Radiographic Axial Spondyloarthritis (ankylosing Spondylitis)
Radiographic axial spondyloarthritis (ankylosing spondylitis) is a chronic inflammatory disease primarily affecting the sacroiliac joints and spine, characterized by definite structural damage (sacroiliitis) visible on conventional radiographs, leading to progressive spinal stiffness and potential ankylosis.
Radiographic Axial Spondyloarthritis (Ankylosing Spondylitis)
Ankylosing spondylitis (AS) is a chronic, progressive inflammatory disease primarily affecting the axial skeleton — the sacroiliac (SI) joints and spine — manifested by inflammatory back pain and progressive stiffness of the spine [1][2].
Breaking down the name:
- "Ankylosing" → from Greek ankylosis = stiffness or rigidity of a joint (specifically through bony or fibrous fusion)
- "Spondylitis" → from Greek spondylos = vertebra + -itis = inflammation
So the name literally tells you: inflammatory fusion of the vertebrae.
AS refers to the inflammatory disorder associated with fibrous or bony bridging of joints in the spine including bridging of intervertebral discs [2].
AS is the prototype and most severe end of a disease spectrum called axial spondyloarthritis (axSpA):
- Ankylosing spondylitis (AS): has definite radiographic sacroiliitis on plain X-ray → more advanced, established disease [3][4]
- Non-radiographic axial spondyloarthritis (nr-axSpA): sacroiliitis visible on MRI or no definite changes on plain X-ray → earlier disease stage [3][4]
The distinction matters because patients with nr-axSpA may not yet show structural damage on X-ray but can have the same degree of pain, inflammation, and functional impairment. Over time, a proportion of nr-axSpA patients will progress to radiographic AS.
AS is one of the four seronegative spondyloarthritides (SpA) — a family of disorders characterised by inflammation around the entheses (sites of tendon and ligament insertion into bone), HLA-B27 association, and negative RF and anti-CCP [1][2][5]:
- Ankylosing spondylitis
- Psoriatic arthritis
- Reactive arthritis (formerly Reiter's disease)
- Arthritis associated with inflammatory bowel disease (IBD) [1][2]
Previously known as seronegative spondyloarthropathies (SNSA) — previously thought to be a variant of RA with negative RF, now considered a separate disease (the term SNSA is now obsolete) [5]
High Yield Concept — Axial vs Peripheral SpA
The ASAS 2009 new classification simplifies SpA into:
- Axial spondyloarthritis (axSpA): predominant axial involvement
- Peripheral spondyloarthritis (peripheral SpA): predominant peripheral involvement
The traditional entities (AS, PsA, ReA, EnA) overlap significantly. The new classification reflects that the approach to diagnosis and management is generally similar across subtypes [1][5].
2. Epidemiology
- Axial SpA prevalence: ~1.4% (in the US); AS specifically: ~0.55% [5]
- Among HLA-B27-positive individuals: ~5–6% will develop AS [5] — i.e., HLA-B27 is necessary but far from sufficient
- Worldwide prevalence of AS mirrors the prevalence of HLA-B27 in different populations (higher in Northern Europeans, lower in Sub-Saharan Africans)
- Male predominance: M:F ≈ 2–3:1 for AS [2][3][5]
- Historically thought to be much higher (up to 10:1) — this was due to under-diagnosis in women who tend to have less radiographic progression
- Age < 16 years: M:F = 6:1; Age 30 years: M:F = 2:1 [6]
- In nr-axSpA: M:F ≈ 1:1 [5] — suggesting women are just as commonly affected early on but less likely to develop radiographic changes
- Peak age of onset: 20–30 years [2][5]
- Most present before age 45 → inflammatory back pain starting after age 45 should prompt consideration of other diagnoses
- Delay in diagnosis can be up to 6–11 years [1] — this is a frequently examined point; the delay occurs because young patients with back pain are common and AS is initially misdiagnosed as mechanical back pain
Delay in diagnosis: up to 6–11 years [1]. This is because early symptoms are non-specific (young person with back pain), and radiographic sacroiliitis takes time to develop on plain X-ray.
- Family history positive with strong genetic contribution [5]:
- HLA-B27 prevalence:
HLA-B27 in Clinical Context
HLA-B27 is most useful when clinical suspicion is moderate and radiological findings are equivocal. A positive result increases post-test probability significantly in the right clinical context (young male, inflammatory back pain, family history). A negative result substantially lowers the probability but does not exclude it.
3. Anatomy and Function — Relevant Structures
Understanding why AS targets specific structures requires knowledge of the anatomy it affects:
- The SI joint is a large, partially synovial/partially ligamentous joint connecting the sacrum to the ilium
- It transmits the entire weight of the upper body to the lower limbs → it is a high-stress, low-mobility joint with abundant ligamentous/entheseal attachments
- Why does AS start here? Because the SI joint has extensive entheses (where ligaments insert into bone), and SpA is fundamentally an entheseal disease — inflammation at entheses
- The spinal column consists of vertebral bodies connected by:
- Intervertebral discs (annulus fibrosus + nucleus pulposus)
- Anterior and posterior longitudinal ligaments
- Interspinous ligaments, supraspinous ligaments
- Facet (zygapophyseal) joints — true synovial joints
- Costovertebral and costotransverse joints (thoracic spine)
- The annulus fibrosus inserts into the vertebral endplate via Sharpey's fibres — these are entheses, and inflammation here produces the characteristic Romanus lesion (see below)
- Enthesis (plural: entheses) = the site where a tendon, ligament, joint capsule, or fascia attaches to bone
- Enthesitis = inflammation at these sites → this is the hallmark pathological process of SpA (as opposed to RA, which is primarily a synovitis)
- Common entheseal sites affected: Achilles tendon insertion, plantar fascia insertion, tibial tuberosity, iliac crest, ischial tuberosity, greater trochanter, spinous processes
- Aortic root: why does AS cause aortic regurgitation? Because the aortic root has fibrous tissue that is analogous to entheses, and fibrosis/inflammation here leads to aortic root dilatation → valve incompetence
- Eye (anterior uveal tract): the iris and ciliary body share HLA-B27-related immunological susceptibility → anterior uveitis
- Lung apices: apical fibrosis in AS is thought to result from chronic restriction of chest wall movement with secondary atelectasis/fibrosis
4. Aetiology (Focus on Hong Kong)
4.1 Genetic Factors
- HLA-B27: a class I Major Histocompatibility Complex (MHC-I) molecule, present on the surface of all nucleated cells, involved in presenting intracellular peptides to CD8+ T cells [5]
- Present in > 95% of AS patients [5] in Western populations; in Hong Kong/Chinese populations, the association is still strong but the background prevalence of HLA-B27 is lower (~6–8%)
- Over 200 subtypes of HLA-B27 exist (B27:01 to B27:xx); B27:05 is the most common disease-associated subtype worldwide; in Chinese populations, B27:04 is also prevalent
Pathogenic role of HLA-B27 — three main hypotheses [5]:
- Arthritogenic peptide hypothesis: HLA-B27 presents specific microbial peptides that cross-react with self-peptides (molecular mimicry), triggering autoimmune T-cell responses against joint tissues
- Misfolding hypothesis: HLA-B27 heavy chain tends to misfold in the endoplasmic reticulum → this triggers the unfolded protein response (UPR) → activation of NF-κB → pro-inflammatory cytokine production (IL-23, TNF-α) → Th17 cell differentiation → IL-17 production → entheseal/bone inflammation
- Free heavy chain / homodimer hypothesis: HLA-B27 heavy chains can form homodimers on the cell surface that are recognised by innate immune receptors (e.g., KIR3DL2 on NK cells and T cells), promoting inflammation
- Multiple non-HLA genes contribute (accounting for ~50% of genetic risk):
- ERAP1 (endoplasmic reticulum aminopeptidase 1): trims peptides for loading onto HLA-B27; polymorphisms only confer risk in HLA-B27-positive individuals (epistasis)
- IL-23R, IL-12B: variants in the IL-23/IL-17 axis
- CARD9, STAT3, TYK2: innate immunity genes
- Aberrant immune response towards an infection in a genetically predisposed individual [5]
- The exact triggering infection is often not identified (unlike reactive arthritis where a preceding urogenital or enteric infection is clear)
- Gut microbiome: subclinical gut inflammation is found in up to 60% of AS patients; altered microbiome composition (dysbiosis) may trigger or perpetuate the disease
- Mechanical stress: entheses at sites of high mechanical loading (SI joints, Achilles tendon) are preferentially affected — suggesting that biomechanical microtrauma may initiate inflammation in susceptible individuals
- AS is well-recognised in Hong Kong Chinese, though less common than in Northern European populations (reflecting lower HLA-B27 prevalence)
- Smoking is an important modifiable risk factor — accelerates radiographic progression and worsens functional outcomes
- IBD-associated SpA is less common in Chinese (primary sclerosing cholangitis association with IBD is ~1% in Chinese vs higher in Caucasians [8])
- Late presentation is common due to diagnostic delay — patients often see multiple practitioners before diagnosis
5. Pathophysiology
The key difference between SpA and RA:
- RA = primarily a synovitis (inflammation of the synovial membrane lining joints)
- SpA = primarily an enthesitis (inflammation at the site where tendons/ligaments insert into bone)
The pathophysiological sequence in AS:
Genetic susceptibility (HLA-B27 + other genes)
↓
Environmental trigger (infection, mechanical stress, gut dysbiosis)
↓
Entheseal inflammation (enthesitis)
↓
Local production of TNF-α, IL-17, IL-23 by innate immune cells
↓
Bone erosion (osteitis) + reactive new bone formation
↓
Syndesmophyte formation → bridging of vertebral bodies
↓
Ankylosis (fusion) → "bamboo spine"This is a critical concept that distinguishes SpA from RA:
- In RA, inflammation causes bone erosion and osteopenia (destruction without repair)
- In SpA, there is a paradox: inflammation causes initial erosion, but this is followed by excessive new bone formation (syndesmophytes, enthesophytes)
- The mechanism involves:
- Wnt signalling pathway activation at entheseal sites → osteoblast differentiation
- BMP (bone morphogenetic protein) signalling → new bone formation
- DKK-1 (Dickkopf-1, a Wnt inhibitor) levels are low in AS → unopposed Wnt signalling → bone formation
- TNF-α initially inhibits new bone formation, but once inflammation resolves, the repair response overshoots → this partly explains why anti-TNF therapy controls inflammation but may not fully prevent radiographic progression
- Chronic inflammation at the aortic root → fibrosis and thickening of the aortic wall → dilatation of the aortic annulus → aortic regurgitation [9]
- Can also involve the conduction system (subaortic fibrosis extending into the interventricular septum) → conduction defects (AV block)
- Apical fibrosis: restrictive chest wall disease (from costovertebral joint ankylosis) → reduced ventilation of apices → atelectasis → secondary fibrosis
- Rarely, apical cavitation can mimic tuberculosis
- Acute anterior uveitis: thought to relate to HLA-B27-mediated immune dysregulation in the uveal tract; the iris and ciliary body are HLA-B27-rich tissues
- Typically unilateral, acute, and recurrent (alternating eyes)
- IgA nephropathy: elevated serum IgA is common in AS (possibly related to mucosal immune activation from subclinical gut inflammation)
- Secondary amyloidosis (AA amyloidosis): chronic inflammation → elevated serum amyloid A → deposition in kidneys (rare in the modern biologic era)
6. Classification
| Entity | Key Distinguishing Feature |
|---|---|
| Ankylosing spondylitis | Prototype; predominant axial disease; radiographic sacroiliitis |
| Psoriatic arthritis | Associated with psoriasis |
| Reactive arthritis | Following extra-articular infection (enteric or urogenital) |
| Enteropathic arthritis | Associated with IBD (Crohn's or UC) |
| Undifferentiated SpA | Features of SpA but doesn't fit neatly into above categories |
| Juvenile-onset SpA | Onset < 16 years |
The Assessment of SpondyloArthritis International Society (ASAS) reclassified SpA into [5]:
| Category | Definition |
|---|---|
| Axial SpA (axSpA) | Predominant axial (spine/SI joint) involvement; includes AS and nr-axSpA |
| Peripheral SpA | Predominant peripheral involvement (arthritis, enthesitis, dactylitis) |
This is a more practical classification because:
- Many patients present with overlapping features
- Management principles are similar within each category
- It captures early disease (nr-axSpA) that would be missed by the Modified New York criteria
| Grade | Description |
|---|---|
| Grade 0 | Normal |
| Grade 1 | Suspicious changes |
| Grade 2 | Sclerosis + no narrowing of joint space (minimal abnormality) [3] |
| Grade 3 | Narrowed joint space + sclerosis + erosions [3] |
| Grade 4 | Ankylosis (complete fusion) [3] |
Modified New York criteria for definite AS (1984): requires sacroiliitis ≥ Grade II bilateral OR Grade III–IV unilateral PLUS at least one clinical criterion [2][3][5].
Key differences between SpA subtypes [5][7]:
| Feature | AS | PsA | ReA | IBD-associated |
|---|---|---|---|---|
| Axial involvement | 100% | 20–40% | 40–60% | 5–20% |
| Sacroiliitis | Symmetric | Asymmetric | Asymmetric | Symmetric |
| Peripheral involvement | Less common (50%) | Frequent | Frequent | Frequent |
| Limb predominance | Lower > upper | Upper > lower | Lower > upper | Lower > upper |
| HLA-B27 | 80–90% | 60% | 60–80% | 50% |
| Enthesitis | Frequent | Frequent | Frequent | Rare |
| Dactylitis | Uncommon | Common | Common | Common |
| Ocular | Uveitis 25–40% | Conjunctivitis, uveitis, episcleritis | Conjunctivitis, uveitis, keratitis | Uveitis |
| Skin | None | Psoriasis | Circinate balanitis, keratoderma blennorrhagica | Erythema nodosum, pyoderma gangrenosum |
| Other | CAD, aortitis, AR, conduction defects | CAD | Urethritis, AR, conduction defects | — |
7. Clinical Features
7.1 Symptoms
(i) Inflammatory back pain / buttock pain [2][3]
This is the cardinal symptom of AS and the single most important feature to elicit in the history.
