Ankylosing Spondylitis

1. Overview

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease primarily affecting the axial skeleton, characterised by sacroiliitis and progressive spinal fusion. It is the prototypical and most severe form of axial spondyloarthritis (axSpA), a group of related inflammatory conditions sharing clinical features and strong association with HLA-B27 positivity.

AS predominantly affects young adults, with symptom onset typically before age 45 years. The hallmark clinical feature is chronic inflammatory back pain with characteristic features: insidious onset, duration exceeding 3 months, morning stiffness lasting more than 30 minutes, and improvement with exercise but not rest. Left untreated, progressive inflammation leads to syndesmophyte formation, vertebral fusion, and the classic "bamboo spine" deformity, resulting in significant functional impairment and reduced quality of life.

The condition has important extra-articular manifestations including anterior uveitis (25-40% of patients), inflammatory bowel disease (5-10%), and cardiovascular complications. Early diagnosis and treatment with NSAIDs and biological disease-modifying agents (TNF inhibitors, IL-17 inhibitors) can significantly reduce disease activity, preserve spinal mobility, and prevent structural damage. The introduction of biological therapies has revolutionised AS management, with evidence demonstrating sustained clinical improvement and radiographic progression reduction.

2. Epidemiology

Prevalence and Incidence

AS affects approximately 0.1-1.4% of the general population worldwide, with significant geographic variation correlating with HLA-B27 prevalence. [1] In populations with high HLA-B27 carriage rates (Northern Europe, certain Native American groups), AS prevalence approaches 1%, while in populations with low HLA-B27 prevalence (Japan, sub-Saharan Africa), AS is correspondingly rare.

Annual incidence ranges from 0.4-14 per 100,000 person-years, with higher rates in Scandinavian countries and lower rates in Southern Europe and Asia. [2]

Risk Factors

Genetic Factors: HLA-B27 is the strongest genetic risk factor, contributing approximately 20% of total disease heritability. [4] However, only 1-2% of HLA-B27-positive individuals develop AS, indicating other genetic and environmental factors are required. Genome-wide association studies have identified over 100 susceptibility loci, including genes involved in IL-23/IL-17 pathway (IL23R, IL12B), antigen processing (ERAP1, ERAP2), and innate immunity. [5]

Non-Genetic Risk Factors:

• Male sex: 2-3 times higher prevalence, potentially related to sex hormones modulating immune responses
• Gut dysbiosis: 50-70% of AS patients demonstrate subclinical intestinal inflammation; alterations in gut microbiome composition implicated in pathogenesis [6]
• Mechanical stress: Occupational heavy physical work may trigger inflammation in genetically susceptible individuals
• Smoking: Associated with increased disease activity, radiographic progression, and extra-articular manifestations [7]

3. Aetiology and Pathophysiology

Genetic Basis: The Central Role of HLA-B27

HLA-B27 contributes approximately 20-25% of AS heritability, with 85-95% of AS patients carrying this allele. [4] Multiple mechanisms have been proposed for how HLA-B27 contributes to pathogenesis:

1. Arthritogenic Peptide Hypothesis: HLA-B27 may present specific arthritogenic peptides (potentially bacterial in origin) to CD8+ T cells, triggering autoimmune responses targeting joint tissues. The nature of these peptides remains unidentified.

2. HLA-B27 Misfolding Hypothesis: HLA-B27 heavy chains are prone to misfolding in the endoplasmic reticulum, forming homodimers and aggregates. This triggers the unfolded protein response (UPR), activating inflammatory pathways including IL-23 production by antigen-presenting cells. [8]

3. HLA-B27 Free Heavy Chain Hypothesis: HLA-B27 heavy chains can reach the cell surface without β2-microglobulin, forming homodimers recognized by specific receptors on NK cells and CD4+ T cells, triggering inflammatory cytokine production.

4. Gut Microbiome Hypothesis: HLA-B27 may influence gut microbiome composition, promoting dysbiosis. Increased gut permeability allows bacterial antigens to access systemic circulation, triggering immune responses in genetically susceptible individuals. Up to 70% of AS patients have subclinical gut inflammation, supporting this mechanism. [6]

Exam Detail: ### Molecular Pathogenesis: The IL-23/IL-17 Axis

The discovery of the IL-23/IL-17 pathway has fundamentally reshaped understanding of AS pathogenesis. Key observations supporting this pathway's centrality:

Genetic Evidence: Polymorphisms in IL23R (interleukin-23 receptor) and IL12B (encoding IL-23 p40 subunit) are strongly associated with AS susceptibility. [5] These genes directly regulate Th17 cell differentiation and function.

Inflammatory Cascade:

1. Initiation: HLA-B27 misfolding or bacterial antigens activate antigen-presenting cells (dendritic cells, macrophages)
2. IL-23 Production: Activated APCs secrete IL-23, a heterodimeric cytokine composed of p19 and p40 subunits
3. Th17 Cell Activation: IL-23 drives differentiation of CD4+ T cells into Th17 cells and maintains their pro-inflammatory phenotype
4. IL-17 Secretion: Th17 cells (and other IL-17-producing cells including γδ T cells, innate lymphoid cells type 3) secrete IL-17A and IL-17F
5. Tissue Inflammation: IL-17 acts on synovial fibroblasts, chondrocytes, and osteoblasts, inducing:
   • Production of pro-inflammatory cytokines (TNF-α, IL-1, IL-6)
   • Matrix metalloproteinases causing cartilage degradation
   • RANKL expression promoting osteoclast activation and bone erosion
   • Paradoxically, activation of Wnt signaling promoting new bone formation

TNF-α's Role: TNF-α remains critically important, acting synergistically with IL-17. TNF-α drives acute inflammation, promotes angiogenesis, and activates osteoclasts. The clinical efficacy of TNF inhibitors validates this pathway's importance.

