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.

Exam domain	One-glance essentials
Definition / diagnosis	nr-axSpA is axial spondyloarthritis without definite sacroiliitis on plain radiograph ^[1] It lies on the same disease spectrum as radiographic axSpA/ankylosing spondylitis ^[2]
Epidemiology / risks	Onset is typically before 45 years; sex ratio is approximately 1:1 ^[1] HLA-B27 prevalence is ~6–8% in southern Chinese, but carriage alone is not diagnostic ^[2]
Core mechanism	Enthesitis-centred inflammation driven by TNF and the IL-23/IL-17 axis ^[1] Inflammation causes erosion and later new bone formation; some patients progress to radiographic sacroiliitis ^[1]
Clinical picture	Inflammatory back pain: insidious onset, night pain, morning stiffness, improves with exercise but not rest ^[1] Alternating buttock pain, heel enthesitis, asymmetric lower-limb oligoarthritis and anterior uveitis ^[1]
Investigations	ASAS: back pain ≥ 3 months, onset < 45, then imaging arm or HLA-B27 clinical arm ^[1]^[2] Plain SI-joint X-ray is normal/equivocal; MRI STIR bone-marrow oedema supports active sacroiliitis ^[1]
Management	Lifelong exercise, posture training, physiotherapy and smoking cessation; NSAIDs first line ^[1] Persistent active axial disease → anti-TNF or anti-IL-17; csDMARDs do not treat axial disease ^[1]
Complications	Progression to radiographic axSpA, especially with male sex, smoking, high CRP and MRI inflammation ^[1]^[2] Uveitis, hip disease, osteoporosis/fracture, aortitis/AR and IBD ^[2]
Prevention / follow-up	Stop smoking; maintain extension/posture and chest mobility; assess baseline bone health ^[1] Screen TB and HBV before biologic therapy and monitor extra-articular disease ^[3]
Exam traps	A normal X-ray is expected and does not exclude nr-axSpA; obtain MRI when suspicion persists ^[1] Normal CRP and negative HLA-B27 do not exclude disease; avoid Achilles-tendon steroid injection ^[1]

References

^[1] Senior notes: Maksim Medicine Notes.pdf (Spondyloarthritides, pp.321–325) ^[2] Senior notes: Ryan Ho Rheumatology.pdf (Axial spondyloarthritis, pp.57–62) ^[3] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (anti-TNF screening and contraindications, pp.659–673)

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:
1. Back pain is extremely common in the general population (mechanical causes predominate).
2. nr-axSpA has no structural radiographic changes by definition — so normal X-rays can falsely reassure clinicians.
3. 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).

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:

Sacroiliitis on imaging (MRI showing active inflammation consistent with sacroiliitis, OR definite sacroiliitis on plain radiograph per modified New York criteria) PLUS ≥ 1 SpA feature ^[1]^[2]^[6]

HLA-B27 positive PLUS ≥ 2 other SpA features ^[1]^[2]^[6]

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

Instrument	What It Measures
BASFI	Functional disability (patient-reported) — 10 questions about daily activities ^[6]
BASMI	Spinal mobility (physician-measured) — tragus-to-wall, lumbar flexion, cervical rotation, lateral flexion, intermalleolar distance ^[6]
BAS-G	Global well-being (patient-reported) ^[6]

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:

NSAIDs as first-line for axial symptoms
No proven effective DMARD for axial disease — DMARDs only for peripheral joints ^[1]
Biologics (anti-TNFα, anti-IL-17) for persistent high disease activity despite adequate NSAID trial ^[1]

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

NSAIDs are the MOST important pharmacological treatment for axial SpA ^[1]^[2]. Unlike RA (where DMARDs are first-line), in axSpA, NSAIDs are often the only medication needed. A trial of ≥ 2 different NSAIDs, each for ≥ 1 month at full dose, is required before escalating to biologics ^[1]^[2].

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:

Efficacy: especially useful if started early for a long period of time and may prevent development of established AS ^[2]
Duration: attempt dose reduction if stable for ≥ 1 year in remission or low disease activity ^[2]

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].

