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Chapter 36 Reiter's Syndrome and Reactive Arthritis

Manual of Rheumatology and Outpatient Orthopedic Disorders

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Chapter 36 Reiter's Syndrome and Reactive Arthritis

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Robert D. Inman

Pathogenesis
Diagnosis
Laboratory studies
Differential diagnosis
Treatment
Prognosis

In 1916, Hans Reiter reported the case of a Prussian lieutenant in whom diarrhea developed; shortly thereafter, he experienced arthritis, conjunctivitis, and urethritis. Ironically, Reiter attributed this symptom complex to a spirochetal infection, but the association of the syndrome with his name has persisted . Although the early descriptions of Reiter's syndrome (RS) define a clinical triad of arthritis, conjunctivitis, and urethritis, most authors now accept the presence of a seronegative asymmetric arthritis plus one characteristic extraarticular feature (described below) as sufficient for the diagnosis. An antecedent infection of the gastrointestinal or genitourinary tract can often be identified, but not invariably. The pathogens implicated in such infections are Yersinia, Salmonella, Shigella, Campylobacter (gastrointestinal infections), and Chlamydia (genitourinary infections). It is not clear whether a wider range of arthritogenic organisms should be included in this list, but the evidence for other organisms playing a triggering role in RS has remained circumstantial.

Although RS occurs in children and the elderly, it is usually seen in young adults, with a significant male predominance. It may be that RS is underrecognized in female patients, as some clinical features (e.g., cervicitis) may be less symptomatic than the extraarticular features in male patients (e.g., balanitis). However, serious, even refractory, RS does occur in women, and the clinician should be alert to a typical constellation of symptoms in either sex. Despite the strong immunogenetic influence on the disease, a positive family history for RS is uncommon. It has been observed that if there is a positive family history, it tends to be for RS, whereas patients with ankylosing spondylitis are more likely to have relatives with that disease than with RS. At present, there are no predictive features that discriminate systemic target organ involvement from disease limited to the joints, or that discriminate a benign , self-limited course (averaging 3 to 4 months) from a more chronic course. Retrospective studies have noted that a sustained antibody response against the triggering pathogen is characteristic of those patients in whom a more chronic course of RS develops.

I. Pathogenesis. Despite the strong association with the HLA-B27 antigen, the mechanism whereby this HLA gene might confer disease susceptibility to RS remains unknown. There are three hypothetical routes by which HLA might interact with a triggering infectious agent. The first is molecular mimicry, whereby an autoimmune response develops after the infection because of cross-reactivity of host and microbial antigens. The clinical significance of cross- reacting antibodies in such studies remains undefined. The second is an altered cellular immune response to the pathogen; proponents argue that unique determinants in the antigen-binding groove of the HLA-B27 molecule specifically present arthritogenic peptides to the responding CD8+ T-cell population. The idenficiation of such pathogenic T cells has proved problematic in both clinical and experimental systems, although CD8+ T cells recognizing microbial peptides have been isolated. The third possibility is an altered microbial-host cell interaction, by which certain HLA alleles modulate host response to arthritogenic organisms. This might implicate altered invasion, intracellular killing pathways , or cytokine production. Whatever the mechanism, it is likely that the synovitis that ensues is related to local deposition and persistence of microbial antigens, but definitive proof is lacking to resolve the issue.

