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.
Non-Radiographic Axial Spondyloarthritis (nr-axSpA)
Non-radiographic axial spondyloarthritis (nr-axSpA) is a subtype of axial spondyloarthritis (axSpA) characterised by chronic inflammatory back pain with evidence of axial inflammation — typically on MRI or through clinical/laboratory features — but without definite structural sacroiliitis on conventional plain radiographs (i.e., not meeting the radiographic criterion of the modified New York criteria for ankylosing spondylitis) [1][2].
Let's break down the terminology:
- Non-radiographic = plain X-ray does not show definite sacroiliitis (grade ≥ II bilateral or grade III–IV unilateral).
- Axial = predominantly affecting the axial skeleton (sacroiliac joints and spine).
- Spondyloarthritis = "spondylo" (Greek: σπόνδυλος, vertebra) + "arthritis" (Greek: ἄρθρον, joint + -itis, inflammation) → inflammation of vertebral joints.
The key concept: nr-axSpA and ankylosing spondylitis (AS) sit on a single disease spectrum of axial SpA [1][2]. The distinction is purely radiographic — clinically, the disease burden, symptoms, and impact on quality of life can be identical. Some patients with nr-axSpA will progress to AS over time (developing structural radiographic sacroiliitis), while others never progress.
High Yield — The axSpA Spectrum
axSpA is now classified into two subtypes based on radiographic findings [1][2]:
- Ankylosing spondylitis (AS) = radiographic axSpA (r-axSpA): meets modified New York radiological criteria.
- Non-radiographic axial spondyloarthritis (nr-axSpA): does NOT meet radiographic criteria but has clinical ± MRI evidence of axial inflammation.
Both share the same pathophysiology, clinical approach, and treatment principles.
Epidemiology
- The overall prevalence of axSpA is approximately 1.0–1.4% in Western populations [2].
- nr-axSpA constitutes roughly half of all axSpA cases — meaning its prevalence is approximately 0.5–0.7%, though exact figures vary by population and the method of ascertainment.
- In Hong Kong, the prevalence of HLA-B27 in southern Chinese is approximately 6–8% [2], which is lower than in Northern European populations (~8–10%). Correspondingly, the absolute prevalence of axSpA is somewhat lower but remains clinically significant.
- Age of onset: typically 20–30 years (most patients present before age 45) [1][2].
- Sex ratio in nr-axSpA: approximately M:F ≈ 1:1 [2], unlike classical AS which has a male predominance of M:F ≈ 3:1 [1][2].
- Why the difference? AS was historically defined by radiographic damage, and males tend to develop structural radiographic changes earlier and more frequently. When MRI-detected disease (nr-axSpA) is included, the sex ratio evens out. This means axSpA was historically under-diagnosed in women.
- Family history is significant: concordance rate of 63% in monozygotic twins; 8.2% risk in first-degree relatives [2].
- One of the most important epidemiological points: there is a notoriously long diagnostic delay averaging 7–10 years from symptom onset to diagnosis. This is because:
- Back pain is extremely common in the general population (mechanical causes predominate).
- nr-axSpA has no structural radiographic changes by definition — so normal X-rays can falsely reassure clinicians.
- Awareness of inflammatory back pain (IBP) criteria among primary care physicians remains suboptimal.
- Approximately 10–20% of nr-axSpA patients progress to AS (r-axSpA) over 2–10 years.
- Risk factors for progression: male sex, positive HLA-B27, elevated CRP, smoking, and presence of MRI sacroiliitis with bone marrow oedema.
| Risk Factor | Mechanism / Explanation |
|---|---|
| HLA-B27 positivity | Present in ~80–90% of AS and ~60–70% of nr-axSpA; an MHC class I molecule that predisposes to aberrant immune activation at entheses (see Pathophysiology) [2] |
| Family history of SpA | Strong genetic component (heritability ~90% for axSpA); polygenic but HLA-B27 contributes ~20–30% of heritability |
| Male sex (for progression to AS) | Males progress to structural damage faster; females have equivalent symptom burden but less radiographic progression |
| Smoking | Accelerates structural damage, increases CRP, worsens disease activity and functional outcomes |
| Gut inflammation | Subclinical gut inflammation is found in up to 50% of axSpA patients; gut dysbiosis may trigger aberrant immune responses |
| Prior infections (in reactive SpA overlap) | Certain enteric (Salmonella, Shigella, Campylobacter, Yersinia) and urogenital (Chlamydia) infections can trigger SpA in HLA-B27-positive individuals |
Anatomy and Functional Considerations
Understanding nr-axSpA requires understanding the key anatomical targets of the disease:
- The SIJ is the earliest and most characteristic site of involvement in axSpA.
- It is a synovial joint (lower two-thirds) and a ligamentous/syndesmotic joint (upper one-third).
- The iliac side has thinner cartilage than the sacral side → the iliac side is affected first (because thinner cartilage is more susceptible to inflammation and erosion).
- In nr-axSpA, inflammation (osteitis/bone marrow oedema) is present in the subchondral bone of the SIJ on MRI, but structural damage (erosions, sclerosis, ankylosis) has not yet appeared on plain X-ray.
- Enthesitis (inflammation of tendon/ligament/capsule insertion into bone) is the hallmark pathological lesion of SpA [1][2], distinguishing it from RA (which is primarily synovitis-driven).
- Common entheseal sites: Achilles tendon insertion, plantar fascia, iliac crest, ischial tuberosity, spinous processes, costochondral junctions, and the annulus fibrosus of intervertebral discs.
- Enthesitis leads to secondary synovitis (because the enthesis is adjacent to the joint space).
- Inflammation begins at the discovertebral junction (where the annulus fibrosus inserts into the vertebral body — an enthesis).
- Romanus lesion: inflammatory erosion at the vertebral corner (anterior or posterior), seen as a "shiny corner" on MRI due to bone marrow oedema [1].
- Progressive disease leads to syndesmophytes (bony bridges between vertebral bodies) and eventually the "bamboo spine" [1] of advanced AS — but this takes years and is NOT seen in nr-axSpA by definition.
- Peripheral joints (especially hips, shoulders, knees) can be affected, though axial symptoms predominate.
- The eye (uveal tract), aortic root, lung apices, and gut are extra-articular sites affected by the same inflammatory process.
Etiology and Pathophysiology
Genetic Factors
- HLA-B27 is the strongest genetic risk factor, present in 80–90% of AS and ~60–70% of nr-axSpA [2].
- Prevalence of HLA-B27 in southern Chinese: approximately 6–8% [2], but only a minority of HLA-B27-positive individuals develop SpA (about 5–6% lifetime risk).
- HLA-B27 is a class I MHC molecule expressed on the surface of all nucleated cells. It presents intracellular peptides to CD8+ T cells.
Several hypotheses explain HLA-B27's pathogenic role [2]:
| Hypothesis | Mechanism |
|---|---|
| Arthritogenic peptide hypothesis | HLA-B27 presents unique self or microbial peptides that activate autoreactive CD8+ T cells. Molecular mimicry between microbial peptides and self-peptides at entheseal sites triggers immune attack. |
| HLA-B27 misfolding / unfolded protein response | HLA-B27 heavy chains tend to misfold in the endoplasmic reticulum (ER), triggering the unfolded protein response (UPR), which activates NF-κB and produces pro-inflammatory cytokines (especially IL-23 and TNF-α). This is the currently favoured mechanism. |
| HLA-B27 homodimer hypothesis | HLA-B27 free heavy chains can form homodimers on the cell surface that are recognised by NK cell receptors (KIR3DL2), promoting IL-17-producing T cell (Th17) expansion. |
- Over 100 non-HLA genetic loci contribute to axSpA susceptibility, including:
- ERAP1 (endoplasmic reticulum aminopeptidase 1): trims peptides for loading onto HLA-B27. Variants alter the peptide repertoire presented.
- IL-23R: polymorphisms in the IL-23 receptor gene affect Th17 pathway activation.
- CARD9, STAT3, TYK2: genes involved in innate immunity and the IL-23/IL-17 axis.
This is the key pathway to understand:
Why does SpA cause both erosion AND new bone formation (unlike RA, which predominantly causes erosion)?
- Early disease: TNF-α and IL-17 drive osteoclastogenesis → erosion at the enthesis and subchondral bone.
- Simultaneously and in later stages: IL-22 and other mediators stimulate osteoblast-driven new bone formation via Wnt signalling, producing syndesmophytes and ankylosis.
- This dual process explains why anti-TNF treatment suppresses inflammation and erosion but may not fully prevent new bone formation.
| Factor | Role |
|---|---|
| Gut microbiome dysbiosis | Up to 50% of axSpA patients have subclinical gut inflammation. The gut-joint axis is critical: gut barrier dysfunction allows microbial products (e.g., LPS) to access systemic circulation, activating innate immune cells. Certain bacteria (e.g., Klebsiella pneumoniae) have been implicated in molecular mimicry with HLA-B27. |
| Prior infection (in reactive arthritis overlap) | Urogenital (Chlamydia trachomatis) or enteric (Salmonella, Shigella, Campylobacter, Yersinia) infections can trigger SpA in genetically predisposed individuals. |
| Mechanical stress | Entheses at biomechanically stressed sites (Achilles, plantar fascia, SIJ) are preferentially affected, supporting the concept that micro-damage at entheses initiates inflammation in predisposed individuals. |
| Smoking | Increases TNF-α production, accelerates radiographic progression, and worsens disease outcomes. |
Pathophysiology in a Nutshell
Spondyloarthritis is driven by enthesitis and secondary synovitis [1]. The genetic predisposition (HLA-B27) combined with environmental triggers (gut dysbiosis, mechanical stress, infection) leads to aberrant activation of the IL-23/IL-17 axis at entheseal sites, producing both bone erosion (osteoclasts) and paradoxical new bone formation (osteoblasts). In nr-axSpA, this process is in its early phase — inflammation is present (detectable on MRI) but structural damage has not yet appeared on plain X-ray.
Classification
The ASAS Framework (2009)
The Assessment of SpondyloArthritis International Society (ASAS) introduced a modern classification that replaced the old rigid categories [1][2]:
| Old Classification | New ASAS Classification (2009) |
|---|---|
| Ankylosing spondylitis | Axial SpA (axSpA) |
| Reactive arthritis | — Radiographic axSpA (r-axSpA) = AS |
| Psoriatic arthritis | — Non-radiographic axSpA (nr-axSpA) |
| Enteropathic arthritis | Peripheral SpA |
| Undifferentiated SpA | |
| Juvenile-onset SpA |
The ASAS classification criteria for axSpA apply to patients with chronic back pain (≥ 3 months) and age of onset < 45 years [1][2].
The criteria have two arms (either arm can be fulfilled):
- Sacroiliitis on imaging (either MRI showing active inflammation consistent with sacroiliitis, OR definite sacroiliitis on plain radiograph per modified New York criteria) PLUS ≥ 1 SpA feature
- HLA-B27 positive PLUS ≥ 2 other SpA features
These are the building blocks used in both arms [1][2]:
| SpA Feature | Explanation |
|---|---|
| 1. Inflammatory back pain | Insidious onset, age < 40, improves with exercise, no improvement with rest, night pain (improving on getting up) — satisfies ≥ 4/5 criteria |
| 2. Arthritis | Past/present peripheral arthritis (synovitis) confirmed by a doctor |
| 3. Enthesitis (heel) | Past/present enthesitis, especially Achilles or plantar fascia |
| 4. Uveitis | Past/present anterior uveitis confirmed by an ophthalmologist |
| 5. Dactylitis | Past/present dactylitis ("sausage digit") confirmed by a doctor |
| 6. Psoriasis | Past/present psoriasis confirmed by a doctor |
| 7. Crohn's/colitis | Past/present IBD confirmed by a doctor |
| 8. Good response to NSAIDs | Resolution or significant improvement of back pain within 24–48 hours of full-dose NSAID |
| 9. Family history of SpA | First- or second-degree relative with AS, psoriasis, uveitis, reactive arthritis, or IBD |
| 10. HLA-B27 | Positive test |
| 11. Elevated CRP | Elevated CRP after exclusion of other causes |
How Does nr-axSpA Fit Into the ASAS Criteria?
A patient with chronic back pain (onset < 45 years, duration ≥ 3 months) who:
- Has MRI sacroiliitis (but normal plain X-ray) + ≥ 1 SpA feature → classified as nr-axSpA via the imaging arm.
- Is HLA-B27 positive + ≥ 2 other SpA features (even without imaging abnormality) → classified as nr-axSpA via the clinical arm.
In both cases, the plain X-ray is normal or insufficient to meet modified New York criteria — that's what makes it "non-radiographic."
These are the older criteria used specifically for AS (r-axSpA) [2]:
| Radiological Criterion | Clinical Criteria (≥ 1 of 3) |
|---|---|
| Sacroiliitis on plain XR: ≥ grade II bilaterally; or grade III–IV unilaterally | 1. LBP + stiffness > 3 months, improves with exercise, not relieved by rest |
| 2. Limitation of lumbar spine ROM in sagittal and frontal planes | |
| 3. Limitation of chest expansion relative to age/sex norms |
Definite AS = radiological criterion + ≥ 1 clinical criterion.
nr-axSpA by definition does not meet this radiological criterion.
| Grade | Description |
|---|---|
| 0 | Normal |
| I | Suspicious changes (equivocal) |
| II | Minimal abnormality — small localised erosions, sclerosis; no joint space alteration |
| III | Unequivocal abnormality — moderate/advanced sacroiliitis with erosions, sclerosis, widening, narrowing, or partial ankylosis |
| IV | Severe abnormality — total ankylosis |
Clinical Features
A. Symptoms (with pathophysiological basis)
Inflammatory back pain is the hallmark presenting symptom of axSpA, including nr-axSpA [1][2].
