Reactive Arthritis

Reactive arthritis is a seronegative autoimmune spondyloarthropathy that occurs in response to a previous gastrointestinal (GI) or genitourinary (GU) infection. The pathophysiology of this disease is unclear, but a significant proportion of affected patients are positive for HLA-B27. The disease manifests as asymmetric oligoarthritis (particularly of large joints in the lower extremities), enthesopathy, dactylitis, and/or sacroiliitis. Ocular, mucocutaneous, GI, GU, and cardiac manifestations may also occur. The diagnosis is clinical, and efforts should be made to rule out alternative diagnoses. Management focuses on controlling symptoms, typically with nonsteroidal anti-inflammatory drugs. An active infection should also be treated, particularly Chlamydia trachomatis.

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Overview

Definition

Reactive arthritis (ReA) is an autoimmune, post-infectious, seronegative spondyloarthritis.

Mnemonic

The seronegative arthropathies can be remembered as “PAIR.” 

  • Psoriatic arthritis 
  • Ankylosing spondylitis
  • Inflammatory bowel disease–associated arthritis
  • Reactive Arthritis

Epidemiology

  • ReA develops in:
    • 1%–3% of patients with urethritis
    • 1%–4% of patients with an enteric infection
  • Incidence: 0.6–27 cases per 100,000 worldwide
  • Prevalence: 30–40 per 100,000 adults
  • More common in men 
  • Occurs more frequently in young adults (< 40 years of age)
  • 70%–90% have the HLA-B27 allele

Etiology

  • Generally occurs 1–4 weeks after certain infections: 
    • Genitourinary (GU): 
      • Chlamydia trachomatis (most common)
      • Neisseria gonorrhoeae
      • Ureaplasma urealyticum
    • Gastrointestinal (GI): 
      • Campylobacter jejuni (most common)
      • Shigella flexneri, S. dysenteriae, and S. sonnei
      • Salmonella enterica
      • Yersinia enterocolitica and Yersinia pseudotuberculosis
      • Clostridioides difficile
      • Escherichia coli
    • Pulmonary (less common): 
      • Chlamydia pneumonia
      • Mycobacterium tuberculosis
  • Genetic associations:
    • HLA-B27 (most common)
    • HLA-B51
    • HLA-DRB1
  • The exact pathophysiology is unknown.

Clinical Presentation

Articular manifestations

Onset is acute, within 1–4 weeks of an inciting infection.

Peripheral arthritis:

  • Asymmetric oligoarthritis
  • Predominantly of the large weight-bearing joints of the lower extremities:
    • Knees
    • Ankles
  • Other common joints:
    • Shoulders
    • Wrists
    • Elbows
    • Small joints of hands and feet
  • On exam, joints will be:
    • Tender
    • Warm
    • Swollen

Enthesopathy:

  • Inflammation at the site of ligament, tendon, fascia, or joint capsule insertion to bone
  • Causes focal tenderness and swelling
  • Common insertion sites:
    • Achilles tendon
    • Plantar fascia insertion site on the calcaneus
    • Ischial tuberosities
    • Iliac crests
    • Tibial tuberosities
    • Ribs

Tendonitis and periostitis:

  • Inflammation of the tendon or periosteum, respectively
  • Common locations:
    • Achilles tendonitis
    • Plantar fasciitis
    • Digital periostitis

Dactylitis:

  • Swollen fingers and toes (“sausage digits”)

Sacroiliitis:

  • Inflammation of the sacroiliac joints
  • Signs and symptoms:
    • Low back pain
    • Decreased lumbar flexion

Common inflammatory sites in ReA: Image demonstrates the common joints involved in ReA. Conjunctivitis and urethritis are also frequent manifestations, and are part of the clinical triad for Reiter’s syndrome.

Image by Lecturio.

Extra-articular manifestations

Ocular:

  • Conjunctivitis
  • Anterior uveitis
  • Episcleritis
  • Keratitis

Genitourinary:

  • Urethritis
  • Cervicitis
  • Prostatitis
  • Cystitis
  • Salpingo-oophoritis

Mucocutaneous:

  • Keratoderma blennorrhagicum 
    • Vesicles of the palms, soles, and around nails
    • Become hyperkeratotic and form crusts
    • Appears similar to pustular psoriasis
  • Balanitis circinata 
    • Shallow, painless ulcers of the glans penis
  • Painless oral ulcers
  • Nail dystrophy
  • Erythema nodosum (uncommon)

GI:

  • Intermittent diarrhea
    • Abdominal pain
    • Colitis

Cardiac:

  • Aortitis
  • Aortic regurgitation
  • Conduction abnormalities

Clinical triad

Formerly called Reiter’s syndrome, this classic triad of symptoms is found in only about 30% of patients with ReA: 

  • Post-infectious arthritis
  • Conjunctivitis
  • Urethritis 

Diagnosis

Reactive arthritis is a clinical diagnosis based on: 

  • Acute oligoarthritis and typical articular manifestations
  • Preceding GI or genitourinary (GU) infection
  • Presence of ≥ 1 extra-articular manifestation
  • Exclusion of other diagnoses 

Supporting work-up

Synovial fluid analysis:

  • Performed in patients with joint effusions
  • ↑ leukocytes with neutrophil predominance may be seen
  • Evaluations to rule out other etiologies:
    • Crystal analysis
    • Gram stain and culture → rule out gonococcal arthritis

Laboratory findings: 

  • ↑ or normal erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
  • Mild leukocytosis on complete blood cell count (CBC)
  • Stool cultures → evaluate for causative organisms if the patient is having diarrhea
  • Urine or genital swab → evaluate for C. trachomatis
  • Urine culture → Ureaplasma or Chlamydia
  • HLA-B27 testing
  • HIV and tuberculin skin testing in high-risk individuals (high association with ReA)
  • Rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) → rule out rheumatoid arthritis

Radiographs of affected joints:

  • Can be used to evaluate for fractures
  • Evaluate for evidence of ankylosing spondylitis in patients with sacroiliitis
  • Findings are generally nonspecific.