Characteristics of inflammatory back pain (contrast with mechanical back pain):
- Age of onset < 45 years [3]
- Duration > 3 months [3]
- Insidious onset (not sudden) [3]
- Nocturnal pain (especially second half of the night, waking the patient) [3]
- Morning stiffness > 30 minutes [3]
- Improved with movement/exercise but NOT with rest [3] — this is the opposite of mechanical back pain, which improves with rest
- Alternating buttock pain — because the SI joints are affected alternately
Why does inflammatory back pain improve with exercise?
- During rest (especially sleep), inflammatory mediators accumulate in the joint → stiffness and pain on waking
- Movement increases blood flow, clears inflammatory mediators, and stretches the stiffened tissues → symptom relief
- This is the same reason why RA patients have morning stiffness — it is a hallmark of inflammatory joint disease
The back pain starts at the SI joints and ascends upwards [3] — reflecting the typical ascending pattern of spinal involvement in AS (sacroiliac → lumbar → thoracic → cervical).
(ii) Neck pain [3]
- Occurs with cervical spine involvement — typically a later feature as disease ascends
- May present with reduced cervical rotation and extension
(iii) Chest wall pain
- Due to involvement of costosternal and manubriosternal joints, and costovertebral joints
- Patients may describe chest tightness or difficulty taking a deep breath
- Reduced chest expansion [3] — normally > 4 cm at the nipple line; reduced expansion reflects costovertebral joint disease and is an important clinical criterion
(iv) Peripheral joint pain [3]
- Typically asymmetrical oligoarthritis (≤ 4 joints) [3][5]
- Lower limbs > upper limbs [7]
- Hip involvement is a poor prognostic factor [3] — because hip disease causes significant functional limitation and often requires joint replacement
(v) Enthesitis symptoms [3]
- Pain at tendon/ligament insertions:
Why is enthesitis characteristic of SpA and not RA? Because the fundamental pathology in SpA is at the enthesis (bone-tendon junction), not the synovium. RA causes synovitis; SpA causes enthesitis that may secondarily involve adjacent synovium.
(vi) Dactylitis [3]
(vii) Eye symptoms — Acute anterior uveitis [3][7][10]
- The most common extra-articular manifestation of AS
- Occurs in 25–40% of AS patients [7]
- Symptoms: acute onset unilateral eye pain, photophobia, blurred vision, tearing
- Typically unilateral, acute, and recurrent (may alternate between eyes)
- Due to HLA-B27-associated inflammation of the anterior uveal tract (iris + ciliary body)
(viii) Cardiovascular symptoms
- Aortic regurgitation (AR) [3][9]: may cause dyspnoea, palpitations; occurs due to aortic root inflammation and fibrosis
- Conduction defects [7]: palpitations, syncope; due to fibrosis of the subaortic region extending to the conduction system (AV node/Bundle of His)
(ix) Respiratory symptoms
- Apical pulmonary fibrosis [3]: usually asymptomatic; may cause dry cough
- Restrictive ventilatory defect from chest wall rigidity
(x) Gastrointestinal symptoms
- Autoimmune IBD [3]: subclinical gut inflammation is common (up to 60%); overt IBD (Crohn's or UC) develops in ~5–10%
(xi) Renal symptoms
- Usually asymptomatic; IgA nephropathy may present with haematuria
- Secondary amyloidosis [3]: nephrotic syndrome (rare)
(xii) Neurological symptoms
- Cauda equina syndrome [3]: very rare, late complication from arachnoiditis or dural ectasia; presents with urinary retention, saddle anaesthesia, lower limb weakness
- Atlantoaxial subluxation [3]: cervical myelopathy from C1-C2 instability; presents with upper motor neuron signs in all four limbs
(xiii) Constitutional symptoms
- Fatigue (often prominent and debilitating)
- Weight loss
- Low-grade fever (uncommon)
The 6A Mnemonic for Extra-Articular Manifestations of AS
6A's [3]:
- Anterior uveitis (eye)
- Apical fibrosis (lung)
- Aortic regurgitation (CVS)
- Autoimmune IBD (GI)
- Amyloidosis / IgA nephropathy (renal)
- Atlantoaxial subluxation (neurological)
7.2 Signs
(i) Lumbar spine assessment
- Modified Schober's test [3]: measures lumbar flexion
- Technique: mark the skin at the level of the posterior superior iliac spines (dimples of Venus, approximately L5) and 10 cm above. Ask the patient to bend forward maximally. Measure the increase in distance between the two marks
- Normal: increase by ≥ 5 cm [3]
- Reduced in AS due to lumbar spine stiffness/ankylosis
- Lateral flexion: middle finger-to-floor distance (normal < 10 cm) [3]
- Loss of lumbar lordosis: flattening of the normal lumbar curve — an early sign of spinal rigidity
(ii) Thoracic spine assessment
- Chest expansion [3]:
- Measured at the nipple line (T4 level)
- Normal: > 4 cm [3]
- Reduced expansion reflects costovertebral and costosternal joint involvement → restrictive chest wall disease
(iii) Cervical spine assessment
- Occiput-to-wall distance [3]:
- Patient stands with heels and back against a wall, attempts to touch the wall with the occiput
- Normal: 0 cm [3] (occiput touches the wall)
- Increased distance indicates fixed cervical flexion deformity
- Tragus-to-wall distance: normal < 14 cm [3]
- Reduced cervical rotation, lateral flexion
(iv) Postural deformity
- "Question mark" deformity [3]: the classic late posture of AS
- Loss of lumbar lordosis → flattened lower back
- Fixed thoracic kyphosis → stooped forward
- Compensatory cervical flexion → chin on chest
- The patient cannot look straight ahead when standing → looks at the ground
- When viewed from the side, the spine curves like a "?"
(v) Spine fractures
- Prone to spine fractures and whiplash injury [3]
- The fused, osteoporotic "bamboo spine" is brittle like a long bone — even minor trauma (e.g., a fall from standing) can cause an unstable fracture
- These fractures often extend through the disc space (transdiscal) and are highly unstable
- Always suspect spinal fracture in an AS patient with new-onset neck/back pain after trauma
- FABER test [3] (also called Patrick's test):
- Flexion, ABduction, External Rotation of the hip
- Patient supine, places ankle on opposite knee, examiner pushes the flexed knee towards the bed
- Positive: reproduces pain in the ipsilateral SI joint or groin
- Gaenslen's test [3]:
- Patient lies supine with one leg hanging off the edge of the bed (extended); the other hip and knee are flexed towards the chest
- Positive: pain in the SI joint on the extended side
- This stresses the SI joint by hyperextending it
- Lower limbs [3]:
- Palpate the Achilles tendon insertion for tenderness (enthesitis)
- Palpate the plantar fascia insertion (medial calcaneal tubercle) for tenderness
- Intermalleolar distance [3]: measures hip abduction (reduced in hip disease)
- Assess for peripheral joint swelling (typically asymmetric oligoarthritis of large joints in lower limbs)
- Eyes: Acute anterior uveitis [3] — ciliary flush (circumlimbal conjunctival injection), miotic pupil (iris spasm), anterior chamber cells/flare [10]
- CVS: Aortic regurgitation murmur [3] — early diastolic decrescendo murmur at the left sternal edge, best heard with patient sitting up and leaning forward in expiration
- Lungs: Apical fibrosis [3] — may have reduced breath sounds or crackles at the apices (rare)
High Yield — Physical Examination Checklist for AS
A systematic examination of a patient with suspected AS should cover [3]:
- Lumbar spine: Modified Schober's test, lateral flexion
- Thoracic spine: Chest expansion at nipple line
- Cervical spine: Occiput-to-wall distance, tragus-to-wall distance
- SI joints: FABER test, Gaenslen's test
- Lower limbs: Achilles tendon, plantar fascia, intermalleolar distance
- Extra-articular: Eyes (uveitis), CVS (AR murmur), Lungs (apical fibrosis)
8. Disease Activity Assessment
Understanding disease activity indices is important for monitoring and for determining eligibility for biologic therapy:
- A patient-reported questionnaire scored 0–10 (0 = none; 10 = very severe)
- Active disease: total score ≥ 4 out of 10 [3]
- 6 questions covering [2]:
- Overall level of fatigue/tiredness
- Overall level of AS neck, back or hip pain
- Overall level of pain/swelling in joints other than neck, back and hips
- Overall level of discomfort from areas tender to touch or pressure (enthesitis)
- Overall level of morning stiffness from wake-up
- Duration of morning stiffness (0 = 0 hours; 5 = 1 hour; 10 = ≥ 2 hours)
- Calculation: mean of Q5 + Q6, then add Q1–Q4, then divide by 5
- ASAS 50 response criteria: BASDAI decreases by ≥ 50% [3] — used to assess treatment response
| Index | What It Measures |
|---|---|
| BASFI | Functional disability |
| BASMI | Metrology (physical measurements of spinal mobility) |
| BAS-G | Global assessment (patient's and physician's overall assessment) |
| ASDAS | AS Disease Activity Score — composite index incorporating CRP and patient-reported outcomes; preferred by ASAS over BASDAI for treatment decisions |
Investigations for AS (SAQ!) [3]
- Bloods: CBC, LRFT, ESR/CRP, RF (to exclude RA), HLA-B27 (useful if no radiological evidence) [3]
- Imaging [3]:
- X-ray SI joints: grading of sacroiliitis (Grade 0–4)
- X-ray spine: Romanus lesion, syndesmophytes, bamboo spine, Anderson lesion
- MRI SI joints: subchondral bone marrow oedema (early disease, before X-ray changes)
- DEXA scan: baseline for osteopenia [3]
High Yield Summary
Radiographic Axial Spondyloarthritis (Ankylosing Spondylitis) — Key Points:
- Definition: Chronic inflammatory disease of the axial skeleton with radiographic sacroiliitis; prototype of the seronegative spondyloarthritides
- Demographics: Young adults (peak 20–30s), M:F = 2–3:1, diagnosis delayed 6–11 years
- Genetics: HLA-B27 positive in 80–90%; 6–8% prevalence in southern Chinese; NOT diagnostic alone
- Pathophysiology: Enthesitis-centred (not synovitis like RA); involves TNF-α, IL-17/IL-23 axis; unique paradox of bone erosion followed by new bone formation (Wnt pathway) → syndesmophytes → ankylosis
- Cardinal symptom: Inflammatory back pain — onset < 45y, > 3 months, insidious, nocturnal, morning stiffness > 30 min, improves with exercise NOT rest, starts at SI joints and ascends
- Peripheral features: Asymmetric oligoarthritis (LL > UL), enthesitis (Achilles, plantar fascia), dactylitis (uncommon but poor prognosis)
- Extra-articular — 6A's: Anterior uveitis, Apical fibrosis, Aortic regurgitation, Autoimmune IBD, Amyloidosis/IgA nephropathy, Atlantoaxial subluxation
- Key examination: Modified Schober's (lumbar), chest expansion (thoracic), occiput-to-wall (cervical), FABER/Gaenslen's (SI joints)
- Disease activity: BASDAI ≥ 4/10 = active disease
- Classification: Modified New York 1984 (radiographic); ASAS 2009 (imaging or HLA-B27 + SpA features); current approach distinguishes AS from nr-axSpA
Active Recall — Ankylosing Spondylitis (Definition to Clinical Features)
[1] Lecture slides: GC 074. Multiple joint pain.pdf (slides on SpA concept and diagnosis delay) [2] Lecture slides: Block A - Multiple joint pain: Rheumatoid arthritis and the concept of inflammatory arthritis.pdf [3] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — Ankylosing spondylitis, pp. 322–325) [4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Ankylosing spondylitis, pp. 1699–1703) [5] Senior notes: Ryan Ho Rheumatology.pdf (Spondyloarthritis, pp. 57–58) [6] Lecture slides: GC 226. Lumbar Spine Pathology_Part E.pdf (slide on AS demographics and HLA-B27) [7] Senior notes: Ryan Ho Rheumatology.pdf (SpA comparison table, p. 58) [8] Senior notes: Block A - Chronic diarrhoea: irritable bowel syndrome and inflammatory bowel disease.pdf (extraintestinal manifestations, p. 34) [9] Senior notes: Block A - Fever and a murmur: Valvular heart diseases; Infective endocarditis.pdf (aortic regurgitation etiologies, p. 22) [10] Senior notes: Ryan Ho Ophthalmology.pdf (Uveitis, p. 30)
Differential Diagnosis of Ankylosing Spondylitis
When a young patient walks into your clinic with chronic back pain, your primary job is to answer two sequential questions:
- Is this inflammatory or mechanical back pain? — This is the single most important first branch point. The vast majority of chronic back pain is mechanical (~97%), while non-mechanical causes (including AS) account for only ~3% [11].
- If inflammatory, which specific spondyloarthritis (or other inflammatory condition) is it? — Once you've established an inflammatory pattern, you then differentiate among the SpA subtypes and other inflammatory/infiltrative causes.
