Reactive Arthritis (Reiter Syndrome)

Reactive arthritis is an acute, sterile, inflammatory arthritis that develops after a distant infection, typically genitourinary or gastrointestinal. It is classified as a seronegative spondyloarthropathy.

Who. Incidence is 30-40 per 100,000 following enteric infection and 4-8 per 100,000 following chlamydial infection, and population-based annual incidence is 0.6 to 27 per 100,000. Peak age is 20-40 years. The male to female ratio is 3:1 for the post-venereal form and 1:1 after enteric infection.

Risk factors. Recognised risk factors are these:

• Recent GU or enteric infection, 1-4 weeks before
• HLA-B27 positivity, which increases both risk and severity
• Male sex, for the post-venereal form
• Immunocompromise: HIV increases the risk

Against the other spondyloarthropathies. The temporal relationship to infection is the key distinguishing feature. Unlike ankylosing spondylitis, axial involvement is asymmetric and not always present. Unlike psoriatic arthritis, the skin lesions are different, and the disease is triggered by infection.

Reactive arthritis is an aberrant immune response to microbial antigens in a genetically susceptible host. The triggering infection may be subclinical, or may have resolved by the time the arthritis appears.

Triggering infections. Chlamydia trachomatis is the most common trigger overall.

• Genitourinary: Chlamydia trachomatis; Ureaplasma urealyticum (less common); Mycoplasma genitalium
• Enteric: Salmonella (typhimurium, enteritidis), from food poisoning; Shigella (flexneri the most arthritogenic); Campylobacter jejuni, a common cause of gastroenteritis; Yersinia enterocolitica, from undercooked pork
• Respiratory: Chlamydia pneumoniae, less common
• Other: C. difficile

Molecular mimicry and bacterial persistence. Infection triggers the initial immune response, and bacterial antigens or DNA then persist in the synovium, as has been demonstrated for Chlamydia. Bacterial and self-antigens cross-react, HLA-B27 may present bacterial peptides inefficiently, and Th17 cells and the IL-17/IL-23 axis drive the synovial inflammation.

HLA-B27. Present in 60-80% of patients, against 8% of the general population. It is associated with more severe disease and with axial involvement, and it heads the chronicity factors below. The mechanisms described are arthritogenic peptide presentation, protein misfolding and homodimer formation.

Chronicity. These factors are associated with chronic disease:

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

The triad. Arthritis, urethritis and conjunctivitis form the classic triad, but the full triad is present in only 30%. Most patients present with arthritis plus a recent trigger only, and waiting for the complete triad delays the diagnosis.

Arthritis (95-100%). It appears 1-4 weeks after the triggering infection as an asymmetric oligoarthritis of fewer than five joints, with lower-limb predominance in the knee, ankle and feet. It may be additive, with new joints joining over days or weeks.

Enthesitis and dactylitis are characteristic. Enthesitis shows as Achilles tendonitis and plantar fasciitis; dactylitis is the "sausage digit", the entire toe or finger swollen.

Urethritis (90% of post-venereal cases). Dysuria and urethral discharge, though it may be mild or asymptomatic and may precede the arthritis. A sterile urethritis can occur in enteric-triggered disease.

Conjunctivitis (30-60%). Usually bilateral, mild and self-limiting. It may progress to anterior uveitis, which is more serious and is separated from conjunctivitis in the section on the eye below.

Mucocutaneous features. Circinate balanitis is the pathognomonic one, and it may be missed if the glans is not specifically examined.

• Keratoderma blennorrhagicum - psoriasiform hyperkeratotic lesions, characteristically on the palms and soles, histologically identical to pustular psoriasis
• Circinate balanitis - painless erythematous erosions on the glans penis
• Oral ulcers - painless aphthous-like ulcerations of the tongue, palate and buccal mucosa
• Nail changes - onycholysis and subungual hyperkeratosis, similar to psoriatic changes

Examination. Look for swollen, erythematous joints in an asymmetric pattern, sausage digits, skin lesions on the palms and soles, and conjunctival injection. Palpate the joints and the entheses, particularly the Achilles tendon and the plantar fascia, for tenderness.

Aspirate first. Joint aspiration is mandatory in any acute monoarthritis, and septic arthritis must always be excluded before the joint is attributed to reactive arthritis. Synovial fluid analysis is the gold standard for excluding it.

• WBC greater than 50,000/microL - septic until proven otherwise
• WBC 10,000-50,000/microL - inflammatory: reactive, crystal or early septic
• Reactive arthritis gives inflammatory fluid, predominantly neutrophils, with Gram stain, culture and crystal analysis all negative

Bloods. ESR and CRP are elevated during the acute phase and are useful for monitoring the response to treatment. Rheumatoid factor and anti-CCP are negative: this is a seronegative spondyloarthropathy.