The ASAS criteria for IBP (≥ 4 out of 5 satisfies IBP):
- Age of onset < 40 years
- Insidious onset
- Improvement with exercise
- No improvement with rest
- Pain at night (with improvement upon getting up)
Pathophysiological explanation:
- The pain arises from inflammation at the SIJ and spinal entheses. During rest and sleep, inflammatory cytokines (TNF-α, IL-17) accumulate in the joint due to reduced blood flow and immobility, causing stiffness and pain.
- Exercise increases blood flow, which clears inflammatory mediators and loosens stiffened joints → pain improves with activity.
- Night pain occurs because the recumbent position for prolonged periods allows inflammatory exudate to accumulate. Patients characteristically wake in the second half of the night and may need to get up and move around to relieve stiffness.
- This pattern is the opposite of mechanical back pain, which worsens with activity and improves with rest.
Inflammatory back pain vs. mechanical back pain [1]:
| Feature | Inflammatory Back Pain | Mechanical Back Pain |
|---|---|---|
| Age of onset | < 40 years | Any age |
| Onset | Insidious | Acute or variable |
| Duration | > 3 months | Variable |
| Morning stiffness | > 30 minutes (often > 1 hour) | < 30 minutes |
| Effect of exercise | Improves | Worsens |
| Effect of rest | No improvement / worsens | Improves |
| Night pain | Yes, especially 2nd half of night | Usually absent |
| Response to NSAIDs | Good (often dramatic) | Variable |
- Prolonged morning stiffness lasting > 30 minutes (often 1–2 hours) is characteristic.
- Mechanism: overnight immobility → accumulation of inflammatory cytokines and exudate → joint stiffness that gradually resolves as the patient moves and inflammation is mechanically dispersed.
- Alternating buttock pain is highly suggestive of sacroiliitis and is one of the most specific clinical pointers to axSpA.
- Mechanism: inflammation alternates between the left and right SIJs, producing pain that switches sides over weeks to months. This alternation reflects the bilateral (but often asymmetric at any given time) nature of SIJ inflammation.
- Up to 50% of axSpA patients have peripheral joint involvement at some point [1].
- Lower limb > upper limb involvement is characteristic (unlike RA, which affects UL > LL) [1].
- Typically asymmetric oligoarthritis (≤ 4 joints), affecting hips, knees, and ankles preferentially.
- Hip involvement is particularly important because it is a poor prognostic factor [1] and may cause early functional disability.
- Patients report posterior heel pain (Achilles enthesitis) or plantar heel pain (plantar fasciitis).
- Mechanism: enthesitis at the insertion of the Achilles tendon or plantar fascia into the calcaneus.
- Often worse with the first steps in the morning (like the axial stiffness, this reflects overnight inflammation accumulation at the enthesis).
- Involvement of costochondral and costovertebral joints causes chest wall pain and restricted chest expansion.
- Mechanism: enthesitis and synovitis at the articulations of the ribs with the sternum and spine → reduced thoracic cage mobility → restrictive ventilatory defect.
- Patients may describe difficulty taking a deep breath.
- Fatigue is very common and often under-appreciated — it reflects the systemic inflammatory burden.
- Weight loss and low-grade fever are less common but can occur.
The "6A" mnemonic for extra-articular manifestations of axSpA (EAM) [1]:
| EAM | Clinical Significance |
|---|---|
| Acute anterior uveitis | Most common EAM (25–40%); presents with unilateral painful red eye, photophobia, blurred vision; HLA-B27-associated; typically recurrent and alternating between eyes |
| Apical pulmonary fibrosis | Rare, late manifestation; restrictive lung disease; upper lobe fibrosis mimicking TB on CXR |
| Aortic regurgitation (AR) | Aortitis and fibrosis at aortic root → aortic valve incompetence; also causes conduction defects (AV block) |
| Autoimmune: IBD | Subclinical gut inflammation in up to 50%; clinical Crohn's disease or ulcerative colitis |
| Amyloidosis (AA type) | Secondary amyloidosis from chronic inflammation → nephrotic syndrome, renal failure |
| Atlanto-axial subluxation | Inflammation and erosion at C1/C2 → instability; risk of cord compression (similar to RA but less common) |
Anterior Uveitis in SpA
Anterior uveitis is the most common extra-articular manifestation of axSpA [1][3]. It is typically:
- Acute (sudden onset)
- Unilateral (but alternating between eyes over episodes)
- Anterior (iritis / iridocyclitis)
- Non-granulomatous (unlike sarcoidosis, which causes granulomatous uveitis)
- Associated with HLA-B27 [3]
Presentation: painful red eye, photophobia, blurred vision, ciliary flush (circumlimbal injection), cells and flare in the anterior chamber. A hypopyon (pus) may form in severe cases. Refer urgently to ophthalmology [3].
B. Signs (with pathophysiological basis)
- Direct pressure over the SIJs (posterior superior iliac spines) or provocative tests (FABER/Patrick's test, Gaenslen's test, sacral compression) may elicit pain.
- Mechanism: inflamed SIJ periosteum and subchondral bone are tender to mechanical stress.
- In early nr-axSpA, spinal mobility may be normal or only mildly reduced. However, as inflammation progresses:
- Reduced lumbar flexion: measured by Schober's test (modified) — a distance of < 5 cm increase from the 10 cm mark between L5 and 10 cm above when the patient bends forward indicates reduced lumbar flexion.
- Normal: ≥ 5 cm increase.
- Reduced lateral flexion: measured by lateral spinal flexion (finger-to-floor distance or specific goniometric measurements).
- Reduced cervical rotation: occiput-to-wall distance (normally 0 cm; increased in forward-stooped posture of advanced disease).
- Increased thoracic kyphosis: progressive loss of lumbar lordosis and exaggerated thoracic kyphosis → the classic "question mark posture" of advanced AS (not usually seen in nr-axSpA).
- Reduced lumbar flexion: measured by Schober's test (modified) — a distance of < 5 cm increase from the 10 cm mark between L5 and 10 cm above when the patient bends forward indicates reduced lumbar flexion.
- Chest expansion < 2.5 cm (measured at the 4th intercostal space / nipple line) is abnormal and suggests costovertebral/costochondral joint involvement.
- Mechanism: ankylosis or inflammation of costovertebral joints restricts rib excursion → reduced chest expansion → restrictive pattern on PFT.
- Tenderness at entheseal sites — Achilles tendon insertion, plantar fascia origin, tibial tuberosity, iliac crests, ischial tuberosities, greater trochanters, spinous processes.
- Swelling and thickening at the Achilles insertion may be visible.
- Mechanism: active inflammation at the bone-tendon/ligament junction.
Avoid intra-tendinous corticosteroid injection at the Achilles tendon: risk of tendon rupture [1].
- Diffuse swelling of an entire digit (toe more common than finger in axSpA).
- Mechanism: combined inflammation of the flexor tendon sheath (tenosynovitis), interphalangeal joints, and surrounding soft tissue.
- More common in PsA and ReA than in axSpA, but can occur.
- Warm, swollen, tender joints — typically asymmetric, oligoarticular, lower limb predominant.
- Joint effusions may be present, especially at the knee.
- During a uveitis flare: unilateral red eye with ciliary flush (injection concentrated around the limbus), photophobia, and miosis.
- Slit-lamp examination reveals cells and flare in the anterior chamber [3].
- Aortic regurgitation murmur (early diastolic, best heard at left sternal edge with patient sitting up and leaning forward, in expiration) — in late/severe disease.
- Conduction defects (bradycardia if AV block present) — auscultate for irregular heart rate.
- Psoriasis: check extensor surfaces (elbows, knees), scalp, umbilicus, natal cleft ("hidden areas") [1].
- Nail changes: pitting, onycholysis, ridging — suggest PsA overlap [1].
Clinical Pearl — What to Look For on Examination in Suspected axSpA
On examination of a young patient with chronic back pain, systematically assess:
- Spine: Schober's test, occiput-to-wall distance, lateral flexion, thoracic kyphosis
- Chest expansion: measured at nipple line (< 2.5 cm is abnormal)
- SIJ: direct tenderness, FABER/Patrick's test
- Entheses: Achilles, plantar fascia, iliac crests
- Peripheral joints: especially hips, knees (asymmetric oligoarthritis)
- Eyes: red eye (uveitis)
- Skin: psoriasis, nail changes
- Cardiovascular: aortic regurgitation murmur, conduction abnormalities
Understanding how we monitor disease activity is essential for management decisions:
- BASDAI (Bath Ankylosing Spondylitis Disease Activity Index): a patient-reported questionnaire scoring 0–10 across 6 domains (fatigue, spinal pain, joint pain/swelling, enthesitis, morning stiffness severity, and morning stiffness duration). Active disease is defined as BASDAI ≥ 4 out of 10 [1].
- ASAS 50 response criteria: BASDAI decrease of ≥ 50% [1].
- ASDAS (Ankylosing Spondylitis Disease Activity Score): incorporates CRP and is more objective than BASDAI.
- Inactive: < 1.3 | Low: 1.3–2.1 | High: 2.1–3.5 | Very high: > 3.5.
- BASFI (Bath AS Functional Index), BASMI (Bath AS Metrology Index), BAS-G (Bath AS Global score) [1].
- Acute phase reactants: ESR/CRP — may be elevated but can be normal in nr-axSpA (CRP is normal in up to 40–60% of nr-axSpA patients, so a normal CRP does NOT exclude the diagnosis) [1].
| Feature | nr-axSpA | AS (r-axSpA) |
|---|---|---|
| Plain X-ray sacroiliitis | Absent (by definition) | Present (≥ grade II bilateral or III–IV unilateral) |
| MRI sacroiliitis | Often present (bone marrow oedema) | May be present or quiescent |
| Sex ratio | M:F ≈ 1:1 | M:F ≈ 3:1 |
| CRP elevation | Less frequent (~40–60% normal) | More frequent |
| Disease burden/symptoms | Similar to AS | Similar to nr-axSpA |
| Response to biologics | Similar to AS | Similar to nr-axSpA |
| Progression to AS | ~10–20% over 2–10 years | Already AS |
High Yield Summary
- nr-axSpA is part of the axSpA spectrum — same disease as AS but without definite radiographic sacroiliitis on plain X-ray.
- Classified via ASAS criteria [1][2]: imaging arm (sacroiliitis on MRI + ≥ 1 SpA feature) OR clinical arm (HLA-B27 + ≥ 2 SpA features), in patients with chronic back pain ≥ 3 months and onset < 45 years.
- Sex ratio is ~1:1 in nr-axSpA (vs. 3:1 in AS) — historically, women were under-diagnosed because they had less radiographic damage.
- HLA-B27 prevalence in southern Chinese is 6–8% [2]; only a minority develop SpA.
- Pathophysiology centres on enthesitis [1] and the IL-23/IL-17 axis, with both bone erosion and new bone formation.
- Cardinal symptom = inflammatory back pain (onset < 40, insidious, improves with exercise, not with rest, night pain).
- Morning stiffness > 30 minutes, alternating buttock pain, heel pain (enthesitis), peripheral oligoarthritis (LL > UL) are key features.
- Extra-articular: anterior uveitis (most common), aortitis/AR, apical fibrosis, IBD, amyloidosis, atlantoaxial subluxation (6A mnemonic).
- BASDAI ≥ 4/10 = active disease [1]; ASAS 50 = BASDAI drop of ≥ 50% [1].
- Diagnostic delay averages 7–10 years — suspect IBP in any young patient with chronic back pain and refer appropriately.
Active Recall - nr-axSpA Definition, Epidemiology, Pathophysiology and Clinical Features
[1] Senior notes: Maksim Medicine Notes.pdf (Section 13.6 Spondyloarthritides, pp. 321–323) [2] Senior notes: Ryan Ho Rheumatology.pdf (Section 2.7 Spondyloarthritis, pp. 57–58) [3] Senior notes: Ryan Ho Ophthalmology.pdf (Section 2.5 Uveitis and Endophthalmitis, p. 30) [4] Lecture slides: GC 074. Multiple joint pain.pdf [5] Lecture slides: Block A - Multiple joint pain_ Rheumatoid arthritis and the concept of inflammatory arthritis.pdf [6] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Ankylosing spondylitis section, pp. 1699–1710)
Differential Diagnosis of Non-Radiographic Axial Spondyloarthritis (nr-axSpA)
The core clinical challenge of nr-axSpA is that the patient presents with chronic back pain — an extraordinarily common complaint. Approximately 80% of the general population experience back pain at some point in life, and the vast majority (~97%) have mechanical causes [7][8]. The task is to identify the ~3% with a non-mechanical cause, and within that group, to distinguish nr-axSpA from its mimics. Because nr-axSpA has no definitive radiographic finding on plain X-ray (by definition) and CRP can be normal, the differential diagnosis relies heavily on pattern recognition from history, examination, and judicious investigation.
The differential diagnosis can be conceptualised in two layers:
- Broad differential of chronic back pain — separating inflammatory from mechanical and other causes.
- Focused differential within the SpA/inflammatory back pain category — distinguishing nr-axSpA from other causes of inflammatory back pain and sacroiliitis.
