Ankylosing Spondylitis (AS)

Definition and Classification

Epidemiology

• Occurs in approximately 0.2% of the general population
• Found in ~2% of HLA-B27-positive individuals, rising to ~20% if they also have an affected family member
• Most common onset age: 15-25 years (can also occur in adolescence)
• Male-to-female ratio historically 2.5:1 to 5:1, though more recent data suggest a lower ratio
• HLA-B27 is present in 90-95% of White patients with AS; prevalence of B27 varies widely by ethnicity (absent in Australian aboriginals, 1% in Japan, 7% in northern Europeans)

Pathobiology

1. Molecular mimicry - sequence homology between B27 and gram-negative enteric bacteria (e.g., Klebsiella) may trigger cross-reactive immune responses
2. Unfolded protein response (UPR) - B27 is distinctive in its tendency to misfold in the endoplasmic reticulum, inducing a pro-inflammatory cascade
3. Heavy-chain homodimers - B27 can form homodimers at the cell surface, potentially activating NK and CD4+ T cells

Clinical Manifestations

Axial Disease (core)

• Inflammatory back pain - the hallmark: insidious onset, worse with rest/at night, improves with activity (distinguishes from mechanical back pain)
• Morning stiffness lasting >1 hour
• Sacroiliitis - bilateral, symmetrical; tenderness over SI joints
• Progressive spinal stiffness, loss of lumbar lordosis, increased thoracic kyphosis
• Reduced chest expansion (<2.5 cm at 4th intercostal space)
• Enthesitis - inflammation at tendon and ligament insertion sites (Achilles, plantar fascia, spinous processes)

Peripheral Joint Involvement

• Up to 30% of patients
• Hip joint is the most commonly affected peripheral joint after the SI joints
• Entheseal new bone forms around the femoral head

Extra-Articular Manifestations

Imaging Findings

Plain Radiography

• Sacroiliitis: erosions, subchondral sclerosis, joint space loss progressing to ankylosis
• Romanus lesions: sclerotic "shiny corners" at vertebral body corners (enthesitis at Sharpey fibers)
• Vertebral squaring: loss of normal concave anterior vertebral border
• Syndesmophytes: thin vertical bony outgrowths at Sharpey fiber insertions (distinguish from the coarser, more horizontal osteophytes of psoriatic or reactive arthritis)
• Bamboo spine: complete fusion of vertebral bodies with bridging syndesmophytes - the end-stage appearance

MRI

• Most sensitive for early sacroiliitis - detects subchondral bone marrow oedema before radiographic changes
• MRI equivalent of Romanus lesions: bone oedema at vertebral corners
• STIR sequences show active inflammation at costovertebral joints and entheseal sites

Important Complication

Diagnostic Criteria

1. Low back pain >3 months, improves with exercise, not relieved by rest
2. Limited lumbar spine motion in sagittal AND frontal planes
3. Reduced chest expansion relative to normal
4. Radiographic sacroiliitis (Grade ≥2 bilateral or Grade 3-4 unilateral)

Laboratory Findings

• HLA-B27: positive in ~90% of cases (not diagnostic alone; present in ~7% of general population)
• ESR and CRP: elevated in ~50-70% of active cases; can be normal
• RF and ANA: negative (seronegative arthritis)
• Mild normochromic anaemia in active disease
• Elevated alkaline phosphatase occasionally

Treatment

Non-pharmacological

• Exercise and physiotherapy programs are fundamental - improve cardiorespiratory fitness, spinal mobility
• Patient education, posture training
• Aquatic therapy, hydrotherapy

Step 1: NSAIDs

• First-line therapy for pain and stiffness
• Continuous NSAID use may slow radiographic progression (debated)
• Full anti-inflammatory doses required (e.g., naproxen, indomethacin, diclofenac)
• Cochrane evidence (Grade A) supports NSAIDs for axial SpA

Step 2: Local injections

• Corticosteroid injections into SI joints or peripheral entheses
• Systemic corticosteroids do NOT prevent progression and are not recommended for spinal disease

Step 3: Biologics (when NSAIDs fail after 6 weeks)

• TNF-α inhibitors are the most established; Cochrane evidence confirms efficacy (Grade A)
• Secukinumab (IL-17A) is highly effective, especially for radiographic AS
• NB: Screen for latent TB before starting anti-TNF therapy
• DMARDs (methotrexate, sulfasalazine) have limited efficacy for axial disease but may help peripheral arthritis

ACR/SAA/SPARTAN 2019 Guidelines framework:

Prognosis and Complications

• Clinical course is highly variable - some patients have mild, stable disease; others develop severe deformity
• Strongest predictor of new syndesmophyte formation: presence of syndesmophytes at baseline
• Late complications:
  • Cauda equina syndrome
  • Osteoporotic vertebral fractures
  • Spondylodiscitis (Andersson lesion)
  • Restrictive lung disease
  • Aortic regurgitation
  • Renal amyloidosis
• Ankylosing spondylitis rarely leads to pulmonary disability unless fibrobullous disease develops
• Work disability and quality-of-life impact are significant, especially with late diagnosis

