• Incidence: 0.6–26 per 100,000 per year; prevalence: 30–40 per 100,000 ^[3]
• The wide range in incidence reflects variation by geographic region, prevalence of triggering infections, and HLA-B27 prevalence in the population
• Post-enteric ReA occurs in approximately 1–4% of individuals following a documented enteric infection (e.g., Salmonella, Shigella outbreak)
• Post-chlamydial ReA occurs in approximately 4–8% of patients with Chlamydia trachomatis urethritis

• Male-to-female ratio ≈ 15:1 (marked male predominance) ^[2]
  • This extreme male predominance is most apparent in post-venereal (post-chlamydial) ReA
  • Post-enteric ReA has a more equal sex distribution (~1:1)
  • Why the difference? Chlamydial urethritis is more commonly symptomatic and detected in males; the enteric route affects both sexes equally
• Age of onset: Typically 20–40 years old (young adults), coinciding with peak sexual activity and exposure to enteric pathogens
• Uncommon in children, though it can occur (especially post-enteric)

• HLA-B27 prevalence in Southern Chinese is approximately 6–8% ^[3] — lower than in Caucasians (~8%) but not negligible
• Enteric triggers are particularly relevant in Hong Kong given the high prevalence of:
  • Salmonellosis (food-borne, from contaminated poultry, eggs)
  • Campylobacter (undercooked poultry, unpasteurised dairy)
  • Shigella (travellers returning from mainland China, Southeast Asia)
• Chlamydia trachomatis is the most common notifiable STI in Hong Kong, making post-chlamydial ReA an important consideration in young adults
• Overall, ReA is uncommon but not rare in Hong Kong clinical practice

• A synovial joint consists of:
  • Articular cartilage: Smooth hyaline cartilage covering bone ends — avascular, nourished by synovial fluid
  • Synovial membrane (synovium): Lines the inner surface of the joint capsule; responsible for producing synovial fluid (which lubricates and nourishes cartilage)
  • Joint capsule: Fibrous outer layer providing structural integrity
  • Synovial fluid: Normally clear, viscous, contains < 200 WBC/mm³

In ReA, the synovium becomes the primary target of inflammation (synovitis), leading to effusion, pain, and — if chronic — potential erosive damage.

• The enthesis is the site where tendons, ligaments, or joint capsules insert into bone ^[1][3]
• Examples: Achilles tendon insertion at the calcaneus, plantar fascia insertion, patellar tendon insertion at the tibial tuberosity
• Enthesitis (inflammation of the enthesis) is a hallmark of all spondyloarthropathies, including ReA
• The enthesis is a biomechanically stressed structure with rich vascularisation at the bone–tendon junction, which may predispose to immune-mediated inflammation
• Why enthesitis in SpA? The enthesis is rich in resident immune cells (macrophages, innate lymphoid cells) and is subject to mechanical stress — a "danger zone" where microbial antigens may localise

• Dactylitis ("sausage digit") results from inflammation of the entire digit, involving the flexor tendon, tendon sheath, and surrounding soft tissues
• Distinguishes SpA from RA (where joint swelling is typically localised to the joint itself)

• Uvea = iris + ciliary body + choroid
• Anterior uveitis (iritis): Inflammation of the iris and anterior ciliary body — the most common ocular manifestation of SpA
• Conjunctivitis: Inflammation of the conjunctival membrane — classically part of the Reiter's triad

• A partly synovial, partly fibrous joint connecting the sacrum to the ilium
• Sacroiliitis (inflammation of the SI joint) is characteristic of axial SpA and may occur in reactive arthritis, though axial involvement is less common than peripheral

