Reactive Arthritis

Key Points

• ReA is an inflammatory syndrome that can develop 1 to 6 weeks after infection with triggering bacteria, including Chlamydia trachomatis, Salmonella, Shigella, Campylobacter, and Yersinia
• Symptoms of ReA include inflammatory spondyloarthritis that can involve axial skeleton with a predilection for large joints of lower extremities
• Classic triad of symptoms (arthritis, conjunctivitis, and urethritis) is often not seen
• 50% to 70% of patients with ReA will spontaneously remit within weeks to months; the remainder will develop chronic but generally milder disease
• Patients who are HLA-B27–positive are more likely to develop chronic disease
• Treatment for acute ReA is supportive and may include antibiotic therapy when causative organism has been identified in addition to anti-inflammatory therapy
• Treatment for chronic ReA is less well-defined but may include disease-modifying drugs, such as sulfasalazine or TNF inhibitors, under guidance of rheumatology specialists
• Patients with ReA should be closely monitored to assess for appropriate therapeutic response, complications, or progression to chronic disease

Terminology

• ReA (reactive arthritis): a type of spondyloarthritis that can result from certain gastrointestinal or genitourinary infections
  • Classic triad of symptoms:
    • Acute inflammatory arthritis
    • Inflammatory eye conditions (eg, conjunctivitis, uveitis)
    • Dysuria (urethritis)
  • Majority of patients who develop ReA do not present with classic triad and many other associated clinical manifestations have been described^1,2
• Spondyloarthritis: an inflammatory arthritis that has a predilection for the axial skeleton and large proximal joints
  • The term ReA was introduced in 1969 and is still used today to describe the syndrome; however, many terms and eponyms have been used historically over the years^1,3
• Attack rate: term that represents the percentage of patients who develop ReA after causative gastrointestinal or genitourinary infection

Epidemiology

• ReA is rare, with an estimated 3.5 to 5 per 100,000 patients in the United States⁴
  • Listed with National Organization of Rare Diseases
  • Some recent data suggest prevalence is decreasing, perhaps because of better recognition and treatment of causative organisms
  • Ct (Chlamydia trachomatis) is the most common etiologic agent causing ReA in the United States^1,5
• Males are more likely to develop Ct-induced ReA whereas the gender prevalence is approximately equal in the postdysentery form of ReA^1,5
• Adults are more likely to develop ReA than children^1,5
• True attack rate of Ct-induced ReA might be difficult to ascertain because data suggest asymptomatic Ct infections can cause ReA⁶

Etiology and Risk Factors

Approach to Diagnosis

• Clinical features of postvenereal and postdysentery ReA are quite congruent regardless of the initiating infection
• The clinical syndrome can involve many different organ systems, with a predilection for the synovium, urethra, eye, and skin
• Symptoms typically start within 1 to 6 weeks after the inciting infection, with more significant symptoms during acute phase of disease
• Symptoms may wax and wane in chronic cases
• Articular features include synovitis, enthesitis, and dactylitis (Figures 1, 2, and 3)
  • ReA can present as a peripheral or axial arthritis or a combination of both
    • Peripheral arthritis of ReA most typically involves the large joints of the lower extremities
  • Some data suggest that enthesitis is more common than synovitis¹⁷
    • Common sites of enthesitis include Achilles tendon, plantar insertion/fascia, and patellar tendon (see Figure 2)
  • Dactylitis has been suggested in up to 28% of patients presenting with ReA¹⁸ and can be a distinguishing feature of ReA (see Figure 3)
• Evaluate for cystitis/urethritis, prostatitis, cervicitis, or salpingo-oophoritis, which occurs frequently in postchlamydial ReA, but can also be seen in postenteric ReA
• Evaluate for presence of skin lesions, which may include keratoderma blennorrhagicum (Figure 4), circinate balanitis, or nail changes; oral ulcers may occasionally be present
  • Keratoderma blennorrhagicum occurs in about 20% of cases¹⁹
  • Circinate balanitis resembles pustular psoriasis and occurs in approximately 10% to 15% of cases^20,21
  • Nail changes include onycholysis and pitting; these occur in about 10% of patients¹⁹
• Ophthalmologic evaluation should assess for presence of conjunctivitis or anterior uveitis, although other manifestations have also been described²²
  • Ocular involvement is unilateral in about two-thirds of cases; all ocular manifestations can become chronic and/or recurrent, requiring systemic therapy

