What is the best approach to diagnose and manage a patient with suspected spondyloarthropathy, negative HLA-B27 (Human Leukocyte Antigen B27), and no bowel symptoms?

Diagnosis and Management of Suspected Spondyloarthropathy with Negative HLA-B27 and No Bowel Symptoms

In patients with suspected spondyloarthropathy who are HLA-B27 negative and lack bowel symptoms, proceed with clinical assessment using inflammatory back pain criteria and imaging with plain radiographs of sacroiliac joints first, followed by MRI if radiographs are normal, as HLA-B27 negativity does not exclude the diagnosis and occurs in 25-40% of axial spondyloarthritis cases. 1, 2, 3

Diagnostic Approach

Initial Clinical Assessment

Evaluate for inflammatory back pain characteristics before proceeding with imaging:

• Back pain onset before age 45 years that has persisted for more than 3 months 4, 1
• Morning stiffness lasting more than 30 minutes 4
• Pain that improves with movement but not with rest 4
• Waking at night due to back pain requiring movement for relief 4
• Buttock pain (may alternate sides) 4
• Pain improvement within 48 hours of NSAID use 4

Assess for peripheral and extra-articular manifestations:

• Peripheral arthritis (particularly large joints of lower limbs, often asymmetric) 5
• Enthesitis (especially heel pain) 5
• Dactylitis 1
• Current or previous psoriasis 4
• Acute anterior uveitis 4
• First-degree family history of spondyloarthritis 4, 1

Laboratory Testing

Obtain inflammatory markers to support the diagnosis:

• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) 6
• Use ASDAS-CRP score for disease activity assessment if axial disease is confirmed (cut-offs: ≤1.3 inactive, >1.3-≤2.1 low, >2.1-≤3.5 high, >3.5 very high activity) 4

Important caveat: HLA-B27 negativity does not exclude spondyloarthropathy, as 15-40% of patients with axial spondyloarthritis are HLA-B27 negative, and this proportion may be higher in certain ethnic populations 1, 2, 3

Imaging Strategy

Follow this algorithmic imaging approach:

1. Start with plain radiographs of sacroiliac joints and symptomatic spine regions 4, 6

   • Look for sacroiliitis meeting modified New York criteria (erosions, sclerosis, joint space changes) 4
   • Assess for syndesmophytes or other structural changes 4

2. If radiographs are normal but clinical suspicion remains high, proceed to MRI of sacroiliac joints without contrast 4

   • MRI is essential for identifying early inflammatory disease before radiographic changes develop 4
   • Request fluid-sensitive sequences (STIR or T2-weighted fat-saturated) specifically for spondyloarthropathy evaluation 4
   • Standard spine MRI protocols for disc disease may not include necessary fat suppression sequences 4

3. If sacroiliac joint MRI is negative but suspicion persists, consider MRI of the spine 4

   • Sagittal imaging is the optimal plane for evaluating axial spondyloarthritis spinal lesions 4
   • May reveal inflammatory changes not visible on sacroiliac imaging 4

Critical distinction: HLA-B27 negative patients have less frequent MRI inflammation of sacroiliac joints (OR 0.47) and spine (OR 0.63) compared to HLA-B27 positive patients, making imaging interpretation more challenging 3

Management Approach

Non-Pharmacologic Treatment

All patients with confirmed axial spondyloarthropathy require referral to a structured exercise program 4

• This is a first-line intervention regardless of HLA-B27 status 4

Pharmacologic Treatment Algorithm

For axial disease:

1. First-line: NSAIDs at the lowest effective dose 4

   • Trial for 2-4 weeks 4
   • If ineffective, switch to a different NSAID 4
   • COXIBs are acceptable for short courses (2-4 weeks) 4

2. Important limitation: Sulfasalazine and methotrexate are NOT effective for purely axial disease 4

   • Do not use these agents for axial manifestations 4

3. If NSAIDs fail, advance to TNF inhibitors 4

   • Infliximab or adalimumab are first-line biologic options 4
   • Certolizumab pegol is also effective 4
   • Avoid etanercept as it may trigger inflammatory bowel disease 4

4. If primary non-response to TNF inhibitor, switch to JAK inhibitors 4

For peripheral disease:

1. Corticosteroid injections for monoarthritis 4
2. Standard DMARDs (sulfasalazine 2-3 g/day or methotrexate) for polyarthritis or persistent monoarthritis 4
3. Add NSAIDs at lowest effective dose if needed 4
4. If DMARD fails after 3 months at maximum tolerable dose, advance to TNF inhibitors 4

Key Clinical Pearls

HLA-B27 negative patients differ from HLA-B27 positive patients in several ways:

• Later age at symptom onset (mean 2.6 years older) 3
• Longer diagnostic delay (mean 1 year longer) 3
• Higher frequency of psoriasis 3
• Less severe radiographic damage and fewer marginal syndesmophytes 7
• Less symmetric syndesmophyte distribution 7

Common diagnostic pitfalls to avoid:

• Do not dismiss spondyloarthropathy diagnosis based solely on negative HLA-B27, as 25-40% of cases are HLA-B27 negative 1, 2, 3
• Do not use standard spine MRI protocols; specifically request sequences for inflammatory arthropathy evaluation 4
• Do not prescribe sulfasalazine or methotrexate for axial symptoms, as they lack efficacy 4
• Do not delay imaging if clinical criteria are met, as early diagnosis prevents irreversible structural damage 4

Referral indications:

• Refer to rheumatology if patient has back pain since before age 45 lasting >3 months plus at least 4 inflammatory features, or 3 features with positive HLA-B27 4
• Immediate ophthalmology referral for any eye pain or redness suggesting uveitis 4