NORD gratefully acknowledges John D. Carter, MD, Associate Professor of Medicine, Chief of Rheumatology, University of South Florida College of Medicine, for assistance in the preparation of this report.
Reactive arthritis is a general term for a form of joint inflammation (arthritis) that develops as a "reaction" to an infection in another area of the body (i.e., outside of the joints). Joint inflammation is characterized by redness, swelling, pain and warmth in and around the affected joint. In reactive arthritis, the large joints of the lower limbs and the sacroiliac joints are most often affected. Two other common symptoms of reactive arthritis are inflammation of the urinary tract and inflammation of the membrane (conjunctiva) that lines the eyelids (conjunctivitis). These three characteristic symptoms may occur separately, all at once or not at all. Additional symptoms such as fever, weight loss, lower back pain and heel pain may also occur. Reactive arthritis usually develops following a bout with certain bacterial infections including Chlamydia, Salmonella, Shigella, Yersinia, and Campylobacter.
Reactive arthritis belongs to a group of related disorders known as the spondyloarthritidies. These disorders are linked by the association of similar symptoms and a specific genetic marker called HLA-B27. Symptoms common to these disorders include arthritis, especially of the lower limbs, lower back pain and enthesitis, a condition characterized by inflammation at the spot where tendons attach to bone. This group of disorders includes reactive arthritis, ankylosing spondylitis, psoriatic arthritis, undifferentiated spondyloarthritis and spondyloarthritis associated with inflammatory bowel disease.
Reactive arthritis is a poorly defined disorder that has been described in the medical literature under many different names. No precise diagnostic or classification criteria have been developed that are universally agreed upon in the medical community.
The specific symptoms and their severity can vary greatly from one person to another. Some individuals with reactive arthritis may only develop mild arthritis without eye or urinary tract involvement. Other individuals may develop a severe case of reactive arthritis that can dramatically limit daily activity. Symptoms usually last anywhere from 3 to 12 months and may come and go. In approximately 30-50 percent of patients, symptoms may return later or become a chronic (greater than 6 month) long-term problem. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
The symptoms of reactive arthritis may come and go over a period of time ranging from several weeks to several months. Symptoms usually develop one to six weeks after a gastrointestinal or genitourinary infection. Inflammation of the joints, urinary tract and eyes are the most common findings. Additional symptoms may also develop.
Arthritis can occur before or at the same time as eye and urinary symptoms or after they have subsided. Arthritis usually affects the joints of the lower legs causing pain, redness and swelling in the knees, ankles and feet. Other joints such as the wrists, elbows, and fingers are affected less frequently. Onset is usually rapid with two to four joints becoming involved within a few days. Heel pain is also common. Heel pain is caused by enthesitis, a condition characterized by inflammation at the spot where the tendon attaches to bone. In some cases, the toes and/or fingers may become inflamed and swollen (dactylitis) so that they appear large and stubby. Pain in the lower back or buttocks may also occur.
Urinary tract involvement in reactive arthritis may not cause any symptoms (asymptomatic). In other cases, urinary tract inflammation may be the first symptom to develop, especially in men. Urinary tract symptoms are often absent in women. In some men, urinary tract inflammation can cause pain or a burning sensation when urinating, increased frequency of urination, or fluid discharge when urinating. In severe cases, inflammation of the prostate gland (prostatitis) may occur. In spite of these symptoms, the urine culture will typically be negative.
Women with urinary tract inflammation due to reactive arthritis may develop inflammation of the cervix, inflammation of the fallopian tubes (salpingitis), or inflammation of the vulva and vagina (vulvovaginitis). Some affected women may experience a burning sensation when urinating.
Some affected individuals develop inflammation of the membrane (conjunctiva) lining the eyelids (conjunctivitis). Some people may also develop inflammation of the anterior uvea (uveitis), the part of the eye that consists of the iris, choroid and the ciliary body. Conjunctivitis and uveitis may cause redness and swelling of the eyes, eye pain, blurred vision, an abnormal sensitivity to light (photophobia) and crusting in the morning. Blurred vision and photophobia are more common with uveitis. Eye symptoms may occur early in the course of reactive arthritis. In some cases, symptoms may come and go during the duration of the disease (wax and wane).
General, vague symptoms that can be associated with many different diseases may also occur in individuals with reactive arthritis. Such symptoms including fatigue, fever, unintended weight loss, and a general feeling of poor health (malaise).
Additional symptoms may potentially affect individuals with reactive arthritis. In some men, small, shallow, painless ulcers may form on the penis; this is referred to as circinate balanitis. These ulcers may precede the development of arthritis. Occasionally these ulcers can form a plaque-like lesion and become chronic. In addition, some individuals may develop small, superficial ulcers in the mouth, especially the tongue or hard palate. These lesions may come and go, are usually painless and often go unnoticed. Acute diarrhea may occur in cases that develop after infection with Shigella, Yersinia, Campylobacter or Salmonella. Diarrhea may precede the development of musculoskeletal symptoms by up to one month.