The differential can therefore be organised into three tiers:
- Tier 1: Mechanical/degenerative causes of back pain (the most common mimics)
- Tier 2: Other spondyloarthritides and inflammatory arthritides (the "SpA family" — share overlapping features with AS)
- Tier 3: Non-inflammatory, non-mechanical causes (infection, neoplasia, metabolic bone disease, referred pain)
These are by far the most common causes of back pain and the conditions most frequently confused with AS, especially early in the disease course. The key distinguishing feature is the pattern of pain: mechanical pain is worse with activity and relieved by rest; inflammatory pain is the opposite.
| Condition | Key Distinguishing Features from AS | Why It Can Mimic AS |
|---|---|---|
| Back sprain / muscular strain [11] | Acute onset, often post-trauma/exertion; improves with rest; no morning stiffness > 30 min; no sacroiliitis on imaging; normal inflammatory markers | Young patients with chronic postural strain can have prolonged symptoms; may have mild morning stiffness |
| Lumbar disc degeneration / spondylosis [11][12] | Older age (typically > 40); pain worse with activity; generally readily differentiated on imaging [5]; osteophytes and disc space narrowing on XR (not syndesmophytes) | Can cause chronic LBP with stiffness; but pattern is mechanical, not inflammatory |
| Lumbar disc herniation [11] | Acute radiculopathy (dermatomal pain, numbness, weakness); positive straight leg raise; disc protrusion on MRI | Occasionally buttock pain from S1 root involvement can mimic SI joint pain |
| Spondylolysis / spondylolisthesis [11][13] | Pain exacerbated by hyperextension; stress fracture of pars interarticularis; visible on oblique XR or CT; more common in adolescents/athletes | Can cause chronic LBP in young patients; but no inflammatory features and different imaging findings |
| Vertebral compression fracture [11] | Acute onset after trauma (or minimal trauma in osteoporosis); localised tenderness; wedge/compression deformity on XR | In older patients with established AS, the fused spine is itself prone to fractures — but in a new patient, osteoporotic fracture is a separate entity |
GC High Yield — DDx of Back Pain from Orthopaedics Lecture
Mechanical pain accounts for ~97% of back pain [11]. The differential includes:
- Back sprain ( > 70%)
- Lumbar disc degeneration
- Lumbar disc herniation
- Spondylolisthesis
- Fracture (vertebral body, spondylolysis)
Non-mechanical pain (~3%) includes:
- Neoplasia
- Inflammatory arthritis (AS/spondyloarthropathy)
- Infection
- Non-spinal diseases (pelvic inflammatory disease, endometriosis, nephrolithiasis, pyelonephritis, aortic aneurysm) [11]
"Musculoskeletal back pain: usually more acute, lasts shorter, and may be associated with trauma/injury" [5]. "Spinal spondylosis and other changes: generally readily differentiated on imaging" [5].
Tier 2: Other Spondyloarthritides and Inflammatory Arthritides
These are the most clinically important differentials because they share the same disease family as AS and have overlapping clinical features. Distinguishing them requires attention to extra-articular features, pattern of joint involvement, and associated conditions.
| Condition | Key Distinguishing Features from AS | Shared Features with AS |
|---|---|---|
| Psoriatic arthritis (PsA) [4][7] | Psoriasis (check hidden areas: scalp, umbilicus, natal cleft, ears); nail dystrophy (pitting, onycholysis, ridging); DIP joint involvement; asymmetric sacroiliitis; pencil-in-cup deformity on XR [7]; M:F = 1:1 | HLA-B27+; enthesitis; dactylitis (more common than AS); sacroiliitis; spondylitis; anterior uveitis |
| Reactive arthritis (ReA) [4][7] | History of antecedent infection (1–4 weeks prior): GU (Chlamydia) or enteric (Salmonella, Shigella, Yersinia, Campylobacter); asymmetric oligoarthritis predominantly lower limbs; conjunctivitis (more than uveitis); circinate balanitis; keratoderma blennorrhagica [7]; usually self-limiting | HLA-B27+; enthesitis; dactylitis; asymmetric sacroiliitis; can progress to chronic SpA |
| Enteropathic arthritis (IBD-associated) [7][8] | Inflammatory bowel disease (Crohn's or UC) — confirmed by endoscopy + biopsy; erythema nodosum, pyoderma gangrenosum [8]; peripheral arthritis often mirrors IBD activity; sacroiliitis is symmetric (like AS); dactylitis common but enthesitis rare [7] | HLA-B27+; symmetric sacroiliitis; spondylitis; anterior uveitis |
| Undifferentiated SpA [1][5] | Features of SpA but does not fit neatly into any specific category; may be early disease that has not yet declared itself | Any combination of SpA features |
Key distinguishing points from GC lecture slides [1]:
Clinical features of SpA include: 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 [1].
How to differentiate within the SpA family in practice:
- Ask about skin: psoriasis → PsA; erythema nodosum/pyoderma gangrenosum → enteropathic
- Ask about preceding infection: GU/enteric infection 1–4 weeks before → reactive arthritis
- Ask about GI symptoms: chronic diarrhoea, bloody stool, abdominal pain → IBD-associated
- Check pattern of sacroiliitis on imaging: symmetric → AS or enteropathic; asymmetric → PsA or ReA
Differences between RA and PsA — frequently examined [3]:
| Feature | RA | PsA |
|---|---|---|
| Sex ratio | M:F = 1:3 | M:F = 1:1 |
| Joint pattern | Symmetrical polyarthritis; spares DIP | Asymmetrical (5 patterns); DIP involvement |
| Tenderness vs deformity | Tenderness precedes deformity | Less tender, may present with deformity |
| Extra-articular | Rheumatoid nodules | Psoriasis; nail dystrophy; enthesitis, dactylitis, spondylitis/sacroiliitis |
| Serology | RF+, anti-CCP+ | Usually RF−, anti-CCP− |
| Feature | How to Differentiate from AS |
|---|---|
| Joint pattern | Symmetric polyarthritis affecting small joints of hands (MCP, PIP); spares DIP [2]; predominantly upper limb involvement — contrast with AS which has asymmetric oligoarthritis of lower limbs |
| Spinal involvement | Cervical spine (C1-C2 erosive disease with atlantoaxial subluxation) but does NOT cause sacroiliitis or lumbar/thoracic spondylitis |
| Serology | RF+ and anti-CCP+ in majority — AS is seronegative |
| Morning stiffness | Present (> 30 min) but in small joints of hands, not axial skeleton |
| Extra-articular | Rheumatoid nodules, Felty syndrome, rheumatoid lung — different from the 6A's of AS |
RA spares DIP [2] — this is a critical exam pearl to remember.
In paediatric patients, the JIA subtype that most closely resembles AS is enthesitis-related arthritis (ERA) [14]:
| Feature | How to Differentiate from AS |
|---|---|
| Demographics | Older patients (> 50), often with metabolic syndrome/diabetes |
| Pain pattern | Mechanical stiffness rather than inflammatory pain; no significant morning stiffness |
| Imaging | Flowing ossification along anterolateral aspect of ≥ 4 contiguous vertebral bodies with preservation of disc height and no SI joint involvement — contrast with syndesmophytes in AS which are thin, vertical, marginal, and arise from the vertebral body margins |
| Inflammatory markers | Normal ESR/CRP |
| HLA-B27 | Negative |
This is an important radiological mimic — both DISH and AS cause spinal stiffness and flowing new bone formation, but the patterns are distinct.
"Fibromyalgia: back pain usually not typical inflammatory type with modest response to NSAIDs, tender points may be useful" [5]
| Feature | How to Differentiate from AS |
|---|---|
| Pain pattern | Widespread pain (not localised to axial skeleton); does not follow typical inflammatory pattern |
| Tender points | Multiple specific tender points (American College of Rheumatology criteria) |
| Imaging | Normal — no sacroiliitis |
| Inflammatory markers | Normal ESR/CRP |
| Response to NSAIDs | Modest (contrast with AS which typically shows good response to NSAIDs) |
| Comorbidity | Can coexist with AS — fibromyalgia is common in the general population and can complicate the assessment of disease activity in established AS patients |
Tier 3: Non-Inflammatory, Non-Mechanical Causes
These are less common but clinically important "can't miss" diagnoses:
| Condition | Key Features | Why It's in the DDx |
|---|---|---|
| TB spondylitis (Pott's disease) [16] | Lower thoracic/upper lumbar involvement; begins at anterior vertebral body (disc-sparing early); paraspinal abscess; kyphosis (Gibbus deformity); constitutional symptoms; endemic in Hong Kong | Can cause chronic back pain and stiffness; but has constitutional symptoms, elevated inflammatory markers, and characteristic MRI findings (disc-sparing early, then late disc destruction) |
| Pyogenic spondylodiscitis | Fever, localised tenderness; starts in the disc (contrast with TB which starts in the vertebral body); positive blood cultures; MRI shows disc signal abnormality early | Acute/subacute back pain with fever; raised inflammatory markers |
| Epidural abscess [16] | Fever, severe localised pain, rapidly progressive neurological deficit; risk factors: IVDU, diabetes, immunosuppression; MRI shows epidural collection | Medical emergency — always exclude if new back pain + fever + neurological signs |
| Condition | Key Features | Why It's in the DDx |
|---|---|---|
| Spinal metastases [11] | Older age; history of primary malignancy (lung, breast, prostate, kidney, thyroid); night pain (but also rest pain); weight loss; bone destruction on imaging (lytic or sclerotic lesions in vertebral body, pedicle destruction — "winking owl" sign) | Night pain is shared with AS; but metastatic pain does NOT improve with exercise and patients are typically older with red flag features |
| Multiple myeloma | Age > 60; bone pain; anaemia; hypercalcaemia; elevated globulins/paraprotein; lytic lesions on XR (no blastic response) | Chronic bone/back pain in older patients; elevated ESR |
| Primary bone tumours [13] | Night waking, persistent pain; osteoid osteoma (adolescents); spine is a common site for osteoid osteoma [13] | Can present with back pain in young patients — but pain is typically constant, not inflammatory pattern, and CT shows characteristic nidus |
| Condition | Key Features |
|---|---|
| Osteoporotic vertebral fracture | Elderly, postmenopausal women; acute onset after minimal trauma; localised tenderness; wedge/compression deformity on XR; normal inflammatory markers |
| Paget's disease | Older patients; bone pain, enlargement, deformity; elevated ALP with normal Ca/PO4; characteristic mixed lytic/sclerotic XR appearance; pelvis and skull commonly affected |
In the context of spinal cord compression or myelopathy, AS is in the differential alongside other inflammatory causes [17]:
- Rheumatoid arthritis (C1-C2 erosive disease) [17]
- Ankylosing spondylitis (atlantoaxial subluxation, fractures, cauda equina) [17]
- Neuromyelitis optica, multiple sclerosis [17]
- Spondylosis (degenerative cervical myelopathy)
| Diagnosis | Age | Pain Pattern | Sacroiliitis | HLA-B27 | RF/anti-CCP | Key Distinguishing Feature |
|---|---|---|---|---|---|---|
| AS | 20–30s | Inflammatory | Symmetric, bilateral | 80–90%+ | Negative | Prototype axial SpA; bamboo spine |
| nr-axSpA | 20–30s | Inflammatory | MRI only (no XR changes) | Variable | Negative | Earlier disease; same symptoms |
| PsA | Any | Mixed | Asymmetric | 60% | Usually negative | Psoriasis + nail changes + DIP |
| ReA | 20–40s | Inflammatory | Asymmetric | 60–80% | Negative | Preceding GU/enteric infection |
| Enteropathic | Any | Mixed | Symmetric | 50% | Negative | IBD (Crohn's/UC) |
| RA | 30–50s | Inflammatory (hands) | Absent | Variable | Positive | Symmetric polyarthritis; spares DIP |
| DISH | > 50 | Mechanical stiffness | Absent | Negative | Negative | Flowing ossification ≥ 4 vertebrae; preserved disc height |
| Mechanical LBP | Any | Mechanical | Absent | Negative | Negative | Improves with rest; trauma-related |
| TB spine | Any | Subacute; constitutional | Absent | Variable | Negative | Disc-sparing early; paraspinal abscess |
| Malignancy | > 50 | Constant; night pain | Absent | Negative | Negative | Red flags; pedicle destruction |
2023 Fourth Summative SAQ Question 4 [18]: A 30-year-old gentleman with LBP for 6 months, HLA-B27 positive, suspected axial SpA.
- (a) Name four SpA features in addition to HLA-B27: inflammatory back pain, arthritis, enthesitis, anterior uveitis, dactylitis, psoriasis, Crohn's/UC, good response to NSAIDs, family history of SpA, elevated CRP (any 4)
- (b) Two clinical examinations for spinal mobility: Modified Schober's test, chest expansion, occiput-to-wall distance, tragus-to-wall distance (any 2)
- (c) Two XR findings of sacroiliitis in AS: sclerosis, erosions, joint space narrowing, ankylosis/fusion (any 2)
Exam Approach — When to Think of AS in a DDx Question
Think of AS when:
- Young male ( < 45y) with chronic back pain > 3 months
- Pain has inflammatory characteristics (morning stiffness, improves with exercise, worse at rest)
- Buttock pain (alternating sides)
- Associated features: anterior uveitis, heel pain (enthesitis), asymmetric oligoarthritis of lower limbs
- HLA-B27 positive and/or family history of SpA
- Good response to NSAIDs
Always differentiate from:
- Mechanical LBP (the commonest cause — pattern is the key differentiator)
- Other SpA subtypes (skin, preceding infection, GI symptoms guide you)
- Infection and malignancy (red flags: fever, weight loss, neurological deficit, age > 50)
Common Exam Mistake
Students commonly forget that DISH is an important radiological mimic of AS. Both cause spinal stiffness and new bone formation, but DISH has flowing anterolateral ossification bridging ≥ 4 vertebrae with preserved disc height and no SI joint involvement — whereas AS has thin marginal syndesmophytes arising from vertebral corners with sacroiliitis. DISH also has normal inflammatory markers and negative HLA-B27.
Active Recall — Differential Diagnosis of Ankylosing Spondylitis
References
[1] Lecture slides: GC 074. Multiple joint pain.pdf (slides on SpA concept, clinical features, and diagnosis delay) [2] Lecture slides: Block A - Multiple joint pain: Rheumatoid arthritis and the concept of inflammatory arthritis.pdf [3] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — Ankylosing spondylitis, pp. 322–325) [4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Ankylosing spondylitis pp. 1699–1703; Psoriatic arthritis pp. 1708–1710) [5] Senior notes: Ryan Ho Rheumatology.pdf (Spondyloarthritis pp. 57–61) [7] Senior notes: Ryan Ho Rheumatology.pdf (SpA comparison table, p. 58) [8] Senior notes: Block A - Chronic diarrhoea: irritable bowel syndrome and inflammatory bowel disease.pdf (extraintestinal manifestations, p. 34) [11] Lecture slides: Ortho and Trauma - Spine.pdf (Differential Diagnosis of back pain, p. 7; AS features, p. 43) [12] Senior notes: Maksim Surgery Notes.pdf (Approach to spine diseases — DDx of back pain, p. 222) [13] Senior notes: Adrian Lui Pediatrics Notes.pdf (Back pain DDx in children, p. 449) [14] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (JIA classification — enthesitis-related arthritis, pp. 692–695) [15] Senior notes: Ryan Ho Fundamentals.pdf (Examination of rheumatological system, p. 125) [16] Senior notes: Ryan Ho Respiratory.pdf (TB spondylitis / Pott's disease, p. 80) [17] Lecture slides: Neurology - Two cases of lower limb weakness.pdf (Differential diagnosis of myelopathy, p. 29) [18] Past papers: 2023 Fourth Summative SAQ.pdf (Question 4, p. 5)
Diagnostic Criteria, Diagnostic Algorithm and Investigations for Ankylosing Spondylitis
Understanding the history of diagnostic criteria for AS helps you appreciate why we have both the Modified New York (MNY) criteria and the ASAS criteria, and when to use each:
-
Modified New York criteria (1984): the classic, well-established criteria for definite AS. They require radiographic sacroiliitis on plain X-ray — meaning they can only diagnose established disease with structural damage. The problem? It takes years for bony changes to appear on X-ray, contributing to the diagnostic delay of 6–11 years [1].