Infection screen. Send a urethral swab or first-void urine for Chlamydia PCR, and stool culture if an enteric trigger is suspected. Either may be negative if the infection has cleared.

HLA-B27 is prognostic, not diagnostic. It predicts chronicity and axial involvement and is not required for the diagnosis. A negative result does not exclude reactive arthritis, and a positive result in an unselected patient has poor specificity, so it should not be used to make the diagnosis (Hannu 2011).

Imaging. Plain radiographs are often normal early in the disease.

• Radiographs - fluffy periostitis (periosteal reaction at the entheses), asymmetric sacroiliitis if the axial skeleton is involved, and erosions in chronic disease
• MRI - synovitis, enthesitis and bone marrow oedema; useful for assessing the sacroiliac joints and detecting early axial involvement
• Ultrasound - synovial thickening and effusion, and enthesitis at the Achilles and plantar fascia; power Doppler shows active inflammation

In a young, sexually active patient who presents with arthritis after a genitourinary infection, the two diagnoses on the table are reactive arthritis, sterile and post-infectious, and disseminated gonococcal infection (DGI), a true and treatable infection. DGI is the most important specific mimic, and getting it wrong is dangerous: it is a septic process that needs urgent antibiotics, not NSAIDs.

Two presentations. DGI presents in two overlapping forms:

• The arthritis-dermatitis (bacteraemic) syndrome - migratory polyarthralgia, tenosynovitis (classically of the wrist, hand or ankle, and a distinguishing feature) and a sparse vesiculopustular or haemorrhagic rash
• A purulent (septic) monoarthritis or oligoarthritis, usually of a large joint

Find the organism anywhere. Any acutely inflamed joint is aspirated and cultured first. In the sexually active patient, add mucosal nucleic-acid amplification tests (urethral, cervical, pharyngeal and rectal) and blood cultures, because gonococcus is fastidious and the joint fluid culture is often negative even in true DGI. If gonococcus is found anywhere, treat as DGI with ceftriaxone: it is not reactive arthritis, even though both can follow the same sexual exposure.

Pain and photophobia with a unilateral red eye are the decisive features: they flag uveitis, not conjunctivitis. Acute anterior uveitis is the shared eye lesion of the whole HLA-B27 spondyloarthritis family, also seen in ankylosing spondylitis, and it recurs.

Untreated, it scars the eye through posterior synechiae, secondary glaucoma and cataract, and it can cause permanent visual loss, hence the same-day ophthalmology referral. Conjunctivitis is benign and needs only reassurance.

Surgical intervention is rarely required in reactive arthritis. The indications:

• Arthroscopic synovectomy - for persistent effusion in refractory cases; rarely required, and may provide temporary relief
• Tendon repair - for Achilles rupture from chronic enthesitis, by standard repair or reconstruction techniques
• Arthroplasty - very rarely indicated, for end-stage joint destruction, with standard techniques

Knee aspiration is both diagnostic and therapeutic.

1. Sterile preparation
2. Superomedial or superolateral approach
3. Aspirate as much fluid as possible
4. Send for cell count, Gram stain, culture and crystals

Natural history. 50% recover fully within 6 months, and 30-50% develop chronic or recurrent disease. Separately, 15-30% have recurrent episodes and 15-30% develop chronic disease.

Other complications. Beyond chronic arthritis:

• Evolution to ankylosing spondylitis, which may occur in HLA-B27-positive patients
• Aortitis and conduction defects (rare)
• Secondary amyloidosis in chronic disease

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):

Related pages: Seronegative Spondyloarthropathy is the family this belongs to and the framework the HLA-B27 association comes from; Ankylosing Spondylitis is where a minority of these patients end up, which is the reason the long-term follow-up studies carded above exist and the reason an HLA-B27-positive patient is followed rather than discharged; Psoriatic Arthritis of the Hand for the other peripheral spondyloarthropathy that shares dactylitis, enthesitis and nail change - and for the CASPAR criteria, which are classification rather than diagnostic criteria, exactly as HLA-B27 is prognostic rather than diagnostic here; Septic Arthritis Pathophysiology for the diagnosis that must be excluded by aspiration before any of this applies, since a sterile inflammatory effusion and an infected one are indistinguishable clinically; and Gout and Crystal Arthropathy and Pseudogout (CPPD) for the crystal causes of an acute hot monoarthritis in the same age group, which the same aspirate settles.

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 term "reactive arthritis" itself is applied inconsistently, which inflates the reported incidence range and undermines cross-study comparison (Townes 2010).

Biologics and a persistent organism. TNF inhibitors help refractory disease, but the theoretical risk of reactivating a persistent intra-articular organism remains debated. The available data (Flagg 2005) showed no clinical flare despite synovial bacterial DNA.