Ankylosing Spondylitis (AS) - A Complete Guide

Overview and Nomenclature

Epidemiology

• Prevalence roughly 0.1-1.4% in Western populations; varies with HLA-B27 frequency
• Onset typically in adolescents and young adults (usually before age 45)
• Historically thought to be male-predominant (3:1), but modern data suggest women are equally affected though often diagnosed later due to milder radiographic changes
• Sibling recurrence risk: ~9.2% vs. 0.1-0.4% in the general population, with heritability estimated >95%

Pathogenesis and Genetics

HLA-B27 - The Key Genetic Factor

90% of White AS patients carry HLA-B27, compared to ~8% of unaffected individuals, giving a relative risk of 50-100 or higher. Despite this strong association, only ~2% of HLA-B27-positive individuals develop AS, confirming that additional genetic and environmental factors are required.

1. Arthritogenic peptide hypothesis - HLA-B27 presents self-peptides to cytotoxic T cells, triggering autoreactivity
2. HLA-B27 misfolding hypothesis - misfolded heavy chains accumulate in the ER, inducing an unfolded protein response and IL-23 production
3. HLA-B27 homodimer hypothesis - surface homodimers activate NK and T cells

Beyond HLA-B27

• ERAP1/ERAP2 - aminopeptidase genes involved in peptide trimming for HLA presentation (ERAP1 only associates in HLA-B27-positive patients - a classic example of genetic epistasis)
• IL-23R, IL-12B, IL-27 - genes in the IL-23/IL-17 axis, explaining why IL-17 inhibitors work in AS
• Notably, IL-23 inhibitors (e.g. risankizumab, ustekinumab) have failed in AS trials despite working in psoriasis and IBD - suggesting the pathogenic IL-17 in AS may be driven by an IL-23-independent, innate-like lymphocyte pathway

Clinical Features

Axial (Spinal and SI Joint) Disease

• Onset before age 45
• Insidious onset over weeks to months
• Morning stiffness lasting >60 minutes
• Improvement with exercise, NOT with rest
• Nocturnal pain (often waking the patient in the second half of the night)
• Alternating buttock pain (suggesting SI joint involvement)

Peripheral Joint Involvement

Enthesitis

• Achilles tendon insertion
• Plantar fascia
• Iliac crests
• Tibial tuberosities
• Elbow epicondyles

Extra-Articular Manifestations

Imaging

Plain Radiography

• Grade 0: Normal
• Grade 1: Suspicious
• Grade 2: Erosions + sclerosis
• Grade 3: Definite erosions with sclerosis and partial ankylosis
• Grade 4: Complete fusion

• Shiny corner sign / Romanus lesions - sclerosis at vertebral corners from enthesitis at Sharpey fiber insertions
• Squared vertebral bodies - from erosion and anterior longitudinal ligament ossification
• Syndesmophytes - thin, vertical bone outgrowths bridging vertebral bodies (distinguishable from the coarser, non-marginal syndesmophytes of psoriatic/reactive arthritis and the horizontal osteophytes of degenerative disease)
• Bamboo spine - complete fusion of vertebral bodies and facet joints (end-stage)

MRI

CT

Diagnosis and Classification

Modified New York Criteria (1984) - for AS

1. Low back pain and stiffness >3 months, improving with exercise, not relieved by rest
2. Limitation of lumbar spine motion in both sagittal and frontal planes
3. Limitation of chest expansion relative to normal values for age and sex

• Bilateral sacroiliitis grade 2-4, OR unilateral sacroiliitis grade 3-4

ASAS Classification Criteria (2009) - for axial SpA (broader)

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

Laboratory Tests

• HLA-B27: Positive in >90% of White AS patients; useful for diagnosis but not sufficient alone
• CRP / ESR: Elevated in only 50-60% of patients; ESR and CRP often correlate poorly with disease activity, but elevated CRP is a risk factor for radiographic progression
• No specific autoantibodies - RF and ANA are typically negative (hence "seronegative")

Disease Activity Scores

• BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) - patient-reported; scores six domains; ≥4 = active disease
• ASDAS (Ankylosing Spondylitis Disease Activity Score) - incorporates CRP or ESR; preferred in guidelines
  • <1.3 = inactive disease
  • 1.3-2.1 = low disease activity
  • 2.1-3.5 = high disease activity

  • 3.5 = very high disease activity

Treatment

Step 1: Non-Pharmacologic Therapy

• Maintaining spinal mobility and posture
• Strengthening axial and peripheral muscles
• Improving chest expansion and respiratory function