-
ASAS classification criteria (2009): developed to capture the entire spectrum of axial SpA, including early disease (nr-axSpA) where X-ray is normal but MRI shows inflammation. These criteria allow earlier diagnosis and treatment initiation.
In clinical practice, you use both — the MNY criteria to confirm "definite AS" and the ASAS criteria to identify the broader category of axial SpA when X-ray changes are not yet present.
GC High Yield — Modified New York Criteria
Definite AS = radiological criterion PLUS at least one clinical criterion [1][4][5]:
Radiological criterion:
Clinical criteria (≥ 1 out of 3):
- Low back pain and stiffness for more than 3 months, which improves with exercise, but is not relieved by rest [1][4][5]
- Limitation of motion of the lumbar spine in both the sagittal and frontal planes [1][4][5]
- Limitation of chest expansion relative to normal values corrected for age and sex [1][4][5]
Why these specific criteria?
- The radiological criterion is mandatory because sacroiliitis is the hallmark of AS [4] — without it, you cannot call it "definite AS" by MNY criteria
- The clinical criteria each capture a different consequence of spinal inflammation:
- Criterion 1 captures the inflammatory pain pattern (the cardinal symptom)
- Criterion 2 captures structural limitation of lumbar mobility (ankylosis/stiffness from new bone formation)
- Criterion 3 captures thoracic involvement (costovertebral joint disease restricting chest wall expansion)
Limitation: by requiring radiographic sacroiliitis, the MNY criteria miss patients with early disease who have genuine axSpA but have not yet developed bony changes visible on plain X-ray.
Radiographic Grading of Sacroiliitis (New York Grading) [3][5][19]
| Grade | Description | What You See on X-ray |
|---|---|---|
| 0 | Normal | Normal joint margins |
| 1 | Suspicious | Some blurring of joint margins |
| 2 (Minimal) | Localized sclerosis with some erosions, without change in joint width [3][19] | Sclerosis + no narrowed joint space |
| 3 (Unequivocal) | ≥ 1 of: erosions, sclerosis, joint space width changes, partial ankylosis [19] | Narrowed joint space + sclerosis + erosions |
| 4 (Total ankylosis) | Total fusion of SIJ [19] | Complete bony fusion; joint space obliterated |
SIJ erosions begin on the iliac side where the cartilage is thinner [19] — this is a classic teaching point. The iliac side has thinner fibrocartilage compared to the sacral side (which has hyaline cartilage), making it more vulnerable to erosive damage.
These are broader and more sensitive than MNY, designed to capture the full spectrum of axSpA including nr-axSpA.
Entry requirement: Back pain ≥ 3 months with onset < 45 years [4]
Then fulfil ONE of two arms [4]:
| Arm | Criteria |
|---|---|
| Imaging arm | Sacroiliitis on imaging (X-ray or MRI) + ≥ 1 SpA feature [4] |
| Clinical arm | HLA-B27 positive + ≥ 2 SpA features [4] |
- Inflammatory back pain (age of onset < 40) [4]
- Arthritis [4]
- Enthesitis [4]
- Psoriasis [4]
- Uveitis [4]
- Dactylitis [4]
- Crohn's disease / Ulcerative colitis [4]
- Good response to NSAIDs [4]
- Family history for SpA [4]
- Elevated CRP [4]
- HLA-B27 [4]
Past Paper — 2023 Fourth Summative SAQ Q4a
"Name four spondyloarthritis features in addition to HLA-B27" [18] — any 4 from the remaining 10 SpA features: inflammatory back pain, arthritis, enthesitis, psoriasis, uveitis, dactylitis, Crohn's/UC, good response to NSAIDs, family history for SpA, elevated CRP.
Why two arms?
- The imaging arm captures patients who already have objective evidence of sacroiliitis (on X-ray OR MRI) — they only need 1 additional SpA feature because the imaging already strongly supports the diagnosis
- The clinical arm captures patients without definitive imaging evidence but who are HLA-B27 positive — they need 2 additional SpA features to increase specificity (since HLA-B27 alone is found in ~6–8% of the general population and is not diagnostic) [5]
Definition of sacroiliitis on imaging for ASAS criteria:
- On plain X-ray: same as MNY (≥ grade 2 bilateral or grade 3–4 unilateral)
- On MRI: subchondral bone marrow oedema (BME) — the hallmark of active sacroiliitis on MRI [3][4]
How to read this algorithm:
- Start with the clinical picture: young patient ( < 45y), chronic back pain ( > 3 months), inflammatory pattern
- First-line investigations: ESR/CRP (to confirm inflammation), HLA-B27, X-ray pelvis (AP view of SI joints)
- If X-ray shows sacroiliitis: check if ≥ 1 clinical criterion is met → definite AS by MNY
- If X-ray is normal/equivocal: proceed to MRI SI joints (especially if HLA-B27 positive or strong clinical suspicion)
- If MRI shows BME: sacroiliitis on imaging confirmed → check for ≥ 1 SpA feature → axSpA by ASAS imaging arm
- If MRI is also normal: can still diagnose axSpA via ASAS clinical arm if HLA-B27 positive + ≥ 2 SpA features
The ASAS criteria use imaging (X-ray or MRI) to define sacroiliitis; the MNY criteria use X-ray only [1]. This is why the ASAS criteria are more sensitive for early disease.
4. Investigation Modalities — Detailed Breakdown
Investigations for AS (SAQ!) [3]:
| Investigation | Expected Findings in AS | Why / Interpretation |
|---|---|---|
| CBC [3] | Anaemia of chronic disease; mild leukocytosis; thrombocytosis (reactive) | Chronic inflammation drives all three; anaemia from cytokine-mediated suppression of erythropoiesis |
| LRFT [3] | Usually normal; elevated ALP if significant new bone formation | Baseline for monitoring drug side effects (NSAIDs → renal; DMARDs → hepatic) |
| ESR / CRP [3] | Elevated — but may be normal in up to 40% of AS patients with active disease | ESR and CRP reflect systemic inflammation but are imperfect markers in SpA (unlike RA where they correlate well). Elevated CRP is one of the 11 SpA features in ASAS criteria [4]. CRP is more useful than ESR because it responds faster and is less affected by confounders (anaemia, age) |
| RF [3] | Negative | To exclude RA; AS is a seronegative spondyloarthritis. However, RF can be positive in ~5% of the general population, so a low-titre positive RF does not exclude SpA |
| Anti-CCP | Negative | Higher specificity for RA than RF; useful to rule out RA |
| HLA-B27 [3] | Positive in 80–90% of AS patients | Useful if no radiological evidence [3] — i.e., its main clinical utility is when imaging is equivocal or negative. It supports the ASAS clinical arm. Not diagnostic on its own [11] because 6–8% of the general southern Chinese population is HLA-B27 positive [5] |
| Serum IgA | May be elevated | Reflects mucosal immune activation (subclinical gut inflammation in AS); also relevant for IgA nephropathy screening |
Key Concept — When is HLA-B27 Useful?
HLA-B27 is most useful when there is no radiological evidence of sacroiliitis [3]. In this scenario, HLA-B27 positivity combined with ≥ 2 SpA features satisfies the ASAS clinical arm for axSpA diagnosis. If radiographic sacroiliitis is already established, HLA-B27 adds limited diagnostic value (though it has prognostic implications).
4.2 Imaging — Sacroiliac Joints
This is the first-line imaging investigation and the one required for the MNY criteria.
X-ray SI joint findings [3][4][18]:
| Finding | Description | Pathophysiological Basis | Stage |
|---|---|---|---|
| Subchondral sclerosis | Increased bone density along joint margins | Reactive bone formation in response to chronic inflammation at the enthesis/subchondral bone | Early (Grade 2) |
| Erosions | Cortical defects along joint margins | Inflammatory destruction of bone at entheseal insertions; erosions begin on the iliac side where cartilage is thinner [19] | Grade 2–3 |
| Joint space narrowing | Decreased distance between sacral and iliac surfaces | Cartilage destruction from pannus | Grade 3 |
| Partial ankylosis | Incomplete bony bridges across the joint | New bone formation filling in the eroded joint space | Grade 3 |
| Total ankylosis (fusion) | Complete obliteration of joint space with continuous bone | End-stage; complete fibrous → bony fusion | Grade 4 |
Past Paper — 2023 Fourth Summative SAQ Q4c
"Name two findings associated with ankylosing spondylitis on conventional radiographs of the sacroiliac joints" [18]: sclerosis, erosions, joint space narrowing, ankylosis/fusion (any 2).
Practical pearl: SI joint X-rays can be difficult to interpret, especially in young patients where normal developmental variants can mimic early sacroiliitis. This contributes to diagnostic delay. When in doubt, proceed to MRI.
MRI is more sensitive than plain X-ray [19] and is the investigation of choice when X-ray is normal but clinical suspicion is high.
MRI SI joint findings [3][4][19]:
| Sequence | Finding | Significance |
|---|---|---|
| STIR / T2 fat-suppressed | Subchondral bone marrow oedema (BME) — hyperintense signal in bones adjacent to the affected joint [4] | Most characteristic change of active sacroiliitis [4]; this is the primary criterion for ASAS MRI-defined sacroiliitis |
| T1-weighted | Low signal in areas of active inflammation (BME replaces normal fatty marrow) | Corresponds to BME; loss of normal bright fatty marrow signal |
| T1 post-gadolinium | Enhancement of inflamed tissue | Confirms active inflammation (increased vascularity) |
| T1-weighted (post-inflammatory) | Fatty degeneration — high signal replacing previously inflamed areas | Indicates resolved inflammation; structural damage has occurred |
| Various sequences | Erosions, sclerosis, ankylosis | Structural damage — indicates chronic/established disease |
What does ASAS consider "positive" MRI sacroiliitis?
- BME must be clearly present in a subchondral/periarticular location and should be present on ≥ 2 consecutive slices or on ≥ 2 lesions on a single slice
- BME alone without the correct location/pattern is not sufficient — must be clearly associated with the SI joint
Why does BME appear on MRI before X-ray shows changes?
- BME reflects active inflammation (osteitis) at the molecular/cellular level — increased water content in the bone marrow from inflammatory cell infiltration and vasodilation
- X-ray changes (sclerosis, erosions) reflect structural damage — physical alteration of bone that takes months to years to develop
- MRI therefore captures the disease years earlier than X-ray
- More sensitive than plain X-ray for detecting structural changes (erosions, sclerosis, ankylosis) [19]
- However, does not detect active inflammation (BME) — only structural damage
- Used when MRI is contraindicated (e.g., pacemaker) or when X-ray is equivocal and structural assessment is needed
- Higher radiation dose than X-ray — not first-line
4.3 Imaging — Spine
X-ray spine findings — these appear in a characteristic temporal sequence [3][4]:
| Finding | Description | Pathophysiological Basis | Stage |
|---|---|---|---|
| Romanus lesion | Squaring of vertebral body with shiny corners [3] | Reactive sclerosis secondary to inflammatory erosions at the vertebral endplates [3] — the normal anterior concavity of the vertebral body is lost because inflammation at the corners (where the annulus fibrosus inserts via Sharpey's fibres — an enthesis!) causes erosion followed by reactive new bone formation | Early |
| Syndesmophytes | Thin, vertical, marginal bony bridges arising from the corners of adjacent vertebral bodies | Ossification of the outer fibres of the annulus fibrosus (the enthesis) — new bone forms along the direction of the spinal ligaments. Syndesmophytes are marginal (arising from the vertebral rim), as opposed to the non-marginal, chunky osteophytes of DISH | Intermediate |
| Bamboo spine | Complete fusion of vertebral bodies via continuous syndesmophytes across multiple segments, with fusion of facet joints and interspinous ligaments | Signature abnormality in advanced-stage AS [4]; end point of radiographic progression [4]; the entire spine becomes one continuous rigid column | Late |
| Anderson lesion | Erosion at the discovertebral junction [3] | Can represent an inflammatory lesion (spondylodiscitis) or a stress fracture through a fused disc space; the ankylosed spine transmits stress differently, leading to focal destructive lesions | Late |
| Calcification of ligaments | Ossification of anterior longitudinal ligament, interspinous ligaments | Entheseal ossification extending beyond the disc space | Late |
| Facet joint ankylosis | Fusion of the zygapophyseal joints | Synovitis → erosion → ankylosis of these true synovial joints | Late |
Additional plain X-ray findings [4]:
- Squaring of vertebral bodies: Due to anterior and posterior inflammation and bone deposition [4]; early radiographic sign of inflammatory and destructive spinal involvement [4]
- Calcification of anterior longitudinal ligaments [4]
- Bamboo spine: End point of radiographic progression of ankylosing spondylitis [4]
| Finding | Significance |
|---|---|
| Corner inflammatory lesions (CILs) | BME at vertebral corners corresponding to early Romanus lesions — active inflammation before structural change |
| Fatty change at vertebral corners | Characteristic lesion of MRI spine [4]; may be present in several corners of vertebral bodies [4]; indicates resolved inflammation (post-inflammatory structural change) |
| Spondylodiscitis (Anderson lesion) | Inflammatory involvement of the disc and adjacent endplates |
| Syndesmophyte formation | Best assessed on T1-weighted sequences |
- Patients with AS are at risk of spinal fractures even with minor trauma [3]
- In any AS patient with new-onset back/neck pain after trauma, whole-spine imaging (CT or MRI) is mandatory
- Plain XR cannot make or exclude diagnosis of cord compression [20] — MRI is the modality of choice for non-traumatic cord compression
| Modality | Indication | Key Findings |
|---|---|---|
| Ultrasound (USG) [4] | Detection and assessment of enthesitis (e.g., Achilles tendinitis) | Thickening of tendon, hypoechogenicity, increased vascularity on power Doppler, enthesophytes, bony erosions at insertion |
| DEXA scan [3] | Baseline assessment for osteopenia | AS patients have increased risk of osteoporosis due to chronic inflammation, reduced mobility, and possible corticosteroid use; DEXA establishes baseline BMD |
| Echocardiography | If clinical suspicion of aortic regurgitation or conduction defects | Aortic root dilatation, aortic valve regurgitation |
| CXR | Screening for apical fibrosis | Upper lobe fibrosis (rare; late feature) |
| ECG | Screening for conduction defects | AV block (1st, 2nd, or 3rd degree), bundle branch block |
Past Paper — 2023 Fourth Summative SAQ Q4b
"Name two clinical examinations for the assessment of spinal mobility" [18]: Modified Schober's test (lumbar flexion), chest expansion (thoracic), occiput-to-wall distance (cervical), tragus-to-wall distance (cervical), lateral flexion of lumbar spine. Any 2 accepted.