• HLA-B27 is strongly associated with reactive arthritis
  • Present in approximately 60–80% of patients with ReA (vs. 6–8% in the general Southern Chinese population) ^[3]
  • Present in > 95% of ankylosing spondylitis and ~90% of reactive arthritis ^[3] — though the 90% figure varies by study; many sources cite 60–80% for ReA specifically
  • HLA-B27 positivity predicts:
    • More severe disease
    • Greater likelihood of axial involvement (sacroiliitis, spondylitis)
    • Increased risk of chronicity and progression to ankylosing spondylitis
    • Increased risk of anterior uveitis
  • However, HLA-B27 is neither necessary nor sufficient for disease — many HLA-B27+ individuals never develop SpA, and some ReA patients are HLA-B27 negative

• Certain bacterial antigens share structural similarity with self-antigens expressed in the joint, enthesis, or uveal tract
• The immune response initially directed against the infecting organism cross-reacts with self-tissue
• This is analogous to the mechanism in acute rheumatic fever (where anti-streptococcal antibodies cross-react with cardiac myosin) ^[6]

• Viable but non-culturable bacterial antigens (and sometimes bacterial DNA) have been detected in the synovial tissue and fluid of ReA patients
• Particularly demonstrated for Chlamydia trachomatis — chlamydial rRNA, DNA, and even metabolically active organisms have been found in affected joints
• The hypothesis: the triggering organism (or its components) disseminates to the joint via macrophages or dendritic cells, establishing a low-grade persistent infection that drives chronic inflammation
• This is NOT the same as septic arthritis — the organisms are not freely replicating and cannot be cultured by standard microbiological techniques

HLA-B27 contributes to pathogenesis through several proposed mechanisms ^[3]:

1. Arthritogenic peptide hypothesis: HLA-B27 presents certain bacterial peptides to CD8+ T cells that cross-react with self-peptides in the joint (a form of molecular mimicry at the MHC level)
2. HLA-B27 misfolding hypothesis: The HLA-B27 heavy chain has a tendency to misfold in the endoplasmic reticulum (ER), triggering the unfolded protein response (UPR), which activates NF-κB and pro-inflammatory cytokine production (particularly IL-23/IL-17 axis)
3. HLA-B27 homodimer hypothesis: Misfolded HLA-B27 can form homodimers on the cell surface that are recognised by innate immune receptors (e.g., KIR3DL2 on NK cells and CD4+ T cells), promoting a Th17 response and IL-17 production

• This is the dominant cytokine pathway in spondyloarthritis (distinct from the TNF-α–dominant pathway in RA)
• IL-23 (produced by dendritic cells and macrophages in response to bacterial stimulation) drives differentiation of Th17 cells
• IL-17 produced by Th17 cells promotes:
  • Neutrophil recruitment to the synovium and entheses
  • Osteoclast activation → bone erosion
  • Paradoxically, also new bone formation at entheseal sites (syndesmophytes)
• TNF-α also plays a role, which is why anti-TNF biologics are effective

• The enthesis is uniquely susceptible in SpA because:
  • It is subject to mechanical stress (micro-damage → danger signals)
  • It contains resident innate immune cells (γδ T cells, innate lymphoid cells type 3) that express IL-23 receptors
  • Bacterial antigens may preferentially localise here
• The combination of mechanical stress + genetic susceptibility (HLA-B27) + bacterial antigen persistence creates a "perfect storm" for chronic inflammation

As noted above, reactive arthritis is one of the traditional subtypes of SpA. The ASAS (Assessment of SpondyloArthritis International Society) 2009 classification now divides SpA into ^[3][4]:

Reactive arthritis predominantly presents as peripheral SpA but can have axial features (sacroiliitis) — especially in HLA-B27+ patients.

The classic triad is actually present in only about one-third of patients. More commonly, patients present with incomplete forms ^[2][3]:

Important: The absence of the full triad does NOT exclude the diagnosis. Any patient with asymmetric oligoarthritis 1–4 weeks after a GI or GU infection should be considered for ReA.

