Investigation of Ankylosing Spondylitis (AS)

1. Classification / Diagnostic Criteria

Modified New York Criteria (1984) - Still the reference standard for definite AS

Note: Criteria 2 and 3 reflect disease duration and are typically absent in early disease - making modified New York criteria poorly suited for early diagnosis. - Firestein & Kelley's Textbook of Rheumatology

ASAS (Assessment of SpondyloArthritis International Society) Criteria

• Imaging arm: Sacroiliitis on imaging (radiograph or MRI) + ≥1 SpA feature
• Clinical arm: HLA-B27 positive + ≥2 additional SpA features

2. Laboratory Investigations

HLA-B27 Testing

• ~90% of Caucasian AS patients are HLA-B27 positive (vs. 5-10% of healthy controls)
• Performed by flow cytometry (quick, cost-efficient) - but lower sensitivity/specificity than molecular typing due to inability to recognise all B27 subgroups
• Molecular typing is more sensitive/specific but complicated by high polymorphism (>200 alleles described)
• Key subtypes associated with AS: HLA-B*27:05 and *27:02 (Caucasians), *27:04 (Asians)
• NOT diagnostic alone: only ~2% of HLA-B27 positive individuals ever develop AS - best used as a rule-out test (high negative predictive value)
• Henry's Clinical Diagnosis and Management by Laboratory Methods

Inflammatory Markers

• ESR and CRP - elevated in active disease; CRP levels improve with TNF inhibitor therapy and are used to monitor treatment response
• May be normal in up to 40% of AS patients despite active disease
• Firestein & Kelley's Textbook of Rheumatology

Other Bloods

• FBC: normocytic anaemia of chronic disease in active AS
• Rheumatoid factor (RF): negative - AS is a seronegative spondyloarthropathy
• ANA: typically negative
• Alkaline phosphatase: may be mildly elevated in active disease
• Serum IgA: often elevated (reflects mucosal immune activation)

3. Imaging Investigations

A. Plain Radiography (X-Ray) - First-line

• Shiny corners (Romanus lesions): earliest spinal change - sclerosis at corners of vertebral bodies at Sharpey fibre insertion
• Squaring of vertebral bodies: loss of normal concave anterior surface due to erosion + anterior longitudinal ligament ossification
• Syndesmophytes: thin, vertically oriented bony outgrowths at disc margins - distinguishable from osteophytes (horizontal) and psoriatic coarse syndesmophytes
• Bamboo spine: complete fusion of vertebral bodies + facet joints in advanced disease

Romanus lesions (shiny corners) with bridging syndesmophytes - Grainger & Allison's Diagnostic Radiology

Bamboo spine with bridging vertical syndesmophytes (A) and fused SIJs (B) - Grainger & Allison's Diagnostic Radiology

• Bath Ankylosing Spondylitis Radiology Index (BASRI)
• Stoke Ankylosing Spondylitis Spine Score (SASSS)
• Modified SASSS (most sensitive to change)

B. MRI - Investigation of Choice for Early Disease

• Active (inflammatory): Juxta-articular bone marrow oedema (STIR) - most indicative of active sacroiliitis; capsulitis; enthesitis
• Structural (damage): Erosions, sclerosis, periarticular fat metaplasia (T1 bright "fat lesions"), ankylosis

• Bone oedema at vertebral body corners = MRI equivalent of Romanus lesion (detected before sclerosis on X-ray)
• Spondylodiscitis (inflammation along vertebral end plate)
• Costovertebral joint oedema
• Spinous process and facet joint oedema

Semicoronal STIR (A,B) and T1-weighted (C-F) MRI showing: A - bone marrow oedema (sacroiliitis), B - enthesitis at sacrum, C/D - erosion and fat metaplasia, E - "backfill" fat in erosion cavity, F - ankylosis. - Firestein & Kelley's Textbook of Rheumatology

Coronal MRI SI joints: T1 showing erosion and joint space loss (damage); T2 fat-suppressed showing extensive subchondral oedema (activity) - Grainger & Allison's Diagnostic Radiology

C. CT Scan

• Gold standard for detecting structural damage (erosions, sclerosis) - more detail than plain X-ray
• Detects bony changes sooner and with greater resolution than conventional radiography
• Limited by: radiation dose; inability to assess soft tissue or bone marrow (so cannot detect early inflammatory changes)
• Low-dose CT techniques now available at radiation doses similar to plain X-ray - increasingly used as an alternative to CR for SI joint and spinal structural assessment
• Firestein & Kelley's Textbook of Rheumatology