Once the diagnosis is established, you need standardised tools to monitor disease activity and guide treatment decisions (especially for biologic eligibility):
| Tool | Full Name | What It Measures | Key Threshold |
|---|---|---|---|
| BASDAI [3][4] | Bath AS Disease Activity Index | Patient-reported disease activity (6 questions, scale 0–10) | ≥ 4/10 = active disease [3][4] |
| BASFI [3] | Bath AS Functional Index | Functional disability (10 questions on ADLs) | Higher = worse function |
| BASMI [3] | Bath AS Metrology Index | Physical measurements of spinal mobility (tragus-to-wall, Schober's, lateral flexion, intermalleolar distance, cervical rotation) | Higher = worse mobility |
| BAS-G [3] | Bath AS Global Score | Patient's and physician's global assessment | Overall wellbeing |
| ASDAS | AS Disease Activity Score | Composite: combines CRP + 3 BASDAI questions + patient global | > 2.1 = high; > 3.5 = very high; preferred by ASAS for treatment decisions |
| ESR / CRP [3] | Acute phase reactants | Systemic inflammation | Used as objective marker alongside clinical scores |
BASDAI is calculated as: mean of Q5 and Q6, plus sum of Q1–Q4, then divided by 5 [4]. Active disease is ≥ 4/10 [3][4]. ASAS 50 response = BASDAI decreases by ≥ 50% [3].
When you encounter a young patient with suspected AS, here is your systematic approach:
Step 1 — History: Confirm inflammatory back pain pattern (onset < 45y, > 3 months, insidious, morning stiffness > 30 min, improves with exercise, nocturnal pain, alternating buttock pain). Ask about SpA features (enthesitis, peripheral arthritis, dactylitis, uveitis, psoriasis, IBD, family history).
Step 2 — Examination: Modified Schober's test, chest expansion, occiput-to-wall/tragus-to-wall distance, FABER/Gaenslen's for SI joints, Achilles/plantar fascia palpation, eye examination, cardiac auscultation.
Step 3 — First-line investigations: CBC, LRFT, ESR/CRP, RF (to exclude RA), HLA-B27, X-ray pelvis (SI joints), X-ray spine.
Step 4 — Apply MNY criteria: If X-ray shows ≥ grade 2 bilateral or grade 3–4 unilateral sacroiliitis PLUS ≥ 1 clinical criterion → definite AS.
Step 5 — If X-ray normal: Order MRI SI joints. If BME present → sacroiliitis on imaging → apply ASAS imaging arm. If MRI also normal → apply ASAS clinical arm (HLA-B27 + ≥ 2 SpA features).
Step 6 — Baseline assessments: BASDAI, BASFI, BASMI, DEXA scan, ECG, CXR (if clinically indicated), ophthalmology referral if uveitis symptoms.
Common Exam Mistake
Students often confuse the MNY criteria with the ASAS criteria. Remember:
- MNY = requires X-ray sacroiliitis (cannot use MRI) + ≥ 1 of 3 clinical criteria → diagnoses definite AS
- ASAS = uses X-ray OR MRI sacroiliitis + SpA features, or HLA-B27 + SpA features → classifies axial SpA (which includes both AS and nr-axSpA)
- You can have axSpA by ASAS criteria without meeting MNY criteria (if MRI-positive only). You CANNOT have definite AS by MNY without X-ray sacroiliitis.
High Yield Summary
Diagnostic Criteria and Investigations for AS:
- Modified New York criteria (1984): Definite AS = radiographic sacroiliitis (≥ grade 2 bilateral or ≥ grade 3 unilateral) + ≥ 1 clinical criterion (inflammatory LBP, limited lumbar ROM, limited chest expansion)
- ASAS criteria (2009): Back pain ≥ 3 months, onset < 45 → imaging sacroiliitis + ≥ 1 SpA feature OR HLA-B27 + ≥ 2 SpA features
- 11 SpA features: inflammatory back pain, arthritis, enthesitis, psoriasis, uveitis, dactylitis, IBD, good NSAID response, family history, elevated CRP, HLA-B27
- Key bloods: ESR/CRP (inflammation), RF/anti-CCP (exclude RA), HLA-B27 (supports diagnosis when imaging equivocal)
- X-ray SI joints: sclerosis → erosions → narrowing → ankylosis (Grades 2–4). Erosions begin on iliac side
- X-ray spine: Romanus lesion (squaring + shiny corners) → syndesmophytes → bamboo spine
- MRI SI joints: subchondral BME (active sacroiliitis); more sensitive than X-ray; detects disease years earlier
- MRI spine: corner inflammatory lesions, fatty change at vertebral corners
- BASDAI ≥ 4/10 = active disease; ASDAS is the preferred composite score
- DEXA scan: baseline for osteopenia assessment
Active Recall — Diagnostic Criteria and Investigations for AS
References
[1] Lecture slides: GC 074. Multiple joint pain.pdf (Modified New York criteria slide, imaging in axSpA, diagnostic delay) [3] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — Ankylosing spondylitis investigations and diagnostic criteria, pp. 321–324) [4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Ankylosing spondylitis — diagnosis, radiological tests, BASDAI, pp. 1701–1706) [5] Senior notes: Ryan Ho Rheumatology.pdf (Spondyloarthritis overview, Modified New York criteria, pp. 57–61) [11] Lecture slides: Ortho and Trauma - Spine.pdf (AS features — HLA-B27 not diagnostic, p. 43) [18] Past papers: 2023 Fourth Summative SAQ.pdf (Question 4 — SpA features, spinal mobility exam, XR findings, p. 5) [19] Senior notes: Ryan Ho Rheumatology.pdf (Radiographic features of sacroiliitis — grading table, p. 61) [20] Senior notes: Ryan Ho Radiology.pdf (Spinal trauma imaging — cord compression, p. 18) [21] Senior notes: Ryan Ho Fundamentals.pdf (Examination of AS — physical examination checklist, pp. 147)
Management of Ankylosing Spondylitis
Before diving into specific therapies, understand the overarching management philosophy for AS:
- No cure exists — treatment aims to control symptoms, reduce inflammation, prevent structural damage (syndesmophyte formation), maintain function, and improve quality of life
- Axial disease and peripheral disease are treated differently — a critical concept because conventional DMARDs that work in RA and peripheral SpA are NOT effective for axial disease [3][4][22]
- Treatment is stepwise — escalating from non-pharmacological measures and NSAIDs through to biologics based on disease activity assessment (BASDAI/ASDAS)
- Multidisciplinary approach — Rheumatologist (diagnosis, medical treatment, screening of associated disorders) + Orthopaedic Surgeon (hip, spine) [23]
- Screen before biologic therapy — particularly for latent TB, hepatitis B/C, and other infections before starting anti-TNF agents [4]
These measures are for ALL patients regardless of disease severity and form the foundation of AS management.
| Intervention | Rationale / Mechanism | Details |
|---|---|---|
| Patient education and counselling [4][22] | Empowers patients to self-manage; improves adherence to exercise and medication | Disease nature, prognosis, importance of exercise, posture awareness, genetic counselling |
| Physiotherapy and stretching exercises [3][4][22] | Maintains spinal mobility and posture; prevents deformity; strengthens paravertebral muscles | Regular programme; back exercises, hydrotherapy [4]; especially swimming [3] — swimming is ideal because it provides a full range of spinal motion with minimal axial loading |
| Posture education [3] | Prevents/delays fixed kyphotic deformity ("question mark" posture) | Firm mattress, single thin pillow (to avoid neck flexion); sleeping prone or supine (not curled up); upright sitting posture; workstation ergonomics |
| Smoking cessation [3] | Reduces burden to restrictive lungs [3]; smoking accelerates radiographic progression, worsens functional outcomes, and reduces response to anti-TNF therapy | Active counselling + pharmacotherapy (nicotine replacement, varenicline) if needed |
Why Swimming?
Swimming is the single best exercise for AS patients because: (1) the buoyancy of water unloads the spine (reducing axial compression on inflamed entheses); (2) the movements encourage full spinal extension, rotation, and lateral flexion; (3) it strengthens paraspinal and core muscles; (4) the warm water of hydrotherapy pools has an additional analgesic/relaxing effect on stiff muscles.
2. Pharmacological Management
NSAIDs are the 1st line therapy for all patients with ankylosing spondylitis [4].
| Aspect | Detail |
|---|---|
| Mechanism | Non-selective NSAIDs inhibit both COX-1 and COX-2 → reduce prostaglandin synthesis → anti-inflammatory, analgesic, and antipyretic effects. In AS specifically, NSAIDs reduce entheseal inflammation and bone marrow oedema |
| Indication | Treatment of back pain and stiffness [4]; treatment of peripheral arthritis and enthesitis |
| Dosing | At optimal tolerated dose [22] — meaning the highest dose that the patient can tolerate, used regularly (not PRN) |
| Continuous treatment | Continuous treatment slows radiographic progression [3] — this is unique to AS. In OA, we use NSAIDs only for symptom relief; in AS, continuous NSAID use actually retards syndesmophyte formation. The mechanism is thought to be via suppression of prostaglandin-mediated osteoblast activity at entheseal sites |
| Examples | Indomethacin (traditional, potent for AS), naproxen, diclofenac, etoricoxib (COX-2 selective) |
| Trial requirement | At least 2 NSAIDs, each for ≥ 1 month (some guidelines say 2–3 months) before declaring NSAID failure and escalating to biologics [3][22] |
| Good response to NSAIDs | This is itself one of the 11 SpA features in the ASAS criteria [4] — so a dramatic response to NSAIDs supports the diagnosis |
GI Protection with NSAIDs [4][22][24]:
Gastroprotective agents or selective COX-2 inhibitors should be used in patients with high gastrointestinal risks [4][22].
| GI Risk Factor | Strategy |
|---|---|
| High GI risk (elderly, history of peptic ulcer, comorbidity) [22] | Add PPI (first-line gastroprotective agent) [24] OR switch to selective COX-2 inhibitor (e.g., etoricoxib, celecoxib) [24] |
| Moderate risk | Consider co-prescription of PPI |
| Low risk (young, no history) | NSAID alone acceptable |
Why does GI risk matter so much in AS?
- AS patients need long-term, continuous NSAID use — unlike acute conditions where NSAIDs are short-term
- This prolonged exposure increases cumulative risk of peptic ulcer, GI bleeding, and perforation
- Gastric mucosal damage by NSAID is pH-dependent [24] — PPI raises gastric pH, making the mucosal environment less susceptible to NSAID-induced injury
Contraindications to NSAIDs:
- Active peptic ulcer or GI bleeding
- Severe renal impairment (CKD stage 4–5)
- Significant cardiovascular disease (NSAIDs increase CV risk; COX-2 inhibitors carry even higher CV risk)
- Hypersensitivity (NSAID-exacerbated respiratory disease / aspirin-sensitive asthma)
- Pregnancy (especially 3rd trimester — premature closure of ductus arteriosus)
- Concurrent anticoagulant therapy (increased bleeding risk)
Analgesics and opioids are indicated in patients in whom NSAIDs and COX-2 inhibitors are inadequate, intolerable or contraindicated [4][22].
| Drug | Role | Notes |
|---|---|---|
| Paracetamol [4][22] | Simple analgesia; minimal anti-inflammatory effect | Safe first-line adjunct; hepatotoxicity at supratherapeutic doses |
| Tramadol [4][22] | Weak opioid; for moderate pain not controlled by NSAIDs + paracetamol | Risk of dependence, constipation, nausea; avoid in seizure-prone patients |
| Stronger opioids | Rarely needed; avoid long-term use | Risk of dependence, hyperalgesia, constipation |
This is one of the most important conceptual points in AS management:
There is NO proven effective conventional DMARD for axial disease [3][22]
Traditional DMARDs are NOT effective for axial disease [4]. Why? Because axial SpA pathology (enthesitis at spinal and SI joint entheses with new bone formation via Wnt signalling) is driven by different cytokine pathways (TNF-α, IL-17/IL-23) than RA synovitis (which responds to methotrexate-mediated folate antagonism). The fundamental biology is different.