Out of all the investigations, joint aspiration with synovial fluid analysis for leucocyte, Gram stain, culture, and crystal, is the most important test ^[7]

This is a particularly important differential in sexually active young adults presenting with arthritis + urethritis + skin lesions:

The lecture slide highlights the following clinical features of SpA ^[4][6]:

Spondylitis; Peripheral arthritis; Enthesitis (Achilles tendinitis, plantar fasciitis); Anterior uveitis; Aortitis; Associated with HLA-B27; Other associated features: psoriasis, inflammatory bowel disease, dysentery, sexually transmitted disease ^[6]

The key discriminator between SpA subtypes is the associated condition:

When features overlap (e.g., a patient with psoriasis who develops arthritis after Salmonella gastroenteritis), clinical judgement and the temporal relationship to infection guide the diagnosis.

Both are sterile arthritides triggered by infection, but they are fundamentally different diseases:

The common causes of monoarthritis include septic arthritis, crystal deposition arthritis e.g. gouty arthritis and pseudogout, haemarthrosis. Do include other polyarticular diseases with monoarticular presentation. Examples include rheumatoid arthritis, psoriatic arthritis and spondyloarthritis. ^[7]

Differential hierarchy for acute monoarthritis ^[7][11]:

1. Septic arthritis — exclude first, always
2. Crystal arthritis (gout, pseudogout)
3. Trauma / haemarthrosis
4. ReA / SpA with monoarticular onset
5. RA with monoarticular onset
6. OA with acute flare

Clinical features of different arthritis — history ^[4]:

• Rheumatoid Arthritis: Younger age; insidious onset; polyarthritis; small hand joints; sparing DIP joints; early morning stiffness ≥30 mins
• Spondyloarthritis: Younger age; insidious onset; mono or polyarthritis; any joint could be involved; psoriasis, IBD, STD/dysentery, uveitis; back pain; family history
• Osteoarthritis: Insidious onset; DIP joints or weight-bearing joints; older age
• Gout: Acute onset; first metatarsophalangeal joint involvement; usually self-limiting; sometimes fever ^[4]

The differential of anterior uveitis in a young adult includes ^[3][5]:

• SpA (AS, ReA, PsA, EnA) — most common systemic association
• JIA (oligoarticular, ANA+)
• Behçet's disease (panuveitis, retinal vasculitis)
• Sarcoidosis (bilateral granulomatous uveitis)
• Infections (TB, syphilis, HSV, CMV)
• Idiopathic (~30%)

This is the most widely cited attempt at standardising the diagnosis:

Two requirements must be met:

1. Arthritis: Mono- or oligoarthritis, predominantly lower limbs, asymmetric
2. Evidence of preceding infection: Clinical diarrhoea or urethritis 1–4 weeks before onset of arthritis

Plus one of the following to confirm the infection:

• Positive urine ligase chain reaction/PCR for Chlamydia trachomatis
• Positive stool culture for enteric pathogens (Salmonella, Shigella, Yersinia, Campylobacter)

Since reactive arthritis is classified as peripheral spondyloarthritis under the ASAS framework, the ASAS criteria for peripheral SpA can be applied ^[2][3]:

Entry criterion: Peripheral arthritis (usually lower limb, asymmetric) ± enthesitis ± dactylitis

Plus ≥1 of the following SpA features:

• Anterior uveitis
• Psoriasis
• IBD (Crohn's or UC)
• Preceding infection (within 1 month: urethritis/cervicitis or diarrhoea)
• HLA-B27 positive
• Sacroiliitis on imaging

OR ≥2 of the following:

• Arthritis
• Enthesitis
• Dactylitis
• Inflammatory back pain (ever)
• Family history of SpA

SpA features ×11 as listed in ASAS criteria — these are the key clinical and laboratory features that define the SpA spectrum ^[2]

The ASAS criteria conceptualise the SpA family as a spectrum, with reactive arthritis, PsA, EnA, and AS as overlapping entities rather than discrete diseases ^[4][6]

In practice, the diagnosis of ReA is made when all four of the following are satisfied:

The presence of extra-articular features (conjunctivitis, anterior uveitis, keratoderma blennorrhagica, circinate balanitis, enthesitis, dactylitis) strongly supports the diagnosis but is not required.

