Reactive Arthritis (Reiter Syndrome)

Reactive arthritis is an acute, sterile, inflammatory arthritis that develops following a distant infection, typically genitourinary or gastrointestinal. Previously known as Reiter syndrome (now deprecated due to historical associations), it is classified as a seronegative spondyloarthropathy.

Epidemiology:

• Incidence: 30-40 per 100,000 following enteric infection, 4-8 per 100,000 following chlamydial infection
• Male to female ratio: 3:1 for post-venereal, 1:1 for post-enteric
• Peak age: 20-40 years
• HLA-B27 positive in 60-80% of patients

Risk Factors:

• Recent infection: GU or enteric 1-4 weeks prior
• HLA-B27 positivity: Increases risk and severity
• Male sex: Higher incidence of post-venereal form
• Immunocompromised state: HIV increases risk

Understanding the pathophysiology of reactive arthritis is essential for both diagnosis and management. The condition involves an aberrant immune response to microbial antigens in genetically susceptible individuals.

Triggering Infections

Genitourinary triggers:

• Chlamydia trachomatis (most common GU trigger)
• Ureaplasma urealyticum
• Mycoplasma genitalium

Enteric triggers:

• Salmonella (typhimurium, enteritidis)
• Shigella (flexneri most arthritogenic)
• Campylobacter jejuni
• Yersinia enterocolitica

Immunopathogenesis

Molecular mimicry and bacterial persistence:

1. Infection triggers initial immune response
2. Bacterial antigens or DNA persist in synovium (demonstrated for Chlamydia)
3. Cross-reactivity between bacterial and self-antigens
4. HLA-B27 may inefficiently present bacterial peptides
5. Th17 cells and IL-17/IL-23 axis drive synovial inflammation

HLA-B27 role:

• Present in 60-80% of patients (vs 8% general population)
• Associated with more severe and chronic disease
• Associated with axial involvement
• Mechanism: arthritogenic peptide presentation, protein misfolding, homodimer formation

Chronicity Factors

• HLA-B27 positivity
• Enteric rather than GU trigger (Yersinia especially)
• Persistent infection (untreated Chlamydia)
• Early sacroiliac joint involvement

The Classic Triad

Arthritis (95-100%):

• Appears 1-4 weeks after triggering infection
• Asymmetric oligoarthritis (fewer than 5 joints)
• Lower limb predominance (knee, ankle, feet)
• May be additive (new joints over days/weeks)
• Enthesitis: Achilles tendonitis, plantar fasciitis
• Dactylitis: "sausage digit" - entire toe/finger swollen

Urethritis (90% of post-venereal):

• May be mild or asymptomatic
• Dysuria, urethral discharge
• Can occur in enteric-triggered disease (sterile urethritis)
• May precede arthritis

Conjunctivitis (30-60%):

• Usually bilateral
• Mild, self-limiting
• May progress to anterior uveitis (15%) - more serious, requires ophthalmology

Mucocutaneous Features

Keratoderma blennorrhagicum:

• Psoriasiform hyperkeratotic lesions
• Palms and soles characteristic
• Histologically identical to pustular psoriasis

Circinate balanitis:

• Painless erythematous erosions on glans penis
• Pathognomonic for reactive arthritis
• May be missed if not specifically examined

Oral ulcers:

• Painless aphthous-like ulcerations
• Tongue, palate, buccal mucosa

Nail changes:

• Onycholysis, subungual hyperkeratosis
• Similar to psoriatic changes

Physical Examination

Inspection:

• Swollen, erythematous joints (asymmetric)
• Dactylitis ("sausage digits")
• Skin lesions on palms, soles
• Conjunctival injection

Palpation:

• Tender joints and entheses
• Achilles tendon tenderness
• Plantar fascia tenderness

Laboratory Studies

Inflammatory markers:

• ESR and CRP elevated during acute phase
• Useful for monitoring response

HLA-B27:

• Positive in 60-80%
• Supports diagnosis but not required
• Predicts chronicity and axial involvement

Rheumatoid factor and anti-CCP:

• Negative (seronegative spondyloarthropathy)

Infection screen:

• Urethral swab or first-void urine for Chlamydia PCR
• Stool culture if enteric trigger suspected
• May be negative if infection has cleared

Synovial Fluid Analysis

Gold standard to exclude septic arthritis:

• WBC: 10,000-50,000/microL (inflammatory)
• Predominantly neutrophils
• Gram stain and culture NEGATIVE
• Crystal analysis NEGATIVE

