AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1916, Hans Reiter described a triad of nongonococcal urethritis, conjunctivitis, and arthritis in a young German officer who had a bout of bloody dysentery. 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 concentration camp prisoners.

The syndrome has been associated with gastrointestinal infections with Shigella, Salmonella, and Campylobacter species and other microorganisms, along 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 following within 1 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 respiratory infection with Chlamydia may also trigger the disease. 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. HLA-B27 is positive in 65-96% of patients (75% on average). Patients who are HLA-B27 positive have about a 50-fold increased chance of developing reactive arthritis, but this syndrome can 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. 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 spondyloarthropathy¹.

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, or 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 the illness 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 is about 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, the condition has a high tendency to recur, particularly with ocular and urogenital inflammation. Individuals who are HLA-B27 positive have a higher frequency of recurrence. A new infection or other stress factor could cause a reactivation of the disease.

About 15% of patients 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. 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 are predictive of a severe outcome or chronicity in reactive arthritis.

Race

Prevalence of HLA-B27 and reactive arthritis is higher in white people than in black people, as in other spondyloarthropathies.

Sex

Reactive arthritis following food-borne enteric infections affects males and females with the same frequency. Disease associated with venereally acquired infections occurs in a male-to-female ratio of 9:1.

Age

Most patients are aged 20-40 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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. About 10% of patients do not have a preceding symptomatic infection.

Nongonococcal urethritis, if present, can be one of the presenting symptoms for both postvenereal and postenteric forms. Mild dysuria, mucopurulent discharge, prostatitis and epididymitis in men, and vaginal discharge and/or cervicitis in women can be observed.

The onset is most often acute, with 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 is typically asymmetric and most frequently affects the weight-bearing joints (ie, knees, ankles, hips), but the shoulders, wrists, and elbows are also affected.
  • In more chronic and severe cases, the small joints of the hands and feet can also be involved. Dactylitis (ie, sausage digits) can be observed, as in other spondyloarthropathies.
  • While low back pain may be present in 50% of patients, most patients with acute disease have minimal findings on physical examination 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 observed in the palms and soles is indistinguishable from pustular psoriasis and is very suggestive of chronic reactive arthritis.
  • Erythema nodosum can be observed but is uncommon.
  • Nails can become thickened and crumble, resembling mycotic infection or psoriatic onychodystrophy, but nail pitting is not observed.

• Circinate balanitis can also be observed.
• 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 it 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 have a tendency to recur.

• Enteric infections
• • Enteric infections can be the triggering event for 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 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.

• Other manifestations
• • Other manifestations of the disease 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 can be observed, and aortitis with aortic regurgitation occurs in 1-2% of patients.

Causes

Reactive arthritis is usually triggered by a genitourinary or gastrointestinal infection.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Acute phase reactants, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are usually elevated markedly but later return to the reference range with subsidence of the inflammation.
• Other laboratory findings include a normocytic normochromic anemia along with mild leukocytosis and thrombocytosis during the acute phase. IgA antibodies to specific bacterial antigens have been reported. Urinalysis can show aseptic pyuria.
• Synovial fluid analysis reveals a high white blood cell count, most often with elevated polymorphonuclear leukocytes acutely. Gram stain and culture results are negative and are necessary to exclude septic arthritis. Microbial components and antigens have been identified in joint fluid using sophisticated laboratory techniques.
• Throat, stool, or urogenital tract cultures can be performed in an attempt to isolate the causative organism. Other serologic techniques for the detection of Chlamydia species, including PCR, could be considered.
• Test results for rheumatoid factor and antinuclear antibodies are negative.

Imaging Studies

• Early in the disease, no abnormalities are found on radiograph. In more advanced or long-term disease, periosteal reaction and proliferation at sites of tendon insertion can be observed. Exuberant plantar spurs are a common sign in long-term cases. In the hands and feet, marginal erosions with adjacent bone proliferation occur. Spinal radiographic findings include sacroiliitis and syndesmophytes. Sacroiliitis occurs in less than 10% of acute cases but may be observed in 50% of those patients with chronic severe disease. Syndesmophytes are usually asymmetrical and are found most commonly in the thoracolumbar region. Severe ankylosing spondylitis occurs in less than 5% of cases.

Other Tests

• An ECG should be performed in patients having a prolonged course of the disease to evaluate for conduction disturbances.
• HLA-B27 testing yields positive results in 65-96% of cases. HLA-B27 testing is not necessary in classic Reiter syndrome but may be helpful to support the diagnosis of reactive arthritis in patients with joint-restricted symptoms.

Procedures

• Needle aspiration of a joint may be necessary to rule out septic or crystalline arthritis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The treatment of reactive arthritis is modified according to the severity of symptoms.

• Nonsteroidal anti-inflammatory drugs
• • NSAIDs are the foundation of therapy. These agents should be used on a regular basis to achieve a good anti-inflammatory effect.
  
  
  • The choice of a specific agent depends on the individual response to treatment, although the general impression is that indomethacin has greater potency.
  
  
  • Physical therapy needs to be implemented to help reduce pain and to avoid muscle wasting in severe cases.


• Corticosteroids
• • These agents can be used as either intra-articular injection or systemic therapy.
  