A. Broad Differential Diagnosis of Chronic Back Pain in a Young Patient
This is the first-pass differential when any patient < 45 years presents with chronic low back pain. The key step is to separate inflammatory from mechanical from sinister causes [7][8].
| Condition | Why It Can Mimic nr-axSpA | Key Distinguishing Features |
|---|---|---|
| Non-specific mechanical low back pain / back sprain (> 70% of all back pain) | Very common in young adults; can be chronic | Worsens with activity, improves with rest; no morning stiffness > 30 min; no night pain; no systemic features; no response to NSAIDs characteristic of IBP [4][5] |
| Lumbar disc degeneration / spondylosis | Can cause chronic back pain, stiffness | Pain worsened by loading; usually older age (> 40); Schmorl's nodes or disc height loss on imaging; no SIJ involvement; no HLA-B27 association [8] |
| Lumbar disc herniation | Acute-on-chronic back pain with radiculopathy | Radicular pain (dermatomal distribution), positive straight-leg raise, neurological deficit in specific root distribution; pain worse with sitting/Valsalva; MRI shows disc protrusion compressing nerve root [7][8] |
| Spondylolysis / spondylolisthesis | Back pain in young active individuals (especially athletes) | Pain worse with hyperextension; pars interarticularis defect on oblique XR or CT; no inflammatory markers; no SIJ involvement [7][8] |
| Muscle / ligamentous strain | Very common in young adults | Clear history of trauma or overexertion; localised tenderness over paraspinal muscles; resolves with rest/physiotherapy; no systemic features |
| Vertebral compression fracture | Acute/subacute back pain | Usually in osteoporotic patients (elderly, steroid use) or after trauma; wedge/crush deformity on XR; acute onset; no inflammatory pattern [8] |
GC Lecture High Yield — Mechanical vs. Non-Mechanical Back Pain
From the orthopaedic lecture slides [8]:
- Mechanical pain accounts for ~97% of back pain
- Non-mechanical pain (~3%) includes: neoplasia, inflammatory arthritis (AS/spondyloarthropathy), infection, and non-spinal diseases (e.g., PID, endometriosis, nephrolithiasis, aortic aneurysm)
- Always screen for red flags to exclude serious pathology before attributing pain to a benign cause.
These must be actively excluded — they are uncommon but carry high morbidity if missed.
| Condition | Why It Can Mimic nr-axSpA | Key Distinguishing Features |
|---|---|---|
| Spinal infection (discitis, vertebral osteomyelitis, epidural abscess) | Inflammatory markers elevated; night pain; spinal tenderness | Fever, malaise, immunosuppression, IVDU history; focal neurological deficit if abscess; MRI shows disc/vertebral body/epidural enhancement; blood cultures positive [7][8][9] |
| Spinal neoplasia (primary bone tumour or metastasis) | Progressive pain, night pain, weight loss | Persistent pain unrelieved by any position; weight loss; age > 50 or < 20 with bone tumour (e.g., osteoid osteoma); history of primary malignancy (lung, breast, prostate, kidney, thyroid); raised ALP; lytic/blastic lesions on imaging [7][8][9] |
| Cauda equina syndrome | Back pain + bilateral leg symptoms | Saddle anaesthesia, urinary retention/incontinence, faecal incontinence, bilateral leg weakness/numbness — a neurosurgical emergency requiring urgent MRI and decompression [7][8] |
Red Flags for Back Pain
In any patient with chronic back pain, screen for red flags before considering inflammatory/mechanical causes [7][8][9]:
- Age < 5 or > 50 with new-onset back pain
- Fever, night sweats, immunosuppression → infection
- Unexplained weight loss, history of malignancy → neoplasia
- Night pain not improving with movement (cf. nr-axSpA night pain DOES improve on getting up)
- Neurological deficit: weakness, sensory loss, bowel/bladder dysfunction → cord/cauda equina compression
- Trauma + pain → fracture
Red flag night pain from malignancy is constant and progressive regardless of position, unlike axSpA night pain which improves upon getting up and moving.
These are easily forgotten but important — pain is referred to the back from visceral structures:
| Condition | Clue |
|---|---|
| Nephrolithiasis / pyelonephritis | Colicky flank pain radiating to groin; dysuria, haematuria; CVA tenderness |
| Aortic aneurysm | Pulsatile abdominal mass; tearing pain radiating to back; cardiovascular risk factors |
| Endometriosis / pelvic inflammatory disease | Cyclical back pain; gynaecological symptoms |
| Pancreatitis | Epigastric pain radiating to back; worse after meals; raised amylase/lipase |
B. Focused Differential Within the Inflammatory Back Pain / SpA Category
Once you have established that the back pain is inflammatory in nature (IBP criteria met) and are considering axSpA, the differential narrows to conditions that cause inflammatory back pain and/or sacroiliitis [1][2][4][6].
All SpA subtypes share overlapping features (HLA-B27 association, enthesitis, sacroiliitis). The key is to identify distinguishing clinical features that point towards a specific subtype.
| SpA Subtype | Distinguishing Features from nr-axSpA | Key Investigation Clue |
|---|---|---|
| Ankylosing spondylitis (r-axSpA) | Same disease spectrum as nr-axSpA but WITH definite sacroiliitis on plain XR (≥ grade II bilateral or grade III–IV unilateral) | Plain XR SIJ: sclerosis, erosion, narrowing, or ankylosis [1][2][6] |
| Psoriatic arthritis (PsA) with axial involvement | Psoriasis (check hidden areas: scalp, umbilicus, natal cleft, ears); nail dystrophy (pitting, onycholysis, ridging); DIP joint involvement; dactylitis common; asymmetric sacroiliitis on imaging; pencil-in-cup deformity on XR [1][2][4][6] | RF -ve, anti-CCP -ve; asymmetric syndesmophytes [2] |
| Reactive arthritis (ReA) | History of preceding infection (1–4 weeks prior): urogenital (Chlamydia trachomatis — urethritis) or enteric (Salmonella, Shigella, Campylobacter, Yersinia — diarrhoea); classic triad: arthritis + urethritis + conjunctivitis; circinate balanitis, keratoderma blennorrhagica; predominantly young men (M:F ≈ 15:1) [1][2][6] | Stool culture; urine/genital PCR for Chlamydia; HLA-B27 in 60–80%; asymmetric syndesmophytes [2][6] |
| Enteropathic / IBD-associated SpA | History of Crohn's disease or ulcerative colitis (chronic diarrhoea, bloody stool, abdominal pain); erythema nodosum, pyoderma gangrenosum; peripheral arthritis usually correlates with IBD activity; axial disease is independent of gut activity | Endoscopy + biopsy for IBD; symmetric sacroiliitis but rarely erosive [1][2] |
GC Lecture High Yield — Clinical Features of Different Arthritis
From GC 074 Multiple joint pain lecture slides [4]:
Spondyloarthritis key distinguishing history features:
- Younger age
- Insidious onset
- Mono or polyarthritis
- Any joint could be involved
- Psoriasis, IBD, STD/dysentery, uveitis
- Back pain
- Family history
Compare with Rheumatoid Arthritis: polyarthritis, small hand joints, sparing DIP joints, early morning stiffness ≥ 30 min [4]. Compare with Osteoarthritis: DIP joints or weight-bearing joints, older age, insidious onset [4]. Compare with Gout: acute onset, first MTP joint, usually self-limiting, sometimes fever [4].
| Feature | nr-axSpA | RA |
|---|---|---|
| Joint pattern | Asymmetric oligoarthritis, LL > UL, axial (SIJ, spine) [2][4] | Symmetric polyarthritis, small hand joints (MCP, PIP, wrist), spares DIP [4][6] |
| Sex | M:F ≈ 1:1 | M:F = 1:3 [6] |
| Serology | RF -ve, anti-CCP -ve [1][2] | RF +ve, anti-CCP +ve (majority) [6] |
| HLA association | HLA-B27 [2] | HLA-DR4 |
| Enthesitis | Prominent [1][2] | Not a typical feature |
| Morning stiffness | > 30 min (axial) | ≥ 30 min (peripheral) [4] |
| Radiographic changes | Sacroiliitis, syndesmophytes | Erosions, periarticular osteopenia, joint space narrowing [6] |
| Extra-articular | Anterior uveitis, aortitis, apical fibrosis | Rheumatoid nodules, scleritis, ILD, Felty's syndrome [6] |
Why is the distinction important? Treatment pathways differ — DMARDs (methotrexate, sulfasalazine) are effective for RA and peripheral SpA but have NO proven efficacy for axial SpA [1]. Biologics chosen also differ (anti-IL17 for SpA vs. anti-IL6/rituximab for RA).
| Feature | nr-axSpA | OA Spine |
|---|---|---|
| Age | < 45 years | Older age (> 50) [4] |
| Pain pattern | Inflammatory (improves with exercise, worse with rest) | Mechanical (worse with activity, improves with rest) |
| Morning stiffness | > 30 min | < 30 min |
| Joints affected | SIJ, spine | DIP joints (Heberden's nodes), weight-bearing joints [4][6] |
| Inflammatory markers | CRP/ESR may be elevated | Normal |
| HLA-B27 | Frequently positive | Not associated |
| Imaging | MRI bone marrow oedema at SIJ | Osteophytes, disc space narrowing, facet joint hypertrophy |
| Feature | DISH | nr-axSpA |
|---|---|---|
| Age | > 50, often in metabolic syndrome / T2DM | < 45 |
| Pathology | Non-inflammatory enthesopathy — flowing anterior longitudinal ligament calcification | Inflammatory enthesitis |
| Stiffness | Present but not inflammatory pattern | Inflammatory morning stiffness |
| SIJ | Spared — this is the key distinguishing feature | Involved |
| Imaging | Flowing calcification/ossification along ≥ 4 contiguous vertebral bodies on the anterolateral aspect; SIJ and facet joints are preserved | MRI sacroiliitis; no flowing ossification |
| Inflammatory markers | Normal | May be elevated |
| Feature | Fibromyalgia | nr-axSpA |
|---|---|---|
| Pain | Widespread, diffuse; tender points in characteristic locations | Localised to axial skeleton + entheses; specific inflammatory pattern |
| Morning stiffness | May be present but not truly inflammatory | > 30 min, improves with exercise |
| Fatigue | Prominent | Can be present |
| Inflammatory markers | Normal | May be elevated |
| Imaging | Normal MRI and XR | MRI sacroiliitis in imaging arm |
| HLA-B27 | Not associated | Frequently positive |
| Coexistence | Can coexist with axSpA (complicating assessment) | — |
Clinical pearl: Fibromyalgia and axSpA can coexist, and patients with axSpA who also have fibromyalgia report higher BASDAI scores (because BASDAI is patient-reported). This can lead to inappropriate escalation of biologics if the fibromyalgia component is not recognised.
| Condition | Key Differentiating Points |
|---|---|
| Osteitis condensans ilii | Dense sclerosis on the iliac side of SIJ (triangular); typically in young parous women; no erosion; no inflammatory markers; asymptomatic or mild pain; SIJ joint space is preserved |
| Septic sacroiliitis | Unilateral, acute onset; fever, leukocytosis; usually in IVDU or immunocompromised; MRI shows joint effusion and periarticular abscess; blood/joint cultures positive |
| Sarcoidosis | Can cause sacroiliitis and axial disease; look for bilateral hilar lymphadenopathy, erythema nodosum, raised ACE level; non-caseating granulomas on biopsy |
| Behçet's disease | Recurrent oral and genital ulcers, pathergy, uveitis (posterior, unlike SpA which is anterior); can cause sacroiliitis but predominantly a vasculitis |
| SLE-associated arthritis | Typically non-deforming, non-erosive; symmetrical small joint involvement; migratory pattern; morning stiffness usually in minutes (less prolonged than RA or SpA); ANA and anti-dsDNA positive [6][10] |
| Differential | Key Distinguishing Feature(s) from nr-axSpA |
|---|---|
| Ankylosing spondylitis (r-axSpA) | Definite sacroiliitis on plain XR |
| Psoriatic arthritis | Psoriasis, nail changes, DIP involvement, pencil-in-cup deformity |
| Reactive arthritis | Preceding infection (urogenital/enteric), conjunctivitis, circinate balanitis |
| IBD-associated SpA | Known Crohn's/UC; erythema nodosum, pyoderma gangrenosum |
| Rheumatoid arthritis | Symmetric polyarthritis, MCP/PIP/wrist, RF+, anti-CCP+, spares DIP |
| Osteoarthritis of spine | Older age, mechanical pain pattern, DIP nodes, no SIJ disease |
| Mechanical back pain | Worsens with activity, improves with rest, no morning stiffness > 30 min |
| DISH | Older, flowing ossification ≥ 4 vertebrae, SIJ spared |
| Fibromyalgia | Widespread tender points, normal imaging and labs, no SIJ disease |
| Spinal infection | Fever, focal tenderness, raised WCC, MRI enhancement, cultures positive |
| Spinal malignancy | Progressive pain unrelieved by position, weight loss, lytic/blastic lesions |
| Osteitis condensans ilii | Triangular iliac sclerosis, preserved joint space, young parous women |
| SLE | Non-deforming, ANA+, anti-dsDNA+, multisystem involvement |
When you see a young patient with chronic back pain, think through these steps systematically:
Step 1: Is this inflammatory or mechanical?
- Apply the 5 IBP criteria (age < 40, insidious, improves with exercise, no improvement with rest, night pain improving on getting up). If ≥ 4/5 → inflammatory back pain is likely.
- Also check: morning stiffness > 30 min? Good response to NSAIDs? Alternating buttock pain? These all support an inflammatory cause.
Step 2: Exclude red flags
- Fever, weight loss, neurological deficit, history of malignancy, bowel/bladder dysfunction, trauma → refer for urgent investigation.
Step 3: If inflammatory — is this SpA?
- Look for SpA features: enthesitis (heel pain), dactylitis, uveitis, psoriasis, IBD, family history of SpA, HLA-B27, elevated CRP, good NSAID response [1][2][4][6].
- Check for RF and anti-CCP → if positive, think RA instead [4][6].
Step 4: If SpA — is it axial or peripheral predominant?
- Axial predominant (back pain, sacroiliitis) → axSpA.
- Peripheral predominant (arthritis, dactylitis, enthesitis without significant back pain) → peripheral SpA.
Step 5: If axSpA — is it nr-axSpA or AS?
- Plain XR SIJ: if definite sacroiliitis (≥ grade II bilateral or grade III–IV unilateral) → AS (r-axSpA) [1][2].
- If XR normal/equivocal → obtain MRI SIJ: if bone marrow oedema consistent with sacroiliitis → nr-axSpA (imaging arm).
- If MRI also negative → apply clinical arm (HLA-B27 + ≥ 2 other SpA features) → nr-axSpA [1][2].
Step 6: Consider overlap and coexistence
- Psoriasis + axial disease → PsA with axial involvement or concurrent axSpA.
- IBD + sacroiliitis → enteropathic SpA.
- Fibromyalgia may coexist, inflating symptom scores.