Imaging

Plain radiographs:

• Often normal early in disease
• Periosteal reaction at entheses (fluffy periostitis)
• Asymmetric sacroiliitis (if axial involvement)
• Erosions in chronic disease

MRI:

• Synovitis, enthesitis, bone marrow edema
• Useful for sacroiliac joint assessment
• Detects early axial involvement

Ultrasound:

• Synovial thickening and effusion
• Enthesitis at Achilles, plantar fascia
• Power Doppler shows active inflammation

Indications for Surgery

Surgical intervention is rarely required in reactive arthritis. Indications include:

1. Joint destruction: Rare, but end-stage arthropathy may require arthroplasty
2. Tendon rupture: Achilles tendon rupture from chronic enthesitis
3. Persistent effusion: Arthroscopic synovectomy in refractory cases

Disease Complications

• Chronic arthritis: 30-50% develop chronic or recurrent disease
• Ankylosing spondylitis: May evolve to AS in HLA-B27+ patients
• Vision loss: From untreated uveitis
• Cardiovascular: Aortitis and conduction defects (rare)
• Amyloidosis: Secondary amyloidosis in chronic disease

Prognosis

• Self-limiting: 50% recover fully within 6 months
• Recurrent: 15-30% have recurrent episodes
• Chronic: 15-30% develop chronic disease
• HLA-B27: Associated with worse prognosis

• Role of prolonged antibiotics: Only PCR-proven chronic Chlamydia-induced ReA has RCT support for 6-month combination therapy (Carter 2010). For enteric-triggered and acute disease, antibiotics do not alter the natural history (Laasila 2003), yet the practice is sometimes applied too broadly.
• Diagnostic criteria: There are no universally agreed criteria. The very term "reactive arthritis" is applied inconsistently, which inflates the reported incidence range (0.6 to 27 per 100,000) and undermines cross-study comparison (Townes 2010).
• HLA-B27 as a test: HLA-B27 is prognostic, not diagnostic. A negative result does not exclude ReA and a positive result in an unselected patient has poor specificity; it should not be used to make the diagnosis (Hannu 2011).
• Triad reliance: The full triad (arthritis, urethritis, conjunctivitis) is present in a minority. Waiting for the complete triad delays diagnosis; most patients present with arthritis plus a recent trigger only.
• Terminology: "Reiter syndrome" is being abandoned for both ethical and descriptive reasons, but lingers in older literature and some exam material.
• Biologic timing and persistence concern: TNF inhibitors help refractory disease, but the theoretical risk of reactivating a persistent intra-articular organism remains debated; available data (Flagg 2005) showed no clinical flare despite synovial bacterial DNA.

Reactive arthritis is a worldwide diagnosis with no single authoritative guideline; management is extrapolated from the broader peripheral spondyloarthritis literature (ASAS/EULAR, ACR).

Global epidemiology:

• Population-based annual incidence 0.6 to 27 per 100,000 (the wide range reflects inconsistent case definitions, not true variation alone)
• Post-enteric ReA dominates where Campylobacter, Salmonella, Shigella and Yersinia are common; post-chlamydial ReA tracks the local burden of Chlamydia trachomatis
• HLA-B27 background prevalence varies markedly by population (high in Northern Europe and some Indigenous groups, very low in equatorial Africa and parts of East Asia), influencing both incidence and chronicity
• Up to 1 to 4% of patients develop reactive joint symptoms after a documented enteric outbreak

Side-by-side guidance (no ReA-specific society guideline exists):

Notification and public health: Chlamydia, gonorrhoea and several enteric pathogens (Salmonella, Shigella, Campylobacter) are statutorily notifiable in most jurisdictions worldwide. Partner notification for post-venereal disease and outbreak investigation for enteric triggers are standard, with thresholds and mechanisms set locally.

High- vs limited-resource practice variation:

• Well-resourced settings: HLA-B27 typing, Chlamydia PCR, MRI for early sacroiliitis, and access to DMARDs/biologics for the refractory minority
• Limited-resource settings: diagnosis is clinical and trigger-based; joint aspiration to exclude sepsis and empirical NSAIDs are the priorities; HLA-B27 and biologics are often unavailable, making early recognition and trigger treatment the highest-value interventions

Registries: There is no dedicated reactive-arthritis registry; long-term outcome data derive from national spondyloarthritis cohorts and post-outbreak follow-up studies rather than implant/arthroplasty registries (surgery is rarely required).