Some individuals with reactive arthritis develop a skin condition called keratoderma blennorrhagia. This skin lesion usually affects the palms or soles and may consist of reddish, raised, waxy bumps or nodules. These bumps usually spread, eventually coming together (coalescing) to form one larger, scaly rash that may resemble psoriasis. The nails of some individuals with reactive arthritis may become thickened.
Reactive arthritis develops because of an infection that occurs in another part of the body. Even mild infections, which may go unnoticed, can cause reactive arthritis. This may be particularly true with chlamydial infections, which appear to be a rather frequent cause of reactive arthritis. The lack of a symptomatic, preceding infection in some cases obscures the diagnosis. The five bacterial infections most commonly associated with reactive arthritis are Chlamydia, Salmonella, Shigella, Yersinia, and Campylobacter. These bacteria usually cause gastrointestinal or genitourinary infections. Chlamydia is the most common cause of reactive arthritis in the United States and is usually acquired through sexual contact. Salmonella, Shigella, Yersinia, and Campylobacter may cause a gastrointestinal infection that can trigger reactive arthritis. Salmonella, Shigella, Yersinia, and Campylobacter are often acquired after eating contaminated food, handling improperly prepared food or coming into contact with the feces of a contaminated person. Less often, several other bacteria have been implicated as causative agents in reactive arthritis. However, some researchers reserve the term reactive arthritis only for those cases caused by the five abovementioned bacteria.
The exact underlying mechanisms that cause reactive arthritis are not fully understood. Researchers believe that reactive arthritis is an autoimmune disorder. An autoimmune disorder occurs when the body’s immune system mistakenly attacks healthy tissue. In reactive arthritis, a preceding infection induces an immune system response. Studies have demonstrated that the bacteria, or bacterial products, travel from the initial site of infection through the blood to the tissue lining the joints (synovial tissue). In the case of chlamydiae, these synovial-based organisms are viable, albeit in an aberrant state. The significance of these synovial-based organisms or bacterial products is not completely understood.
It is important to note that not everyone who develops these bacterial infections will develop reactive arthritis. In fact, reactive arthritis only develops in a minority of individuals exposed to one of the causative organisms. Researchers do not know exactly why some people develop reactive arthritis, while others do not. Some individuals may have a genetic predisposition to developing the disorder. Researchers have determined that many affected individuals have a particular, genetically-determined “human leukocyte antigen” (HLA) known as HLA-B27. HLAs are proteins that play an important role in the body’s immune system; they influence the outcome of organ transplants and appear to affect an individual’s predisposition to certain diseases. Specifically, the HLA-B27 antigen is present in many individuals with reactive arthritis and related disorders. However, it is important to note that the majority of patients who develop reactive arthritis are HLA-B27 negative, so the genetic component of reactive arthritis is not fully understood. Some researchers believe that HLA-B27 is a better indicator of disease severity rather than susceptibility.
Many people who have the HLA-B27 gene do not develop reactive arthritis even after contracting one of the abovementioned infections, which suggests that additional genetic (e.g., additional genes), environmental and/or immunologic factors may all play a role in the development of reactive arthritis. More research is necessary to determine the exact, underlying mechanisms that cause reactive arthritis.
Reactive arthritis most often affects white men between the ages of 20 and 40. However, it has also been reported in children and the elderly. Women usually develop milder symptoms and may often go undiagnosed. Men are estimated to be approximately nine times more likely to develop reactive arthritis following a sexually-acquired infection. The risk of developing reactive arthritis following a gastrointestinal infection is the same between men and women. The exact incidence of reactive arthritis is unknown and estimates vary. Some researchers believe that many cases often go misdiagnosed or undiagnosed.
Reactive arthritis has appeared in the medical literature under many different names including Reiter’s syndrome, named after a physician, Hans Reiter, who reported on the disorder in 1916. However, because of concerns about the unethical activities of Dr. Reiter in Germany during World War II, the term has gradually been replaced by the more appropriate and more descriptive term reactive arthritis.
There is no specific, conclusive diagnostic test for reactive arthritis. Several groups have published diagnostic guidelines for reactive arthritis. However, these guidelines are often in disagreement as to what specifically is required for a diagnosis. Specific, consistent diagnostic guidelines have yet to be established for reactive arthritis.
A diagnosis of reactive arthritis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including blood tests, joint fluid tests, and specialized imaging tests. These tests can aid in a diagnosis of reactive arthritis or rule out the disorder. However, none of these tests is conclusive as to whether a person has the disorder or not. Blood tests can reveal certain findings associated with reactive arthritis, including:
The HLA-B27 genetic marker: This genetic marker is associated with spondyloarthropathies including reactive arthritis. It can aid in the diagnosis of reactive arthritis, but not every person who has this marker develops the disorder.