Enthesitis: The Primary Lesion

AS is fundamentally an entheseal-based disease. The enthesis (site of tendon, ligament, or joint capsule insertion into bone) is the primary site of inflammation. Enthesitis precedes synovitis and drives the characteristic new bone formation (syndesmophytes, ankylosis).

Mechanism of New Bone Formation:

1. Inflammatory Phase: IL-17 and TNF-α drive inflammation at entheses
2. Resolution Phase: As inflammation resolves, reparative processes are activated
3. Aberrant Bone Formation: Dysregulated Wnt/β-catenin and BMP signaling pathways drive excessive new bone formation
4. Syndesmophyte Formation: Vertical bone bridges form at vertebral margins
5. Ankylosis: Complete fusion of vertebrae creates "bamboo spine"

This paradoxical process—inflammation leading to abnormal bone formation—explains why anti-inflammatory treatments reduce symptoms but may not completely prevent structural progression, especially if initiated late in disease.

4. Clinical Presentation

Cardinal Symptoms: Inflammatory Back Pain

Inflammatory back pain (IBP) is the hallmark of AS, present in > 90% of patients. The clinical pattern distinguishes AS from mechanical back pain:

ASAS Inflammatory Back Pain Criteria (≥4 of 5 required for IBP): [9]

1. Age at onset less than 40 years
2. Insidious onset (gradual development over weeks to months)
3. Improvement with exercise (characteristically improves during the day with activity)
4. No improvement with rest (unlike mechanical pain which improves with rest)
5. Pain at night (with improvement upon getting up, often waking patient in second half of night)

Additional Features:

• Morning stiffness > 30 minutes: Often lasts 1-2 hours; severity correlates with disease activity
• Alternating buttock pain: Reflects sacroiliitis; may alternate sides
• Thoracic pain: Mid-back pain from costovertebral joint involvement
• Chest wall pain: Costochondral and manubriosternal joint inflammation
• Progressive spinal stiffness: Developing over years; reduced spinal mobility in all planes

Peripheral and Extra-Axial Manifestations

Peripheral Arthritis (20-30% of patients):

• Typically oligoarticular (≤4 joints), asymmetric, lower limb predominance
• Hip involvement (30%): Often bilateral, may require total hip arthroplasty in severe cases
• Shoulder involvement (30%): Can limit function significantly

Enthesitis (30-50% of patients):

• Achilles tendinitis: Most common site; pain and swelling at heel insertion
• Plantar fasciitis: Heel pain, worse in morning or after rest
• Costochondral junctions: Anterior chest wall pain
• Iliac crest, greater trochanter, ischial tuberosities: Pelvic enthesitis causing regional pain

Dactylitis (5-10% of patients):

• "Sausage digit": Diffuse swelling of entire finger or toe
• More common in psoriatic arthritis and reactive arthritis, but can occur in AS

Extra-Articular Manifestations

Anterior Uveitis (25-40% lifetime prevalence): [10]

• Most common extra-articular manifestation
• Typically acute, unilateral, recurrent
• Presentation: Painful red eye, photophobia, blurred vision, lacrimation
• Timing: Can precede, coincide with, or follow joint symptoms
• Requires urgent ophthalmology assessment to prevent complications (posterior synechiae, glaucoma, cataracts)
• More common in HLA-B27-positive patients

Inflammatory Bowel Disease (5-10%):

• Subclinical gut inflammation in 50-70% on endoscopy [6]
• Overt Crohn's disease or ulcerative colitis in 5-10%
• Gut symptoms may precede or follow musculoskeletal manifestations

Cardiovascular Complications:

• Aortitis (2-10%): Inflammation of aortic root; chronic cases develop aortic regurgitation
• Conduction defects: AV block, bundle branch block (1-9%); may require pacemaker
• Increased cardiovascular risk: Elevated rates of myocardial infarction and stroke due to chronic inflammation [11]

Pulmonary Involvement (1-2%):

• Apical pulmonary fibrosis: Upper lobe predominance; rare but characteristic finding
• Restrictive lung defect: Due to reduced chest wall expansion from costovertebral fusion

Renal Complications:

• IgA nephropathy: Rare association
• AA amyloidosis: Now rare due to effective disease control with biologics

Neurological Complications:

• Spinal fractures: Ankylosed "bamboo spine" is brittle; minor trauma can cause fractures with neurological compromise
• Cauda equina syndrome: Rare late complication from chronic arachnoiditis and nerve root inflammation

Physical Examination Findings

Posture and Gait:

• Loss of lumbar lordosis: Early sign; flattening of lower back
• Hyperkyphosis: Exaggerated thoracic curve; "question mark posture" in advanced disease
• Forward head posture: Compensatory mechanism to maintain horizontal gaze
• Reduced chest expansion: less than 5 cm chest expansion at 4th intercostal space (normal > 5-7 cm)

Spinal Mobility Assessment:

Modified Schober's Test Technique:

1. Patient standing, mark point at level of posterior superior iliac spines (approximately L5)
2. Mark points 10 cm above and 5 cm below this point (15 cm total)
3. Patient maximally flexes spine forward
4. Measure distance between marks; should increase to ≥21 cm (≥6 cm increase)
5. Increase less than 5 cm indicates reduced lumbar flexion

Sacroiliac Joint Assessment:

• Direct pressure over SIJs: Tenderness suggests sacroiliitis
• FABER test (Flexion, Abduction, External Rotation): Pain in hip or SI joint
• Gaenslen's test: Stress to SI joints; pain suggests sacroiliitis
• Sensitivity limited: Clinical examination less sensitive than imaging for detecting sacroiliitis

Peripheral Joint and Entheses Examination:

• Examine hips (limited internal rotation), shoulders
• Palpate Achilles insertions, plantar fascia, anterior chest wall for tenderness

