Ankylosing Spondylitis (AS)

Overview

Epidemiology

• Prevalence: ~0.1-0.5% of the general population; varies by ethnic group and HLA-B27 frequency
• Age of onset: Most commonly 15-25 years; rarely begins after age 40
• Sex: Affects men 2-3x more than women, though women are increasingly recognized (often milder or delayed diagnosis)
• Genetics: Heritability exceeds 95%. Sibling recurrence risk is 9.2% vs. 0.1-0.4% in the general population
• Firestein & Kelley's Textbook of Rheumatology, p. 3122

Pathogenesis

HLA-B27 and Genetics

• HLA-B27 is the strongest genetic susceptibility factor: >90% of White AS patients carry it (vs. ~8% of the general population), giving a relative risk of 50-100
• Only ~2% of HLA-B27-positive individuals develop AS, so additional genetic and environmental factors are required
• Over 80 risk loci outside the HLA region have been identified, including:
  • ERAP1/ERAP2 (aminopeptidase genes) - involved in peptide trimming for HLA presentation; ERAP1 association is only found in HLA-B27-positive individuals (genetic epistasis)
  • IL-23R, IL-12B, IL-27 - genes in the IL-23/IL-17 pathway (key therapeutic target)

Immune Mechanisms

• The IL-23/IL-17 axis plays a central role: IL-23 drives Th17 differentiation, which produces IL-17A/F; this promotes entheseal inflammation
• Notably, anti-IL-17 drugs are effective in AS but anti-IL-23 drugs are not - suggesting IL-23-independent sources of IL-17 at entheses (likely innate immune cells)
• TNF-alpha also mediates spinal and sacroiliac inflammation
• Pathological process: enthesitis (inflammation at ligament/tendon insertions into bone) → new bone formation → syndesmophytes → fusion
• Firestein & Kelley's Textbook of Rheumatology, p. 3154-3166

Clinical Features

Axial (Spine and Sacroiliac)

• Inflammatory back pain is the hallmark - insidious onset, age <40, duration >3 months, worse with rest, improved with exercise, associated with morning stiffness >1 hour
• Sacroiliitis - bilateral and symmetrical; buttock pain may radiate down the thighs
• Reduced spinal mobility in all planes (Schober's test < 5 cm)
• Progressive thoracic kyphosis, loss of lumbar lordosis
• Chest wall restriction: fusion of costovertebral and sternoclavicular joints limits rib cage expansion to <2.5 cm (measured at 4th intercostal space)

Peripheral Joint Involvement

• Up to 30% of patients have peripheral arthritis (hips are the most important - the second most commonly affected joint after the SIJ)
• Hip involvement leads to diffuse joint space loss and characteristic entheseal new bone around the femoral head (can mimic femoroacetabular impingement)

Extra-articular Manifestations

Late Complications

• Osteoporosis - from chronic inflammation and abnormal biomechanical loading
• Spinal fractures - the rigid, fused spine is paradoxically osteopenic and highly vulnerable; transverse fractures through fused segments are highly unstable and potentially catastrophic
• Spondylodiscitis (Andersson lesion) - inflammatory destructive lesion at unfused disc levels in an otherwise fused spine; can mimic infection
• Restrictive lung disease - from rib cage fixation; diaphragm compensates but eventually may cause respiratory failure
• Goldman-Cecil Medicine, p. 3943-3945; Grainger & Allison's Diagnostic Radiology, p. 3659-3661

Diagnosis

Modified New York Criteria (for AS)

1. Low back pain and stiffness for >3 months, improved with exercise and not relieved by rest
2. Limited lumbar spine motion in sagittal and frontal planes
3. Limited chest expansion (relative to normal values for age and sex; <2.5 cm at 4th ICS)

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

ASAS Classification Criteria (axial SpA, broader)

Laboratory

• HLA-B27: positive in >90% of White patients (lower in other ethnic groups, e.g., ~70% in African Americans)
• Elevated CRP/ESR: in active disease (~50-60% of patients; normal does not exclude active disease)
• RF and ANA: negative (hence "seronegative" spondyloarthropathy)
• Henry's Clinical Diagnosis and Management by Laboratory Methods: HLA-B27 testing is confirmatory but not sufficient alone