However, csDMARDs do have a role in peripheral manifestations:
| Drug | Indication | Mechanism | Important Notes |
|---|---|---|---|
| Sulphasalazine [3][4][22] | Peripheral arthritis only [3][4] | Sulfapyridine + 5-aminosalicylic acid (5-ASA); anti-inflammatory action; exact mechanism in SpA unclear; may modulate T-cell function | More effective for peripheral arthritis than for axial disease (in general ineffective for axial disease) [4]; dose: start 500 mg OD, increase to 1 g BD; monitor CBC and LFT; side effects include GI upset, rash, haemolysis, neutropenia, male infertility [24] |
| Methotrexate [22] | Peripheral arthritis only [22] | Folate antagonist; anti-inflammatory via adenosine pathway | Same principle — no proven axial efficacy; useful for peripheral joint involvement |
| Local corticosteroid injection [3] | Peripheral joints or enthesitis (e.g., SI joint injection, knee injection) | Direct anti-inflammatory at injection site | Avoid intra-articular steroid use in Achilles tendon: risk of tendon rupture [3] — this is because corticosteroids weaken the collagen structure of tendons, and the Achilles tendon is already under high mechanical stress; injection here can precipitate catastrophic rupture |
High Yield — Axial vs Peripheral Treatment
| Disease Domain | csDMARDs Effective? | Biologics Effective? |
|---|---|---|
| Axial disease | NO | YES (anti-TNF, anti-IL-17, JAK inhibitors) |
| Peripheral disease | YES (sulphasalazine, methotrexate) | YES |
This distinction is tested repeatedly in exams. If a question asks about treating back pain/sacroiliitis in AS, the answer is NSAIDs → biologics. csDMARDs have no role in the axial spine [3][4][22].
Common Exam Mistake
Students sometimes write "methotrexate" or "sulphasalazine" as treatment for axial AS because they recall these drugs from RA management. Remember: NO proven effective DMARD for axial disease [3]. These drugs only help peripheral joint involvement in SpA.
- NOT routinely used in AS management (unlike RA where low-dose prednisolone is common as bridging therapy)
- Short courses may occasionally be considered for severe flares, but evidence is limited
- Long-term systemic steroids carry significant side effects (osteoporosis — especially problematic in AS patients already at risk; weight gain; diabetes; infections)
- Local injection of steroids (SI joint, peripheral joints) is more appropriate than systemic therapy
2.5 Step 2B — Biologic Therapy (for Axial Disease)
Biologics are indicated for patients with persistent high disease activity despite adequate trials of the above treatment [3][4][22].
Eligibility criteria for biologic therapy (based on ASAS/EULAR 2023 updated recommendations):
Persistent high disease activity despite 2–3 NSAIDs (at least 1–2 months for each unless contraindicated) [3][22]:
- BASDAI ≥ 4/10 [3] (or ASDAS ≥ 2.1)
- Plus elevated CRP and/or positive MRI findings (ideally)
- Plus failure of ≥ 2 NSAIDs
TNF-α ("tumour necrosis factor alpha") is a master pro-inflammatory cytokine heavily involved in entheseal inflammation, osteitis, and systemic inflammation in SpA. Blocking TNF-α dramatically reduces inflammation, symptoms, and (to some extent) radiographic progression.
| Agent | Type | Route | Key Features |
|---|---|---|---|
| Infliximab [4] | Chimeric (mouse/human) anti-TNF monoclonal antibody | IV infusion (0, 2, 6 weeks then q6-8w) | Binds soluble and membrane-bound TNF; effective for AS, IBD (dual utility if coexisting IBD); risk of infusion reactions; immunogenicity → may need concomitant methotrexate to reduce anti-drug antibodies |
| Etanercept [3][4] | Soluble TNF receptor fusion protein | SC (weekly or biweekly) | Binds soluble TNF (NOT membrane-bound); effective for AS and PsA; BUT not effective for IBD (avoid if coexisting IBD — this is a crucial point because TNF receptor fusion proteins do not adequately suppress the mucosal immune response in the gut) |
| Adalimumab [4] | Fully human anti-TNF monoclonal antibody | SC (every 2 weeks) | Binds both soluble and membrane-bound TNF; effective for AS, PsA, IBD; widely used |
| Certolizumab pegol [4] | PEGylated Fab' fragment of anti-TNF antibody | SC (every 2 weeks after loading) | No Fc portion → does not cross placenta → safe to use in pregnancy (unique among anti-TNF agents); effective for AS and IBD |
| Golimumab [4] | Fully human anti-TNF monoclonal antibody | SC (monthly) | Convenient monthly dosing; effective for AS |
Pre-biologic screening — mandatory before starting anti-TNF [4][22]:
| Screening | Why |
|---|---|
| Latent TB: tuberculin skin test (TST) or IGRA | Anti-TNF is the classical example that can increase risk of developing TB, given the importance of TNF-α in confining TB to the tuberculoma [25]. If latent TB detected → isoniazid chemoprophylaxis for 3 months before starting anti-TNF [25] |
| Hepatitis B serology (HBsAg, anti-HBs, anti-HBc) | Risk of HBV reactivation with anti-TNF; prophylactic antiviral (entecavir) if HBsAg positive |
| Hepatitis C serology | Screen and treat if positive |
| CXR | Rule out active TB |
| Baseline bloods (CBC, LRFT) | Monitor for cytopenias, hepatotoxicity |
| HIV screening | If risk factors present |
| Vaccination update | No live vaccines while on anti-TNF; ensure pneumococcal, influenza, HBV vaccination up-to-date |
Anti-TNF and TB — The Classical Scenario
Classical presentation [25]:
- Patient with rheumatological disease starts anti-TNF-α
- TNF-α suppressed → tuberculoma can no longer contain Mycobacterium tuberculosis → TB reactivation with rapid proliferation
- Patient diagnosed with TB → stops anti-TNF, starts anti-TB treatment
- TNF-α returns → body mounts massive exaggerated response towards the TB (paradoxical reaction) → worsening clinical/radiological parameters
- Over time, this reverts to normal
This is a very commonly tested scenario. The key learning point: always screen for latent TB before starting anti-TNF.
Side effects of anti-TNF agents:
- Increased susceptibility to infections (especially TB, opportunistic infections, serious bacterial infections)
- Injection site reactions (SC agents) or infusion reactions (infliximab)
- Risk of lymphoma (slight increase, debated)
- Demyelinating disease (rare; avoid in MS)
- Heart failure exacerbation (avoid in NYHA III–IV; TNF-α paradoxically supports cardiac function in HF)
- Drug-induced lupus-like syndrome (rare)
- Hepatotoxicity (monitor LFT)
IL-17 is a pro-inflammatory cytokine produced by Th17 cells, critically involved in entheseal inflammation and new bone formation in SpA. The IL-23/IL-17 axis is the central pathogenic pathway in axSpA.
| Agent | Type | Route | Key Features |
|---|---|---|---|
| Secukinumab [3] | Fully human anti-IL-17A monoclonal antibody | SC [3] | Effective for axial SpA, PsA, and psoriasis; loading dose (150–300 mg SC weekly × 4 weeks) then monthly; NOT recommended for IBD (may exacerbate Crohn's — IL-17 plays a protective role in gut mucosal immunity) |
| Ixekizumab | Humanised anti-IL-17A monoclonal antibody | SC | Similar efficacy and profile to secukinumab |
Key point: Anti-IL-17 and IBD
- Avoid anti-IL-17 in patients with coexisting IBD because IL-17 has a dual role: it is pro-inflammatory in joints but protective in the gut mucosa. Blocking IL-17 can therefore worsen gut inflammation. If a patient has AS + IBD, use an anti-TNF monoclonal antibody (infliximab, adalimumab) instead.
Anti-IL-1 / anti-IL-6: not useful for SpA (cf. RA) [3]:
- This is a key distinction from RA management. In RA, tocilizumab (anti-IL-6) and anakinra (anti-IL-1) are effective. In SpA, the IL-1/IL-6 pathways are less relevant to entheseal pathology, so these drugs do not work.
JAK = "Janus kinase" — intracellular enzymes that transduce signals from multiple cytokine receptors (including IL-6, IL-12, IL-23 receptors). JAK inhibitors are small molecules (oral tablets) that block multiple inflammatory signalling pathways simultaneously.
| Agent | Type | Route | Key Features |
|---|---|---|---|
| Tofacitinib | JAK1/3 inhibitor | Oral | Approved for AS; convenient oral dosing; monitor for infections, VTE, herpes zoster reactivation, lipid derangement, cytopenias |
| Upadacitinib | Selective JAK1 inhibitor | Oral | Approved for axSpA (2022); strong efficacy data; same monitoring concerns |
When to use JAK inhibitors: typically after failure of or intolerance to at least one biologic (anti-TNF or anti-IL-17), though current ASAS-EULAR 2023 recommendations allow them as an alternative to biologics in certain situations.
Important safety considerations (from the ORAL Surveillance trial with tofacitinib in RA):
- Increased risk of major adverse cardiovascular events (MACE)
- Increased risk of malignancy
- Increased risk of venous thromboembolism (VTE)
- These risks are most relevant in patients > 50 with ≥ 1 CV risk factor — important to consider in patient selection
| Clinical Scenario | Preferred Agent | Why |
|---|---|---|
| Axial SpA, first biologic | Anti-TNF (adalimumab, etanercept, infliximab) or anti-IL-17 (secukinumab) | Both have strong evidence for axial disease; choice depends on patient factors |
| AS + coexisting IBD | Anti-TNF monoclonal antibody (infliximab or adalimumab) | Effective for both AS and IBD; avoid etanercept (no IBD efficacy) and anti-IL-17 (may worsen IBD) |
| AS + coexisting psoriasis | Anti-IL-17 (secukinumab) or anti-TNF | Both effective; anti-IL-17 has excellent psoriasis data |
| Failure of anti-TNF | Switch to anti-IL-17 or JAK inhibitor | Different mechanism; may overcome primary/secondary anti-TNF failure |
| Failure of anti-IL-17 | Switch to anti-TNF or JAK inhibitor | |
| Patient preference for oral therapy | JAK inhibitor (upadacitinib, tofacitinib) | Only oral option; discuss CV/VTE risks |
| Pregnancy | Certolizumab pegol | No Fc → does not cross placenta |
| Criterion | Definition |
|---|---|
| ASAS 50 response | BASDAI decreases by ≥ 50% [3][22] |
| ASAS 40 response | ≥ 40% improvement in ≥ 3 of 4 ASAS domains (patient global, pain, function, inflammation) with no deterioration in the remaining domain |
| ASDAS improvement | Clinically important: decrease ≥ 1.1; Major: decrease ≥ 2.0 |
| Time to assess response | 12–16 weeks of biologic therapy before declaring treatment failure |
Surgical intervention is rarely required now [3] with modern biologic therapy, but is indicated in specific situations:
| Procedure | Indication | Details |
|---|---|---|
| Total hip replacement (THR) [3][23] | Severe hip disease with significant functional limitation and pain | Hip involvement is a poor prognostic factor [3]; may need surgery in young patients → consider bearing surfaces (ceramic-on-ceramic) for durability |
| Corrective spinal osteotomy [3] | Severe fixed kyphotic deformity ("question mark" posture) that impairs forward gaze or function | High-risk surgery; involves controlled fracture and re-alignment of the fused spine; performed at specialised centres |
| Spinal fracture fixation | Unstable fracture through the ankylosed spine | Even minor trauma can cause highly unstable transdiscal fractures → surgical stabilisation often required |
| Spinal decompression | Cauda equina syndrome, cervical myelopathy from atlantoaxial subluxation | Emergency/urgent surgery depending on presentation |
| Manifestation | Management |
|---|---|
| Acute anterior uveitis | Topical corticosteroid eye drops (e.g., 1% prednisolone acetate) + topical cycloplegic (e.g., cyclopentolate) → ophthalmology referral; recurrent uveitis may indicate need for systemic biologic therapy (anti-TNF reduces uveitis flares) |
| Aortic regurgitation | Cardiology follow-up; medical management of HF if present; aortic valve replacement if severe |
| Conduction defects | ECG monitoring; pacemaker if symptomatic bradycardia/high-degree AV block |
| Apical fibrosis | Usually no specific treatment; monitor with CXR; avoid superadded infection |
| IBD | Gastroenterology co-management; use anti-TNF monoclonal antibody (dual benefit for joints and gut); avoid anti-IL-17 |
| Osteoporosis | DEXA scan; bisphosphonates or denosumab if indicated; calcium + vitamin D supplementation; weight-bearing exercise |
| IgA nephropathy / amyloidosis | Nephrology referral; controlling underlying inflammation is key (biologics) |
Understanding these helps identify patients who need early aggressive treatment (early biologic therapy):
Poor prognostic factors [3]:
- Young onset [3]
- Clinical: hip arthritis, dactylitis [3]
- Biochemical: high ESR [3]
- Treatment: poor response to NSAID [3]
Additional poor prognostic indicators (from 2023 guidelines):
- Smoking
- Elevated CRP persistently
- Extensive radiographic damage at baseline
- Restricted spinal mobility early in disease course
| Step | Treatment | Indication | Key Points |
|---|---|---|---|
| All patients | Non-pharmacological | Every patient with AS | Education, physiotherapy, swimming, posture, smoking cessation |
| Step 1 | NSAIDs ± GI protection | First-line for all symptomatic patients | Continuous use slows radiographic progression; try ≥ 2 NSAIDs before escalating |
| Step 1 adjunct | Paracetamol / tramadol | NSAIDs insufficient or contraindicated | Symptom relief only; no disease-modifying effect |
| Step 2 (peripheral) | Sulphasalazine / methotrexate | Peripheral arthritis only | NOT effective for axial disease |
| Step 2 (axial) | Anti-TNF or anti-IL-17 | Persistent BASDAI ≥ 4 despite ≥ 2 NSAIDs | Screen for latent TB; assess response at 12–16 weeks |
| Step 3 | Switch biologic / JAK inhibitor | Failure of first biologic | Different mechanism of action |
| Surgical | THR, spinal osteotomy | Severe hip disease or fixed deformity | Rarely needed with modern biologics |
High Yield Summary
Management of AS — Key Points:
- Non-pharmacological for ALL: education, physiotherapy (especially swimming), posture training, smoking cessation
- NSAIDs are first-line for all patients; use at optimal dose continuously (slows radiographic progression); add PPI or use COX-2 inhibitor if high GI risk
- No csDMARD works for axial disease — sulphasalazine and methotrexate only for peripheral joints
- Avoid IA steroid in Achilles tendon (tendon rupture risk)
- Biologics for persistent high disease activity (BASDAI ≥ 4) despite ≥ 2 NSAIDs: anti-TNF (first-line) or anti-IL-17 (secukinumab) or JAK inhibitors
- Anti-IL-1 / anti-IL-6: NOT useful for SpA (cf. RA)
- If coexisting IBD: use anti-TNF monoclonal antibody (infliximab/adalimumab); avoid etanercept (no IBD efficacy) and anti-IL-17 (may worsen IBD)
- Always screen for latent TB before anti-TNF (isoniazid chemoprophylaxis × 3 months if positive)
- ASAS 50 response = BASDAI decrease by ≥ 50%
- Surgery rarely needed: THR for hip disease, corrective osteotomy for severe kyphosis
Active Recall — Management of Ankylosing Spondylitis
References
[1] Lecture slides: GC 074. Multiple joint pain.pdf (SpA concept, diagnostic criteria, imaging in axSpA) [3] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — AS management, pp. 323–325) [4] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (AS treatment — NSAIDs, DMARDs, anti-TNF, pp. 1705–1707) [5] Senior notes: Ryan Ho Rheumatology.pdf (SpA overview, pp. 57–61) [22] Lecture slides / Medicine handbook: Handbook of Internal Medicine 2024.pdf (AS treatment algorithm, pp. R10–R11) [23] Lecture slides: GC 229. Hip Arthritis.pdf (Multidisciplinary approach — Rheumatologist + Orthopaedic Surgeon) [24] Senior notes: Block A - Upper abdominal pain: peptic ulcer; pancreatitis and gallstone.pdf (NSAID GI protection, PPI, COX-2 strategy) [25] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (Anti-TNF and TB — classical presentation, isoniazid chemoprophylaxis)
Complications of Ankylosing Spondylitis
Complications of AS can be organised using the 6A mnemonic for extra-articular manifestations [3] plus skeletal/structural complications. Think of them as consequences of either (a) the chronic inflammatory process extending beyond the entheses to other organ systems, or (b) the structural damage from spinal ankylosis itself.