Management

Management of arthritis

Symptoms of ReA typically resolve in 3‒4 months, but prolonged or recurrent symptoms can occur in up to 50% of patients.

Acute ReA (duration < 6 months):

  • Physical therapy
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy.
    • Naproxen
    • Diclofenac
    • Indomethacin
  • Intraarticular or systemic glucocorticoids
    • Reserved for those with an inadequate response to NSAIDs
  • Disease-modifying antirheumatic drugs (DMARDs)
    • Indicated if a patient fails the above treatments

Chronic ReA (duration > 6 months):

  • DMARDs
    • Sulfasalazine
    • Methotrexate
  • Tumor necrosis factor (TNF) inhibitors 
    • Considered in patients who do not respond to DMARDs
    • Limited data 

Management of extra-articular manifestations

Ocular:

  • Referral for ophthalmologic evaluation
  • Anterior uveitis: corticosteroid and mydriatic eye drops
  • Conjunctivitis: symptomatic treatment

Mucocutaneous: 

  • Symptomatic treatment for mild lesions
  • Topical steroids
  • Topical salicylates
  • Severe keratoderma blennorrhagica: DMARDs or TNF inhibitors
  • Balanitis circinata: genital hygiene and topical steroids

Management of underlying infections

  • GI infection
    • Antibiotics are generally not indicated.
    • Exceptions:
      • Severe disease
      • Elderly
      • Immunocompromised patients
  • GU infection
    • C. trachomatis treatment
      • Azithromycin
      • Doxycycline
      • Fluoroquinolones (alternative therapy)
    • N. gonorrhoeae: ceftriaxone

Differential Diagnosis

  • Gonococcal arthritis: an infection due to N. gonorrhoeae. Disseminated disease can present similar to ReA with an acute, inflammatory, asymmetric arthritis with urethritis. Diagnosis is based on the clinical history, synovial fluid analysis, and culture results. Management includes antibiotics. 
  • Behcet’s disease: an inflammatory vasculitis of small and large vessels. Symptoms can include arthritis and painful oral and genital ulcers, unlike the painless lesions in ReA. Ocular, neurologic, GI, and vascular manifestations are also seen. Diagnosis is based on clinical criteria. Management depends on the clinical manifestations and includes corticosteroids, DMARDs, and TNF inhibitors.
  • Rheumatoid arthritis: an autoimmune disease resulting in joint inflammation and destruction. This arthritis is typically symmetric, and patients will frequently have tender inflammation in the joints of the hands and feet (although any peripheral joints can be involved). The axial skeleton is less commonly included. Diagnosis is made with positive RF and anti-CCP laboratory studies. Management includes NSAIDs, DMARDs, corticosteroids, immunosuppressive medications, biologics, and TNF inhibitors.
  • Psoriatic arthritis: a spondyloarthropathy that occurs in patients with psoriasis. This inflammatory arthritis is frequently asymmetric. The small and large joints are involved, including the distal interphalangeal joints and the sacroiliac spine. Enthesopathy and dactylitis are also seen. The diagnosis is clinical, and the condition should be suspected in patients with psoriasis. Management includes DMARDs and biologic agents.
  • Ankylosing spondylitis: a spondyloarthropathy involving inflammation of the axial skeleton, resulting in back pain, kyphosis, and loss of lumbar lordosis. Some patients may also have peripheral joint involvement, anterior uveitis, aortic insufficiency, aortitis, cardiac conduction abnormalities, and cavitary lung lesions. Diagnosis is based on lumbosacral radiographic findings (sacroiliitis and “bamboo spine”) and the presence of HLA-B27. Management includes NSAIDs, TNF inhibitors, or interleukin-17 antagonists.
  • Inflammatory bowel disease (IBD): includes Crohn’s disease and ulcerative colitis, and is characterized by chronic inflammation of the GI tract due to a cell-mediated immune response to the GI mucosa. Symptoms include diarrhea, abdominal pain, and weight loss. Extraintestinal manifestations can include a migratory peripheral arthritis of large joints. Inflammatory bowel disease is also associated with other disorders, such as ankylosing spondylitis, sacroillitis, and uveitis. Diagnosis includes imaging, endoscopy, and biopsy. Treatment involves steroids, aminosalicylates, immunomodulators, and biologic agents

References

  1. Papadakis, M. A., In McPhee, S. J., & In Rabow, M. W. (2020). Current medical diagnosis & treatment. 59th ed. McGraw-Hill Education.
  2. Yu, D.T., and van Tubergen, A. (2020). Reactive arthritis. UpToDate. Retrieved January 1, 2021, from https://www.uptodate.com/contents/reactive-arthritis
  3. Lozada, C.J., Carpintero, M.F., and Schwartz, R.A. (2020). Reactive arthritis. https://emedicine.medscape.com/article/331347-overview
  4. Kontzias, A. (2020). Reactive arthritis. MSD Manual Professional Version. https://www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/joint-disorders/reactive-arthritis

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