Non-radiographic Axial Spondyloarthritis

References

Non-Radiographic Axial Spondyloarthritis (nr-axSpA)

Epidemiology

Anatomy and Functional Considerations

Etiology and Pathophysiology

Genetic Factors

Classification

The ASAS Framework (2009)

Clinical Features

A. Symptoms (with pathophysiological basis)

B. Signs (with pathophysiological basis)

Active Recall - nr-axSpA Definition, Epidemiology, Pathophysiology and Clinical Features

Differential Diagnosis of Non-Radiographic Axial Spondyloarthritis (nr-axSpA)

A. Broad Differential Diagnosis of Chronic Back Pain in a Young Patient

B. Focused Differential Within the Inflammatory Back Pain / SpA Category

Active Recall - Differential Diagnosis of nr-axSpA

References

Diagnostic Criteria, Diagnostic Algorithm, and Investigations for nr-axSpA

A. Diagnostic Criteria

1. ASAS Classification Criteria for Axial Spondyloarthritis (2009)

C. Investigation Modalities — Detailed Breakdown

1. Laboratory Investigations

2. Imaging Investigations

D. Disease Activity Assessment Instruments

Active Recall - Diagnostic Criteria, Algorithm, and Investigations for nr-axSpA

References

Management of Non-Radiographic Axial Spondyloarthritis (nr-axSpA)

B. Pharmacological Management

Step 2: Biologic Therapy — Second-Line for Axial Disease

Active Recall - Management of nr-axSpA

References

Complications of Non-Radiographic Axial Spondyloarthritis (nr-axSpA)

B. Musculoskeletal Complications

C. Extra-Articular / Systemic Complications

Active Recall - Complications of nr-axSpA

References

On this page

Non-radiographic Axial Spondyloarthritis

Definition

Epidemiology

Prevalence and Incidence

Demographics

Diagnostic Delay

Progression

Risk Factors

Anatomy and Functional Considerations

1. Sacroiliac Joints (SIJ)

2. Entheses

3. Spine

4. Peripheral Joints and Other Structures

Etiology and Pathophysiology

Genetic Factors

HLA-B27

Non-HLA Genes

The IL-23/IL-17 Axis — Central Pathogenic Pathway

Environmental Factors

Classification

The ASAS Framework (2009)

Imaging Arm

Clinical Arm

The 11 SpA Features (ASAS)

Modified New York Criteria for AS (1984) — For Comparison

Grading of Sacroiliitis on Plain Radiograph

Clinical Features

A. Symptoms (with pathophysiological basis)

1. Inflammatory Back Pain (IBP) — The Cardinal Symptom

2. Morning Stiffness

3. Buttock Pain (Alternating)

4. Peripheral Joint Pain

5. Heel Pain (Enthesitis Symptoms)

6. Chest Pain / Reduced Chest Expansion

7. Constitutional Symptoms

8. Extra-Articular Symptoms

B. Signs (with pathophysiological basis)

1. Sacroiliac Joint Tenderness

2. Reduced Spinal Mobility

3. Reduced Chest Expansion

4. Enthesitis Signs

5. Dactylitis ("Sausage Digit")

6. Peripheral Arthritis Signs

7. Eye Examination

8. Cardiovascular Examination

9. Skin and Nail Examination (to assess for overlap features)

Disease Activity Assessment

Summary Table — nr-axSpA vs. AS (r-axSpA)

Active Recall - nr-axSpA Definition, Epidemiology, Pathophysiology and Clinical Features

References

Why Differential Diagnosis Matters in nr-axSpA

Approach to the Differential Diagnosis

A. Broad Differential Diagnosis of Chronic Back Pain in a Young Patient

1. Mechanical Back Pain (~97% of all back pain) [8]

2. Serious / "Red Flag" Pathology

3. Non-Spinal Causes (Referred Pain) [8]

B. Focused Differential Within the Inflammatory Back Pain / SpA Category

1. Other Spondyloarthritis Subtypes

2. Rheumatoid Arthritis (RA)

3. Osteoarthritis (OA) of the Spine

4. Diffuse Idiopathic Skeletal Hyperostosis (DISH)

5. Fibromyalgia

6. Other Causes of Sacroiliitis / Inflammatory Back Pain

C. Summary Differential Diagnosis Table for nr-axSpA

D. The Clinical Reasoning Process — First Principles Approach

Active Recall - Differential Diagnosis of nr-axSpA

The Diagnostic Challenge — Why We Need Specific Criteria

A. Diagnostic Criteria

1. ASAS Classification Criteria for Axial Spondyloarthritis (2009)

Imaging Arm

Clinical Arm

The 11 SpA Features (Building Blocks of Both Arms)

2. Modified New York Criteria for AS (1984) — For Comparison Only

3. ASAS MRI Definition of Sacroiliitis — What Counts?

4. Sacroiliitis Grading on Plain Radiograph

B. Diagnostic Algorithm

C. Investigation Modalities — Detailed Breakdown

1. Laboratory Investigations

a) Inflammatory Markers: CRP and ESR

b) HLA-B27