  
  • Joint injections can produce long-lasting symptomatic improvement and help avoid the use of other systemic therapy. Sacroiliac joints can be injected, usually under fluoroscopic guidance.
  
  
  • Systemic corticosteroids can be used, particularly in patients with poor response to NSAIDs or in those who develop adverse effects related to their use. The starting dose is guided by a patient's symptoms and objective evidence of inflammation. Prednisone 0.5-1 mg/kg/d can be used initially and tapered according to response.


• Antibiotics
• • The current concepts on the pathogenesis of reactive arthritis indicate that an infectious agent is the trigger of the disease, but antibiotic treatment does not change the course of the disease, even when a microorganism is isolated. In these cases, antibiotics are used to treat the underlying infection, but specific treatment for reactive arthritis is lacking. However, in chlamydial-induced reactive arthritis, studies have suggested that appropriate treatment of the acute urogenital infection can prevent reactive arthritis and that treatment of acute reactive arthritis with a 3-month course of tetracycline reduces the duration of illness. No evidence indicates that antibiotic therapy benefits enteric-related reactive arthritis or chronic reactive arthritis of any cause.
  
  
  • Quinolones have been studied because of their broad coverage, but no beneficial effect has been noted.
  
  
  • Lymecycline was studied in a double-blind placebo-controlled study of patients with chronic reactive arthritis for a treatment period of 3 months.
  
  
  • Those patients with Chlamydia-induced disease had a significant decrease in duration of illness, as opposed to those with disease triggered by enteric infections. More studies are needed before definite recommendations can be made as to the role of antibiotics in the management of reactive arthritis.


• Disease-modifying antirheumatic drugs
• • In patients with chronic symptoms or in patients with persistent inflammation despite the use of the agents mentioned above, other second-line drugs may be used. Clinical experience with these so-called disease-modifying antirheumatic drugs (DMARDs) has been mostly in rheumatoid arthritis and in psoriatic arthritis. DMARDs have also been used in reactive arthritis, although their disease-modifying effects in the reactive arthritis setting are uncertain.
  
  
  • Sulfasalazine can be beneficial in some patients. The use of this drug in reactive arthritis is of interest because of the finding of clinical or subclinical inflammation of the bowel in many patients. Sulfasalazine is more widely used in ankylosing spondylitis. In a recent 36-week trial of sulfasalazine versus a placebo in the spondyloarthropathies, patients with reactive arthritis who were taking sulfasalazine had a 62.3% response rate compared to 47.7% for the placebo group in peripheral arthritis (P = 0.09).
  
  
  • In patients who present with rheumatoid-like disease, methotrexate can be used. Several reports have shown good response, but controlled studies are lacking. Reports also describe the use of azathioprine and bromocriptine in reactive arthritis, but, again, large studies have not been published. Patients with reactive arthritis and HIV/AIDS should not be placed on methotrexate or other immunosuppressive agents.
  
  
  • Although biologic agents such as TNF-blockers have been demonstrated to be beneficial and formally approved for the treatment of psoriatic arthritis and ankylosing spondylitis, double-blind, randomized trials have not been performed to prove clinical benefit in reactive arthritis or in undifferentiated spondyloarthropathy. A recent uncontrolled study in patients with either undifferentiated spondyloarthropathy or reactive arthritis showed potential efficacy in symptom relief.

Surgical Care

No surgical treatment of reactive arthritis is recommended.

Consultations

A rheumatologist should be consulted for confirmation of diagnosis and formulation of management plan. Consultation with a urologist may be necessary if particularly prominent genitourinary manifestations develop. An ophthalmologist may be consulted to confirm the diagnosis and to treat the ophthalmologic manifestations of the syndrome.

Activity

Physical therapy may be instituted to avoid muscle wasting and to reduce pain. Activities should otherwise be as tolerated by the patient.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity, prevent joint damage, and alleviate extra-articular disease.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)

Several NSAIDs are available and have similar effectiveness, although indomethacin may be more effective in the spondyloarthropathies. Used to treat symptoms; cyclooxygenase-2 (COX-2)–specific inhibitors can be used in those at high risk of GI complications.

Drug Category: Tetracyclines

Treat urethritis or cervicitis caused by chlamydial organisms. Some evidence shows that, in Chlamydia-induced Reiter syndrome, tetracycline treatment may reduce duration and perhaps severity of illness. Collagenase inhibitors have been used to treat early rheumatoid arthritis.

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Category: Aminosalicylic acid derivatives

Used to reduce inflammation.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Hospitalization of a patient with uncomplicated reactive arthritis is not indicated.

Deterrence/Prevention

• Even when a causal microorganism is isolated, antibiotic therapy does not change the course of the disease.

Patient Education

• For excellent patient education resources, visit eMedicine's Arthritis Center. Also, see eMedicine's patient education article Psoriatic Arthritis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Septic arthritis must be ruled out if suspected before the diagnosis of reactive arthritis is made. Failure to appropriately treat septic arthritis in a timely manner could result in joint destruction. Medicolegal liability could result from this oversight.
• HIV/AIDS should be considered before instituting immunosuppressive therapy in severe cases.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Dec 5, 2006