5. Differential Diagnosis

Inflammatory back pain in a young adult requires systematic consideration of alternative diagnoses:

Red Flags Requiring Urgent Investigation:

• Age less than 20 or > 55 years at onset
• Acute severe pain with fever
• Progressive neurological deficits
• Bladder/bowel dysfunction
• Constitutional symptoms (weight loss, night sweats)
• History of malignancy

6. Investigations

Initial Assessment

Blood Tests:

HLA-B27 Interpretation:

• Positive result increases diagnostic probability but is NOT diagnostic of AS
• 8% of general population is HLA-B27-positive; only 1-2% develop AS
• Negative HLA-B27 does NOT exclude AS (10-15% of AS patients are HLA-B27-negative)
• Most useful in patients with suggestive clinical features but equivocal imaging

Imaging

Radiography (X-rays):

Pelvis X-ray (anteroposterior view):

• Sacroiliitis grading (Modified New York criteria): [15]
  • "Grade 0: Normal"
  • "Grade 1: Suspicious changes (minimal blurring of joint margins)"
  • "Grade 2: Minimal abnormality (small erosions, sclerosis)"
  • "Grade 3: Moderate/advanced sacroiliitis (erosions, sclerosis, widening/narrowing of joint space)"
  • "Grade 4: Ankylosis (complete fusion)"
• Requirement for radiographic AS: Bilateral grade ≥2 OR unilateral grade 3-4

Spine X-rays (lateral cervical, thoracic, lumbar): Early changes:

• Squaring of vertebral bodies: Loss of normal anterior concavity
• Shiny corners (Romanus lesions): Sclerosis at vertebral corners from enthesitis
• Syndesmophytes: Vertical bony bridges between vertebrae (distinguish from osteophytes which are horizontal)

Late changes:

• Bamboo spine: Complete fusion creating single rigid column
• Fractures: May occur through ankylosed segments; often unstable
• Atlantoaxial subluxation: Rare; may cause cord compression

Limitations of Plain Radiography:

• Low sensitivity early in disease: Structural changes take 5-10 years to develop
• Does not detect active inflammation: Only shows structural damage consequences
• Cannot diagnose non-radiographic axial SpA

Magnetic Resonance Imaging (MRI):

MRI of Sacroiliac Joints and Spine is the GOLD STANDARD for detecting active inflammation and early disease:

Sequences:

• STIR (Short TI Inversion Recovery): Best for detecting bone marrow edema (BME), highly sensitive for inflammation
• T1-weighted post-gadolinium: Detects active inflammation, synovitis, enthesitis

ASAS Positive MRI Criteria for Sacroiliitis: [9]

• Bone marrow edema highly suggestive of sacroiliitis if:
  • Present in ≥2 consecutive slices, OR
  • Present in ≥2 different locations on single slice
• BME should be located in anatomical locations typical for sacroiliitis (subchondral bone adjacent to SI joint)

MRI Findings:

• Active inflammation: Bone marrow edema (bright signal on STIR), synovitis, enthesitis, capsulitis
• Structural changes: Erosions, fat metaplasia (sign of previous inflammation), sclerosis, ankylosis

Advantages of MRI:

• Detects inflammation years before radiographic changes
• Enables diagnosis of non-radiographic axial SpA
• Can assess disease activity and response to treatment
• Detects spinal inflammation (spondylitis, spondylodiscitis)

CT Scan:

• Not routinely recommended due to radiation exposure
• Detects erosions and structural changes earlier than X-ray but less sensitive than MRI for inflammation
• May be used when MRI contraindicated and X-rays equivocal

Classification and Diagnostic Criteria

ASAS Classification Criteria for Axial Spondyloarthritis (2009): [9]

For patients with chronic back pain ≥3 months, onset less than 45 years:

Pathway 1: Imaging Arm

• Sacroiliitis on imaging (X-ray or MRI as defined above)
• PLUS ≥1 SpA feature:
  • Inflammatory back pain
  • Arthritis
  • Enthesitis
  • Uveitis
  • Dactylitis
  • Psoriasis
  • Crohn's/colitis
  • Good response to NSAIDs
  • Family history of SpA
  • HLA-B27 positive
  • Elevated CRP

Pathway 2: Clinical Arm (no sacroiliitis on imaging)

• HLA-B27 positive
• PLUS ≥2 other SpA features (from list above)

These criteria classify patients as having axial SpA. Patients are then sub-classified as:

• Radiographic axial SpA (ankylosing spondylitis): Meet modified New York criteria with definite sacroiliitis on X-ray
• Non-radiographic axial SpA: Meet ASAS criteria but no definite sacroiliitis on X-ray (may have MRI evidence only)

Modified New York Criteria for Ankylosing Spondylitis (1984): [15]

Clinical Criteria:

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

Radiological Criterion:

• Sacroiliitis grade ≥2 bilaterally OR grade 3-4 unilaterally

Diagnosis requires:

• Radiological criterion + ≥1 clinical criterion

Important Note: Modified New York criteria require radiographic sacroiliitis, so cannot diagnose early disease or non-radiographic axial SpA. ASAS criteria are now preferred for classification.