II. Diagnosis

1. History. A careful history should be taken to address any recent exposure to an enteric pathogen (a diarrheal illness after travel) or a sexually transmitted pathogen (a new sexual partner). The typical interval between the triggering infection and RS is 1 to 4 weeks, but exceptions earlier or later have been described. A prior history of low back pain or recurrent tendinitis is not uncommon. A history of recent antibiotic therapy is relevant to interpretation of any culture results. Prior episodes of uveitis may not be mentioned by the patient unless specifically sought.
2. Constitutional symptoms. Fatigue may not be present in the acute phase but can become significant in chronic RS.
3. Physical findings
   1. Fever is usually low-grade (<38 °C) in most patients. Significant or sustained fever should suggest that the original infection may still be active.
   2. Arthritis. The cardinal feature is an asymmetric arthritis, typically oligoarticular and predominantly in the lower extremities. Most common are knees, ankles, and metatarsophalangeal joints, but involvement of an upper extremity can be seen. Acute sacroiliitis may present as a diffuse low back pain that is difficult to localize but may be felt in the deep gluteal area.
   3. Enthesitis. Plantar fasciitis and Achilles tendinitis are quite specific for RS and should be sought carefully . Any tendinous insertion into bone can be involved, and tendinitis of hip adductors may be misdiagnosed as arthritis of the hip joint.
   4. Genitourinary symptoms. Urethritis can be manifested by dysuria and by urethral discharge in male patients. Cervicitis in female patients is usually asymptomatic. Prostatitis and hemorrhagic cystitis may also occur.
   5. Ocular symptoms. Conjunctivitis may be mildly or markedly symptomatic, with a burning sensation and local crusting around the eye. Uveitis is generally associated with pain and photophobia and sometimes loss of visual acuity.
   6. Gastrointestinal symptoms. Antecedent diarrhea has generally resolved by the onset of arthritis but may persist at a low level for prolonged periods.
   7. Mucocutaneous symptoms
      1. Circinate balanitis appears as coalescing , superficial genital ulcers.
      2. Keratoderma blennorrhagicum is characterized by the appearance of keratotic skin lesions on the palms and soles.
      3. Mucosal ulcers can appear on the tongue or buccal mucosa and are generally painless, but not invariably so.
   8. Cardiac and neurologic features are rare.
      1. Heart block, pericarditis, aortic insufficiency.
      2. Myelopathy, cranial nerve lesions.

III. Laboratory studies

1. Hematologic findings. An elevated erythrocyte sedimentation rate is usually present in an acute episode. The anemia of chronic disease usually accompanies a more prolonged course.
2. Urinary findings. Pyuria is common, hematuria less common. Urethral discharge contains abundant neutrophils.
3. Synovial fluid. An elevated white blood cell count (10,000 to 50,000), with a predominance of neutrophils, is usually seen in active disease. Synovial fluid glucose and complement levels are generally normal, and determinations are not routinely ordered. Results of a Gram's stain are carefully examined, and a synovial fluid specimen is sent for culture.
4. Culture. In general, a careful search for persistent pathogens should be undertaken. The arthritogenic organisms listed above (e.g., Salmonella ) may on occasion be associated with a true septic arthritis, so that appropriate cultures of synovial fluid should always be performed. Urethral discharge or persistent diarrhea should also occasion appropriate cultures (for chlamydial infection and gonorrhea in the former, for gram-negative enteric pathogens in the latter). Immunofluorescence studies of urethral swabs are increasingly being used for assessing chlamydial urethritis. Polymerase chain reaction to identify pathogens in synovial fluid is a valuable research tool, but its use has not yet been established in routine clinical practice.
5. Tissue typing. The HLA-B27 antigen is present in 70% to 80% of patients with RS but is of diagnostic value only in the appropriate clinical setting (i.e., high pretest probability). A negative test result does not exclude the diagnosis but may alert the clinician to the possibility of alternative diagnoses.
6. Radiographs. Generally, radiographic findings are normal in the acute disease, but reactive new bone at entheses may accompany chronic disease. Radiographic sacroiliitis may occur in the course of RS and is classically asymmetric. Clinical suspicion of sacroiliac disease with normal radiographic findings is an indication for bone scan confirmation of sacroiliitis. Evaluation of sacroiliac joints by computed tomography (CT) or magnetic resonance imaging (MRI) has been shown to increase the sensitivity of imaging, but the specificity of these techniques is not clearly defined. CT can demonstrate sacroiliac erosions, as can a properly taken Ferguson view of the sacroiliac joints that is interpreted by an experienced bone radiologist.