High Yield Summary — Differential Diagnosis of nr-axSpA
- The most important first step is distinguishing inflammatory from mechanical back pain using IBP criteria (≥ 4/5: onset < 40, insidious, improves with exercise, no improvement with rest, night pain improving on getting up).
- Mechanical back pain accounts for ~97% of all back pain [8] — always exclude this and red-flag pathology (infection, malignancy, cauda equina) before pursuing an inflammatory diagnosis.
- Within the SpA family, nr-axSpA is distinguished from AS by the absence of definite sacroiliitis on plain XR; from PsA by absence of psoriasis/nail changes/DIP involvement; from ReA by absence of preceding infection; from IBD-SpA by absence of Crohn's/UC.
- RA is excluded by its symmetric polyarthritis pattern (MCP/PIP/wrist, sparing DIP), RF+/anti-CCP+ serology [4][6], and lack of enthesitis/sacroiliitis.
- OA is distinguished by older age, mechanical pain pattern, DIP involvement (Heberden's nodes) [4].
- DISH is distinguished by flowing ossification ≥ 4 vertebrae with SIJ spared, in older patients.
- Fibromyalgia can coexist with axSpA — normal labs and imaging, widespread pain without true inflammatory features.
- Always check for SpA features (11 ASAS features) systematically: IBP, arthritis, enthesitis, uveitis, dactylitis, psoriasis, Crohn's/UC, good NSAID response, family history, HLA-B27, elevated CRP [1][2][6].
Active Recall - Differential Diagnosis of nr-axSpA
References
[1] Senior notes: Maksim Medicine Notes.pdf (Section 13.6 Spondyloarthritides, pp. 321–325) [2] Senior notes: Ryan Ho Rheumatology.pdf (Section 2.7 Spondyloarthritis, pp. 57–58) [4] Lecture slides: GC 074. Multiple joint pain.pdf (p. 4) [6] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Ankylosing spondylitis section pp. 1699–1703; Psoriatic arthritis pp. 1708–1710; Reactive arthritis pp. 1715–1717; RA differential pp. 1677–1679) [7] Senior notes: Maksim Surgery Notes.pdf (Section 2.3 Approach to spine diseases, p. 222–223) [8] Lecture slides: Ortho and Trauma - Spine.pdf (p. 7) [9] Senior notes: Adrian Lui Pediatrics Notes.pdf (Section C: Back Pain, p. 449) [10] Senior notes: Ryan Ho Fundamentals.pdf (Section 3.7.1–3.7.2 Monoarthritis and Polyarthritis, pp. 406–409)
Diagnostic Criteria, Diagnostic Algorithm, and Investigations for nr-axSpA
Plain radiographs are normal by definition in nr-axSpA. Unlike AS, where sacroiliitis on X-ray is the "hallmark" finding, nr-axSpA requires a more nuanced combination of clinical features, laboratory markers, and advanced imaging (MRI). Without a single pathognomonic test, we rely on validated classification criteria that combine multiple pieces of evidence to reach a diagnosis. Understanding these criteria from first principles means understanding what each component adds diagnostically.
A. Diagnostic Criteria
1. ASAS Classification Criteria for Axial Spondyloarthritis (2009)
These are the gold-standard criteria used to classify axSpA (both AS and nr-axSpA). They apply to patients who satisfy the entry criterion [1][2][6]:
Entry criterion: Back pain ≥ 3 months duration AND age of onset < 45 years [1][2][6]
Once the entry criterion is met, the patient can be classified via either of two arms:
Critical Distinction — Imaging Arm vs Clinical Arm
- The imaging arm captures patients with objective imaging evidence of sacroiliitis (either XR or MRI) who also have at least one additional SpA feature. For nr-axSpA specifically, this means MRI sacroiliitis with normal plain XR.
- The clinical arm captures patients who may have no imaging abnormality at all but whose combination of HLA-B27 positivity and multiple SpA features makes axSpA highly likely. This arm is especially important early in the disease course when even MRI may be negative [1].
| # | SpA Feature | Explanation / Why It's Included |
|---|---|---|
| 1 | Inflammatory back pain (IBP) | The cardinal symptom — ≥ 4/5 ASAS IBP criteria (onset < 40, insidious, improves with exercise, no improvement with rest, night pain improving on getting up) |
| 2 | Arthritis | Past/present peripheral synovitis (confirmed by physician); reflects SpA's tendency for asymmetric oligoarthritis |
| 3 | Enthesitis (heel) | Past/present enthesitis, especially Achilles or plantar fascia — the pathological hallmark of SpA |
| 4 | Uveitis | Past/present acute anterior uveitis (confirmed by ophthalmologist) — most common EAM of axSpA |
| 5 | Dactylitis | "Sausage digit" (confirmed by physician) — reflects combined tenosynovitis + joint inflammation |
| 6 | Psoriasis | Past/present psoriasis (confirmed by physician) — links to PsA overlap within SpA family |
| 7 | Crohn's disease / ulcerative colitis | Past/present IBD (confirmed by physician) — links to enteropathic SpA |
| 8 | Good response to NSAIDs | Resolution or major improvement of back pain within 24–48h of full-dose NSAID — highly characteristic of SpA |
| 9 | Family history of SpA | 1st or 2nd degree relative with AS, psoriasis, uveitis, reactive arthritis, or IBD — reflects strong genetic predisposition |
| 10 | HLA-B27 | Positive test — the strongest single genetic risk factor |
| 11 | Elevated CRP | After exclusion of other causes — reflects systemic inflammation (but normal in 40–60% of nr-axSpA) |
GC Lecture High Yield — ASAS Criteria SpA Features
From GC 074 and the Block A lecture on multiple joint pain [4][5]:
SpA features to look for in history: psoriasis, IBD, STD/dysentery, uveitis, back pain, family history [4]. These directly correspond to the 11 ASAS SpA features. In exam settings, systematically list these features when asked about the diagnostic approach to suspected axSpA.
These criteria apply specifically to AS (r-axSpA), NOT to nr-axSpA. They are presented here because understanding what nr-axSpA fails to meet is essential [1][2][6]:
| Radiological Criterion | Clinical Criteria (≥ 1 of 3) |
|---|---|
| Sacroiliitis on plain XR: ≥ grade II bilaterally; or grade III–IV unilaterally [1][2][6] | 1. LBP + stiffness > 3 months, improves with exercise, not relieved by rest |
| 2. Limitation of lumbar spine ROM in sagittal and frontal planes | |
| 3. Limitation of chest expansion relative to age/sex norms |
Definite AS = radiological criterion + ≥ 1 clinical criterion.
nr-axSpA by definition does NOT meet this radiological criterion — the plain XR is normal or shows only grade 0–I changes (equivocal). This is precisely why the ASAS criteria were developed: to capture patients earlier in the disease course before structural X-ray damage appears.
Since MRI is the pivotal investigation that separates nr-axSpA from "no imaging evidence," understanding what constitutes a positive MRI is critical:
ASAS/OMERACT definition: Active inflammatory lesions in the sacroiliac joints on MRI that are clearly present and located in a typical anatomical area (subchondral or periarticular bone marrow). The hallmark lesion is bone marrow oedema (BME) on STIR (Short Tau Inversion Recovery) or T2-weighted fat-saturated sequences, appearing as subchondral hyperintense signal [1][6].
Key points:
- Bone marrow oedema must be present in ≥ 2 sites on a single slice, OR in ≥ 1 site on ≥ 2 consecutive slices — this is the minimum threshold to call it "positive" [6].
- A single small focus of BME alone is insufficient — it can be seen in healthy individuals, especially postpartum women.
- Structural MRI lesions (erosions, fat metaplasia/fatty degeneration, sclerosis, ankylosis) support the diagnosis but are NOT sufficient alone to define active sacroiliitis for the imaging arm — you need BME for active inflammation.
- Gadolinium enhancement (post-contrast T1) can also demonstrate active inflammation (enhancing bone marrow or synovitis) but is not routinely required if STIR sequences are adequate.
MRI Sacroiliitis — What the Radiologist Reports
When requesting MRI SIJ for suspected axSpA, the radiologist looks for:
Active inflammatory lesions (reflecting current disease):
- Bone marrow oedema (BME): high signal on STIR/T2-FS adjacent to the joint surface — the key finding [1][6]
- Capsulitis / enthesitis: enhancement of joint capsule or entheses
- Synovitis: enhancement of the synovial lining of the SIJ
Structural lesions (reflecting past damage):
- Erosions: defects in the subchondral bone plate
- Sclerosis: low signal band adjacent to the joint
- Fat metaplasia / fatty degeneration: high signal on T1 at previous inflammation sites — represents "post-inflammatory" change
- Ankylosis: bridging of the joint space
In nr-axSpA, you typically see active lesions (BME) WITHOUT or with minimal structural damage.
Even though nr-axSpA has a normal or equivocal XR, you must understand the grading system because it defines the boundary between nr-axSpA and AS [1][2][6]:
| Grade | Description | Implication |
|---|---|---|
| 0 | Normal | — |
| I | Suspicious / equivocal changes | NOT sufficient for AS diagnosis |
| II | Minimal abnormality: small localised erosions, sclerosis; no joint space alteration [1] | ≥ Grade II bilateral = meets modified New York criteria |
| III | Unequivocal abnormality: moderate/advanced sacroiliitis with erosions, sclerosis, widening, narrowing, or partial ankylosis [1] | Grade III–IV unilateral also meets criteria |
| IV | Severe abnormality: total ankylosis [1] | End-stage fusion |
Grades 0 and I on plain XR → the patient is in the nr-axSpA category (if ASAS criteria are otherwise met).
The following algorithm represents the systematic approach to diagnosing nr-axSpA in clinical practice:
Algorithm Logic — Why This Order?
- IBP screening first: filters out the ~97% with mechanical pain.
- Bloods early: CRP/ESR for inflammation; HLA-B27 adds diagnostic weight; RF/anti-CCP to exclude RA.
- Plain XR SIJ first: cheap, widely available; if positive → already AS. No need for MRI to classify.
- MRI SIJ if XR negative/equivocal: the crucial step for nr-axSpA — detects active inflammation years before structural XR damage.
- Clinical arm as fallback: if even MRI is negative, HLA-B27 + ≥ 2 SpA features still allows classification.
- Follow-up: patients who don't currently meet criteria may develop features over time — reassess.
C. Investigation Modalities — Detailed Breakdown
1. Laboratory Investigations
| Marker | Findings in nr-axSpA | Interpretation |
|---|---|---|
| CRP | Elevated in ~40–60% of nr-axSpA (cf. ~60–80% in AS) [1] | Reflects systemic inflammation; one of the 11 SpA features. BUT a normal CRP does NOT exclude nr-axSpA — this is a critical point. CRP is more useful for monitoring disease activity (ASDAS score includes CRP) than for initial diagnosis. |
| ESR | May be elevated [1][6] | Less specific than CRP; affected by anaemia, age, sex. Useful as supportive evidence. |
Why can CRP be normal in active nr-axSpA? Because the inflammatory burden in early disease may be localised to the SIJ/entheses with insufficient systemic spillover to raise CRP. Additionally, some patients have a genetically lower CRP response.
| Aspect | Detail |
|---|---|
| Prevalence in axSpA | 80–90% in AS; ~60–70% in nr-axSpA [2] |
| Prevalence in southern Chinese | 6–8% [2] |
| Diagnostic role | Not diagnostic alone — only ~5–6% of HLA-B27-positive individuals develop SpA. However, in the right clinical context (IBP + SpA features), a positive HLA-B27 substantially raises the post-test probability. It is essential for the clinical arm (required) and adds weight to the imaging arm (as one of the 11 SpA features). |
| If HLA-B27 negative | Does NOT exclude axSpA — ~10–20% of AS and ~30–40% of nr-axSpA patients are HLA-B27 negative. However, HLA-B27 negativity makes the clinical arm impossible and should prompt more careful evaluation of imaging and alternative diagnoses. |
| Marker | Expected Result | Why Check? |
|---|---|---|
| RF | Typically negative [1][2] | To exclude RA. SpA is classically "seronegative." However, RF can be positive in ~5% of the general population and occasionally in SpA patients — a positive RF does not automatically mean RA. |
| Anti-CCP | Typically negative [1][2] | More specific for RA than RF. If positive, strongly reconsider RA diagnosis. |
Investigations for SpA: Bloods: CBC, CRP/ESR, HLA-B27, RF (-ve). Imaging: XR, MRI [1]
| Finding | Explanation |
|---|---|
| Anaemia of chronic disease | Normocytic normochromic anaemia from chronic inflammation (hepcidin-mediated iron sequestration) — seen in longstanding disease [6] |
| Leukocytosis | Non-specific inflammatory response [6] |
| Thrombocytosis | Reactive thrombocytosis from chronic inflammation (IL-6 drives megakaryocyte proliferation) |
| Test | Purpose |
|---|---|
| Serum urate | Exclude gout (if peripheral joint symptoms present) |
| ANA | Exclude SLE (if multisystem features) |
| Liver function tests | Baseline before starting NSAIDs or DMARDs |
| Renal function tests | Baseline; NSAID nephrotoxicity monitoring |
| Stool culture / Chlamydia PCR | If reactive arthritis is in the differential (preceding diarrhoea or urogenital symptoms) [6] |
2. Imaging Investigations
This is always the first-line imaging investigation — cheap, widely available, and classifies AS if positive.
| Finding | Grade | Significance |
|---|---|---|
| Normal | 0 | Does not exclude axSpA → proceed to MRI |
| Equivocal/suspicious | I | Does not meet criteria → proceed to MRI |
| Sclerosis + no joint space narrowing | II | Meets modified New York criteria if bilateral [1] → AS |
| Sclerosis + narrowed joint space ± erosions ± partial ankylosis | III | Meets criteria unilaterally or bilaterally [1] → AS |
| Total ankylosis | IV | Complete SIJ fusion [1] → late AS |
In nr-axSpA: plain XR is normal or grade 0–I. This is the defining feature.