The presence of bacteria such as Chlamydia, which can cause reactive arthritis: However, because the symptoms of reactive arthritis often do not become apparent until after an individual has recovered from the infection, no signs of the infection may be present. If the patient had an acute diarrheal illness and tested positive for Salmonella, Shigella, Campylobacter, or Yersinia 1-6 weeks prior to the onset of symptoms, then this is a very good indicator the patient probably has post-enteric reactive arthritis.
An elevated sedimentation rate: Sedimentation rate is the time it takes red blood cells to settle on the bottom of a test tube. An elevated sedimentation rate is indicative of inflammation somewhere in the body, but cannot distinguish between disorders that cause inflammation. This is most useful during the acute stage of reactive arthritis and is typically normal with the chronic form of this condition.
Rule out other conditions: Blood tests can reveal certain findings associated with other disorders that have similar symptoms to reactive arthritis such as rheumatoid arthritis, which is associated with a specific antibody called rheumatoid factor or an anti-cyclic citrullinate peptide (CCP) antibody, or lupus, which is associated with antinuclear antibodies.
Physicians may also test the fluid in the joints (synovial fluid). Examining synovial fluid is done to rule out an infection in the joint, assess the amount of inflammation in the joint, and rule out other conditions such as gout or other types of crystal-related arthritis.
Physicians may also use specialized imaging techniques (x-rays) to aid in the diagnosis of reactive arthritis or to rule out other conditions. X-ray studies may reveal distinctive characteristics of spondyloarthropathies such as reactive arthritis including inflammation of the sacroiliac joints (sacroiliitis). X-ray examination can also rule out other conditions. It is important to note that the typical changes on x-rays can take months to develop so x-rays are less useful in the acute setting. Specialized imaging techniques that may be used include computed tomography (CT) scans, magnetic resonance imaging (MRIs), or ultrasound. These advanced imaging techniques are more useful at detecting early or acute changes.
The treatment of reactive arthritis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Orthopedists, ophthalmologists, dermatologists, urologists, gynecologists and other health care professionals may need to systematically and comprehensively plan appropriate therapy.
Individuals with reactive arthritis may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), which include ibuprofen, naproxen sodium, and aspirin. NSAIDs can help minimize the inflammation and pain associated with reactive arthritis. Corticosteroids may be used to treat joint inflammation. Usually, corticosteroids are injected directly (locally) into the affected joints and/or around tendons to relieve severe inflammation. Topical corticosteroids, usually a cream or lotion, can be applied to skin abnormalities to reduce inflammation and promote healing. Systemic corticosteroids have generally been less effective than treating other types of inflammatory arthritis.
Physical therapy and exercise can be beneficial in promoting and improving joint function. Strengthening and range-of-motion exercises can be used to help preserve or improve joint function. These techniques can build muscle around the joints, which strengthens support, improve the flexibility of joints, and help to reduce joint stiffness.
Because reactive arthritis occurs following a bacterial infection, the use of antibiotics has been studied as a potential therapy. Antibiotics are prescribed to eradicate the bacterial infection that causes reactive arthritis. The type of antibiotic used depends on the type of infection. Studies into the benefit of prolonged antibiotic therapy for individuals with reactive arthritis have been inconsistent and inconclusive and, consequently, there is disagreement in the medical literature as to the overall value and benefit of antibiotic therapy for individuals with reactive arthritis. Recent data suggest that Chlamydia-induced reactive arthritis might respond to prolonged (6-month) administration of a combination of antibiotics.
Additional therapies have studied for individuals with reactive arthritis including disease modifying antirheumatic drugs and biologics including tumor necrosis antagonists. More research is necessary to determine to the long-term safety and effectiveness of such therapies for the treatment of individuals with reactive arthritis.
Disease-modifying antirheumatic drugs (DMARDs) have been used to treat individuals with reactive arthritis who do not respond to treatment with nonsteroidal anti-inflammatory medications. These drugs can help to relieve severe inflammation and joint pain. Drugs in this category include sulfasalazine and methotrexate. Sulfasalazine is the best studied of these drugs for the treatment of individuals with reactive arthritis.
In recent years, drugs known as biologics including tumor necrosis factor (TNF) inhibitors have been studied to treat individuals with spondyloarthropathies (although there have been no formal studies with anti-TNF therapy in reactive arthritis). Examples of these drugs include etanercept, adalimumab and infliximab. More studies have been conducted with these drugs for individuals with ankylosing spondylitis and psoriatic arthritis and in many cases affected individuals demonstrated rapid and significant improvement in symptoms. Other biologics including those that target a different inflammatory chemical in the body, interleukin-17 (e.g. secukinumab), have also been studied as a treatment for ankylosing spondylitis and psoriatic arthritis. The Food and Drug Administration (FDA) eventually approved Enbrel® (etanercept) for the treatment of individuals with ankylosing spondylitis and psoriatic arthritis. Very recently Cosentyx® (secukinumab) was also approved by the FDA as a treatment for these same two conditions. Although these drugs have proven well-tolerated and effective for individuals with related disorders, the effectiveness for reactive arthritis has yet to be established.
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