1. Skeletal and Structural Complications
These are the most common and functionally significant complications, arising directly from the cardinal pathology — progressive spinal ankylosis and entheseal new bone formation.
Prone to spine fractures and whiplash injury [3].
Why does this happen?
- The fused "bamboo spine" loses its normal segmental flexibility. Normally, the spine distributes mechanical stress across multiple mobile segments (each intervertebral disc acts as a shock absorber). In advanced AS, the entire spine behaves like a single long rigid bone — like a dry stick.
- Additionally, chronic inflammation and reduced mobility cause osteoporosis (both systemic inflammation increases osteoclast activity via RANKL, and immobility-related bone loss compounds this).
- The result: a brittle, rigid column that is highly vulnerable to fracture from even trivial trauma (a fall from standing height, a minor car accident, or even sudden deceleration).
Clinical features of spinal fractures in AS:
- New-onset acute back or neck pain after trauma (even minor)
- Fractures are characteristically transdiscal (through the fused disc space or through the vertebral body) and are highly unstable — unlike typical osteoporotic compression fractures
- High risk of associated spinal cord injury because the fracture can displace, and the narrowed spinal canal in AS leaves no margin for cord compression
- Cervicothoracic junction (C6–T1) is the most common site due to the biomechanics of the rigid kyphotic spine meeting the relatively mobile cervical region
Imaging considerations:
- Patients with AS are at risk of fractures — this is an indication for imaging even with low-energy trauma [20]
- Plain X-ray may miss fractures in AS due to osteoporosis and the difficulty of interpreting fused spine images
- CT is more sensitive for bony detail; MRI is essential if neurological deficit is present [20]
Clinical Pearl — Spinal Fractures in AS
Any AS patient presenting with new-onset severe back or neck pain — even after trivial trauma — must be assumed to have a spinal fracture until proven otherwise. These fractures are highly unstable and carry significant risk of secondary spinal cord injury. A normal plain X-ray does NOT exclude a fracture. CT or MRI is mandatory.
Question mark deformity: loss of lumbar lordosis, fixed thoracic kyphosis, cervical flexion [3].
Mechanism: progressive ankylosis of the facet joints, costovertebral joints, and intervertebral discs causes the spine to fuse in a flexed position. Without intervention:
- Loss of lumbar lordosis → flattened lower back (the normal inward curve disappears)
- Fixed thoracic kyphosis → the upper back curves forward excessively
- Compensatory cervical flexion → chin drops towards chest
- The patient cannot look straight ahead → impaired forward gaze (measured by the chin-brow vertical angle [21])
- Compensatory hip and knee flexion to maintain balance [21]
Functional consequences:
- Difficulty looking ahead while walking → falls risk
- Difficulty lying flat → sleep disturbance
- Reduced visual field → impaired driving safety
- Social and psychological impact (appearance, loss of independence)
Prevention and management:
- Regular physiotherapy and posture education are the mainstay of prevention
- Corrective spinal osteotomy for severe fixed deformity — high-risk surgery involving controlled fracture and realignment of the fused spine [3]
Reduced chest expansion (costosternal and manubriosternal joint) [3].
Mechanism: ankylosis of the costovertebral, costotransverse, costosternal, and manubriosternal joints restricts the thoracic cage from expanding during inspiration. This creates a restrictive pattern on pulmonary function testing (reduced FVC and TLC, but preserved or increased FEV1/FVC ratio).
Clinical significance:
- Patients rely increasingly on diaphragmatic breathing to compensate (the diaphragm is the only remaining mobile respiratory muscle unit)
- Normally well-compensated at rest, but exercise tolerance may be reduced
- Chest wall rigidity makes the patient more vulnerable to respiratory infections (impaired cough mechanism) and atelectasis
- Smoking cessation is critical to reduce burden to restrictive lungs [3] — because any additional insult (COPD from smoking + restrictive from chest wall rigidity) compounds respiratory compromise
Cauda equina syndrome [3].
Mechanism: long-standing AS can cause arachnoiditis (chronic inflammation of the arachnoid membrane around the cauda equina) or dural ectasia (dilatation of the dural sac in the lower lumbar region, thought to be from chronic CSF pressure changes in a rigid spine). Both mechanisms can compress the cauda equina nerve roots.
Clinical features:
- Urinary retention with overflow incontinence (S2–S4 sacral parasympathetics)
- Faecal incontinence
- Saddle anaesthesia (perineal numbness)
- Lower limb weakness and areflexia (LMN pattern — the cauda equina is peripheral nerve, not cord)
- Bilateral radicular pain
This is rare but represents a surgical emergency when it occurs — requires urgent MRI and neurosurgical/orthopaedic assessment.
Arthritis: typically asymmetrical oligoarthritis, e.g. hip (poor prognostic factors) [3].
Why is hip involvement a poor prognostic factor?
- The hips bear the body's full weight → disease here causes severe functional limitation (difficulty walking, rising from chairs, climbing stairs)
- Hip disease in AS tends to be bilateral and progressive
- Often requires total hip replacement at a young age — posing durability and revision challenges
- Associated with more rapid radiographic progression in the spine
- Combined hip and spine disease severely limits overall function
2. Extra-Articular Complications — The 6A's
Extra-articular manifestations (6A): eye (acute anterior uveitis), lung (apical fibrosis), CVS (AR), GI (Autoimmune IBD), renal (Amyloidosis, IgA nephropathy), neurologic (Atlantoaxial subluxation) [3].
Acute anterior uveitis — ciliary flush, miotic pupils [3]. Uveitis in 25–40% of AS patients [7].
Pathophysiology: HLA-B27 is expressed on uveal tissue (iris, ciliary body). In genetically predisposed individuals, aberrant immune activation against uveal antigens → infiltration of the anterior chamber with inflammatory cells → iritis/anterior cyclitis.
Clinical presentation:
- Acute onset, unilateral (may alternate between eyes over time), recurrent
- Ocular pain, photophobia, blurred vision, tearing, red eye
- Signs: ciliary flush (circumlimbal conjunctival injection — a ring of redness around the corneal limbus, indicating deep vascular congestion), miotic pupil (iris spasm from inflammation), anterior chamber cells and flare on slit-lamp examination
Complications of uveitis itself:
- Posterior synechiae: adhesions between the posterior iris and the anterior lens capsule → irregular pupil shape → if 360° (seclusio pupillae) → pupillary block → secondary angle-closure glaucoma
- Band keratopathy: calcium deposits in the cornea from chronic inflammation
- Cataract: from chronic inflammation or long-term topical steroid use
- Cystoid macular oedema (CMO): fluid accumulation in the macula → central vision loss
- Glaucoma: from trabecular meshwork inflammation or steroid-induced
Management: topical corticosteroid eye drops (1% prednisolone acetate) + topical cycloplegic (1% cyclopentolate to break/prevent posterior synechiae and relieve ciliary spasm) → ophthalmology referral. Recurrent uveitis is an indication for systemic biologic therapy (anti-TNF reduces uveitis flare frequency).
GC High Yield — Extra-articular Eye Complications in SpA
Anterior uveitis is the most common extra-articular manifestation of AS. It is HLA-B27 associated, unilateral and recurrent. On the GC lecture slides, uveitis is listed among the clinical features of SpA alongside spondylitis, peripheral arthritis, enthesitis, and aortitis [1].
Pathophysiology: the exact mechanism is debated, but two theories predominate:
- Chronic atelectasis: the rigid chest wall and reduced ventilation preferentially affect the lung apices (which receive the least ventilation in the upright position) → chronic hypoventilation → collapse → secondary fibrosis
- Direct inflammatory fibrosis: analogous to the entheseal fibrotic process in the spine, chronic immune-mediated inflammation may directly fibrosed the apical pleura and parenchyma
Clinical features:
- Usually asymptomatic — found incidentally on CXR or as progressive upper lobe fibrosis
- When symptomatic: dry cough, mild dyspnoea
- Rarely, cavitation of the fibrotic apices can occur → may be colonised by Aspergillus (mycetoma/aspergilloma) or may mimic tuberculosis on CXR
- Important differential: in a patient with AS and apical cavitary lesions, you must exclude TB and aspergilloma before attributing it to AS alone
CVS (AR) [3]. CAD, aortitis, AR, conduction defects [7].
Aortic regurgitation is listed as an etiology under seronegative rheumatoid syndromes — ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy [26].
Pathophysiology of aortic regurgitation:
- Chronic inflammation at the aortic root (aortitis) → fibrous thickening and dilatation of the aortic wall, particularly the sinuses of Valsalva and the ascending aorta → aortic annular dilatation → the aortic valve leaflets can no longer coapt (come together) during diastole → aortic regurgitation
- The fibrosis can extend below the aortic valve into the subaortic region and the membranous interventricular septum → involvement of the AV node and Bundle of His → conduction defects (1st, 2nd, or 3rd degree AV block; bundle branch block)
Clinical significance:
- AR in AS is typically slowly progressive and may be asymptomatic for years
- Symptoms of severe AR: exertional dyspnoea, orthopnoea, palpitations (wide pulse pressure), eventually heart failure
- Conduction defects: may cause syncope, pre-syncope, or asymptomatic bradycardia detected on ECG
- Screening: baseline ECG in all AS patients; echocardiography if murmur detected or symptoms of HF; periodic monitoring
Management: medical management of HF; aortic valve replacement if severe symptomatic AR; pacemaker implantation for symptomatic high-degree AV block.
GI (Autoimmune IBD) [3].
Pathophysiology: AS and IBD share common genetic susceptibility (HLA-B27, IL-23R polymorphisms) and immunological pathways (IL-23/IL-17 axis, gut mucosal inflammation). Subclinical gut inflammation (detected on ileocolonoscopy with biopsies) is found in up to 60% of AS patients. A proportion of these (5–10%) progress to overt Crohn's disease or ulcerative colitis.
Clinical significance:
- May present with chronic diarrhoea, abdominal pain, bloody stools, weight loss
- IBD in AS patients is a spondylitis-like ankylosing spondylitis pattern — one of the extraintestinal manifestations of IBD [8][27]
- The coexistence of IBD and AS has important therapeutic implications: avoid anti-IL-17 (may worsen gut disease) and etanercept (ineffective for IBD); use anti-TNF monoclonal antibodies (infliximab or adalimumab) which treat both conditions
2.5 Renal Complications
Renal (Amyloidosis, IgA nephropathy) [3].
Pathophysiology: chronic mucosal immune activation (from subclinical gut inflammation) → elevated serum IgA → mesangial deposition of IgA in the glomeruli → IgA nephropathy.
Clinical features: microscopic or gross haematuria, proteinuria; slowly progressive renal impairment if untreated.
Pathophysiology: chronic, poorly controlled inflammation → persistently elevated serum amyloid A (SAA) protein (an acute phase reactant produced by the liver) → misfolding and extracellular deposition of amyloid fibrils (AA type) in organs, especially the kidneys.
Clinical features: nephrotic syndrome (proteinuria, hypoalbuminaemia, oedema), progressive renal failure. May also deposit in GI tract (malabsorption, diarrhoea), liver, spleen, heart.
Important note: AA amyloidosis is rare in the modern biologic era because effective anti-inflammatory therapy (biologics) suppresses SAA production. It was historically a significant cause of mortality in poorly treated AS.
Neurologic (Atlantoaxial subluxation) [3].
Pathophysiology: chronic inflammation at the C1–C2 articulation (the atlantoaxial joint has synovium and ligamentous attachments that can be affected by SpA) → erosion of the transverse ligament of the atlas (which normally holds the odontoid process of C2 against the anterior arch of C1) → C1–C2 instability → subluxation → compression of the cervicomedullary junction (upper spinal cord).
Clinical features (cervical myelopathy):
- Upper motor neuron (UMN) signs in all four limbs: spasticity, hyperreflexia, extensor plantars (Babinski positive)
- Posterior column signs: loss of proprioception and vibration sense → sensory ataxia
- Lower motor neuron signs at C1–C2 level (if nerve root compressed)
- In severe cases: quadriplegia, respiratory failure (C3–C5 innervates the diaphragm)
Management: surgical stabilisation (posterior C1–C2 fusion) if symptomatic or if subluxation is severe (anterior atlanto-dental interval > 9 mm or evidence of cord compression on MRI).