What to send synovial fluid for ^[17][18]:

• Gram stain (urgent if septic arthritis suspected)
• Culture with sensitivity testing
• WBC count with differential
• Crystal analysis by polarised microscopy
• Glucose (low in septic arthritis compared to serum) ^[17]

Interpretation of synovial fluid results:

The synovial fluid classification table ^[1][19]:

Expected findings in reactive arthritis ^[1]:

• Inflammatory synovial fluid
• WBC count = 2,000–64,000/mm³ with neutrophil predominance ^[1]
• Culture negative (by definition — this is what makes it "reactive" rather than "septic")
• No crystals on polarised microscopy

Why is viscosity LOW in inflammatory fluid? Because inflammatory enzymes (notably hyaluronidase from neutrophils) degrade hyaluronic acid — the glycosaminoglycan responsible for the normal viscosity of synovial fluid. The "string test" (ability of fluid to form a long string when dripped) is reduced.

The purpose of infection workup is to identify the preceding infection that triggered the reactive process. This confirms the diagnosis but — critically — inability to identify the causative organisms does not exclude the diagnosis ^[1].

Slit lamp for chronic anterior uveitis should be part of the assessment in any SpA patient ^[8]

ALWAYS check HLA-B27 when evaluating uveitis — particularly if bilateral, severe, or recurrent ^[20]

NSAIDs are the 1st line therapy for anti-inflammatory effects in patients with reactive arthritis ^[1]

Mechanism: NSAIDs inhibit cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis → decreased pain, swelling, and stiffness. In SpA, they have a modest disease-modifying effect — continuous use (even when asymptomatic) may slow structural progression, particularly in axial SpA ^[3].

Why NSAIDs work well in SpA/ReA: The inflammatory process in SpA is heavily prostaglandin-dependent (more so than in RA), which is why NSAIDs provide ~70–80% symptom relief in SpA ^[3].

Arthritis: NSAID / IA steroid ^[2]

Contraindications (unless contraindicated e.g. GI bleeding / CVS disease / renal failure ^[1]):

NSAID with concurrent corticosteroids for treatment of arthritis/rheumatism of any kind: increased risk of peptic ulcer disease ^[22]

GI risk mitigation if NSAIDs must be used:

• Co-prescribe PPI (e.g., omeprazole 20mg OD) — PPI raises gastric pH, ulcerogenic effects become reduced ^[23]
• Or use a selective COX-2 inhibitor (e.g., celecoxib) — lower GI risk but still present
• Check and eradicate H. pylori if positive

Non-biological DMARDs are indicated in patients who do not respond adequately to all initial therapy or in patients who develop refractory reactive arthritis defined as disease lasting > 6 months ^[1]

Key points about DMARDs in ReA:

• DMARDs are effective for peripheral arthritis but generally NOT effective for axial symptoms (sacroiliitis, spondylitis) or enthesitis ^[3]
• Onset of action is slow (weeks to months) — hence the need for bridging therapy with steroids
• Sulphasalazine is preferred in reactive arthritis specifically because it has fewer dermatological side effects than methotrexate (important given the skin manifestations of ReA)
• Methotrexate is contraindicated in pregnancy and CKD ^[24]; requires regular monitoring (FBC, LFT, RFT)

Sulphasalazine or methotrexate for patients with peripheral arthritis ^[24]

Name breakdown — Sulphasalazine: "sulpha" = sulphapyridine (sulphonamide antibiotic moiety) + "salazine" = 5-aminosalicylic acid (5-ASA, anti-inflammatory). The two moieties are linked by an azo bond and cleaved by colonic bacteria. Originally designed for RA (the sulphapyridine component) and IBD (the 5-ASA component) — hence its dual utility.