While spinal changes are not expected in nr-axSpA (they develop in established AS), understanding them is important for recognising progression and for exam purposes:
| Finding | Description | Pathophysiology |
|---|---|---|
| Romanus lesion ("shiny corners") | Squaring of vertebral body with reactive sclerosis at endplates [1][6] | Inflammatory erosions at discovertebral junction → reactive sclerosis = "shiny corner" sign [1] |
| Syndesmophytes | Bony bridges between vertebral bodies [1] | Ossification of the outer fibres of the annulus fibrosus (enthesitis → new bone formation via Wnt pathway) |
| Bamboo spine | Complete fusion of spine with bilateral syndesmophytes [1][6] | End-stage radiographic progression [6] — "bamboo" because the fused spine looks like a bamboo stalk |
| Anderson lesion | Erosion at discovertebral junction [1] | Inflammatory destruction ± pseudarthrosis at a previously fused segment |
| Calcification of anterior longitudinal ligament | Flowing ossification along anterior spine [6] | Enthesitis at ligamentous attachment to vertebral body |
In nr-axSpA, spinal XR is typically normal. These findings are listed for completeness and progression monitoring.
MRI is the single most important investigation for diagnosing nr-axSpA because it detects active inflammation years before structural changes appear on plain XR.
Protocol: MRI should include:
- STIR (Short Tau Inversion Recovery) or T2-weighted fat-saturated sequences — to detect bone marrow oedema (high signal = water/oedema)
- T1-weighted sequences — to assess structural changes (erosions appear as cortical defects; fat metaplasia appears as high T1 signal)
| MRI Finding | Sequence | Significance |
|---|---|---|
| Bone marrow oedema (BME) | High signal on STIR/T2-FS [1][6] | Most characteristic change of active sacroiliitis [6]. Reflects active inflammation with increased water content in subchondral bone. Must be in typical anatomical area (subchondral/periarticular). |
| Synovitis | Post-contrast T1 enhancement | Enhancing synovial tissue within the SIJ cavity |
| Capsulitis / enthesitis | Post-contrast T1 enhancement | Inflammation of the joint capsule and ligamentous attachments |
| Erosions | Low signal defects on T1 at joint surface | Early structural damage — cortical bone destruction |
| Fat metaplasia / fatty degeneration | High signal on T1 at subchondral bone [6] | Post-inflammatory change — represents healing/scarring at sites of previous BME. Supports chronicity. |
| Sclerosis | Low signal on all sequences | Reactive bone formation — late structural change |
| Ankylosis | Bridging of joint space | Late finding = progression towards AS |
High Yield — ASAS Positive MRI Sacroiliitis Definition
Bone marrow oedema must be present in ≥ 2 locations on a single MRI slice, OR in ≥ 1 location on ≥ 2 consecutive slices to qualify as positive sacroiliitis on MRI for the ASAS imaging arm.
A single small focus of BME alone is NOT sufficient — this avoids false positives from mechanical stress, postpartum changes, or degenerative disease.
Structural changes (erosions, fat metaplasia, sclerosis) support the diagnosis but are not sufficient alone to satisfy the imaging arm — active BME is required.
| Finding | Significance |
|---|---|
| Corner inflammatory lesions (CILs) | BME at vertebral corners — the MRI equivalent of the Romanus lesion; indicates active spondylitis |
| Fatty Romanus lesion | Fat metaplasia at vertebral corners on T1 — indicates prior inflammation (post-inflammatory) |
| Spondylodiscitis | Inflammation at the disc-vertebral interface |
Spinal MRI is NOT required for ASAS classification but may be performed if spinal symptoms are prominent or to assess disease extent.
| Application | Utility |
|---|---|
| Detection and assessment of enthesitis (e.g., Achilles tendonitis, plantar fasciitis) [6] | US with Power Doppler can demonstrate thickening of the tendon insertion, hypoechogenicity, erosion at the enthesis, and increased vascularity (active inflammation). Useful for confirming enthesitis clinically. |
| Peripheral joint synovitis | Can detect effusion and synovial hypertrophy in peripheral joints |
| Application | Rationale |
|---|---|
| Baseline assessment for osteopenia/osteoporosis [1] | Chronic inflammation → increased osteoclast activity → bone loss. Patients with axSpA have increased fracture risk (especially vertebral fractures in ankylosed spines). Paradoxically, spinal DEXA can overestimate BMD in advanced AS due to syndesmophytes, so femoral neck DEXA is more reliable. |
| Application | When Used |
|---|---|
| Better delineation of structural changes (erosions, sclerosis, ankylosis) | If XR is equivocal and MRI is contraindicated (e.g., pacemaker). CT shows structural damage but cannot detect BME/active inflammation — this limits its utility in nr-axSpA. |
D. Disease Activity Assessment Instruments
These are not "diagnostic" per se but are integral to the diagnostic workup because they quantify disease burden and guide treatment decisions:
| Aspect | Detail |
|---|---|
| What it measures | Patient-reported questionnaire across 6 domains: fatigue, spinal pain, peripheral joint pain/swelling, enthesitis tenderness, morning stiffness severity, morning stiffness duration |
| Scoring | 0–10 scale; total score ≥ 4/10 indicates active disease [6] |
| Calculation | Mean of Q5–Q6 (morning stiffness questions) + sum of Q1–Q4, then divide by 5 [6] |
| ASAS 50 response | BASDAI decrease of ≥ 50% [1] — used to assess treatment response |
| Aspect | Detail |
|---|---|
| Advantage over BASDAI | Incorporates CRP (objective marker), making it more reliable than purely patient-reported BASDAI |
| Cut-offs | Inactive: < 1.3; Low: 1.3–2.1; High: 2.1–3.5; Very high: > 3.5 |
| Clinically important improvement | ASDAS decrease ≥ 1.1 |
| Major improvement | ASDAS decrease ≥ 2.0 |
| Investigation | What It Shows | Role in nr-axSpA Diagnosis |
|---|---|---|
| CRP/ESR | Systemic inflammation | Supportive (SpA feature); may be normal |
| HLA-B27 | Genetic predisposition | Essential for clinical arm; supportive for imaging arm |
| RF, anti-CCP | Autoantibodies | Should be negative — to exclude RA |
| CBC | Anaemia, leukocytosis | Supportive; baseline |
| Plain XR SIJ | Structural sacroiliitis | Must be normal/equivocal for nr-axSpA (otherwise = AS) |
| MRI SIJ | Active inflammation (BME) | Key investigation — positive MRI satisfies imaging arm |
| Plain XR spine | Structural spinal changes | Usually normal in nr-axSpA; for progression monitoring |
| USG | Enthesitis, synovitis | Confirms peripheral features |
| DEXA | Bone mineral density | Baseline for osteoporosis assessment |
| BASDAI/ASDAS | Disease activity | Guides treatment decisions |
High Yield Summary — Diagnosis of nr-axSpA
- ASAS classification criteria for axSpA require chronic back pain ≥ 3 months with onset < 45 years, then either: Imaging arm (sacroiliitis on imaging + ≥ 1 SpA feature) OR Clinical arm (HLA-B27 + ≥ 2 other SpA features) [1][2][6].
- In nr-axSpA, plain XR SIJ is normal or equivocal (grade 0–I) — this is what makes it "non-radiographic."
- MRI SIJ is the pivotal investigation: look for bone marrow oedema (BME) on STIR/T2-FS sequences — the most characteristic change of active sacroiliitis [1][6]. Must be in ≥ 2 locations on one slice or ≥ 1 location on ≥ 2 consecutive slices.
- HLA-B27 is essential for the clinical arm and a strong supportive feature; prevalence in southern Chinese is 6–8% [2].
- RF and anti-CCP should be negative — positive results point towards RA [1][2].
- CRP may be normal in 40–60% of nr-axSpA — a normal CRP does NOT exclude the diagnosis.
- BASDAI ≥ 4/10 = active disease [1][6]; ASDAS (incorporating CRP) is more objective.
- Key XR spine findings (for AS/progression): Romanus lesion (shiny corners), syndesmophytes, bamboo spine, Anderson lesion [1][6].
- Investigations: CBC, CRP/ESR, HLA-B27, RF (-ve), anti-CCP (-ve); Imaging: XR, MRI [1].
- DEXA scan for baseline osteopenia assessment [1]; USG for enthesitis assessment [6].
Active Recall - Diagnostic Criteria, Algorithm, and Investigations for nr-axSpA
References
[1] Senior notes: Maksim Medicine Notes.pdf (Section 13.6 Spondyloarthritides, pp. 321–325) [2] Senior notes: Ryan Ho Rheumatology.pdf (Section 2.7 Spondyloarthritis, pp. 57–58) [4] Lecture slides: GC 074. Multiple joint pain.pdf (p. 4) [5] Lecture slides: Block A - Multiple joint pain_ Rheumatoid arthritis and the concept of inflammatory arthritis.pdf [6] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (AS diagnosis pp. 1701–1706; PsA pp. 1708–1713) [10] Senior notes: Ryan Ho Fundamentals.pdf (Section 3.7 Rheumatological System, pp. 406–410) [11] Senior notes: Ryan Ho Ophthalmology.pdf (Section 2.5 Uveitis, p. 31)
Management of Non-Radiographic Axial Spondyloarthritis (nr-axSpA)
The management of nr-axSpA follows the same principles as axSpA broadly. The key concepts to grasp are:
- There is no cure — nr-axSpA is a chronic inflammatory disease. The goals are to control symptoms, suppress inflammation, prevent structural progression, and maintain function.
- Axial disease and peripheral disease respond to different treatments — this is the single most important pharmacological principle in SpA management. No proven effective conventional DMARD exists for axial disease [1]. DMARDs (methotrexate, sulfasalazine) work for peripheral joints only. Axial disease responds to NSAIDs and biologics/targeted therapies.
- Treatment is stepped — escalation from non-pharmacological measures → NSAIDs → biologics/targeted therapy, based on disease activity assessment (BASDAI/ASDAS).
- Treat the whole patient — extra-articular manifestations (uveitis, IBD, psoriasis) may require specific additional treatments and influence biologic choice.
GC Lecture High Yield — Key Management Principles
From the Block A lecture on multiple joint pain and the concept of spondyloarthritis [5]:
The management approach for SpA emphasises:
These measures are the foundation of treatment and should be instituted in every patient regardless of disease severity.
| Intervention | Rationale / Mechanism | Details |
|---|---|---|
| Patient education [2] | Empowers patients to self-manage; improves adherence; reduces anxiety about chronic disease | Explain nature of disease, prognosis, importance of exercise, medication rationale |
| Stretching exercise and physiotherapy [1][2] | Exercise maintains spinal mobility, prevents stiffness and deformity; counteracts the natural tendency of the disease to cause fusion in a kyphotic posture | Swimming is especially recommended [1] — buoyancy offloads joints while allowing full spinal ROM. Daily stretching, extension exercises, and breathing exercises are critical. |
| Posture education [1] | Prevents fixed kyphotic deformity; maintains functional posture | Firm mattress, sleeping supine without a pillow (or with a thin pillow), maintaining erect posture during daily activities |
| Smoking cessation [1][2] | Reduces burden to restrictive lungs [1]; smoking accelerates structural progression, increases CRP, worsens disease activity, and reduces treatment response | Offer smoking cessation support (NRT, varenicline, counselling) |
| Psychological support | Chronic pain and fatigue cause significant psychological burden; depression and anxiety are common comorbidities | Screen for mood disorders; CBT; peer support groups |
Why Is Exercise So Important in axSpA?
Unlike most musculoskeletal conditions where rest helps, in axSpA, immobility is the enemy. The disease process tends to ankylose (fuse) joints in the position they are held in. If a patient remains sedentary with a flexed thoracic spine, fusion occurs in kyphosis → fixed "question mark posture." Regular extension exercises and maintaining an upright posture ensure that if fusion does occur, it happens in a functional position.
Swimming is ideal because it provides:
- Full ROM of spine and peripheral joints
- Chest expansion (counteracts costovertebral restriction)
- Low impact on joints
- Cardiovascular fitness without excessive mechanical stress
B. Pharmacological Management
| Aspect | Detail |
|---|---|
| Indication | First-line in ALL symptomatic axSpA (including nr-axSpA) [1][2]; often the only medication required in mild–moderate disease |
| Efficacy | ~70–80% of patients report substantial relief of back pain and stiffness [2] |
| Mechanism | NSAIDs inhibit cyclooxygenase (COX) enzymes → reduce prostaglandin synthesis → decrease inflammation, pain, and stiffness at entheseal and synovial sites |
| Continuous vs on-demand use | Continuous treatment may slow radiographic progression [1] (modest disease-modifying effect even when asymptomatic). However, this benefit must be weighed against long-term side-effect risk. Current guidelines (ASAS-EULAR 2023) recommend continuous use if symptoms require it, but on-demand use is acceptable if disease is well controlled. |
| Good response to NSAIDs | One of the 11 ASAS SpA features — resolution or major improvement within 24–48 hours of full-dose NSAID is characteristic of SpA and supports the diagnosis |
Commonly used NSAIDs [2]:
| Drug | Dose | Notes |
|---|---|---|
| Naproxen | 500 mg BD | Long-acting; relatively lower CV risk among non-selective NSAIDs |
| Ibuprofen | 800 mg TDS | Short-acting; widely available |
| Diclofenac | 50 mg TDS or 75 mg BD | Effective but higher CV risk |
| Celecoxib (COX-2 selective) | 200 mg BD | Recommended if the patient has a known pre-existing GI risk factor [12]; lower GI side effects but similar CV risk |
| Etoricoxib (COX-2 selective) | 60–90 mg OD | Once-daily dosing; potent |
Side effects and mitigation:
| Side Effect | Mechanism | Mitigation |
|---|---|---|
| GI (peptic ulcer, GI bleeding) | COX-1 inhibition → reduced mucosal-protective prostaglandins (PGE2) → gastric mucosal damage | Co-prescribe PPI (e.g., omeprazole 20 mg OD) in patients with GI risk factors (age > 65, prior GI bleed, H. pylori, concurrent anticoagulant/corticosteroid/antiplatelet use) [12]. Or use COX-2 selective inhibitor [1][12]. |
| Renal (AKI, CKD progression) | COX-2 inhibition → reduced renal prostaglandin-mediated afferent arteriolar vasodilation → ↓GFR | Monitor RFT; avoid in eGFR < 30; use lowest effective dose; adequate hydration |
| Cardiovascular (MI, stroke) | COX-2 inhibition → ↓endothelial prostacyclin (PGI2) → prothrombotic imbalance | Assess CV risk; naproxen may have lowest CV risk; avoid in established CVD if possible |
| Hepatic | Idiosyncratic hepatotoxicity | Monitor LFTs periodically |
High Yield — NSAIDs Are the Cornerstone
NO proven effective DMARD for axial disease [1]
This is a critical exam point. Let's understand why:
- Methotrexate, sulfasalazine, and leflunomide work by modulating adaptive immunity (T/B cell proliferation, cytokine production) and are effective in synovitis-driven diseases (RA, peripheral SpA).