Exam Detail: ### Disease Activity and Functional Assessment Tools

BASDAI (Bath Ankylosing Spondylitis Disease Activity Index): [16]

• Patient-reported outcome measuring disease activity
• 6 questions on 0-10 numerical rating scale:
  1. Fatigue
  2. Spinal pain
  3. Peripheral joint pain/swelling
  4. Enthesitis
  5. Morning stiffness severity
  6. Morning stiffness duration
• Score calculation: Mean of Q1-4, plus mean of Q5-6, divided by 2 (total 0-10)
• BASDAI ≥4 indicates high disease activity requiring treatment escalation
• BASDAI reduction ≥2 or 50% indicates clinically meaningful improvement

BASFI (Bath Ankylosing Spondylitis Functional Index):

• 10 questions assessing functional impairment in daily activities
• Score 0-10; higher scores indicate worse function
• Useful for monitoring functional impact and treatment response

BASMI (Bath Ankylosing Spondylitis Metrology Index):

• Objective measure of spinal mobility
• Assesses 5 measurements: cervical rotation, tragus-to-wall distance, lumbar flexion (Schober's), lateral flexion, intermalleolar distance
• Each scored 0-2; total 0-10
• Tracks structural progression over time

ASDAS (Ankylosing Spondylitis Disease Activity Score): [17]

• Combines patient-reported outcomes with CRP or ESR
• More sensitive to change than BASDAI
• Preferred in clinical trials and increasingly used in practice
• Cut-offs: less than 1.3 inactive disease; 1.3-2.0 moderate; 2.1-3.5 high; > 3.5 very high activity

7. Management

Management goals in AS are to:

1. Control pain and inflammation
2. Maintain spinal mobility and function
3. Prevent structural damage and deformity
4. Screen for and manage extra-articular manifestations and comorbidities
5. Optimize quality of life and work participation

Non-Pharmacological Management

Physiotherapy and Exercise - CORNERSTONE OF MANAGEMENT:

Exercise therapy is as important as pharmacological treatment in AS. Multiple systematic reviews and meta-analyses demonstrate that exercise programs significantly improve disease activity (BASDAI), function (BASFI), and spinal mobility (BASMI). [18,19]

Evidence Base:

• Meta-analysis of RCTs shows exercise reduces BASDAI by 0.6-0.9 points and BASFI by 0.6-0.7 points [18]
• Programs combining flexibility, strengthening, and aerobic exercise show largest effects [19]
• Benefits maintained only with continued regular exercise; effects diminish if exercise stopped

Recommended Exercise Components:

1. Flexibility exercises: Spinal stretching, range of motion exercises
2. Strengthening exercises: Core strengthening, postural muscles, spinal extensors
3. Aerobic exercise: Swimming (particularly beneficial as low-impact), cycling, walking
4. Breathing exercises: Maintain chest expansion

Frequency and Intensity:

• Minimum 30 minutes daily home exercises
• Supervised physiotherapy programs (group or individual) improve adherence and outcomes
• Hydrotherapy/aquatic therapy particularly beneficial

Patient Education:

• Posture awareness and correction
• Ergonomic adaptations at work and home
• Avoid prolonged static positions
• Sleep on firm mattress, avoid excessive pillows (prevent flexion deformity)

Smoking Cessation:

• Strong evidence that smoking increases disease activity, radiographic progression, and functional impairment [7]
• Smoking cessation counseling should be provided to all patients who smoke

Pharmacological Management

Exam Detail: #### First-Line: NSAIDs

Rationale: NSAIDs are first-line pharmacological treatment for AS. Unique among rheumatic diseases, NSAIDs in AS may have disease-modifying effects, potentially slowing radiographic progression if used continuously. [20]

Evidence:

• RCTs show NSAIDs significantly reduce pain and improve function
• Continuous NSAID use may reduce radiographic progression compared to on-demand use, though data are conflicting [20]
• No single NSAID consistently superior; choice based on efficacy, tolerability, patient preference

Recommended NSAIDs:

• Naproxen 500-1000 mg/day (divided doses)
• Diclofenac 100-150 mg/day (divided doses or modified-release)
• Indomethacin 75-150 mg/day (effective but more side effects; reserve for resistant cases)
• Etoricoxib 90 mg once daily (COX-2 selective; consider in GI risk patients)
• Celecoxib 200 mg once daily (COX-2 selective)

Dosing Strategy:

• Start with regular full-dose NSAID (not as-needed dosing)
• Continue for 2-4 weeks to assess efficacy
• If inadequate response, switch to alternative NSAID (up to 2-3 trials)
• Once symptoms controlled, may attempt dose reduction or on-demand use
• Some patients require long-term continuous NSAID therapy

Monitoring:

• Baseline: Renal function, liver function, blood pressure
• Regular monitoring: Renal function (especially elderly, CKD), blood pressure, GI symptoms
• Consider PPI co-prescription in patients with GI risk factors

Contraindications and Precautions:

• Active peptic ulcer disease (absolute contraindication)
• Severe renal impairment (eGFR less than 30 mL/min)
• Severe heart failure
• Cardiovascular disease (COX-2 inhibitors increase CV risk; use lowest effective dose)
• Pregnancy (especially 3rd trimester)

Second-Line: Conventional DMARDs (Limited Role)

Sulfasalazine:

• Only indicated for peripheral arthritis in AS; no efficacy for axial symptoms [21]
• Dose: 2-3 g/day (start 500 mg daily, increase gradually)
• May consider if predominant peripheral arthritis and TNF inhibitors contraindicated/unavailable
• No role in purely axial disease

Methotrexate:

• Not recommended for AS; no evidence of efficacy for axial or peripheral symptoms [21]
• May be used in psoriatic arthritis with axial involvement

Third-Line: Biological DMARDs

Biological therapy is indicated for patients with persistently high disease activity despite adequate trial of NSAIDs. The 2019 ACR/SAA/SPARTAN guidelines provide clear criteria. [21]

Indications for Biological Therapy:

According to 2019 ACR/SAA/SPARTAN recommendations: [21]

• Active AS (BASDAI ≥4 or ASDAS ≥2.1) despite:
  • Adequate trial of ≥2 NSAIDs at maximum tolerated dose for ≥4 weeks total, OR
  • Contraindication/intolerance to NSAIDs
• Plus: Objective evidence of inflammation (elevated CRP and/or active inflammation on MRI), OR
  • Meeting ASAS classification criteria

TNF Inhibitors - First-Line Biologics:

Five TNF inhibitors approved for AS:

Efficacy:

• 50-60% of patients achieve ASAS20 response (20% improvement)
• 40-50% achieve ASAS40 response
• Rapid onset: Significant improvement often within 2-4 weeks
• Improvements in pain, stiffness, function, quality of life, and inflammatory markers
• Reduce spinal inflammation on MRI
• May slow radiographic progression, though effect modest and data conflicting

Important Differences Among TNF Inhibitors:

Anterior Uveitis:

• Monoclonal antibodies (adalimumab, infliximab, golimumab) reduce uveitis flares by 50-70%
• Etanercept increases uveitis risk and does NOT prevent uveitis flares [22]
• Recommendation: If history of uveitis or high uveitis risk, prefer monoclonal antibody TNF inhibitor over etanercept

Choice of First TNF Inhibitor:

• All five are effective; choice based on patient preference (SC vs IV), dosing frequency, cost, and comorbidities
• If history of uveitis: Prefer adalimumab, infliximab, or golimumab (NOT etanercept) [21]
• If concomitant IBD: Prefer adalimumab or infliximab (better evidence in IBD)

IL-17 Inhibitors - Alternative Biologics:

Efficacy:

• Similar efficacy to TNF inhibitors for axial symptoms
• ASAS20 response rates 60-65%
• May be more effective for enthesitis and dactylitis compared to TNF inhibitors

When to Use IL-17 Inhibitors: According to 2019 ACR/SAA guidelines: [21]

• Preferred over 2nd TNF inhibitor if primary non-response (inadequate efficacy) to first TNF inhibitor
• Can be used as first-line biologic, but TNF inhibitors are generally preferred initially due to longer track record and broader extra-articular efficacy

Important Caveat - Uveitis Risk:

• Secukinumab and ixekizumab (selective IL-17A inhibitors) may increase risk of uveitis or worsen existing uveitis [22]
• Bimekizumab (dual IL-17A/F inhibitor) appears to reduce uveitis risk, likely because IL-17F inhibition counteracts IL-17A inhibition effects
• Recommendation: If history of uveitis, prefer TNF inhibitor (monoclonal antibody type) or consider bimekizumab; avoid secukinumab/ixekizumab

Inflammatory Bowel Disease:

• IL-17 inhibitors can worsen or induce IBD (paradoxical effect)
• If active IBD or high IBD risk, prefer TNF inhibitor (adalimumab, infliximab)

JAK Inhibitors

Tofacitinib (JAK1/3 inhibitor) and upadacitinib (selective JAK1 inhibitor) show efficacy in AS, but are recommended AFTER TNF inhibitors and IL-17 inhibitors due to less robust evidence and safety concerns. [21]

Biosimilar TNF Inhibitors

Biosimilar versions of infliximab and adalimumab are approved and recommended as equivalent alternatives to originator products, offering cost savings. [21]

Treatment Strategy

Treatment Algorithm:

Active AS Diagnosis (BASDAI ≥4 or ASDAS ≥2.1)
          ↓
Exercise/Physiotherapy + NSAID (full dose, 2-4 weeks)
          ↓
    Adequate Response? ─────YES─────→ Continue NSAID + Exercise
          │                              Monitor every 3-6 months
          NO
          ↓
    Try 2nd NSAID (2-4 weeks)
          ↓
    Adequate Response? ─────YES─────→ Continue NSAID + Exercise
          │
          NO
          ↓
    High Disease Activity + Objective Inflammation?
    (BASDAI ≥4, elevated CRP or MRI inflammation)
          ↓
         YES
          ↓
    Start Biologic DMARD
    
    First Biologic:
    - TNF inhibitor (preferred)
    - If uveitis history: adalimumab/infliximab/golimumab (NOT etanercept)
    - If IBD: adalimumab or infliximab
          ↓
    Assess Response at 12 weeks (ASAS20/40, BASDAI reduction)
          ↓
    Adequate Response? ─────YES─────→ Continue long-term
          │                              Monitor every 3-6 months
          NO
          ↓
    Primary Non-Response (no improvement)?
          ↓
         YES → Switch to IL-17 inhibitor
          │      (secukinumab, ixekizumab, bimekizumab)
          │
    OR secondary loss of response (initially worked, then lost efficacy)?
          ↓
         YES → Increase dose OR switch to different TNF inhibitor
                OR switch to IL-17 inhibitor

Definitions:

• Adequate response: ASAS20 (≥20% improvement + absolute improvement ≥1 unit in ≥3 of 4 domains: patient global, pain, function, inflammation), ideally ASAS40, OR BASDAI reduction ≥2 points or ≥50%
• Assessment timing: 12 weeks (minimum); some patients require up to 24 weeks for full response

Monitoring on Biologic Therapy:

• Tuberculosis screening before initiating TNF inhibitor (chest X-ray, QuantiFERON or TST); treat latent TB if positive
• Hepatitis B and C screening
• Vaccination status: Update before biologics (especially pneumococcal, influenza); avoid live vaccines on biologics
• Regular monitoring: FBC, renal and liver function every 3-6 months
• Disease activity assessment: BASDAI/ASDAS every 3-6 months
• Screening for extra-articular manifestations: Regular ophthalmology review if uveitis history; consider screening for IBD, cardiac involvement

Treatment Targets:

• Target: ASDAS less than 1.3 (inactive disease) or less than 2.1 (low disease activity)
• Alternatively: BASDAI less than 4
• Maintain spinal mobility (BASMI stable or improving)

Can Biologics Be Stopped?