D. Bone Scintigraphy (Skeletal Scintigraphy)

• Historically used for early detection of sacroiliitis
• Now generally superseded - MRI has greater sensitivity and specificity than scintigraphy, conventional radiography, and CT for early sacroiliitis detection
• Grainger & Allison's Diagnostic Radiology

4. Functional Assessments

• Schober's test - lumbar flexion (mark 10 cm above + 5 cm below L5; normal expansion >5 cm)
• Occiput-to-wall distance - forward stooped posture in advanced disease
• Chest expansion - should be >5 cm at the 4th intercostal space (reduced in thoracic disease)
• FABER test (Flexion, ABduction, External Rotation) and Gaenslen's test - provoke sacroiliac joint pain

5. Investigations for Extra-Articular Manifestations

6. Summary Algorithm

Chronic inflammatory back pain <45 years + morning stiffness >30 min
                         ↓
        X-ray SI joints + HLA-B27 + CRP/ESR
                         ↓
    ┌─────────────────────────────────────┐
    │ X-ray sacroiliitis grade 2-4 bilateral  │  → Modified New York Criteria = Definite AS
    │ or grade 3-4 unilateral              │
    └─────────────────────────────────────┘
                         ↓ (if X-ray negative/equivocal)
              MRI SI joints (STIR + T1)
                         ↓
    ┌──────────────────────────────────────────────────────┐
    │ Active BME on STIR + SpA feature = Axial SpA (nr-axSpA) │
    └──────────────────────────────────────────────────────┘
                         ↓ (if MRI equivocal)
         HLA-B27 + ≥2 SpA features = Clinical arm AxSpA

• Grainger & Allison's Diagnostic Radiology (9780323760751), Chapter 44
• Firestein & Kelley's Textbook of Rheumatology (9780323935364), Chapters 75-76
• Henry's Clinical Diagnosis and Management by Laboratory Methods (9780323673204), Chapter on HLA-B27
• Goldman-Cecil Medicine International Edition (9780323930345)
• ROSEN's Emergency Medicine (9780323757898)
• Rheumatology 2-Volume Set (Elsevier 2022) (9780702081330)

Investigations of Seronegative Spondyloarthropathy (SpA)

• Absence of rheumatoid factor (seronegative)
• Involvement of entheses (the bone-ligament/tendon interface)
• Association with HLA-B27
• Tendency to affect the axial skeleton and sacroiliac joints
• Destruction of fibrocartilage and collagen more than synovial cartilage

1. Ankylosing Spondylitis (AS) - covered separately; see previous answer
2. Psoriatic Arthritis (PsA)
3. Reactive Arthritis (formerly Reiter syndrome)
4. Enteropathic Arthritis (associated with IBD)
5. Undifferentiated Spondyloarthritis

Comparative Differential Table

I. COMMON INVESTIGATIONS FOR ALL SERONEGATIVE SpA

A. Laboratory

B. Imaging - General Principles

C. ASAS Classification Criteria (for Axial SpA)

II. PSORIATIC ARTHRITIS (PsA)

Clinical Subtypes (Moll & Wright)

1. Asymmetric oligoarthritis (most common, ~70%)
2. Symmetric polyarthritis (RA-like but seronegative)
3. Distal interphalangeal (DIP) arthropathy
4. Spondylitis with or without sacroiliitis
5. Arthritis mutilans (severe destructive form)

Laboratory Investigations

• RF: Negative (distinguishes from RA)
• Anti-CCP: Usually negative
• HLA-B27: Positive in ~50% with axial/spinal disease
• ESR, CRP: Elevated in active disease
• Skin biopsy: If psoriasis diagnosis is uncertain

Imaging Investigations

• No periarticular osteopenia (unlike RA - useful distinguishing feature)
• Marginal entheseal erosions with new bone formation at the erosion site - "fluffy, whiskered" appearance
• "Pencil-in-cup" deformity: Erosions on distal side of joint merge together; proximal phalanx has pointed "pencil" shape sitting in the cup of the distal phalanx - considered pathognomonic
• Acro-osteolysis: Distal tuft resorption giving peg-like appearance to terminal phalanges
• Dactylitis ("sausage digit"): Global soft-tissue swelling of a digit on plain film

Pencil-in-cup deformity in psoriatic arthritis - Grainger & Allison's Diagnostic Radiology

• Asymmetric sacroiliitis (unlike the bilateral symmetrical sacroiliitis of AS)
• Coarse, non-marginal (bulky) syndesmophytes in a horizontal orientation - contrast with the fine, vertical syndesmophytes of AS
• Asymmetric distribution about the spine
• Costovertebral disease is rare in PsA (common in AS)