Diagnostic Criteria

• No sets of classification or diagnostic criteria are universally accepted
• Third International Workshop on ReA proposed the following diagnostic criteria in 1995:²³
  • Patient must have the typical peripheral arthritis; that is, asymmetric oligoarthritis predominately of lower limbs
  • Patient must have evidence of preceding infection (clinical diarrhea or urethritis within preceding 4 weeks) and, when there is no clear clinical infection, laboratory confirmation of infection is required
    • Specification of 4 weeks is somewhat arbitrary because some patients develop arthritis 6 or more weeks after infection, but it was felt that extension of the time beyond 4 weeks would make criteria less specific
  • Presence of HLA-B27 is not part of these diagnostic criteria
• Fourth International Workshop on ReA added that clinicians should differentiate between acute and chronic ReA using a recommended cutoff of 6 months’ duration²⁴

History

• Obtain history of any recent gastrointestinal or genitourinary infection, particularly within 1 to 6 weeks before onset of symptoms
  • Obtain any documented history of causative organisms of recent infection
  • Postenteric ReA is always preceded by a symptomatic infection,^1,5 but symptoms can be mild and may be overlooked by patient
  • Postvenereal ReA may follow an asymptomatic infection^1,5
• Assess for history of classic triad of symptoms seen with acute ReA: arthritis, conjunctivitis, and urethritis^1,5
  • Note that many patients do not present with involvement of all 3 organ systems
  • Initial symptoms may range from mild to fulminant
  • Initial symptoms spontaneously remit within 1 to 6 months in most patients
  • Note that HLA-B27–positive patients are more likely to present with:
    • Classic triad of symptoms
    • More fulminant acute symptoms
    • Increased likelihood of chronic disease
• Patients with symptoms for longer than 6 months’ duration may represent chronic disease presentation, with a tendency of symptoms to wax and wane⁵
• The arthritis of ReA is consistent with an inflammatory arthritis consisting of:
  • Prolonged morning stiffness
  • Improvement with activity
  • Can involve both axial and peripheral skeletal system
• Ocular symptoms may range from mild symptoms consistent with a conjunctivitis (scleral injection, irritation, and excess tear production) to severe symptoms consistent with acute anterior uveitis/iritis (pain, photophobia)
• Symptoms of urethritis, such as dysuria, can be observed in both postvenereal and postenteric ReA and typically resolve early in disease course^1,5
• Associated cardiac complications are rare, but may include conduction abnormalities, aortic insufficiency, and pericarditis^1,5

Physical Examination

• Proceed with comprehensive physical examination given potential for involvement of multiple organ systems
• Examine peripheral joints for presence of synovitis (see Figure 1), paying particular attention to joints of lower extremities and wrists
• Assess axial skeleton for signs of inflammatory arthritis
  • Sacroiliac joints are frequently involved
  • Perform Patrick test and Schober test
    • Patrick test: place 1 hand on patient’s abducted knee and the other on patient’s anterior superior iliac spine; pain localized to the back when pressure is applied suggests sacroiliitis
    • Schober test: evaluate flexion of patient’s lumbar spine while patient is standing; decreased lumbar spinal flexion (less than 5 cm at level of fifth lumbar vertebra) or decreased lateral lumbar flexion can be seen with ReA or ankylosing spondylitis
• Assess for presence of enthesitis (ie, inflammation at the tendon insertion site into the bone) (see Figure 2)
  • Common sites of enthesitis include the heels, knees, and elbows
• Examine fingers and toes for dactylitis (sausage digit) (see Figure 3)
• Perform ocular examination to assess for scleral injection, discharge, and photophobia
• Evaluate palms, soles, genitals, nails, and oral cavity for the typical mucocutaneous findings, such as keratoderma blennorrhagicum (see Figure 4), circinate balanitis, nail changes, or oral ulcers
• Perform cardiac examination to assess for presence of an arrhythmia or heart murmur, which may suggest a rare cardiac manifestation