• ACR/SAA guidelines recommend AGAINST routine tapering or discontinuation of biologics in patients with stable disease [21]
• Reason: High relapse rates (50-80% within 1 year) after stopping biologics
• May consider tapering in highly selected patients with prolonged remission (ASDAS inactive disease ≥2 years), but requires close monitoring and willingness to restart promptly if relapse

Methotrexate Co-Administration:

• Co-administration of low-dose methotrexate with TNF inhibitors is NOT recommended in AS (unlike rheumatoid arthritis), as it does not improve outcomes [21]

Management of Extra-Articular Manifestations

Anterior Uveitis:

• Acute flare: Urgent ophthalmology referral
• Treatment: Topical corticosteroids + cycloplegics
• Prevention: Monoclonal antibody TNF inhibitors (adalimumab, infliximab, golimumab) reduce flare frequency by 50-70% [10]

Inflammatory Bowel Disease:

• Co-manage with gastroenterology
• TNF inhibitors (adalimumab, infliximab) effective for both AS and IBD
• Avoid IL-17 inhibitors if active IBD (may worsen disease)

Cardiovascular Disease:

• Screen for traditional CV risk factors; aggressive risk modification
• Control inflammation (reduces CV risk)
• Echocardiography if murmur or symptoms (screen for aortic regurgitation)
• ECG to detect conduction defects

Surgical Management

Indications for Surgery:

Total Hip Arthroplasty (THA):

• Indication: Severe hip joint damage with pain and functional limitation refractory to medical therapy
• Occurs in ~30% of AS patients with hip involvement
• Excellent outcomes with THA; most patients achieve significant pain relief and functional improvement

Spinal Surgery:

• Corrective osteotomy: For severe kyphotic deformity impairing horizontal gaze or causing functional limitation
• Spinal fusion: For unstable fractures or pseudarthrosis
• Decompression: For neurological compromise (rare)
• High-risk procedures in ankylosed spine; requires specialized centers

8. Complications

Spinal Fracture - Critical Complication:

• Ankylosed "bamboo spine" is rigid and brittle
• Minor trauma can cause fractures (even falls from standing)
• Fractures are often unstable (through ALL three columns)
• Neurological injury occurs in 60-90% of fractures
• High index of suspicion: Any AS patient with trauma and neck/back pain requires imaging (CT preferred over X-ray)
• Immobilization: Rigid collar or spinal immobilization until fracture excluded
• Neurosurgical consultation: Urgent for any fracture with or without neurological deficit

9. Prognosis

Natural History

Disease Course: AS is a chronic, progressive disease with variable course:

• Early disease (first 10 years): Inflammatory symptoms predominate; highest disease activity
• Established disease (10-20 years): Progressive structural changes; syndesmophyte formation
• Late disease (> 20 years): Ankylosis, fixed deformities; inflammation may "burn out" but structural damage irreversible

Functional Outcomes:

• 20-40% of patients develop significant functional limitation over 10-20 years
• Hip involvement (30%) major driver of poor functional outcome
• Work disability: 3-30% cease work due to AS (wide variation across studies and countries)

Mortality: Overall survival is reduced compared to general population:

• Standardized mortality ratio (SMR) 1.5-1.9 (50-90% increased mortality) [11]
• Causes: Cardiovascular disease (most important), spinal fractures, respiratory disease, infections, amyloidosis

Prognostic Factors

Predictors of Poor Prognosis:

• Hip involvement (strong predictor of poor function and need for arthroplasty)
• Elevated inflammatory markers (ESR, CRP) at diagnosis
• Poor response to NSAIDs
• Young age at onset (less than 20 years)
• Peripheral arthritis
• Smoking (associated with worse disease activity and radiographic progression) [7]
• Delayed diagnosis (> 2 years from symptom onset)

Predictors of Radiographic Progression:

• Baseline syndesmophytes (strongest predictor)
• Elevated CRP
• Smoking
• Male sex

Impact of Treatment on Outcomes

NSAIDs:

• Continuous NSAID use may slow radiographic progression, though data conflicting [20]
• Significant symptom relief improves quality of life

TNF Inhibitors:

• Dramatic improvements in symptoms, function, quality of life
• Reduce inflammation on MRI
• Radiographic progression: Effect on structural damage modest and debated; some studies show slowing of syndesmophyte formation, others show no effect
• May need to start early (before structural damage) for maximal benefit
• Reduce extra-articular manifestations (uveitis)

IL-17 Inhibitors:

• Similar symptomatic benefits to TNF inhibitors
• Long-term radiographic data still emerging

Exercise:

• Maintains spinal mobility and function
• Improves quality of life
• Effects require ongoing participation; benefits lost if exercise stopped

Overall: With modern treatment (NSAIDs, biologics, physiotherapy), most patients can achieve good disease control with maintained function and quality of life. However, treatment must be lifelong, and structural damage prevention remains challenging.

10. Prevention and Screening

Primary Prevention: No established primary prevention strategies, as environmental triggers beyond smoking are poorly defined.

Secondary Prevention (Early Diagnosis):

• Awareness of inflammatory back pain features in primary care
• Prompt referral to rheumatology if IBP in patient less than 45 years
• Target: Diagnosis within 3 months of presentation to rheumatology (often 5-10 year delay from symptom onset to diagnosis; reducing this is major goal)

Screening in High-Risk Populations:

• First-degree relatives of AS patients (especially if HLA-B27 positive): Educate about symptoms; low threshold for evaluation if IBP develops
• Patients with IBD, psoriasis, recurrent uveitis: Screen for musculoskeletal symptoms

Screening for Comorbidities in Established AS:

• Osteoporosis: DEXA scan at diagnosis and periodically (note: syndesmophytes falsely elevate DEXA; consider lateral spine imaging)
• Cardiovascular disease: Regular CV risk assessment; screening echocardiography if murmur or long disease duration
• Ophthalmology: Educate about uveitis symptoms; urgent evaluation if red eye/photophobia
• Tuberculosis: Screen before starting biologics
• Vaccinations: Ensure up-to-date (pneumococcal, influenza, COVID-19) before biologics; avoid live vaccines on biologics