- Axial SpA pathology is primarily enthesitis-driven with inflammation deeply seated in subchondral bone and at entheseal sites. These tissues have different immunological microenvironments (dominated by innate immune cells, IL-23/IL-17 axis, and TNF-α) that are less responsive to conventional DMARDs.
- Multiple randomised controlled trials have shown methotrexate and sulfasalazine have no significant benefit for axial symptoms in SpA.
| cDMARD | Role in SpA |
|---|---|
| Sulfasalazine | Only for peripheral joints [1][2]; preferred in non-psoriatic SpA and IBD-associated SpA. Dose: 2–3 g/day. |
| Methotrexate | Only for peripheral joints [1][2]; preferred in PsA (co-treats skin psoriasis). Dose: up to 25 mg weekly. |
| Leflunomide | Only for peripheral joints. Dose: 20 mg daily. |
| Local steroid injection | Only for peripheral joints, enthesitis (except Achilles tendon — risk of rupture), dactylitis [1][2] |
Must Know
Avoid intra-articular/intra-tendinous steroid injection in the Achilles tendon: risk of tendon rupture [1][2]. This is because corticosteroids inhibit collagen synthesis and weaken the already inflamed tendon, predisposing to catastrophic rupture. Instead, use peri-tendinous injection or systemic therapy.
Step 2: Biologic Therapy — Second-Line for Axial Disease
Biologics are indicated when NSAIDs fail. The threshold for escalation:
Persistent high disease activity (BASDAI ≥ 4 or ASDAS ≥ 2.1) despite adequate trial of ≥ 2 NSAIDs, each for ≥ 1 month (some guidelines say ≥ 2 months each), unless contraindicated [1][2]
The two main biologic classes for axial SpA are anti-TNFα and anti-IL-17A. JAK inhibitors have also been approved.
TNF-α is a key pro-inflammatory cytokine in SpA pathogenesis — it drives osteoclast activation (bone erosion), entheseal inflammation, and systemic inflammatory response.
| Drug | Route / Dose | Mechanism |
|---|---|---|
| Etanercept | 50 mg SC weekly [2] | Soluble TNF receptor fusion protein — acts as a "decoy receptor" that binds circulating TNF-α before it can bind cellular TNF receptors |
| Infliximab | 5 mg/kg IV at 0, 2, 6 weeks (induction), then Q8 weeks (maintenance) [13] | Chimeric (mouse/human) monoclonal antibody against TNF-α — binds both soluble and membrane-bound TNF-α |
| Adalimumab | 40 mg SC every 2 weeks [13] | Fully humanised monoclonal antibody against TNF-α |
| Golimumab | 50 mg SC monthly | Fully human monoclonal antibody against TNF-α |
| Certolizumab pegol | 200 mg SC every 2 weeks (after loading) | PEGylated Fab' fragment of humanised anti-TNF antibody; no Fc region → lower risk of placental transfer (preferred in pregnancy) |
Key points on anti-TNFα:
IL-17A is produced by Th17 cells, γδ T cells, and ILC3s at entheseal sites. It drives both inflammation and new bone formation via the Wnt pathway.
| Drug | Route / Dose | Mechanism |
|---|---|---|
| Secukinumab | 150 mg SC (loading at weeks 0, 1, 2, 3, 4; then monthly maintenance) [1] | Fully human monoclonal antibody against IL-17A |
| Ixekizumab | 80 mg SC (loading, then Q4 weeks) | Humanised monoclonal antibody against IL-17A |
Anti-IL-17A vs anti-TNFα — when to prefer which?
| Scenario | Preferred Agent | Reason |
|---|---|---|
| Concomitant IBD | Anti-TNFα (infliximab or adalimumab preferred over etanercept) [2] | Anti-IL-17A can paradoxically worsen IBD (IL-17 has a protective role in gut mucosal immunity). Etanercept is also less effective for IBD than infliximab/adalimumab. |
| Concomitant psoriasis | Either anti-TNFα or anti-IL-17A | Both are effective for skin psoriasis. Anti-IL-17A has particularly high skin clearance rates. |
| Concomitant uveitis | Anti-TNFα (infliximab or adalimumab) [2] | Etanercept is less effective for uveitis [2]; anti-IL-17A has limited evidence for uveitis prevention |
| Latent TB concern | Anti-IL-17A may be safer | Anti-TNFα carries higher TB reactivation risk (TNF-α is critical for granuloma maintenance in latent TB) |
| Demyelinating disease | Anti-IL-17A | Anti-TNFα is contraindicated in demyelinating disease |
JAK inhibitors are oral small molecules (not technically "biologics" but targeted therapies) that block intracellular signalling downstream of multiple cytokine receptors.
| Drug | Route / Dose | Mechanism |
|---|---|---|
| Tofacitinib | 5 mg PO BD | Preferential JAK1/JAK3 inhibitor |
| Upadacitinib | 15 mg PO OD | Selective JAK1 inhibitor — approved for axSpA (both AS and nr-axSpA) |
Advantages: oral administration; rapid onset of action. Risks: herpes zoster reactivation, thromboembolic events [14], infection, cytopenias, lipid elevation, potential malignancy risk (from post-marketing surveillance of tofacitinib in RA).
What Does NOT Work for Axial SpA?
Anti-IL-1 and anti-IL-6 agents are NOT useful for SpA [1] (cf. RA, where anti-IL-6 [tocilizumab] is very effective). This is because the IL-1 and IL-6 pathways, while important in RA synovitis, are not the dominant pathogenic pathways in enthesitis-driven axSpA. The IL-23/IL-17 and TNF-α pathways are the key targets.
Systemic corticosteroids have a very limited role in axSpA — they do not provide sustained benefit for axial symptoms and carry significant long-term side effects. They should NOT be used routinely for axial disease. Short courses may be used as bridging therapy for severe peripheral arthritis while awaiting DMARD onset of action, but with caution in psoriasis (risk of rebound flare upon tapering) [2].
Before starting any biologic, screening for infections is mandatory:
| Screening Test | Purpose | Action If Positive |
|---|---|---|
| CXR + QuantiFERON-TB Gold (or tuberculin skin test) [13] | Screen for latent TB | TB prophylaxis with isoniazid (9 months) or rifampicin (4 months) before or concurrent with biologic initiation [13] |
| HBsAg, anti-HBc, anti-HBs [13] | Screen for HBV infection | HBV prophylaxis with entecavir [13] if HBsAg positive or anti-HBc positive (risk of reactivation under immunosuppression) |
| Anti-HCV | Screen for HCV | Treat HCV before or during biologic if active infection |
| HIV test | Screen for HIV | Manage accordingly; biologics can be used with caution in well-controlled HIV |
| Hepatitis B/C serology, LFTs, CBC, RFT | Baseline safety bloods | Identify contraindications (cytopenias, liver disease, renal impairment) |
| Varicella serostatus | Risk of VZV reactivation (especially with JAK inhibitors) | Consider vaccination if seronegative BEFORE starting immunosuppression |
High Yield — Anti-TNFα Contraindications
Contraindications to anti-TNFα agents [2][13]:
- Active infection (including active TB)
- Latent untreated TB (must treat first)
- Demyelinating disease (e.g., multiple sclerosis, optic neuritis) — TNFα inhibition can worsen demyelination
- Heart failure NYHA Class III–IV — TNFα is involved in cardiac remodelling; inhibition can worsen HF
- Active or recent malignancy (especially lymphoma) — TNFα has anti-tumour surveillance roles
- Pregnancy (except certolizumab pegol, which lacks Fc region and has minimal placental transfer)
| Biologic Class | Key Adverse Effects |
|---|---|
| Anti-TNFα | TB reactivation, HBV reactivation, serious infections, lymphoma, non-melanoma skin cancer [13]; injection site reactions (SC agents); infusion reactions (infliximab); paradoxical psoriasis; drug-induced lupus |
| Anti-IL-17A | Candidiasis (mucocutaneous — IL-17 is important for anti-fungal mucosal immunity); IBD exacerbation/new onset (do NOT use in concomitant IBD); neutropenia; injection site reactions |
| JAK inhibitors | Herpes zoster, thromboembolic events [14]; infection; cytopenias; lipid elevation; potential malignancy risk; GI perforation (rare) |
Extra-articular manifestations require targeted additional treatment that may influence the choice of biologic:
| Manifestation | Treatment | Biologic Consideration |
|---|---|---|
| Acute anterior uveitis | Topical glucocorticoid eye drops (e.g., 1% prednisolone acetate) + topical cycloplegics (e.g., 1% cyclopentolate) [3]; oral analgesics; urgent ophthalmology referral | If recurrent: anti-TNFα (prefer infliximab or adalimumab over etanercept) [2][3]. Etanercept is least effective for uveitis among anti-TNFα agents. |
| IBD (Crohn's / UC) | As per IBD management (5-ASA, immunomodulators, biologics) | Anti-TNFα (infliximab or adalimumab) preferred [2]. AVOID etanercept (not effective for IBD) and AVOID anti-IL-17A (can worsen IBD) [2]. |
| Psoriasis | Topical therapy (steroids, vitamin D analogues, tar); phototherapy (UVA/B); systemic therapy if severe | Anti-TNFα or anti-IL-17A both effective. AVOID systemic corticosteroids (risk of rebound flare on tapering) [2]. |
| Enthesitis (non-Achilles) | NSAIDs first-line; local steroid injection (peri-lesional) [1][2]; anti-TNFα if refractory | cDMARDs NOT effective for enthesitis [2] |
| Dactylitis | NSAIDs first-line; anti-TNFα if refractory [2] | — |
| Aortic regurgitation / conduction defects | Cardiology referral; valve replacement if severe AR; pacemaker if significant AV block | — |
| Osteoporosis | DEXA monitoring; calcium + vitamin D; bisphosphonates if indicated | — |
Surgical intervention is rarely required now [1] with modern biologic therapy, but remains an option for:
| Indication | Procedure |
|---|---|
| Severe hip involvement (leading cause of disability) | Total hip replacement [1][2] — hip arthritis is a poor prognostic factor and an indication for early biologic therapy |
| Severe fixed spinal deformity | Corrective spinal osteotomy [1] — rare; performed by specialist spinal surgeons for patients with severe kyphosis affecting forward gaze and function |
| Atlantoaxial subluxation with cord compression | Posterior cervical fusion |
| Spinal fracture | Surgical stabilisation — note that the ankylosed bamboo spine is extremely fracture-prone even with minor trauma (behaves like a long bone). Patients with AS/axSpA and spinal trauma should have whole-spine imaging [15]. |
Understanding who will do worse helps guide earlier biologic escalation [1][2]:
| Factor | Why It Predicts Poor Outcome |
|---|---|
| Young onset | Longer disease duration → more cumulative damage |
| Hip arthritis | Most important clinical poor prognostic factor — leads to early functional disability; may require joint replacement |
| Dactylitis | Indicates more aggressive inflammatory phenotype |
| High ESR / CRP | Reflects greater systemic inflammatory burden → faster structural progression |
| Poor response to NSAIDs | Indicates more treatment-resistant disease; may need early biologic escalation |
| Smoking | Accelerates radiographic progression, increases CRP, reduces treatment response |
| Male sex | Higher rates of structural progression |
| HLA-B27 positive | Associated with more severe axial disease |
| Syndesmophytes at diagnosis | Indicates structural damage already present → higher risk of further progression |
| Parameter | Frequency | Purpose |
|---|---|---|
| BASDAI / ASDAS | Every 3–6 months | Assess disease activity; guide treatment decisions |
| CRP / ESR | Every 3–6 months | Objective inflammatory marker; component of ASDAS |
| BASFI / BASMI | Every 6–12 months | Functional and metrology assessment |
| Spinal mobility (Schober's, chest expansion, occiput-to-wall) | Every 6–12 months | Detect progression of spinal restriction |
| CBC, LFT, RFT | Every 3–6 months (on biologics/DMARDs) | Drug safety monitoring |
| Plain XR SIJ | Every 2 years (or if clinical concern) | Detect progression to AS (structural sacroiliitis) |
| MRI SIJ | If disease activity changes or to assess treatment response | Not routinely repeated if stable |
| DEXA scan | Baseline; repeat per osteoporosis guidelines | Osteoporosis monitoring |
| Ophthalmology review | If uveitis symptoms | Screen for complications (posterior synechiae, cataract, glaucoma) |
High Yield Summary — Management of nr-axSpA
- Non-pharmacological measures are lifelong and foundational: patient education, stretching exercise (especially swimming), posture education, smoking cessation, physiotherapy [1][2].
- NSAIDs/COX-2 inhibitors are first-line pharmacological therapy — ~70–80% respond substantially [2]. Continuous use may slow radiographic progression [1]. Trial of ≥ 2 NSAIDs for ≥ 1 month each before escalation.
