Seronegative Arthritis: Types and Classification
Seronegative arthritis encompasses two distinct categories: seronegative rheumatoid arthritis (SNRA), which lacks RF and anti-CCP antibodies but otherwise meets RA criteria, and the seronegative spondyloarthropathies, which include ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis, enteropathic arthritis, and some forms of juvenile chronic arthritis. 1, 2
Primary Categories
Seronegative Rheumatoid Arthritis (SNRA)
- Definition: RA without rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPA) in serum 3
- Clinical presentation: Can manifest as oligoarthritis of large joints or symmetrical polyarthritis affecting small joints (MCPs, PIPs, wrists) 4
- Diagnostic challenge: Ultrasonography should be used to confirm inflammatory activity when clinical assessment is uncertain 5
Seronegative Spondyloarthropathies
These conditions share common features: HLA-B27 association, sacroiliitis/spondylitis, inflammatory peripheral arthritis, enthesopathy, and absence of rheumatoid factor 2, 6:
Ankylosing spondylitis: Primarily affects axial skeleton, strongly HLA-B27 associated, occurs earlier in HLA-B27 positive patients, predominantly affects men 6
Reactive arthritis (Reiter's syndrome): Oligoarthritis of large joints (knees, ankles, wrists) that can present with conjunctivitis, urethritis, and back pain suggestive of sacroiliitis 4
Psoriatic arthritis: Seronegative oligo or polyarthritis starting in medium/large joints, characterized by synovitis with tendon and entheses involvement, with or without erosions 4
Enteropathic arthritis: Associated with inflammatory bowel disease (Crohn's disease and ulcerative colitis) 1, 6
Undifferentiated spondyloarthropathies: Cases not fitting specific diagnostic criteria 6
Treatment Approach for Seronegative Rheumatoid Arthritis
First-Line Therapy
- Methotrexate 15-25 mg/week as cornerstone therapy 5
- Triple DMARD therapy (methotrexate + sulfasalazine + hydroxychloroquine) for moderate to high disease activity 4, 5
Biologic Selection Based on Seronegative Status
Critical distinction: Seronegative patients respond better to abatacept or tocilizumab rather than rituximab after inadequate response to anti-TNF agents 4, 5
- TNF inhibitors: First-line biologic option (maximum 2 trials) 4
- Abatacept (CTLA4:Ig): Preferred for seronegative patients with inadequate anti-TNF response 4, 5
- Tocilizumab (anti-IL-6R): Preferred for seronegative patients with inadequate anti-TNF response 4, 5
- Avoid rituximab: Less effective in seronegative patients 4, 5
Treatment for Spondyloarthropathies
- NSAIDs and physical therapy: Standard initial treatment 2
- DMARDs: Methotrexate, azathioprine for peripheral arthritis 6
- TNF-α antagonists: Effective for both ocular and systemic manifestations 6
- Anti-IL-17A monoclonal antibodies: Particularly for ankylosing spondylitis 6
Monitoring and Reassessment
Timing
- Reassess after 3-6 months of new treatment to evaluate efficacy 4, 5
- Maximum effect may not appear until 6 months in many patients 7
- If no improvement after 3-4 weeks of initial therapy, escalate treatment 4
Tools
- Ultrasonography: Use when clinical assessment is challenging to confirm inflammatory activity 5
- Inflammatory markers (ESR, CRP): Usually highly elevated in immune-related arthritis, useful for differentiation 4
- Disease activity scores: SDAI, CDAI, or DAS28-ESR for monitoring 4
Critical Pitfalls
Misdiagnosis risk: SNRA can be underdiagnosed, potentially missing the "window of opportunity" for early treatment and better prognosis 3. The possibility of misdiagnosis or coexistent mimicking disease should always be considered 5.
Differential diagnoses to exclude: Degenerative joint disease, crystal arthropathies (gout, pseudogout), septic arthritis, rotator cuff tendinitis, fibromyalgia, and statin-induced myopathy 4
Corticosteroid use: Low-dose prednisone (≤10 mg/day) may be used cautiously if needed, but long-term use beyond 1-2 years carries significant risks including cataracts, osteoporosis, fractures, and cardiovascular disease 4, 5