11. Key Guidelines

2019 ACR/SAA/SPARTAN Recommendations for Treatment of AS and Non-Radiographic Axial SpA: [21]

• Key Recommendations:
  • NSAIDs first-line for active disease
  • TNF inhibitors recommended over IL-17 inhibitors or JAK inhibitors as first biologic
  • IL-17 inhibitors recommended over second TNF inhibitor if primary non-response to first TNF inhibitor
  • Monoclonal antibody TNF inhibitors (adalimumab, infliximab, golimumab) preferred over etanercept in patients with history of or at risk for uveitis
  • Do NOT co-administer methotrexate with TNF inhibitors (no added benefit)
  • Do NOT routinely taper or discontinue biologics in stable disease (high relapse risk)
  • Sulfasalazine only for persistent peripheral arthritis when TNF inhibitors contraindicated

2017 ASAS-EULAR Management Recommendations:

• Similar recommendations: NSAIDs, physiotherapy, biologics for inadequate NSAID response
• Emphasize non-pharmacological treatment (exercise, physiotherapy, patient education) as cornerstone

2021 British Society for Rheumatology Guidelines:

• Recommendations align with ACR/SAA guidelines
• Emphasize early referral, MRI for early diagnosis, treat-to-target approach

12. Exam-Focused Sections

Common Viva Questions and Model Answers

Q1: "What is ankylosing spondylitis and how does it present?"

Model Answer: "Ankylosing spondylitis is a chronic inflammatory spondyloarthropathy primarily affecting the axial skeleton, characterised by sacroiliitis and progressive spinal fusion. It is the prototypical form of axial spondyloarthritis and is strongly associated with HLA-B27, which is positive in 85-95% of patients.

The hallmark presentation is inflammatory back pain in a young adult, typically with onset before age 40. The pain has characteristic features: insidious onset, duration over 3 months, morning stiffness lasting over 30 minutes, improvement with exercise but not rest, and nocturnal pain that improves upon rising. Patients may also have alternating buttock pain from sacroiliitis, reduced spinal mobility, and reduced chest expansion.

Important extra-articular manifestations include anterior uveitis in 25-40%, which requires urgent ophthalmology assessment, and less commonly inflammatory bowel disease, aortitis with aortic regurgitation, and cardiac conduction defects. Peripheral arthritis occurs in 20-30%, typically affecting hips and shoulders."

Q2: "How do you differentiate inflammatory from mechanical back pain?"

Model Answer: "The key distinguishing features are captured in the ASAS inflammatory back pain criteria. Inflammatory back pain typically has age of onset under 40 years, insidious onset over weeks to months, improvement with exercise but not rest, nocturnal pain with improvement upon getting up, and morning stiffness lasting over 30 minutes—often 1-2 hours.

In contrast, mechanical back pain usually has onset after specific trauma or heavy lifting, occurs in older patients, worsens with activity and improves with rest, has minimal morning stiffness, and responds well to simple analgesia. Systemic features like weight loss or fever suggest alternative diagnoses such as infection or malignancy and require urgent investigation."

Q3: "What investigations would you perform and how do you diagnose AS?"

Model Answer: "Initial investigations include inflammatory markers—ESR and CRP are elevated in 40-70% but can be normal even with active disease. HLA-B27 testing is useful for diagnostic probability as it's positive in 85-95% of AS patients, but 8% of the general population is also positive, so it's not diagnostic in isolation.

Imaging is crucial. I would start with a plain AP pelvis X-ray to assess for sacroiliitis, graded 0-4. The modified New York criteria define radiographic AS as bilateral grade 2 or higher, or unilateral grade 3-4 sacroiliitis, plus clinical features. However, radiographic changes take 5-10 years to develop.

MRI of the sacroiliac joints and spine is the gold standard for early disease, using STIR sequences to detect bone marrow edema indicating active inflammation. The ASAS criteria for positive MRI sacroiliitis require bone marrow edema in at least 2 consecutive slices or 2 different locations on a single slice.

Diagnosis uses the ASAS classification criteria for axial spondyloarthritis, which has two pathways: the imaging arm requires sacroiliitis on imaging plus one SpA feature, while the clinical arm requires HLA-B27 positivity plus two SpA features such as inflammatory back pain, arthritis, enthesitis, uveitis, or family history."

Q4: "What is your management approach for a patient with newly diagnosed active AS?"

Model Answer: "Management has three key pillars: patient education, non-pharmacological treatment, and pharmacological treatment.

I would emphasize that physiotherapy and exercise are as important as medication. The patient should perform daily home exercises focusing on spinal flexibility, strengthening, and aerobic fitness. Supervised physiotherapy programs improve adherence and outcomes. Evidence from multiple meta-analyses shows exercise reduces disease activity and improves function, but benefits are only maintained with continued participation. I would also strongly advise smoking cessation as smoking worsens disease activity and radiographic progression.

For pharmacological treatment, I would start with a full-dose NSAID—for example, naproxen 500 mg twice daily—as first-line therapy. NSAIDs should be taken regularly, not as-needed, for 2-4 weeks to assess efficacy. If inadequate response, I would trial a second NSAID.

If disease activity remains high despite adequate NSAID trials—defined as BASDAI ≥4 or ASDAS ≥2.1—and there is objective evidence of inflammation with elevated CRP or MRI inflammation, I would initiate biologic therapy. First-line biologics are TNF inhibitors. I would choose adalimumab, infliximab, or golimumab rather than etanercept if the patient has a history of uveitis, as monoclonal antibody TNF inhibitors prevent uveitis flares whereas etanercept may increase uveitis risk. I would assess response at 12 weeks using ASAS response criteria.

I would also screen for and manage extra-articular manifestations, ensure vaccinations are up-to-date before starting biologics, and screen for latent tuberculosis."

Q5: "A patient on adalimumab for AS has inadequate response at 12 weeks. What would you do?"