- NO proven effective conventional DMARD for axial disease [1] — methotrexate, sulfasalazine, leflunomide only work for peripheral joints.
- Biologics (anti-TNFα or anti-IL-17A) are second-line for axial disease: indicated when BASDAI ≥ 4 despite adequate NSAID trial [1][2]. JAK inhibitors (e.g., upadacitinib) are an alternative oral option.
- Pre-biologic screening: CXR + QuantiFERON-TB Gold for latent TB; HBsAg for HBV [13]. TB prophylaxis with isoniazid; HBV prophylaxis with entecavir [13].
- Anti-TNFα contraindications: active infection, latent untreated TB, demyelinating disease, NYHA III–IV heart failure, malignancy [2][13].
- Anti-IL-17A contraindication: avoid in concomitant IBD (can worsen); candidiasis risk.
- Anti-IL-1 and anti-IL-6 are NOT useful for SpA [1].
- Avoid IA steroid in Achilles tendon — risk of rupture [1][2].
- Poor prognostic factors: young onset, hip arthritis, dactylitis, high ESR, poor NSAID response, smoking [1][2].
- Concomitant uveitis → prefer infliximab/adalimumab (not etanercept) [2]. Concomitant IBD → avoid etanercept and anti-IL-17A [2].
- Surgery rarely needed: hip replacement for severe hip disease; corrective osteotomy for fixed spinal deformity [1].
Active Recall - Management of nr-axSpA
References
[1] Senior notes: Maksim Medicine Notes.pdf (Section 13.6 Spondyloarthritides, pp. 323–325) [2] Senior notes: Ryan Ho Rheumatology.pdf (Section 2.7.2 Axial Spondyloarthritis management, pp. 58–62; Section 2.7.3 Peripheral SpA management, pp. 62–66) [3] Senior notes: Ryan Ho Ophthalmology.pdf (Section 2.5 Uveitis management, p. 31) [5] Lecture slides: Block A - Multiple joint pain_ Rheumatoid arthritis and the concept of inflammatory arthritis.pdf [12] Senior notes: Block A - Upper abdominal pain_ peptic ulcer; pancreatitis and gallstone.pdf (NSAID GI protection, p. 25) [13] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (Anti-TNFα screening and contraindications, pp. 659–673) [14] Senior notes: Block A - Chronic diarrhoea_ irritable bowel syndrome and inflammatory bowel disease.pdf (JAK inhibitor risks, pp. 47–48) [15] Senior notes: Ryan Ho Radiology.pdf (Spinal trauma imaging in AS, p. 18)
Complications of Non-Radiographic Axial Spondyloarthritis (nr-axSpA)
nr-axSpA is a chronic systemic inflammatory disease — not merely a "bad back." The same pathological process (IL-23/IL-17 axis activation, TNF-α-driven inflammation, enthesitis) that damages the axial skeleton also targets distant organs and systems. Complications arise from three main mechanisms:
- Direct disease-related inflammation — the inflammatory process attacks extra-articular tissues (eyes, aorta, lungs, gut).
- Structural consequences of chronic inflammation — progressive ankylosis, osteoporosis, deformity, and loss of function.
- Treatment-related complications — adverse effects of NSAIDs, biologics, and other medications.
Additionally, because nr-axSpA is the earlier stage of the axSpA spectrum, some complications are more typical of advanced/established AS. However, the treating clinician must anticipate and screen for them even in nr-axSpA, as they can occur at any stage and some (e.g., uveitis, cardiovascular disease) are common even early.
The most fundamental "complication" of nr-axSpA is its potential progression to established AS (r-axSpA).
| Aspect | Detail |
|---|---|
| Rate of progression | Approximately 10–20% of nr-axSpA patients develop definite radiographic sacroiliitis (i.e., progress to AS) over 2–10 years [1][2] |
| Risk factors for progression | Male sex, HLA-B27 positive, elevated CRP at baseline, MRI bone marrow oedema at SIJ, smoking, syndesmophytes already forming on spine MRI |
| Why does it matter? | Progression implies accumulating structural damage that is irreversible — fusion of the SIJ and spine leads to permanent loss of mobility |
| Can treatment prevent progression? | NSAIDs (continuous use) may modestly slow radiographic progression [1]; anti-TNFα agents, especially if started early, may prevent development of established AS [2]. The goal of early treatment in nr-axSpA is precisely to prevent this progression. |
GC Lecture High Yield — The axSpA Spectrum Over Time
From the GC 074 lecture on the concept of spondyloarthritis [4]:
The SpA spectrum is a continuum over time — undifferentiated SpA → peripheral SpA or axial SpA → ankylosing spondylitis (once radiological sacroiliitis appears) [4]. The dividing line between nr-axSpA and AS is the appearance of radiological sacroiliitis on plain XR [4]. This is why early diagnosis and treatment of nr-axSpA is so important — you are catching the disease before irreversible structural damage.
B. Musculoskeletal Complications
| Complication | Pathophysiology | Clinical Significance |
|---|---|---|
| Progressive spinal fusion | Chronic enthesitis at discovertebral junctions → new bone formation (syndesmophytes) via Wnt signalling → bridging of vertebral bodies → segmental then complete fusion | Loss of spinal flexion, extension, lateral flexion, and rotation; restrictive ventilatory defect from costovertebral fusion; "bamboo spine" [1] in late AS |
| Fixed kyphotic deformity ("question mark posture") | If fusion occurs while patient is in a flexed posture (e.g., due to poor posture habits or pain-driven flexion), the spine fuses in kyphosis | Loss of horizontal gaze (patient cannot look forward); difficulty with ADLs; impaired balance and increased fall risk |
| Reduced chest expansion | Costovertebral and costochondral joint fusion → restricted rib excursion | Restrictive lung disease — the lung parenchyma itself is normal but the chest wall cannot expand. Chest expansion < 2.5 cm is abnormal. This is why smoking cessation is critical — to reduce the additional burden on already restricted lungs [1]. |
In nr-axSpA specifically, full ankylosis is uncommon (by definition, structural damage is early). However, progressive stiffness and reduced spinal mobility can begin even before plain XR changes appear, detectable on BASMI (metrology index).
| Aspect | Detail |
|---|---|
| Prevalence | Up to 25–35% of axSpA patients develop hip involvement |
| Why it matters | Hip arthritis is the most important clinical poor prognostic factor [1][2] — it causes early functional disability, difficulty walking, and often necessitates total hip replacement |
| Pathophysiology | Synovitis and enthesitis at the hip joint capsule → joint space narrowing → secondary OA changes → loss of ROM |
| Management | Early biologic therapy is justified when hip arthritis is present (even if BASDAI < 4, some guidelines recommend earlier escalation); total hip replacement if severe [1][2] |
| Aspect | Detail |
|---|---|
| Mechanism | Chronic systemic inflammation → cytokine-driven osteoclast activation (TNF-α, IL-6, RANKL) → bone resorption exceeds formation → osteopenia/osteoporosis. Additionally, reduced physical activity and immobility contribute. |
| Paradox | In advanced AS, DEXA at the lumbar spine may overestimate BMD because syndesmophytes and ligamentous calcification artificially increase the measured density. Femoral neck DEXA is more reliable. |
| Fracture risk | The ankylosed (bamboo) spine is extremely fracture-prone — it behaves like a rigid long bone rather than a flexible column. Even minor trauma (e.g., a fall from standing height) can cause unstable vertebral fractures with high risk of spinal cord injury. Any new back pain in an axSpA patient after trauma (even minor) should be investigated with imaging. |
| Screening | DEXA scan at baseline for osteopenia [1]; repeat per osteoporosis guidelines; calcium and vitamin D supplementation |
| Aspect | Detail |
|---|---|
| Mechanism | Inflammation and erosion at the C1/C2 articulation → laxity of the transverse ligament of the atlas → anterior subluxation of C1 on C2 |
| Clinical significance | Risk of spinal cord compression at the cervicomedullary junction → myelopathy (upper motor neuron signs, quadriparesis, respiratory failure) |
| Relevance to nr-axSpA | Uncommon at this stage but must be considered if cervical symptoms develop; more common in longstanding AS |
| Investigation | Flexion-extension lateral cervical spine XR; MRI if neurological symptoms |
C. Extra-Articular / Systemic Complications
These are the "6A" extra-articular manifestations (EAMs) — Acute anterior uveitis, Apical pulmonary fibrosis, Aortic regurgitation, Autoimmune (IBD), Amyloidosis, Atlantoaxial subluxation [1]. Each represents a complication of the underlying systemic inflammatory process.
| Aspect | Detail |
|---|---|
| Prevalence | Most common extra-articular complication: 25–40% of axSpA patients [2] |
| Pathophysiology | HLA-B27-associated immune-mediated inflammation of the uveal tract (iris and ciliary body). IL-17 and TNF-α drive the inflammatory process. The exact trigger for individual flares is unknown, but molecular mimicry between HLA-B27-presented peptides and uveal antigens is hypothesised. |
| Presentation | Acute onset, unilateral (but alternating between eyes over episodes), painful red eye, photophobia, blurred vision, ciliary flush, miotic pupil |
| Complications of uveitis itself | Posterior synechiae (iris adheres to lens → irregular pupil, risk of angle closure); cataract (from chronic inflammation or topical steroid use); glaucoma (from trabecular meshwork obstruction by inflammatory debris); cystoid macular oedema (CME) → permanent visual impairment if untreated [3] |
| Management | Topical steroid drops (prednisolone acetate 1%), cycloplegics (cyclopentolate 1%); urgent ophthalmology referral. If recurrent → systemic anti-TNFα (infliximab/adalimumab preferred) [2][3] |
| Complication | Pathophysiology | Clinical Features |
|---|---|---|
| Aortitis and aortic regurgitation (AR) [1][2] | Chronic inflammation of the aortic root → fibrosis and thickening of the aortic wall and valve cusps → valve incompetence. The inflammation extends to the membranous interventricular septum. | Early diastolic murmur (decrescendo, best heard at left sternal edge); wide pulse pressure; may progress to heart failure. Echocardiography confirms. |
| Conduction defects [2] | Fibrosis of the conducting system (AV node, bundle of His) due to extension of aortic root inflammation into the interventricular septum | AV block (1st, 2nd, or 3rd degree); bundle branch block. May require pacemaker. |
| Coronary artery disease (CAD) [2] | Chronic systemic inflammation → accelerated atherosclerosis (TNF-α promotes endothelial dysfunction, oxidative stress, plaque instability). This is analogous to the increased CV risk seen in RA and psoriasis. | Increased risk of MI and stroke. Screen and manage traditional CV risk factors (hypertension, diabetes, hyperlipidaemia, smoking). |
Cardiovascular Risk in axSpA
The chronic inflammatory burden of axSpA increases cardiovascular risk beyond traditional risk factors. This is conceptually similar to the increased CV risk in other chronic inflammatory conditions (RA, SLE, psoriasis). The combination of aortitis (direct inflammation), conduction defects (fibrosis of conducting system), and accelerated atherosclerosis (systemic inflammation) means cardiovascular screening and risk factor management are essential in all axSpA patients [2].