Asymmetric sacroiliitis with coarse horizontal enthesophytes () in psoriatic spondylitis - Grainger & Allison's Diagnostic Radiology*

Validated Assessment Tools

• CASPAR criteria (ClASsification criteria for Psoriatic ARthritis) - used for classification
• DAPSA (Disease Activity in PSoriatic Arthritis)
• MDA (Minimal Disease Activity)

III. REACTIVE ARTHRITIS

Background

Laboratory Investigations

• RF: Negative
• HLA-B27: Positive in ~70-75%
• ESR, CRP: Elevated
• FBC: Neutrophilia during acute phase
• Urethral/cervical swabs: Chlamydia culture, NAAT (nucleic acid amplification test)
• Stool cultures / serology: For Salmonella, Shigella, Yersinia, Campylobacter
• Throat swab: If streptococcal infection suspected
• HIV serology: Important - HIV alters the course, leading to more aggressive and refractory joint disease

Synovial Fluid Analysis

• Sterile inflammatory pattern (WBC 10,000-50,000, predominantly neutrophils)
• Cultures negative (reactive, not septic arthritis)
• Chlamydia antigen / PCR: May be positive in synovial fluid even when peripheral cultures are negative

Imaging Investigations

• X-ray feet: New bone formation at calcaneal entheses (plantar and posterior insertions) - prominent feature; also seen at other entheseal sites
• Soft-tissue swelling, joint space narrowing, proliferative marginal erosions in small joints of the lower limbs
• Sesamoid enlargement due to periostitis
• Sacroiliitis: Bilateral asymmetric (unlike AS which is symmetric) - erosions, pseudowidening, ileal sclerosis

Bilaterally asymmetric sacroiliitis in reactive arthritis - Goldman-Cecil Medicine

Calcaneal enthesophytes () at plantar fascia and Achilles insertions in reactive arthritis - Grainger & Allison's Diagnostic Radiology*

IV. ENTEROPATHIC ARTHRITIS (IBD-associated)

Laboratory Investigations

• RF: Negative
• HLA-B27: Positive in axial disease; negative in peripheral disease
• ESR, CRP, faecal calprotectin: Monitor IBD activity
• FBC: Anaemia (multifactorial - chronic disease, B12/folate malabsorption in Crohn's)
• Colonoscopy / biopsy: Confirms IBD diagnosis - axial disease may precede GI symptoms

Imaging Investigations

• Pelvic X-ray: Sacroiliitis - relatively asymmetric, with bone oedema progressing to erosion, joint space loss, and fusion
• Peripheral arthritis is characteristically non-destructive - wrists, knees, ankles, elbows
• MRI SI joints: Active sacroiliitis; spinal involvement similar to AS
• Small bowel radiology / MRI enterography: For Crohn's disease assessment

V. SUMMARY: KEY DIFFERENTIATING RADIOLOGICAL FEATURES

VI. INVESTIGATION ALGORITHM

Seronegative inflammatory arthritis
(RF negative, asymmetric, lower limb, enthesitis)
               ↓
    ┌──────────────────────────────────┐
    │         FIRST LINE               │
    │  FBC, ESR, CRP, RF (neg),        │
    │  anti-CCP (neg), uric acid       │
    │  HLA-B27                         │
    │  X-ray: SI joints + affected     │
    │         peripheral joints        │
    └──────────────────────────────────┘
               ↓
    ┌──────────────────────────────────────────────────────┐
    │ Are there SpA features?                               │
    │  Axial pain + HLA-B27: MRI SI joints + spine         │
    │  Preceding infection: Chlamydia/stool cultures,       │
    │                       synovial fluid culture + PCR    │
    │  Psoriasis/nail changes: skin biopsy if needed        │
    │  GI symptoms: faecal calprotectin, colonoscopy        │
    │  Uveitis: slit-lamp examination                       │
    └──────────────────────────────────────────────────────┘
               ↓
    ASAS criteria: imaging arm or clinical arm for axial SpA
    CASPAR criteria: for psoriatic arthritis
    Modified New York criteria: for definite AS

• Goldman-Cecil Medicine International Edition (9780323930345), Chapter 244
• Grainger & Allison's Diagnostic Radiology (9780323760751), Chapter 44
• Rheumatology 2-Volume Set, Elsevier 2022 (9780702081330)
• Miller's Review of Orthopaedics 9th Edition (9780443112140)
• Firestein & Kelley's Textbook of Rheumatology (9780323935364)
• ROSEN's Emergency Medicine (9780323757898)