Biological DMARDs (Anti-TNF agents) are indicated in patients who are refractory to NSAIDs, glucocorticoid and DMARDs ^[1]

There are three TNF inhibitors approved for use in RA. Infliximab and adalimumab are anti-TNF-α antibodies whereas etanercept is a recombinant soluble p75 TNF receptor:Fc fusion protein ^[25]

Why anti-TNF works in ReA: TNF-α is a key pro-inflammatory cytokine in the SpA inflammatory cascade. It drives synovial inflammation, enthesitis, and bone erosion. Blocking TNF-α interrupts this cycle.

Contraindications for anti-TNF agents ^[3][24]:

Anti-TNF-alpha is the classical example that can increase risk of developing TB, given the importance of TNF-alpha in confining TB to the tuberculoma ^[26]

Pre-biologic screening checklist:

• IGRA (Interferon-Gamma Release Assay) or tuberculin skin test for latent TB ^[26]
• Hepatitis B and C serology (risk of reactivation)
• HIV serology
• Chest X-ray
• CBC, LFT, RFT
• Vaccination review (avoid live vaccines on biologics)

Isoniazid chemoprophylaxis can be given to patients with latent TB, as demonstrated by tuberculin skin test or IGRA (3 months) ^[26]

Anti-IL-17A (Secukinumab) is an alternative biologic with similar efficacy in SpA, particularly effective for enthesitis and skin disease. However, it is contraindicated in IBD (may worsen gut inflammation) — an important distinction when choosing biologics in the SpA spectrum ^[3].

Choice of biologic in specific extra-articular settings ^[3]:

General measures: education, stretching exercise, physiotherapy, smoking cessation ^[3][8]

• Prognosis: variable, majority remit ≤6–12 months but 15–20% have chronic persistent arthritis ^[3]
• Why does chronicity develop? In HLA-B27+ individuals, the aberrant immune response becomes self-perpetuating — bacterial antigen persistence in the joint (particularly Chlamydia) drives ongoing IL-17/TNF-α production even after the triggering infection has cleared. The unfolded protein response from HLA-B27 misfolding provides a continuous pro-inflammatory stimulus independent of the original infection.
• Chronic ReA is defined as disease lasting > 6 months ^[1]
• Manifests as persistent synovitis, ongoing joint pain and swelling, progressive functional limitation
• Risk factors for chronicity:
  • HLA-B27 positive — HLA-B27 has prognostic value ^[4]
  • Male sex
  • Hip involvement
  • Dactylitis
  • Poor NSAID response
  • High acute-phase reactants at presentation
  • Smoking ^[3]

• Approximately 15–50% of patients experience recurrent attacks
• Recurrences may be triggered by re-exposure to the same or a different triggering organism (e.g., re-infection with Chlamydia in a patient who originally had post-chlamydial ReA, or a new Salmonella exposure)
• Each recurrence carries a risk of cumulative joint damage

• Approximately 5–10% of patients with reactive arthritis progress to established AS
• This occurs almost exclusively in HLA-B27-positive patients with axial involvement (sacroiliitis)
• The pathophysiology: recurrent inflammatory insults to the sacroiliac joints and spine trigger a cycle of erosion followed by new bone formation (syndesmophytes, ankylosis) — the same mechanism that drives AS
• Represents a transition from "peripheral SpA with reactive trigger" to "axial SpA" along the SpA spectrum ^[4]

The concept of SpA as a spectrum: reactive arthritis can evolve over time into other SpA subtypes, particularly axial SpA/AS ^[4]

• In chronic ReA, persistent synovitis (mediated by pannus — a mass of proliferating synovium) can lead to:
  • Cartilage destruction — inflammatory cytokines (TNF-α, IL-1, IL-17) activate metalloproteinases (MMPs) that degrade the cartilage matrix
  • Periarticular bone erosion — osteoclast activation driven by RANKL (upregulated by TNF-α and IL-17)
  • Joint space narrowing — secondary to cartilage loss
• However, erosive disease is less common in ReA than in RA or PsA — rarely erosive in early disease ^[2]
• X-ray findings in chronic ReA: characteristically periostitis with fluffy calcaneal spurs (sacroiliitis and syndesmophytes, if present, tend to be asymmetrical) ^[3]