Recent Evidence (2025-2026)

ANKYLOSING SPONDYLITIS - 15 Mark Answer

1. DEFINITION (1 mark)

2. EPIDEMIOLOGY (1 mark)

• Prevalence: ~0.2% of general population; ~2% of HLA-B27-positive individuals
• Age of onset: most commonly 15-25 years (young adults/adolescents)
• Sex: male predominance (M:F = 2.5-5:1, though gap is narrowing)
• Race: highest in White/Northern European populations; rare in Japanese and Australian aboriginal populations
• HLA-B27 positive in 90-95% of White patients with AS

3. ETIOPATHOGENESIS (2 marks)

• HLA-B27 is the strongest genetic association; present in ~90% of patients
• B27 subtypes B2705 (primordial) confer susceptibility; B2706 and B*2709 do not
• Non-MHC genes (ERAP1, IL-23R) also contribute

1. Molecular mimicry - sequence homology between B27 and gram-negative enteric bacteria (e.g., Klebsiella pneumoniae) triggers cross-reactive immune responses
2. Unfolded protein response (UPR) - B27 misfolds in the endoplasmic reticulum, inducing a pro-inflammatory cascade (IL-23/IL-17 axis activation)
3. Heavy-chain homodimers - B27 forms homodimers at the cell surface, aberrantly activating NK and CD4+ T cells

• Primary lesion is enthesitis - inflammation at the insertion of ligaments, tendons, and joint capsules into bone (especially at Sharpey fibers of the annulus fibrosus)
• Chronic inflammation → erosion → reactive new bone formation
• Syndesmophytes develop → bridging → ankylosis (fusion)

4. CLINICAL FEATURES (3 marks)

A. Spinal and Axial (Core Features)

B. Peripheral Involvement

• ~30% of patients develop peripheral arthritis - asymmetrical, large joints (hips, knees, ankles)
• Hip joint is the most common peripheral joint involved
• Enthesitis at Achilles tendon insertion, plantar fascia, tibial tuberosity

C. Extra-Articular Manifestations (remember: A COPE)

5. INVESTIGATIONS (2 marks)

Laboratory

Imaging

• Sacroiliac joints: erosions, subchondral sclerosis, joint space narrowing → eventual fusion (Grade 0-4 by New York criteria)
• Romanus lesion: sclerotic "shiny corners" of vertebral bodies (earliest spinal radiograph sign)
• Vertebral squaring: loss of normal concave anterior border
• Syndesmophytes: thin, vertical bony outgrowths at Sharpey fiber insertions
• Bamboo spine: complete spinal fusion with bridging syndesmophytes

• Most sensitive for early sacroiliitis before X-ray changes
• Subchondral bone marrow oedema on STIR/T2 fat-suppressed sequences = active inflammation
• Detects enthesitis at costovertebral joints, spinous processes, facet joints
• Preferred in young patients to avoid radiation

6. DIAGNOSIS (2 marks)

Modified New York Criteria (1984) - Still widely used clinically

1. Low back pain and stiffness >3 months, improves with exercise, not relieved by rest
2. Limited lumbar spine motion in sagittal AND frontal planes
3. Limited chest expansion (relative to normal for age and sex)

Definite AS = radiological criterion + at least 1 clinical criterion

ASAS Criteria for Axial SpA (2009) - Captures earlier/non-radiographic disease

• Imaging arm: Sacroiliitis on X-ray or MRI + ≥1 SpA feature
• Clinical arm: HLA-B27 positive + ≥2 SpA features

7. DIFFERENTIAL DIAGNOSIS (1 mark)

8. TREATMENT (3 marks)

A. Non-pharmacological (Always first-line)

• Physiotherapy is the cornerstone - spinal mobility exercises, posture training
• Swimming and hydrotherapy - ideal low-impact exercise
• Deep breathing exercises (to maintain chest expansion)
• Avoid smoking (worsens pulmonary restriction)
• Correct sleep posture (flat, straight back; no pillow under knees)
• Patient education and psychosocial support

B. NSAIDs (First-line pharmacotherapy)

• Indomethacin, diclofenac (up to 150 mg/day), or naproxen (up to 1000 mg/day)
• Continuous use may slow radiographic progression
• Goal: sufficient pain relief to enable exercise
• Use with caution in patients with IBD

C. Local Corticosteroid Injections

• For peripheral joints, SI joints, entheseal sites
• Systemic corticosteroids have no role in axial AS; do NOT prevent progression

D. DMARDs

• Sulfasalazine - for peripheral arthritis only (no benefit for axial disease)
• Methotrexate - limited evidence for AS

E. Biologic Therapies (when NSAIDs fail after 4-6 weeks)

Important: Screen for latent TB before initiating anti-TNF therapy

F. Surgery

• Total hip arthroplasty for severe hip disease
• Corrective osteotomy for severe fixed kyphosis
• Spinal surgery for fracture/instability

9. COMPLICATIONS AND PROGNOSIS (1 mark)