Laboratory Tests

• Obtain genital and/or stool specimens in an effort to culture the causative organism, though results may be negative
  • Patients should have urethral/cervical, anal, and oral swabs obtained for testing by NAAT (nucleic acid amplification test) for Ct, regardless of symptoms, given possibility of asymptomatic infection²⁵
  • Perform stool cultures to detect enteric pathogens if any gastrointestinal symptoms are reported
  • Recovery of any of these pathogens is strongly suggestive of ReA but not diagnostic
• Serum HLA-B27 testing may be considered, especially in patients with chronic ReA, but this is currently not recommended by Third International Workshop on ReA²³

Imaging Studies

• Plain radiographs of involved joints are typically not recommended in acute ReA as they are generally not helpful in making the diagnosis
  • Consider radiographic evaluation of involved joints in the setting of possible chronic ReA to assess for presence of asymmetric or unilateral sacroiliac changes or nonmarginal syndesmophytes (large, bulky, comma-shaped bony growths found in spine) on plain radiographs
• Consider MRI to evaluate for bone edema and inflammation seen in sacroiliitis as plain radiographs may not detect sacroiliac joint involvement²⁶
• Consider musculoskeletal ultrasonography to evaluate for peripheral synovitis or enthesitis
• Consider echocardiogram to further evaluate for cardiac manifestations in patients with concerning history or physical examination

Diagnostic Procedures

• Obtain synovial fluid via arthrocentesis to assess for presence of inflammatory arthritis and to rule out a septic joint²⁶
  • Findings suggestive of inflammatory arthritis consisting of elevated WBC count with neutrophil predominance may be present
  • Although polymerase chain reaction and reverse transcription polymerase chain reaction analyses of synovial tissue in patients with ReA may identify the causative organism, the clinical significance of these findings remains somewhat uncertain and this type of testing is still considered to be experimental^1,5
  • Skin biopsies have not been found to be helpful in establishing a diagnosis of ReA as findings are often indistinguishable from those of psoriasis

Other Diagnostic Tools

• Obtain ECG to evaluate for possible arrhythmia or conduction disease in patients with concerning history or physical examination

Approach to Treatment

• Treatment is directed toward specific symptoms of the individual patient
• Treat acute ReA with NSAIDs and/or topical, intra-articular, or systemic corticosteroids
• Treat chronic ReA with disease-modifying drugs such as sulfasalazine or TNF inhibitors (tumor necrosis factor)
  • Combination antibiotics can be considered in the case of chronic Ct-induced ReA
  • Decisions regarding type and duration of therapy should be made in consultation with rheumatology specialists
• Treatment plan is result of a coordinated effort by multidisciplinary team of specialists that includes rheumatologists, ophthalmologists, dermatologists, gastroenterologists, urologists, and cardiologists

Nondrug and Supportive Care

• Refer patient to physical therapy to support joint function and decrease joint-based inflammation through muscle strengthening and range-of-motion exercises⁵

Drug Therapy

• NSAIDs are initial first line therapy for joint-based inflammation of acute ReA^1,5
  • Consider short-term trial of an NSAID such as naproxen 500 mg twice daily for 2 weeks, in patients properly educated on potential side effects and with no contraindications, to reduce pain and swelling associated with joint-based inflammation²⁶
• Consider corticosteroids to relieve symptoms of severe joint inflammation^1,5
  • Intra-articular route of administration is preferred over systemic dosing, particularly in patients with monoarthritis
  • Oral corticosteroids can be used in patients with severe symptoms refractory to NSAIDs
    • Typical starting doses of oral prednisone range from 20 to 40mg daily with a taper over 4 to 6 weeks²⁶
• Consider topical corticosteroids for treatment of cutaneous or ocular manifestations under consultation of appropriate specialists (dermatologist, ophthalmologist)^1,5
• If the triggering bacterial infection is identified, appropriate antibiotic therapy is indicated^1,5