• Chronic enthesitis at weight-bearing sites can lead to:
  • Achilles tendon thickening and calcification — reactive new bone formation at the enthesis (enthesophyte)
  • Plantar fascia calcification and calcaneal spurs — fluffy calcaneal spurs ^[3]
  • Achilles tendon rupture — particularly if treated with local corticosteroid injection (which weakens collagen cross-linking) or fluoroquinolone antibiotics
• The new bone formation at entheseal sites is paradoxical — the same IL-17 that drives erosion also stimulates osteoblastic activity, leading to pathological ossification

• Chronic inflammation → fibrosis of joint capsule and periarticular soft tissues → flexion contractures
• Particularly problematic at the hip and knee — reduces mobility and independence
• May lead to secondary osteoporosis from disuse
• Joint contracture/erosion is a recognised complication of chronic inflammatory arthritis ^[8]

Persistent uncontrolled anterior uveitis can be sight-threatening and lead to complications ^[27]:

Activity/severity of eye disease is NOT related to disease activity ^[3] — meaning uveitis can flare or persist even when the arthritis is in remission. This is why ongoing ophthalmological surveillance is essential.

• Conjunctivitis in ReA is usually mild and self-limiting ^[3]
• Rarely leads to significant complications
• May occasionally progress to keratitis (corneal involvement) if severe or untreated, but this is uncommon

• Usually self-limiting, but in severe cases the hyperkeratotic lesions on palms and soles can become:
  • Confluent and widespread — covering large areas of the body
  • Functionally disabling — thick plaques on the soles impair walking
  • Secondarily infected — cracked, fissured skin provides a portal of entry for bacteria
• Histologically identical to pustular psoriasis — may be treated with psoriasis-directed therapies (methotrexate, biologics) if severe

• Usually painless and self-limiting
• In uncircumcised men, the moist environment may promote secondary candidal or bacterial infection
• Rarely causes phimosis (scarring of the prepuce) in severe chronic cases

• Nail dystrophy with subungual hyperkeratosis ^[3]
• Similar to psoriatic nail disease — onycholysis, pitting, ridging, subungual debris
• May cause cosmetic concern and functional impairment (pain, difficulty with fine motor tasks)
• Subungual hyperkeratosis can be a site for secondary fungal infection (onychomycosis)

• Aortitis is listed as a clinical feature of SpA ^[4][6]
• Mechanism: chronic inflammation of the aortic root → aortic wall fibrosis and dilatation → aortic valve ring dilatation → aortic regurgitation
• More commonly seen in ankylosing spondylitis (part of the "6A" extra-articular manifestations) but can occur in any SpA subtype, including chronic ReA
• Usually develops only after years of chronic disease

• Aortic root fibrosis can extend to the AV node and bundle of His → heart block (1st degree → complete)
• Again, rare in ReA but important to recognise in the context of chronic SpA

• IgA nephropathy has been reported in association with SpA, including ReA
• Mechanism: mucosal immune dysregulation (the same mucosal immune system implicated in ReA pathogenesis) → overproduction of polymeric IgA → mesangial IgA deposition → glomerulonephritis
• Presents with haematuria ± proteinuria
• Usually mild and self-limiting but may rarely progress to CKD

• A rare complication of any chronic inflammatory condition, including chronic ReA
• Mechanism: persistent systemic inflammation → sustained elevation of serum amyloid A (SAA) protein (an acute-phase reactant produced by the liver in response to IL-6) → SAA misfolding and deposition in organs as AA amyloid fibrils
• Target organs: kidneys (nephrotic syndrome, renal failure), liver, spleen, GI tract
• Only occurs after years of poorly controlled chronic inflammation
• Prevention: aggressive treatment of the underlying inflammation to keep acute-phase reactants suppressed