IV. Differential diagnosis

1. Septic arthritis. Appropriate cultures of synovial fluid, and of all potential portals of entry, should be performed to exclude septic arthritis. The most common diagnosis to exclude in a young patient is gonococcal arthritis. RS and disseminated gonococcal infection may both involve tenosynovitis, urethritis, conjunctivitis, and dermatitis.
2. Colitic arthropathy. Arthritis following diarrhea may represent the rheumatic complication of either Crohn's disease or ulcerative colitis, and gastrointestinal endoscopy and radiology may be required to exclude this possibility. Arthritis may be the presenting manifestation of inflammatory bowel disease and may precede bowel complaints for some period of time.
3. Psoriatic arthritis. Skin rash coincident with arthritis may represent psoriatic arthritis rather than RS, and indeed the histopathologic findings of psoriasis and keratoderma are similar. Coexisting urethritis and conjunctivitis, or antecedent diarrhea, would favor a diagnosis of RS. Pitting of the nails occurs in both conditions, but the nail dystrophy of psoriatic arthritis is generally more severe.
4. Rheumatoid arthritis. If chronic polyarthritis suggests rheumatoid arthritis, the presence of asymmetry and sacroiliitis and negativity for rheumatoid factor would favor RS. The extraarticular features of rheumatoid arthritis are distinct from those of RS.
5. Human immunodeficiency virus (HIV) infection. There are indications from some series that RS may occur with higher frequency and severity in patients with HIV infection. The frequency of this clinical overlap is not known. Patients in a high-risk category should be screened for HIV serology. There may be a unique arthropathy associated with HIV, but this is not fully resolved. In some patients, the episode of RS occurs long before clinically overt acquired immune deficiency syndrome (AIDS). This is an important consideration when any immunosuppressive therapy is being considered .

V. Treatment

1. Antibiotics. It has generally been held that antibiotics do not influence the course of RS, but recent evidence suggests that tetracycline compounds (e.g., doxycycline) may shorten the course of post-chlamydial RS. In any event, it is reasonable to institute appropriate antibiotic therapy if any culture results indicate a persisting infection (e.g., chlamydial urethritis). There is no evidence that antibiotic therapy alters the natural course of post-dysenteric RS.
2. Arthritis therapy
   1. Antiinflammatory drugs. In general, the new nonsteroidal antiinflammatory drugs are superior to aspirin for controlling synovitis. Indomethacin (50 mg three times daily) and diclofenac (50 mg three times daily) are generally well tolerated in the young patients who represent the majority of patients. Recent evidence from a 36-week trial suggests that sulfasalazine is superior to placebo in improving the peripheral arthritis of RS. It is used at a dose of 500 mg to 1 g twice daily, and the granulocyte count is carefully monitored .
   2. Immunosuppressive therapy. There has been favorable experience with methotrexate (5 to 15 mg/wk) and azathioprine (50 to 150 mg/d) in cases of chronic disease refractory to other measures. These agents are generally reserved for severe disease. As is the case in rheumatoid arthritis, clinicians are more commonly using methotrexate earlier, when the response to nonsteroidal antiinflammatory drug therapy is unsatisfactory.
   3. Steroid therapy. Intraarticular steroid injections may be of benefit, but oral steroids are rarely, if ever, indicated. Local steroid injection in the sacroiliac joint under fluoroscopic guidance has a role, particularly when this is the dominant symptomatic joint.
3. Ocular disease. Uveitis should be managed jointly by an ophthalmologist and a rheumatologist. Generally, local steroid drops will suffice, but oral steroids may be required in severe cases. Refractory uveitis can be the indication for intervention with methotrexate or azathioprine therapy.

VI. Prognosis. In most patients, significant improvement with antiinflammatory therapy occurs during a 3- to 4-month period. However, a recent 5-year follow-up study of patients with post- Salmonella RS reported that two- thirds of the patients continued to have subjective complaints at this interval, and that more than a third demonstrated objective changes in the joints. Long- term functional disability occurs in only a minority of patients. This variability in clinical course should be mentioned in discussions with the patient.

Bibliography

Careless D, Inman RD. Etiopathogenesis of reactive arthritis and ankylosing spondylitis. Curr Opin Rheumatol 1995;7:290.

Clegg DO, et al. Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter's syndrome). Arthritis Rheum 1996;39:2021.

Cremers MCW, et al. Second-line treatment in seronegative spondyloarthropathies. Semin Arthritis Rheum 1994;24:71.

Inman RD. Treatment of seronegative spondyloarthropathies. In: Klippel J, Weyand CM, eds. Primer on the rheumatic diseases. Atlanta: Arthritis Foundation, 1997:193.

Thomson GT, et al. Post- Salmonella reactive arthritis: late clinical sequelae in a point source cohort. Am J Med 1995;98:13.

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Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders

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