be found. If the inciting infectious agent can be determined it must be treated aggressively with antibiotics.

Symptomatic treatment with high doses of a nonsteroidal anti-inflammatory drug (NSAID) and steroid injections into affected joints can be helpful for patients with reactive arthritis. [8] 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 voltaren, 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. [21] For people with severe joint inflammation, injections of corticosteroids directly into the affected joint may reduce inflammation. Doctors usually give these injections only after trying unsuccessfully to control arthritis with NSAIDs. In some cases, short courses of oral steroids, such as methylprednisolone or prednisone, may also be required.

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. [22, 23, 21]  If the symptoms do not respond to these agents a newer group of medications, called biologics, can often be very effective. Biologic agents can be either injectables (such as etanercept or adalimumab) or given intravascularly (such as infliximab or rituximab).   These agents can be very immunosuppressive and are very expensive so are not used as first-line treatments.

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. [21]

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. [21] Currently, however, there is no evidence to suggest that antibiotic treatment is beneficial once reactive arthritis has occurred. [1]

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. [21]

What Is the Prognosis for People Who Have Reiter’s Syndrome or Reactive Arthritis?

Most people with reactive arthritis recover fully from the initial flare of symptoms and are able to return to regular activities 2 to 6 months after the first symptoms appear. In some cases, the symptoms of arthritis may last up to 12 months, although these symptoms are usually very mild and do not interfere with daily activities. 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. [15, 21] 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. [13, 24, 21, 15] 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. [17] 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. [1, 24]

How can Reactive Arthritis be prevented?

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.  General sanitary techniques of hand washing and clean drinking water have decreased the incidence of these infections in industrialized countries but they are still very prevalent in less developed countries and the third world.

References

1. Hill Gaston JS, Lillicrap MS.  (2003).  Arthritis associated with enteric infection. Best Practices & Research Clinical Rheumatology.  17(2):219-239, article abstract and paid-access to full text available online at http://www.bprclinrheum.com/article/S1521-6942(02)00104-3/abstract

2. 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, available online at http://cid.oxfordjournals.org/content/33/7/1010.full

3. 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, article abstract and paid-access to full text available online at http://onlinelibrary.wiley.com/doi/10.1111/j.1445-5994.2000.tb01050.x/abstract

4. 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, available online at http://ard.bmj.com/content/60/11/1055.full

5. 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, available online at http://cid.oxfordjournals.org/content/38/Supplement_3/S311.full.pdf+html

6. Pope JE, Krizova A, Garg AX, Thiessen-Philbrook H, Ouimet JM.  (2007).  Campylobacter reactive arthritis:  a systematic review.  Seminars in Arthritis and Rheumatism (in press as of July 2007), available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909271/?tool=pubmed

7. 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, available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1755450/

8. Barth WF, Segal K.  (1999).  “Reactive arthritis (Reiter’s syndrome).”  American Family Physician.  60(2):499-503, 507, available at http://www.aafp.org/afp/1999/0801/p499.html

9. Panush RS, Paraschiv D,  Dorff RE.  (2003).  The tainted legacy of Hans Reiter.  Seminars in Arthritis and Rheumatology.  32:231-236, article abstract and paid-access to full text available online at http://www.journals.elsevierhealth.com/periodicals/ysarh/article/S0049-0172(02)70103-0/abstract

10. Petersel DL, Sigal LH.  (2005).  Reative arthritis.  Infectious Disease Clinics in North America.  19:863-883, article abstract and paid-access to full text available online at http://www.id.theclinics.com/search/quick

11. Lee DA, Barker SM, Su WP, Allen GL, Liesegang TJ, Ilstrup DM. (1986). The clinical diagnosis of Reiter’s syndrome. Ophthalmic and nonophthalmic aspects. Ophthalmology. 93(3):350–356, article abstract available online at http://www.ncbi.nlm.nih.gov/pubmed/3486396

12. Ostler HB, Dawson CR, Schachter J, Engleman EP. (1971). Reiter’s syndrome. Am J Ophthalmol. 71(5):986–991.

13. Kataria RK, Brent LH.  (2004).  Spondyloarthropathies.  American Family Physician 69 (12):2853-2860, available at http://www.aafp.org/afp/2004/0615/p2853.html

14. Lau CS, Burgos-Vargas R, Luothrenoo W, Mok MY, Wordsworth P, Zeng QY. (1998). Features of spondyloarthritis around the world. Rheum Dis Clin North Am. 24(4):753-770, article abstract and paid-access to full text available online at http://www.ncbi.nlm.nih.gov/pubmed/9891709

15. Yu DT, Peng TF. (2001). Reiter’s syndrome. In: Ruddy S, Harris ED Jr, Sledge CB, eds. Kelley’s Textbook of rheumatology. 6th ed. Philadelphia: Saunders, 2001:1055-70.

16. 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, article abstract available online at http://www.ncbi.nlm.nih.gov/pubmed/13129875

17. 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, article abstract and paid-access to full text available online at http://www.amjmed.com/article/S0002-9343(99)80076-X/abstract

18. 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, article abstract available online at http://www.ncbi.nlm.nih.gov/pubmed/10990232

19. Hannu T, Inman R, Granfors K, Lerisalo-Repo M. (2006).  Reactive arthritis or post-infectious arthritis?  Best Practices and Research Clinical Rheumatology 20:419-33, article abstract available online at http://www.ncbi.nlm.nih.gov/pubmed/16777574

20. Kingsley G, Sieper J. (1996).  Third International Workshop on Reactive Arthritis.  23-26 September 1995, Berlin, Germany.  Annals of Rheumatic Diseases 55:564-84, availbe online at http://ard.bmj.com/content/55/8/564.full.pdf?sid=8224781d-9d45-403d-b846-1cdf67466d5a

21. National Institutes of Health. (2011). Questions and Answers about Reactive Arthritis. NIH Publication No. 09-5039, available online at http://www.niams.nih.gov/Health_Info/Reactive_Arthritis/default.asp

22. Clegg DO, Reda DJ, Weisman MH, Cush JJ, Vasey FB, Schumacher HR Jr, Budiman-Mak E, Balestra DJ, Blackburn WD, Cannon GW, Inman RD, Alepa FP, Mejias E, Cohen MR, Makkena R, Mahowald ML, Higashida J, Silverman SL, Parhami N, Buxbaum J, Haakenson CM, Ward RH, Manaster BJ, Anderson RJ, Henderson WG, et al. (1996). Comparison o fsulfasalazine and placebo in the treatment of reactive arthritis (Reiter’s syndrome). A Department of Veterans Affairs Cooperative Study. Arthritis Rheum. 39(12):2021-7, abstract available online at http://www.ncbi.nlm.nih.gov/pubmed/8961907.

23. Creamer P, Lim K, George E, Dieppe P. (1994). Acute inflammatory polyarthritis in association with tamoxifen. Br J Rheumatol. 33(6):583-5, abstract and paid-access to full text available online at http://rheumatology.oxfordjournals.org/content/33/6/583.abstract.

24. 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, available online at http://ard.bmj.com/content/56/9/516.full.pdf?sid=dc192ce4-4995-493e-85a0-90bbc3840350

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