What are the next steps if a patient has a negative Human Leukocyte Antigen B27 (HLA-B27) result but still suspects ankylosing spondylitis or another spondyloarthritis?

Next Steps After Negative HLA-B27 Test in Suspected Spondyloarthritis

A negative HLA-B27 test does not rule out ankylosing spondylitis or other spondyloarthritides, and clinical evaluation with appropriate imaging should proceed based on symptoms and clinical suspicion. 1

Diagnostic Approach for HLA-B27 Negative Patients

Clinical Assessment

• Focus on key clinical features despite negative HLA-B27:
  • Inflammatory back pain (pain that improves with activity, worsens with rest)
  • Morning stiffness lasting >30 minutes
  • Symptom onset before age 45
  • Pain duration >3 months
  • Nocturnal awakening due to pain
  • Buttock pain
  • Response to NSAIDs within 48 hours
  • Extra-articular manifestations (uveitis, psoriasis, inflammatory bowel disease)
  • Family history of spondyloarthritis

Imaging Studies

1. Radiography of sacroiliac joints:

   • First-line imaging for mature skeletons
   • If sacroiliitis meets modified New York criteria, diagnosis can be confirmed
   • If negative but clinical suspicion remains high, proceed to MRI 1

2. MRI of sacroiliac joints and spine:

   • Critical for HLA-B27 negative patients
   • Can detect early inflammatory changes before radiographic damage
   • Follow-up MRI may be warranted when diagnosis remains uncertain 1

3. For peripheral symptoms:

   • Radiography of hands and feet
   • Consider ultrasonography if radiographs are inconclusive 1

Laboratory Testing

• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)
  • May be normal in spondyloarthritis; negative results do not exclude diagnosis 1
• Consider additional autoantibody testing to rule out other rheumatic conditions

Referral Criteria

Refer to rheumatologist if patient has:

• Back pain onset before age 45
• Pain duration >3 months
• Plus at least 4 of the following:
  • Back pain onset before age 35
  • Waking at night due to pain
  • Buttock pain
  • Improvement with movement/NSAIDs
  • First-degree relative with spondyloarthritis
  • Current/previous arthritis, enthesitis, or psoriasis 1

Management Approach

Non-pharmacological

• Structured exercise program (referral to physical therapy specialist)
• Smoking cessation
• Regular physical activity 1

Pharmacological

• First-line: NSAIDs at lowest effective dose with regular monitoring
• If ineffective after 2-4 weeks, try alternative NSAID
• For peripheral symptoms: consider corticosteroid injections for monoarthritis
• For polyarthritis: standard DMARDs may be indicated 1

Important Considerations in HLA-B27 Negative Disease

• Diagnostic delay is common in HLA-B27 negative patients 2
• The proportion of HLA-B27 negative patients may be higher among:
  • Non-white populations
  • Those with non-radiographic axial spondyloarthritis 2
• Disease activity parameters (ESR, CRP) do not significantly differ between HLA-B27 positive and negative patients 3

Monitoring for Complications

• Regular assessment of disease activity using validated tools
• Monitor for extra-articular manifestations, particularly:
  • Uveitis (immediate ophthalmology referral for eye pain/redness) 1
  • Cardiac complications (aortic regurgitation and conduction abnormalities) 4

Key Pitfalls to Avoid

1. Dismissing diagnosis based solely on negative HLA-B27

   • Up to 78% of patients with clinical features of ankylosing spondylitis may be HLA-B27 negative in some populations 3

2. Relying exclusively on radiography

   • Early disease may not show radiographic changes
   • MRI is essential for detecting early inflammation 1

3. Waiting for definitive radiographic changes

   • Leads to delayed diagnosis and treatment
   • Early intervention may prevent irreversible structural damage 5

4. Overlooking peripheral manifestations

   • Enthesitis and peripheral arthritis may be the predominant features in some patients 1