Model Answer: "First, I would confirm this is truly inadequate response by assessing disease activity using validated measures—BASDAI or ASDAS—and comparing to baseline. I would also verify treatment adherence and check that concomitant physiotherapy is being performed.

If confirmed as primary non-response—meaning the patient never had significant improvement—the 2019 ACR/SAA guidelines recommend switching to an IL-17 inhibitor such as secukinumab, ixekizumab, or bimekizumab, rather than trying a second TNF inhibitor. This is based on evidence that patients with primary non-response to one TNF inhibitor are less likely to respond to another.

However, if the patient has a history of uveitis, I would avoid secukinumab or ixekizumab as selective IL-17A inhibition can worsen uveitis. I would consider bimekizumab, which inhibits both IL-17A and IL-17F and appears to reduce uveitis risk, or alternatively try a different TNF inhibitor such as infliximab.

If there is a history of inflammatory bowel disease, IL-17 inhibitors should be avoided as they can worsen IBD, and I would switch to a different TNF inhibitor or consider a JAK inhibitor, though JAK inhibitors are generally reserved for third-line therapy."

Q6: "What are the key extra-articular manifestations of AS and how do they influence management?"

Model Answer: "The most common extra-articular manifestation is anterior uveitis, occurring in 25-40% of AS patients over their lifetime. It presents with acute onset painful red eye, photophobia, and blurred vision, typically unilateral and recurrent. It requires urgent ophthalmology assessment to prevent complications like posterior synechiae and glaucoma. Treatment is with topical corticosteroids and cycloplegics. Importantly, the choice of biologic therapy is influenced by uveitis: monoclonal antibody TNF inhibitors—adalimumab, infliximab, golimumab—reduce uveitis flares by 50-70%, whereas etanercept may increase uveitis risk. IL-17A inhibitors secukinumab and ixekizumab can also worsen uveitis.

Inflammatory bowel disease occurs in 5-10% of patients overtly, with subclinical gut inflammation in up to 70% on endoscopy. If a patient has active IBD, I would choose adalimumab or infliximab as they are effective for both AS and IBD, and avoid IL-17 inhibitors which can worsen or induce IBD.

Cardiovascular complications include aortitis in 2-10%, which can lead to aortic regurgitation requiring valve replacement. Cardiac conduction defects occur in 1-9% and may necessitate pacemaker insertion. AS also increases cardiovascular risk 1.5-2-fold due to chronic inflammation, so aggressive CV risk factor modification is important. I would perform baseline ECG and consider echocardiography if there's a murmur or long disease duration.

Other manifestations include apical pulmonary fibrosis, though rare, and very rarely AA amyloidosis, which is now uncommon due to effective disease control with biologics."

High-Yield Examination Pearls

Clinical Examination:

• Modified Schober's test: Mark L5 level (posterior superior iliac spines), mark 10 cm above and 5 cm below; with maximal flexion, distance should increase to ≥21 cm (≥6 cm increase); less than 5 cm increase indicates reduced lumbar flexion
• Chest expansion: Measure at 4th intercostal space; less than 5 cm suggests costovertebral joint involvement
• Occiput-to-wall distance: Severity marker for cervical kyphosis; should be 0 cm normally
• Question mark posture: Exaggerated thoracic kyphosis with compensatory cervical extension in advanced disease

Key Diagnostic Pitfalls:

• HLA-B27 is NOT diagnostic: 8% of population is positive; only 1-2% of HLA-B27+ individuals develop AS
• Normal inflammatory markers don't exclude AS: ESR/CRP can be normal in 30-50% of active AS patients
• Early disease may have normal X-rays: Radiographic changes take 5-10 years; use MRI for early diagnosis

Treatment Pearls:

• Exercise is as important as medication: Multiple RCTs demonstrate efficacy; must be continued long-term
• NSAIDs may have disease-modifying effects in AS (unlike other inflammatory arthritides)
• Etanercept worsens uveitis: Use adalimumab/infliximab/golimumab if uveitis history
• IL-17A inhibitors can worsen uveitis and IBD: Be cautious with secukinumab/ixekizumab if these comorbidities present
• Don't add methotrexate to TNF inhibitors in AS (no benefit, unlike RA)
• Don't stop biologics in stable disease (high relapse rate)

Red Flags in AS:

• Trauma with neck/back pain: High suspicion for spinal fracture (ankylosed spine is brittle); CT imaging required
• Neurological symptoms: Rare but serious (fracture with cord compression, cauda equina syndrome)
• Painful red eye: Urgent ophthalmology for anterior uveitis assessment
• New cardiac symptoms: Screen for aortic regurgitation, conduction defects

Common Exam Mistakes to Avoid

❌ Stating HLA-B27 is diagnostic of AS – It's a risk factor present in 85-95% of AS patients, but 8% of general population is positive; requires clinical and imaging features for diagnosis

❌ Recommending methotrexate for axial AS – No efficacy for axial symptoms; only sulfasalazine has limited role for peripheral arthritis

❌ Starting biologics without adequate NSAID trial – Guidelines require trial of ≥2 NSAIDs (unless contraindicated) before biologics

❌ Choosing etanercept in patient with uveitis history – Monoclonal antibody TNF inhibitors (adalimumab, infliximab, golimumab) prevent uveitis; etanercept may increase uveitis risk

❌ Forgetting to screen for latent TB before TNF inhibitors – Mandatory screening; treat latent TB before starting biologics

❌ Not emphasizing physiotherapy – Exercise/physiotherapy as important as medications; must be mentioned in any management plan

❌ Assuming AS only affects men – Historical 3:1 male:female ratio narrowing to 2:1 with better recognition in women

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Medical Disclaimer: MedVellum content is for educational purposes only and should not replace professional clinical judgment. Always consult current guidelines and specialist advice for patient management.