| Complication | Pathophysiology | Clinical Features |
|---|---|---|
| Apical pulmonary fibrosis [1] | Rare, late complication. Chronic inflammation at the lung apices → fibrosis → cavitation. Mechanism not fully understood but thought to relate to enthesitis of the costovertebral joints with secondary parenchymal damage, or direct immune-mediated fibrosis. | Upper lobe fibrosis on CXR — can mimic tuberculosis. Cavities may become secondarily infected with Aspergillus (mycetoma/aspergilloma). |
| Restrictive ventilatory defect | Costovertebral joint fusion → reduced chest wall compliance → ↓total lung capacity and ↓vital capacity despite normal lung parenchyma | Dyspnoea on exertion; reduced chest expansion on examination; restrictive pattern on pulmonary function tests (↓FVC, ↓TLC, normal/↑FEV1/FVC ratio). Smoking cessation reduces the burden to these already restrictive lungs [1]. |
| Aspect | Detail |
|---|---|
| Prevalence | Subclinical gut inflammation is found in up to 50% of axSpA patients on ileocolonoscopy; overt Crohn's disease or ulcerative colitis develops in 5–10% |
| Pathophysiology | Shared IL-23/IL-17 immunological pathways between gut and joints; gut dysbiosis → impaired mucosal barrier → systemic immune activation. The gut-joint axis is central to SpA pathogenesis. |
| Clinical relevance | Symptoms of IBD (chronic diarrhoea, bloody stool, abdominal pain, weight loss) should be actively screened for in axSpA patients. The presence of IBD influences biologic choice (prefer infliximab/adalimumab; avoid etanercept and anti-IL-17A) [2][16] |
| Aspect | Detail |
|---|---|
| Mechanism | Longstanding uncontrolled chronic inflammation → hepatic overproduction of serum amyloid A (SAA) protein → misfolding and deposition as AA amyloid in kidneys, liver, spleen, gut |
| Clinical presentation | Nephrotic syndrome (proteinuria, hypoalbuminaemia, oedema) → progressive renal failure; hepatosplenomegaly; GI dysfunction |
| Prevention | Effective control of inflammation with NSAIDs/biologics reduces SAA production and prevents amyloid deposition. AA amyloidosis is now rare with modern treatment. |
| Diagnosis | Rectal/renal biopsy → Congo red staining → apple-green birefringence under polarised light |
| Complication | Mechanism |
|---|---|
| Atlantoaxial subluxation → cord compression (see above) | Erosion of C1/C2 articulation |
| Cauda equina syndrome (rare, late complication of AS) | Arachnoiditis and dural diverticula formation at the lumbosacral level → compression of cauda equina nerve roots → saddle anaesthesia, urinary retention/incontinence, faecal incontinence, bilateral leg weakness |
| Spinal fracture with cord injury | Rigid bamboo spine is fracture-prone; even minor trauma can cause unstable fractures with high-energy cord injury patterns |
| Complication | Mechanism / Explanation |
|---|---|
| Depression and anxiety | Chronic pain, fatigue, loss of function, body image changes (kyphotic posture), impact on work and relationships. Prevalence of depression is significantly higher in axSpA than the general population. |
| Fatigue | Multifactorial: chronic inflammation (TNF-α, IL-6 drive central fatigue), pain-disrupted sleep, anaemia of chronic disease, psychological burden |
| Reduced work productivity | Pain, stiffness, reduced mobility, and fatigue impair work capacity. Early and effective treatment helps maintain employment. |
| Sleep disturbance | Inflammatory back pain characteristically wakes patients in the second half of the night; chronic pain disrupts sleep architecture |
These are iatrogenic complications arising from the medications used to treat nr-axSpA:
| Treatment | Key Complications | Mechanism |
|---|---|---|
| NSAIDs (long-term) | GI ulceration/bleeding; renal impairment; cardiovascular events (MI, stroke); hepatotoxicity | COX-1 inhibition → loss of gastric mucosal protection; COX-2 inhibition → renal vasoconstriction and prothrombotic imbalance |
| Anti-TNFα | TB reactivation (TNF-α is essential for granuloma integrity → inhibition releases dormant mycobacteria); HBV reactivation; serious infections; lymphoma; demyelination; heart failure exacerbation [2][13] | Immunosuppression from TNF-α blockade |
| Anti-IL-17A | Candidiasis (mucocutaneous — IL-17 is critical for anti-fungal defence at mucosal surfaces); IBD exacerbation/new-onset (IL-17 has protective role in gut); neutropenia | Disruption of Th17-mediated mucosal immunity |
| JAK inhibitors | Herpes zoster reactivation; thromboembolic events; cytopenias; lipid elevation; potential malignancy risk [14] | Broad intracellular cytokine signalling blockade |
| Corticosteroids (systemic — when used for peripheral disease) | Osteoporosis, diabetes, hypertension, immunosuppression, adrenal suppression, cataracts, weight gain | Multiple metabolic and immunological effects |
| Sulfasalazine | Bone marrow suppression, hepatotoxicity, GI side effects, male infertility, skin rash [16] | Sulfapyridine component toxicity |
| Category | Specific Complications | Key Mechanism |
|---|---|---|
| Structural progression | Sacroiliitis → syndesmophytes → bamboo spine; fixed kyphosis | Enthesitis → new bone formation |
| Articular | Hip arthritis (poor prognostic); atlantoaxial subluxation | Synovitis/enthesitis at hip; C1/C2 erosion |
| Ocular | Acute anterior uveitis (most common EAM) | HLA-B27-associated uveal inflammation |
| Cardiovascular | Aortitis → AR; conduction defects; accelerated CAD | Aortic root fibrosis; conducting system fibrosis; systemic inflammation |
| Pulmonary | Apical fibrosis; restrictive lung disease | Parenchymal fibrosis; costovertebral fusion |
| Gastrointestinal | IBD (Crohn's/UC) | Shared IL-23/IL-17 gut-joint axis |
| Renal | AA amyloidosis | Chronic inflammation → SAA deposition |
| Neurological | Cord compression (atlanto-axial, fracture); cauda equina syndrome | Subluxation; fracture of rigid spine; arachnoiditis |
| Bone | Osteoporosis → fractures | Inflammation-driven bone resorption; immobility |
| Psychological | Depression, anxiety, fatigue, sleep disturbance | Chronic pain/inflammation; functional impairment |
| Treatment-related | GI bleeding (NSAIDs); TB/HBV reactivation (anti-TNF); candidiasis (anti-IL-17); VZV/VTE (JAKi) | Drug-specific mechanisms |
High Yield Summary — Complications of nr-axSpA
- Progression to AS (r-axSpA) occurs in ~10–20% over 2–10 years; risk factors: male sex, HLA-B27+, elevated CRP, MRI BME, smoking [1][2].
- Acute anterior uveitis is the most common extra-articular complication (25–40%) [2] — acute, unilateral, HLA-B27-associated. Complications of uveitis: posterior synechiae, cataract, glaucoma, CME [3].
- 6A mnemonic for EAMs: Acute anterior uveitis, Apical pulmonary fibrosis, Aortic regurgitation, Autoimmune (IBD), Amyloidosis (AA type), Atlantoaxial subluxation [1].
- Cardiovascular complications: aortitis → AR; conduction defects (AV block); accelerated CAD [2]. Screen and manage CV risk factors.
- Spinal fractures in ankylosed spines are high-risk even with minor trauma — always image the whole spine [15].
- Hip arthritis is the most important poor prognostic factor [1][2] — may require total hip replacement.
- Restrictive ventilatory defect from costovertebral fusion — smoking cessation reduces burden to restrictive lungs [1].
- AA amyloidosis from chronic inflammation — now rare with effective treatment.
- IBD is both an associated disease and a complication — subclinical gut inflammation in up to 50% [16].
- Treatment-related complications: TB reactivation (anti-TNF), candidiasis (anti-IL-17), herpes zoster and VTE (JAK inhibitors) [2][13][14].
- HLA-B27 has prognostic value — positive HLA-B27 predicts more severe axial disease and higher complication rates [4].
Active Recall - Complications of nr-axSpA
References
[1] Senior notes: Maksim Medicine Notes.pdf (Section 13.6 Spondyloarthritides, pp. 323–325) [2] Senior notes: Ryan Ho Rheumatology.pdf (Section 2.7.2 Axial Spondyloarthritis, pp. 58–62) [3] Senior notes: Ryan Ho Ophthalmology.pdf (Section 2.5 Uveitis complications, p. 31) [4] Lecture slides: GC 074. Multiple joint pain.pdf (pp. 30, 38) [6] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (AS overview and complications, pp. 1699–1706) [13] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (Anti-TNFα adverse effects, pp. 659–673) [14] Senior notes: Block A - Chronic diarrhoea_ irritable bowel syndrome and inflammatory bowel disease.pdf (JAK inhibitor risks, pp. 47–48) [15] Senior notes: Ryan Ho Radiology.pdf (Spinal trauma in AS, p. 18) [16] Senior notes: Block A - Chronic diarrhoea_ irritable bowel syndrome and inflammatory bowel disease.pdf (IBD extra-intestinal manifestations, p. 34; sulfasalazine side effects, p. 44)
High Yield Summary
- nr-axSpA is part of the axSpA spectrum — same disease as AS but without definite radiographic sacroiliitis on plain X-ray.
- Classified via ASAS criteria [1][2]: imaging arm (sacroiliitis on MRI + ≥ 1 SpA feature) OR clinical arm (HLA-B27 + ≥ 2 SpA features), in patients with chronic back pain ≥ 3 months and onset < 45 years.
- Sex ratio is ~1:1 in nr-axSpA (vs. 3:1 in AS) — historically, women were under-diagnosed because they had less radiographic damage.
- HLA-B27 prevalence in southern Chinese is 6–8% [2]; only a minority develop SpA.
- Pathophysiology centres on enthesitis [1] and the IL-23/IL-17 axis, with both bone erosion and new bone formation.
- Cardinal symptom = inflammatory back pain (onset < 40, insidious, improves with exercise, not with rest, night pain).
- Morning stiffness > 30 minutes, alternating buttock pain, heel pain (enthesitis), peripheral oligoarthritis (LL > UL) are key features.
- Extra-articular: anterior uveitis (most common), aortitis/AR, apical fibrosis, IBD, amyloidosis, atlantoaxial subluxation (6A mnemonic).
- BASDAI ≥ 4/10 = active disease [1]; ASAS 50 = BASDAI drop of ≥ 50% [1].
- Diagnostic delay averages 7–10 years — suspect IBP in any young patient with chronic back pain and refer appropriately.
High Yield Summary — Differential Diagnosis of nr-axSpA
- The most important first step is distinguishing inflammatory from mechanical back pain using IBP criteria (≥ 4/5: onset < 40, insidious, improves with exercise, no improvement with rest, night pain improving on getting up).
- Mechanical back pain accounts for ~97% of all back pain [8] — always exclude this and red-flag pathology (infection, malignancy, cauda equina) before pursuing an inflammatory diagnosis.
- Within the SpA family, nr-axSpA is distinguished from AS by the absence of definite sacroiliitis on plain XR; from PsA by absence of psoriasis/nail changes/DIP involvement; from ReA by absence of preceding infection; from IBD-SpA by absence of Crohn's/UC.
- RA is excluded by its symmetric polyarthritis pattern (MCP/PIP/wrist, sparing DIP), RF+/anti-CCP+ serology [4][6], and lack of enthesitis/sacroiliitis.
- OA is distinguished by older age, mechanical pain pattern, DIP involvement (Heberden's nodes) [4].
- DISH is distinguished by flowing ossification ≥ 4 vertebrae with SIJ spared, in older patients.
- Fibromyalgia can coexist with axSpA — normal labs and imaging, widespread pain without true inflammatory features.
- Always check for SpA features (11 ASAS features) systematically: IBP, arthritis, enthesitis, uveitis, dactylitis, psoriasis, Crohn's/UC, good NSAID response, family history, HLA-B27, elevated CRP [1][2][6].
High Yield Summary — Diagnosis of nr-axSpA
- ASAS classification criteria for axSpA require chronic back pain ≥ 3 months with onset < 45 years, then either: Imaging arm (sacroiliitis on imaging + ≥ 1 SpA feature) OR Clinical arm (HLA-B27 + ≥ 2 other SpA features) [1][2][6].
- In nr-axSpA, plain XR SIJ is normal or equivocal (grade 0–I) — this is what makes it "non-radiographic."
- MRI SIJ is the pivotal investigation: look for bone marrow oedema (BME) on STIR/T2-FS sequences — the most characteristic change of active sacroiliitis [1][6]. Must be in ≥ 2 locations on one slice or ≥ 1 location on ≥ 2 consecutive slices.
- HLA-B27 is essential for the clinical arm and a strong supportive feature; prevalence in southern Chinese is 6–8% [2].
- RF and anti-CCP should be negative — positive results point towards RA [1][2].
- CRP may be normal in 40–60% of nr-axSpA — a normal CRP does NOT exclude the diagnosis.
- BASDAI ≥ 4/10 = active disease [1][6]; ASDAS (incorporating CRP) is more objective.
- Key XR spine findings (for AS/progression): Romanus lesion (shiny corners), syndesmophytes, bamboo spine, Anderson lesion [1][6].
- Investigations: CBC, CRP/ESR, HLA-B27, RF (-ve), anti-CCP (-ve); Imaging: XR, MRI [1].
- DEXA scan for baseline osteopenia assessment [1]; USG for enthesitis assessment [6].
High Yield Summary — Management of nr-axSpA
- Non-pharmacological measures are lifelong and foundational: patient education, stretching exercise (especially swimming), posture education, smoking cessation, physiotherapy [1][2].
- NSAIDs/COX-2 inhibitors are first-line pharmacological therapy — ~70–80% respond substantially [2]. Continuous use may slow radiographic progression [1]. Trial of ≥ 2 NSAIDs for ≥ 1 month each before escalation.
- NO proven effective conventional DMARD for axial disease [1] — methotrexate, sulfasalazine, leflunomide only work for peripheral joints.
- Biologics (anti-TNFα or anti-IL-17A) are second-line for axial disease: indicated when BASDAI ≥ 4 despite adequate NSAID trial [1][2]. JAK inhibitors (e.g., upadacitinib) are an alternative oral option.
- Pre-biologic screening: CXR + QuantiFERON-TB Gold for latent TB; HBsAg for HBV [13]. TB prophylaxis with isoniazid; HBV prophylaxis with entecavir [13].
- Anti-TNFα contraindications: active infection, latent untreated TB, demyelinating disease, NYHA III–IV heart failure, malignancy [2][13].
- Anti-IL-17A contraindication: avoid in concomitant IBD (can worsen); candidiasis risk.
- Anti-IL-1 and anti-IL-6 are NOT useful for SpA [1].
- Avoid IA steroid in Achilles tendon — risk of rupture [1][2].
- Poor prognostic factors: young onset, hip arthritis, dactylitis, high ESR, poor NSAID response, smoking [1][2].
- Concomitant uveitis → prefer infliximab/adalimumab (not etanercept) [2]. Concomitant IBD → avoid etanercept and anti-IL-17A [2].
- Surgery rarely needed: hip replacement for severe hip disease; corrective osteotomy for fixed spinal deformity [1].
High Yield Summary — Complications of nr-axSpA
- Progression to AS (r-axSpA) occurs in ~10–20% over 2–10 years; risk factors: male sex, HLA-B27+, elevated CRP, MRI BME, smoking [1][2].
- Acute anterior uveitis is the most common extra-articular complication (25–40%) [2] — acute, unilateral, HLA-B27-associated. Complications of uveitis: posterior synechiae, cataract, glaucoma, CME [3].
- 6A mnemonic for EAMs: Acute anterior uveitis, Apical pulmonary fibrosis, Aortic regurgitation, Autoimmune (IBD), Amyloidosis (AA type), Atlantoaxial subluxation [1].
- Cardiovascular complications: aortitis → AR; conduction defects (AV block); accelerated CAD [2]. Screen and manage CV risk factors.
- Spinal fractures in ankylosed spines are high-risk even with minor trauma — always image the whole spine [15].
- Hip arthritis is the most important poor prognostic factor [1][2] — may require total hip replacement.
- Restrictive ventilatory defect from costovertebral fusion — smoking cessation reduces burden to restrictive lungs [1].
- AA amyloidosis from chronic inflammation — now rare with effective treatment.
- IBD is both an associated disease and a complication — subclinical gut inflammation in up to 50% [16].
- Treatment-related complications: TB reactivation (anti-TNF), candidiasis (anti-IL-17), herpes zoster and VTE (JAK inhibitors) [2][13][14].
- HLA-B27 has prognostic value — positive HLA-B27 predicts more severe axial disease and higher complication rates [4].
Rheumatoid Arthritis
Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by symmetric inflammatory polyarthritis with progressive destruction of joints due to synovial inflammation and pannus formation.
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.