Imaging

Plain Radiography

• Sacroiliac joints: erosion, subchondral sclerosis, eventually ankylosis (bilateral, symmetrical)
• Spine:
  • Romanus lesions - sclerotic "shiny corners" at vertebral body corners (earliest X-ray finding; due to enthesitis at Sharpey fiber insertions)
  • Squared vertebrae - due to erosion and anterior longitudinal ligament ossification
  • Syndesmophytes - thin, vertical bone outgrowths (distinguishable from the coarser, horizontal osteophytes of OA or the "chunky" syndesmophytes of psoriatic/reactive arthritis)
  • Bamboo spine - complete fusion of vertebral bodies and posterior elements (end-stage)

MRI (preferred for early disease)

• Most sensitive and specific for early sacroiliitis and spinal inflammation
• Detects subchondral bone marrow oedema before plain radiograph changes appear
• Key distinguishing feature: AS-related oedema is greater in craniocaudal dimension than transverse, and is not associated with disc dehydration or height loss (vs. degenerative disease)
• STIR sequences best for detecting active inflammation

CT

• Best for detecting structural damage, erosions, and degree of ankylosis
• Not preferred for early disease (radiation, poor sensitivity for marrow oedema)
• Grainger & Allison's Diagnostic Radiology, p. 3621-3662

Treatment

Non-Pharmacological

• Exercise and physiotherapy are strongly recommended and improve cardiorespiratory fitness, spinal mobility, and pain - must be started concurrently with drug therapy
• Posture training, hydrotherapy, supervised group exercise
• Smoking cessation (smokers have worse outcomes and more rapid radiographic progression)

NSAIDs (First-Line)

• NSAIDs at maximum tolerated doses are the cornerstone of treatment for active disease
• Continuous treatment is preferred over on-demand use for persistent symptoms
• No particular NSAID is superior to another; patient-specific factors (GI risk, cardiovascular risk) guide selection
• Treatment failure is defined as inadequate response to at least two different NSAIDs
• ACR guidelines: strong evidence for NSAIDs; strong caution against systemic glucocorticoids for active AS

Biologic DMARDs (Second-Line)

• Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab
• Improve symptoms, quality of life, CRP, anemia, sleep, and MRI inflammation scores
• Early and continuous treatment inhibits radiographic progression (syndesmophyte formation)
• Special considerations: For patients with comorbid inflammatory bowel disease or recurrent uveitis, prefer infliximab or adalimumab over etanercept (TNFi monoclonal antibodies > etanercept for these conditions)
• TNFi are also effective in non-radiographic axial SpA

• Secukinumab, ixekizumab (IL-17A inhibitors) - effective in AS
• Bimekizumab (IL-17A and IL-17F dual inhibitor) - also effective
• Preferred in patients who fail or cannot tolerate TNFi, or with predominant skin involvement
• Note: anti-IL-23 agents (guselkumab, risankizumab) do NOT work in AS despite working in psoriatic arthritis

• Tofacitinib (JAK inhibitor) - FDA-approved December 2021 for AS in patients with inadequate response to or intolerance of TNFi
  • ASAS20 achieved in 56.4% vs. 12.5% placebo at 16 weeks; response seen by 2-4 weeks
  • Safety: hepatic events (2.3%), herpes zoster (2.3%), serious infections (0.8%)
• Upadacitinib - also approved for AS

Certolizumab for Non-Radiographic AxSpA

• First anti-TNF agent FDA-approved for non-radiographic axial SpA specifically

Surgery

• Total hip arthroplasty for severe hip involvement
• Spinal osteotomy for severe fixed kyphotic deformity
• Special anesthetic consideration: endotracheal intubation must be performed with great caution due to rigid cervical spine; hyperextension can cause fracture; cricoarytenoid joint involvement may limit mouth opening
• Firestein & Kelley's Textbook of Rheumatology, p. 7809-7823; Goldman-Cecil Medicine, p. 3948

Disease Monitoring

• BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) - validated patient-reported measure
• ASDAS (Ankylosing Spondylitis Disease Activity Score) - incorporates CRP; preferred by guidelines
• Serial MRI for assessing response to biologics
• Serial plain radiographs every 2 years to monitor structural progression

Prognosis

• Clinical course is highly variable
• Strongest predictor of new syndesmophyte formation is presence of syndesmophytes at baseline
• Significant impact on work disability and quality of life
• Osteoporosis occurs in proportion to disease duration and activity
• With early biologic treatment, radiographic progression can be significantly retarded
• Late complications (bamboo spine, fractures, cauda equina syndrome, upper lobe fibrosis) are largely preventable with effective therapy
• Goldman-Cecil Medicine, p. 1004-1008