Pathophysiology: multifactorial —
- Chronic systemic inflammation: pro-inflammatory cytokines (TNF-α, IL-6) upregulate RANKL → increased osteoclast activity → bone resorption
- Reduced mobility: immobility from spinal stiffness and pain leads to disuse osteopenia
- Medications: although systemic corticosteroids are rarely used in AS, patients who received them historically are at additional risk
- Reduced vitamin D: kyphotic posture may limit outdoor activity and sun exposure
Clinical significance:
- Paradox: the AS spine appears sclerotic on X-ray (due to syndesmophytes and facet joint fusion) but the vertebral body trabecular bone is actually osteoporotic → conventional DEXA of the lumbar spine can overestimate BMD in AS (because the densitometer reads the dense cortical syndesmophytes, masking the trabecular osteopenia)
- Better to measure BMD at the femoral neck (not affected by syndesmophytes) or use lateral spine DEXA
- Osteoporotic vertebral fractures can occur even in patients with apparently "dense" bamboo spine
Screening: DEXA scan: baseline for osteopenia [3]. Periodic monitoring especially with active disease.
Management: bisphosphonates (alendronate, zoledronate) or denosumab if DEXA T-score ≤ −2.5 or fragility fracture; calcium and vitamin D supplementation; weight-bearing exercise.
AS patients have an increased cardiovascular risk independent of traditional risk factors. Chronic systemic inflammation accelerates atherosclerosis through:
- Endothelial dysfunction
- Increased oxidative stress
- Pro-atherogenic lipid profile (elevated small dense LDL, reduced HDL)
- Elevated CRP (itself a cardiovascular risk marker)
This translates to increased risk of:
- Ischaemic heart disease
- Stroke
- Peripheral vascular disease
Management: cardiovascular risk assessment and management (lipid screening, blood pressure control, smoking cessation — which has dual benefit for both CV risk and AS disease activity).
These are iatrogenic complications that must be monitored:
| Treatment | Key Complications |
|---|---|
| NSAIDs (long-term) | GI: peptic ulcer, GI bleeding, perforation. Renal: AKI, CKD (chronic interstitial nephritis). CV: increased MI/stroke risk (especially COX-2 inhibitors) |
| Anti-TNF agents | Infection (especially TB reactivation, serious bacterial infections). Demyelination (rare). Drug-induced lupus. Lymphoma (slight increase). Heart failure exacerbation |
| Anti-IL-17 | Candidal infections (mucocutaneous candidiasis — because IL-17 is crucial for mucosal defence against Candida). IBD exacerbation |
| JAK inhibitors | VTE, MACE, malignancy, herpes zoster reactivation, cytopenias, lipid derangement |
| Corticosteroid injections | Avoid IA steroid in Achilles tendon: risk of tendon rupture [3]. Also: local skin atrophy, infection at injection site, transient hyperglycaemia |
Often overlooked but extremely important:
- Depression and anxiety: chronic pain, fatigue, reduced mobility, altered body image from kyphotic deformity, reduced work productivity
- Sleep disturbance: nocturnal pain and stiffness; inability to lie flat with severe kyphosis
- Reduced functional capacity: difficulty with ADLs, work, driving (impaired forward gaze)
- Social isolation: especially in young patients at the peak of their working and social lives
| System | Complication | Mechanism | Prevalence |
|---|---|---|---|
| Skeletal | Spinal fractures | Rigid osteoporotic spine + trivial trauma | Common in advanced disease |
| Question mark deformity | Progressive facet/disc ankylosis in flexion | Late disease | |
| Reduced chest expansion | Costovertebral/costosternal ankylosis | Common | |
| Cauda equina syndrome | Arachnoiditis / dural ectasia | Rare | |
| Hip arthritis | Synovitis of hip joint | ~30–50% (poor prognostic factor) | |
| Eye | Acute anterior uveitis | HLA-B27-mediated uveal inflammation | 25–40% |
| Lung | Apical fibrosis | Chronic atelectasis / direct fibrosis | < 5% |
| CVS | Aortic regurgitation | Aortic root inflammation and fibrosis | ~5–10% |
| Conduction defects | Subaortic fibrosis → AV node/His involvement | ~5% | |
| GI | Autoimmune IBD | Shared HLA-B27/IL-23 pathways | Subclinical: ~60%; overt: 5–10% |
| Renal | IgA nephropathy | Elevated IgA from mucosal immune activation | ~5% |
| AA amyloidosis | Chronic SAA elevation → amyloid deposition | Rare (modern era) | |
| Neuro | Atlantoaxial subluxation | Transverse ligament erosion → C1–C2 instability | Rare |
| Bone | Osteoporosis | Inflammation + immobility + cytokine-driven osteoclast activity | Common (often underdiagnosed) |
| CV | Accelerated atherosclerosis | Chronic inflammation → endothelial dysfunction | Increased relative risk |
| Psych | Depression, anxiety, sleep disturbance | Chronic pain, disability, body image | Common |
High Yield Summary
Complications of AS — Key Points:
- Spinal fractures: the fused osteoporotic "bamboo spine" is brittle; even minor trauma causes highly unstable transdiscal fractures with high risk of cord injury. Always image (CT/MRI) if new pain after any trauma.
- Question mark deformity: loss of lumbar lordosis + fixed thoracic kyphosis + cervical flexion → impaired forward gaze. Prevented by physiotherapy; corrected surgically by osteotomy in severe cases.
- Reduced chest expansion: costovertebral ankylosis → restrictive ventilatory defect → reliance on diaphragmatic breathing. Smoking cessation is critical.
- 6A's of extra-articular complications:
- Anterior uveitis (25–40%) — commonest EAM; unilateral, acute, recurrent; HLA-B27-mediated
- Apical fibrosis ( < 5%) — may cavitate → r/o TB, aspergilloma
- Aortic regurgitation (~5–10%) — aortic root fibrosis; may cause HF
- Autoimmune IBD — subclinical gut inflammation in 60%; overt in 5–10%
- Amyloidosis / IgA nephropathy — renal complications
- Atlantoaxial subluxation — cervical myelopathy; rare but devastating
- Osteoporosis: paradox of sclerotic-looking spine on XR but osteoporotic trabecular bone; DEXA at femoral neck preferred
- Increased cardiovascular risk: chronic inflammation → accelerated atherosclerosis
- Treatment complications: long-term NSAIDs (GI, renal, CV); anti-TNF (TB, infections); anti-IL-17 (candidiasis, IBD worsening); JAK inhibitors (VTE, MACE)
Active Recall — Complications of Ankylosing Spondylitis
References
[1] Lecture slides: GC 074. Multiple joint pain.pdf (SpA clinical features including uveitis, aortitis) [3] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — AS clinical features, extra-articular manifestations 6A, pp. 322–325) [5] Senior notes: Ryan Ho Rheumatology.pdf (SpA overview — extra-articular features, pp. 57–58) [7] Senior notes: Ryan Ho Rheumatology.pdf (SpA comparison table — ocular, skin, other complications, p. 58) [8] Senior notes: Block A - Chronic diarrhoea: irritable bowel syndrome and inflammatory bowel disease.pdf (Extraintestinal complications of IBD including spondylitis, p. 34) [20] Senior notes: Ryan Ho Radiology.pdf (Spinal trauma indications for imaging including AS patients, p. 18) [21] Senior notes: Ryan Ho Fundamentals.pdf (AS examination — chin-brow vertical angle, question mark posture, p. 147) [22] Lecture slides / Medicine handbook: Handbook of Internal Medicine 2024.pdf (AS extra-skeletal features — apical fibrosis, aortic insufficiency, p. R10) [26] Senior notes: Block A - Fever and a murmur: Valvular heart diseases; Infective endocarditis.pdf (AR etiologies — seronegative syndromes including AS, p. 22) [27] Lecture slides: GC 033. Chronic diarrhea: irritable bowel syndrome and inflammatory bowel disease.pdf (Extraintestinal complications — arthritis, uveitis, p. 54)
High Yield Summary
Radiographic Axial Spondyloarthritis (Ankylosing Spondylitis) — Key Points:
- Definition: Chronic inflammatory disease of the axial skeleton with radiographic sacroiliitis; prototype of the seronegative spondyloarthritides
- Demographics: Young adults (peak 20–30s), M:F = 2–3:1, diagnosis delayed 6–11 years
- Genetics: HLA-B27 positive in 80–90%; 6–8% prevalence in southern Chinese; NOT diagnostic alone
- Pathophysiology: Enthesitis-centred (not synovitis like RA); involves TNF-α, IL-17/IL-23 axis; unique paradox of bone erosion followed by new bone formation (Wnt pathway) → syndesmophytes → ankylosis
- Cardinal symptom: Inflammatory back pain — onset < 45y, > 3 months, insidious, nocturnal, morning stiffness > 30 min, improves with exercise NOT rest, starts at SI joints and ascends
- Peripheral features: Asymmetric oligoarthritis (LL > UL), enthesitis (Achilles, plantar fascia), dactylitis (uncommon but poor prognosis)
- Extra-articular — 6A's: Anterior uveitis, Apical fibrosis, Aortic regurgitation, Autoimmune IBD, Amyloidosis/IgA nephropathy, Atlantoaxial subluxation
- Key examination: Modified Schober's (lumbar), chest expansion (thoracic), occiput-to-wall (cervical), FABER/Gaenslen's (SI joints)
- Disease activity: BASDAI ≥ 4/10 = active disease
- Classification: Modified New York 1984 (radiographic); ASAS 2009 (imaging or HLA-B27 + SpA features); current approach distinguishes AS from nr-axSpA
High Yield Summary
Diagnostic Criteria and Investigations for AS:
- Modified New York criteria (1984): Definite AS = radiographic sacroiliitis (≥ grade 2 bilateral or ≥ grade 3 unilateral) + ≥ 1 clinical criterion (inflammatory LBP, limited lumbar ROM, limited chest expansion)
- ASAS criteria (2009): Back pain ≥ 3 months, onset < 45 → imaging sacroiliitis + ≥ 1 SpA feature OR HLA-B27 + ≥ 2 SpA features
- 11 SpA features: inflammatory back pain, arthritis, enthesitis, psoriasis, uveitis, dactylitis, IBD, good NSAID response, family history, elevated CRP, HLA-B27
- Key bloods: ESR/CRP (inflammation), RF/anti-CCP (exclude RA), HLA-B27 (supports diagnosis when imaging equivocal)
- X-ray SI joints: sclerosis → erosions → narrowing → ankylosis (Grades 2–4). Erosions begin on iliac side
- X-ray spine: Romanus lesion (squaring + shiny corners) → syndesmophytes → bamboo spine
- MRI SI joints: subchondral BME (active sacroiliitis); more sensitive than X-ray; detects disease years earlier
- MRI spine: corner inflammatory lesions, fatty change at vertebral corners
- BASDAI ≥ 4/10 = active disease; ASDAS is the preferred composite score
- DEXA scan: baseline for osteopenia assessment
High Yield Summary
Management of AS — Key Points:
- Non-pharmacological for ALL: education, physiotherapy (especially swimming), posture training, smoking cessation
- NSAIDs are first-line for all patients; use at optimal dose continuously (slows radiographic progression); add PPI or use COX-2 inhibitor if high GI risk
- No csDMARD works for axial disease — sulphasalazine and methotrexate only for peripheral joints
- Avoid IA steroid in Achilles tendon (tendon rupture risk)
- Biologics for persistent high disease activity (BASDAI ≥ 4) despite ≥ 2 NSAIDs: anti-TNF (first-line) or anti-IL-17 (secukinumab) or JAK inhibitors
- Anti-IL-1 / anti-IL-6: NOT useful for SpA (cf. RA)
- If coexisting IBD: use anti-TNF monoclonal antibody (infliximab/adalimumab); avoid etanercept (no IBD efficacy) and anti-IL-17 (may worsen IBD)
- Always screen for latent TB before anti-TNF (isoniazid chemoprophylaxis × 3 months if positive)
- ASAS 50 response = BASDAI decrease by ≥ 50%
- Surgery rarely needed: THR for hip disease, corrective osteotomy for severe kyphosis
High Yield Summary
Complications of AS — Key Points:
- Spinal fractures: the fused osteoporotic "bamboo spine" is brittle; even minor trauma causes highly unstable transdiscal fractures with high risk of cord injury. Always image (CT/MRI) if new pain after any trauma.
- Question mark deformity: loss of lumbar lordosis + fixed thoracic kyphosis + cervical flexion → impaired forward gaze. Prevented by physiotherapy; corrected surgically by osteotomy in severe cases.
- Reduced chest expansion: costovertebral ankylosis → restrictive ventilatory defect → reliance on diaphragmatic breathing. Smoking cessation is critical.
- 6A's of extra-articular complications:
- Anterior uveitis (25–40%) — commonest EAM; unilateral, acute, recurrent; HLA-B27-mediated
- Apical fibrosis ( < 5%) — may cavitate → r/o TB, aspergilloma
- Aortic regurgitation (~5–10%) — aortic root fibrosis; may cause HF
- Autoimmune IBD — subclinical gut inflammation in 60%; overt in 5–10%
- Amyloidosis / IgA nephropathy — renal complications
- Atlantoaxial subluxation — cervical myelopathy; rare but devastating
- Osteoporosis: paradox of sclerotic-looking spine on XR but osteoporotic trabecular bone; DEXA at femoral neck preferred
- Increased cardiovascular risk: chronic inflammation → accelerated atherosclerosis
- Treatment complications: long-term NSAIDs (GI, renal, CV); anti-TNF (TB, infections); anti-IL-17 (candidiasis, IBD worsening); JAK inhibitors (VTE, MACE)
Non-radiographic Axial Spondyloarthritis
Non-radiographic axial spondyloarthritis is a form of axial spondyloarthritis characterized by inflammatory back pain and sacroiliitis detectable on MRI but without definitive structural changes visible on conventional radiographs.
Psoriatic Arthritis
Psoriatic arthritis is a chronic inflammatory seronegative spondyloarthropathy associated with psoriasis, characterized by joint inflammation, enthesitis, and dactylitis affecting peripheral and/or axial joints.