RheumatologyTier 1Disease (DEADMAN)

Seronegative spondyloarthropathies - reactive arthritis

Description

Sterile inflammatory arthritis following an extra-articular infection, typically 1-4 weeks later
The organism is NOT in the joint - this is the defining concept and the reason synovial culture is negative
Member of the seronegative spondyloarthropathy family (with AS, psoriatic, enteropathic and undifferentiated SpA)
- Shared features: HLA-B27, enthesitis, dactylitis, asymmetric lower-limb oligoarthritis, axial disease, uveitis, RF-negative
*"Reiter syndrome" is obsolete (eponym abandoned - the triad arthritis + urethritis + conjunctivitis* occurs in only ~1/3)

Incidence ~1-30 per 100,000/yr, depending on the background rate of the triggering infections
Post-venereal: M>>F (up to 9:1); post-enteric: M=F
Peak age 20-40
HLA-B27 positive in 30-70% of cases (~8% of the general Caucasian population)
- HLA-B27 positivity predicts more severe, more axial, more chronic disease and more uveitis
Arthritis develops in ~1-4% after an epidemic enteric infection; up to 20-25% after Chlamydia urethritis in some series

Triggers

Enteric ("the dysentery group"): **Salmonella, Shigella (classically S. flexneri), Campylobacter jejuni, Yersinia enterocolitica, Clostridioides difficile**
Urogenital: *Chlamydia trachomatis (the commonest identifiable trigger), Ureaplasma urealyticum, Mycoplasma genitalium*
Other: Chlamydia pneumoniae; intravesical BCG for bladder cancer; Streptococcus (poststreptococcal reactive arthritis - a distinct entity)
*HIV - screen everyone (reactive arthritis and psoriatic arthritis are far more severe in untreated HIV*)

Mechanism

Bacterial antigens (LPS, DNA) are demonstrable in the synovium; VIABLE organisms are not
HLA-B27 hypotheses:
- Molecular mimicry between bacterial and HLA-B27-presented peptides
- Misfolding/unfolded protein response -> IL-23 -> IL-17 from entheseal-resident T cells
- Arthritogenic peptide presentation to CD8+ T cells
*The IL-23/IL-17 axis at the ENTHESIS is the unifying pathology of all spondyloarthropathies - hence enthesitis, not synovitis, is the primary lesion*

Articular pattern - the recognisable one

ACUTE, ASYMMETRIC, OLIGOARTHRITIS (2-4 joints), LOWER LIMB PREDOMINANT - knee, ankle, subtalar, MTP
ENTHESITIS - Achilles tendon and plantar fascia (heel pain is often the presenting complaint)
DACTYLITIS - "sausage digit" (toe > finger)
Inflammatory back pain and sacroiliitis (often asymmetric/unilateral) in ~20-50%

Extra-articular manifestations

Skin and mucosa
- *Keratoderma blennorrhagica - pustular, hyperkeratotic plaques on soles and palms; histologically indistinguishable from pustular psoriasis*
- *Circinate balanitis* - painless serpiginous penile plaques
- Painless oral ulcers; nail dystrophy, onycholysis, subungual hyperkeratosis
- Erythema nodosum (especially with Yersinia)
Ocular
- Conjunctivitis - early, bilateral, sterile, self-limiting
- Acute ANTERIOR UVEITIS - painful, photophobic, red eye with a constricted irregular pupil; an ophthalmic emergency
Genitourinary - aseptic (sterile) urethritis, cervicitis, prostatitis (occurs after ENTERIC triggers too - it is not proof of an STI)
Constitutional - fever, malaise, fatigue, weight loss
Cardiac (late, rare) - aortitis, aortic regurgitation, conduction block; AA amyloidosis with chronic disease

Investigations

*Aspirate the joint - septic arthritis is the diagnosis you cannot miss*
- Inflammatory fluid (2,000-50,000 WCC), Gram stain and culture NEGATIVE, no crystals
Inflammatory markers raised; RF and ANA negative (hence "seronegative")
HLA-B27 - prognostic, not diagnostic; a negative result does not exclude the disease
Identify the trigger (often already resolved)
- Chlamydia/gonorrhoea NAAT on first-pass urine or swabs (plus pharyngeal and rectal where indicated)
- Stool culture and PCR if a diarrhoeal prodrome
- *HIV and full STI screen, including syphilis serology*
Imaging: X-rays usually normal early; ultrasound/MRI for enthesitis and sacroiliitis; "fluffy" periostitis and enthesophytes later
Exclude: disseminated gonococcal infection (migratory arthralgia -> tenosynovitis -> pustular rash), crystal arthritis, acute rheumatic fever, psoriatic arthritis, IBD-related arthritis, Behcet

1. Treat the trigger - and the contacts

*Antibiotics do NOT treat the arthritis* once established
*But treat an ongoing Chlamydia infection - doxycycline 100 mg bd for 7 days (or azithromycin 1 g stat); treat sexual partners and arrange contact tracing*
- This reduces recurrence and prevents onward transmission and pelvic inflammatory disease - it does not shorten the arthritis
Do not give antibiotics for a resolved enteric infection
Prolonged combination antibiotics for chronic reactive arthritis remain unproven and are not recommended

2. Acute arthritis

NSAIDs at full anti-inflammatory dose, continuously - first line
Intra-articular corticosteroid for a dominant joint (after excluding sepsis)
Systemic prednisolone - short course for polyarticular or severe disease
Rest then graded physiotherapy; splinting for enthesitis

3. Persistent disease (>3-6 months)

Sulfasalazine - the best-evidenced conventional DMARD in reactive arthritis, particularly for peripheral disease
Methotrexate - peripheral arthritis
*Conventional DMARDs do NOT work for axial disease*
TNF inhibitors for refractory or axial disease (etanercept, adalimumab); IL-17 inhibitors (secukinumab, ixekizumab) where the spondyloarthritis phenotype dominates
- *Screen for HIV, hepatitis B/C and latent TB before any biologic*

4. Extra-articular

Anterior uveitis - same-day ophthalmology; topical corticosteroid + mydriatic
Conjunctivitis - supportive only
Skin lesions - topical corticosteroid, keratolytics; treat as for psoriasis if severe
Balanitis - topical corticosteroid

5. Counselling

Most resolve within 3-12 months - say so
Explain the recurrence risk with re-infection; safe sex, food and water hygiene

*HLA-B27* - severity, chronicity, axial disease and uveitis
Other spondyloarthropathies - AS, psoriatic arthritis, enteropathic arthritis, undifferentiated SpA
Anterior uveitis, conjunctivitis, scleritis
*HIV* - more severe, more extensive skin disease
IBD - both as a trigger (Yersinia, C. difficile) and as an evolving diagnosis
Keratoderma blennorrhagica, circinate balanitis, oral ulcers, nail dystrophy
Aortitis, aortic regurgitation, conduction disease (late)
AA amyloidosis (chronic disease)
Intravesical BCG therapy for bladder cancer

Self-limiting in the majority: resolves in 3-12 months (median ~4-6 months)
Recurrence in ~15-50% - usually with re-infection
Chronic disease (>6-12 months) in ~15-30%
- **HLA-B27 positivity, Chlamydia trigger, hip involvement and a family history of spondyloarthritis predict chronicity**
Evolution to ankylosing spondylitis in ~15-30% of HLA-B27-positive patients over years
Long-term complications: chronic peripheral arthritis, sacroiliitis/ankylosis, recurrent uveitis, aortic regurgitation, amyloidosis
Follow-up matters: the patient discharged as "post-infectious" is the one who returns with established axial spondyloarthritis

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