Persistent or Recurrent Disease

• Efficacy of antibiotic therapy for management of chronic ReA has been met with mixed results
  • An early study suggested improvement in ReA with prolonged administration of tetracycline (lymecycline 300 mg twice daily for 3 months),²⁷ but subsequent studies have indicated no response to similar antibiotic therapies^28,29
  • Another study suggested potential benefit with use of a prolonged course of combination antibiotics in Ct-induced ReA³⁰
    • Patients were randomized to combination therapy with either doxycycline (100 mg twice daily) and rifampin (300 mg daily) or azithromycin (500 mg daily for 5 days, then 500 mg twice weekly thereafter) and rifampin (300 mg daily) versus matching placebo groups for 6 months
    • Individual clinical response measurements significantly improved in those patients who received active therapy compared to placebo, with 22% of patients in the active therapy groups reporting complete resolution of symptoms
• Therapy with sulfasalazine has shown modest benefit in chronic ReA³¹
• Additional studies have explored potential benefit of TNF inhibitors in refractory cases, but this has not been evaluated in a formal prospective trial³²
• Some specialists advocate for use of methotrexate as a potential treatment, but it has never been formally studied
• In patients with chronic postdysentery ReA, experts recommend sulfasalazine for first line treatment followed by TNF inhibitors^31,32

Admission Criteria

• Consider hospitalization for patients suffering with intractable pain or inability to ambulate, or if there is concern for possible septic joint, all findings of which are typically present in acute ReA

Monitoring

• Patients with acute ReA need to be closely monitored as outpatients to assess for appropriate therapeutic response and to rule out new or evolving inflammation in various target organs
  • Decreased joint pain, stiffness, or swelling and improvement related to any additional organ involvement signifies decreased inflammation associated with a positive therapeutic response
• If symptoms are refractory to NSAIDs, treat patient with corticosteroids^1,5
• If corticosteroids are efficacious but symptoms worsen with tapering doses, consider alternative therapies^1,5
• ReA most often spontaneously remits in weeks to months^1,5
• Recommend ophthalmology follow-up and monitoring for patients who present with anterior uveitis given risk of recurrence⁵

Complications

• In patients with chronic disease (6 months’ duration or longer), it is unlikely symptoms will spontaneously resolve and alternative therapies used for chronic disease need to be considered
• Monitor patients for potential recurrence of ophthalmologic complications associated with ReA such as anterior uveitis⁵

Prognosis

• In general, prognosis is good with most cases of acute ReA resolving spontaneously^1,5
• In the 30% to 50% of cases that progress to chronic disease, it tends to be mild with waxing/waning symptoms^1,5
• Patients with chronic disease are at risk for developing radiographic damage, but this occurs less often than in similar types of arthritis^1,5

Referral

• Consult rheumatologist for evaluation and management of all patients with ReA
• Referrals to other specialists including dermatologist, ophthalmologist, urologist, cardiologist, and gynecologist are recommended based on any evidence of respective organ involvement upon initial evaluation

Prevention

• There are no universal preventive measures despite the fact that the causative bacteria of ReA are well defined
• Data suggest that the prevalence of ReA has been decreasing in recent years, likely as a result of better recognition and treatment of the causative organism^1,5
• Safe sexual practices can help prevent the occurrence of Ct-induced ReA
• Safer food preparation and handling has decreased the incidence of enteric infections with Salmonella, Shigella, Campylobacter, and Yersinia^1,5
• ReA may still develop in patients despite prompt and appropriate therapy for the triggering infection