Step 2: NSAIDs - First-Line Pharmacologic Therapy

• No single NSAID is preferred over another; evidence shows most are equally effective for axial disease
• Full dose is often needed; response is typically seen within 2 weeks
• If first NSAID fails, try a second NSAID before escalating to biologics
• For nocturnal symptoms, a long-acting nighttime formulation may be sufficient
• Extended-release formulations provide better overnight coverage

Step 3: Glucocorticoids

• Isolated peripheral joint involvement
• Sacroiliac joint injection (conditional recommendation per ACR/SAA/SPARTAN for isolated sacroiliitis) - although benefit is temporary and additional imaging-guided radiation exposure is a concern

Step 4: Conventional Synthetic DMARDs (csDMARDs)

Step 5: Biologic DMARDs (bDMARDs) - For NSAID Inadequate Responders

TNF Inhibitors (TNFi) - First Biologic Choice

• IBD comorbidity: Use a monoclonal antibody (infliximab, adalimumab, or certolizumab for Crohn's; infliximab, adalimumab, or golimumab for UC) - etanercept does NOT work for IBD
• Recurrent anterior uveitis: Prefer monoclonal antibodies (best evidence for adalimumab and infliximab)
• Pregnancy: Certolizumab pegol has minimal placental transfer and is the preferred TNFi in pregnancy
• Early and continuous treatment with anti-TNF agents has been shown to inhibit radiographic progression in longitudinal cohort studies

IL-17A Inhibitors - Alternative First or Second Biologic

Step 6: JAK Inhibitors (tsDMARDs) - For bDMARD Failures or Contraindications

• Rituximab (anti-CD20) - Phase II failure in TNFi inadequate responders
• Abatacept (CTLA4-Ig) - no efficacy
• Tocilizumab / sarilumab (IL-6 pathway) - no efficacy, no MRI improvement
• Ustekinumab (IL-12/23) - Phase III closed early for failure in biologic-naive AS
• Risankizumab (IL-23) - failed primary endpoint

Surgery

• Total hip arthroplasty for severe hip disease - often very successful in improving function
• Spinal osteotomy for severe kyphotic deformity causing inability to look forward - high-risk procedure requiring specialized centers
• Spinal fracture management - transverse fractures through fused segments are highly unstable and frequently catastrophic; treated surgically

Monitoring and Treat-to-Target

• ASDAS - preferred composite measure (includes CRP)
• BASDAI - patient-reported, widely used clinically
• BASFI (Bath Ankylosing Spondylitis Functional Index) - measures functional limitation
• BASMI (Bath Ankylosing Spondylitis Metrology Index) - measures spinal mobility; lateral spinal flexion is the most sensitive single measure
• MRI - for monitoring inflammation; spine scored using SPARCC or Berlin scores
• Modified Stoke AS Spine Score (mSASSS) - radiographic progression in the spine

Prognosis

• Disease course is variable; some have mild intermittent symptoms, others have progressive disabling disease
• Predictors of worse radiographic outcome: elevated CRP, presence of syndesmophytes at baseline, male sex, smoking
• Life expectancy is moderately reduced due to cardiovascular disease, osteoporosis-related fractures, and amyloidosis
• Early biologic therapy reduces inflammation and may slow structural progression
• NSAIDs, physiotherapy, and patient education remain the foundation; biologics and JAK inhibitors have transformed outcomes for moderate-to-severe disease

Summary of Treatment Algorithm

Active AS (BASDAI ≥4 / ASDAS ≥2.1)
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1. NSAID (full dose) + Physiotherapy
   - Trial 2 NSAIDs (4 weeks each)
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   Inadequate response
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2. Biologic DMARD:
   - TNF inhibitor (first choice)
     OR IL-17A inhibitor (especially if psoriasis; avoid if IBD)
         |
   Inadequate response / failure
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3. Switch to different TNFi OR switch class (IL-17A ↔ TNFi)
         |
   Still failing
         ▼
4. JAK inhibitor (tofacitinib, upadacitinib)

Special considerations:
- IBD present → TNFi monoclonal Ab preferred
- Recurrent uveitis → Adalimumab / infliximab preferred
- Peripheral arthritis → Sulfasalazine may add benefit
- Hip disease → Total hip arthroplasty

• Firestein & Kelley's Textbook of Rheumatology, 2-Volume Set - Chapters on axial SpA genetics, TNF inhibitors, JAK inhibitors, and management
• Rheumatology, 2-Volume Set (Elsevier, 2022) - Chapters 125 on AS management, NSAIDs table, bDMARD table, ASAS/EULAR management flowchart
• Grainger & Allison's Diagnostic Radiology - Chapter 44, AS imaging
• Washington Manual of Medical Therapeutics - Chapter 25, SpA clinical presentation and features
• 2024 update on biologic therapies for AS (Allergologia et Immunopathologia)
• 2025 British Society for Rheumatology guideline for axial SpA