What are the biologic therapies and direct contraindications for Seronegative Rheumatoid Arthritis (SNRA) and Seropositive Rheumatoid Arthritis (SPRA)?

Biologic Therapies for Rheumatoid Arthritis (Seronegative and Seropositive)

Available Biologic Agents

Both seronegative (SNRA) and seropositive (SPRA) rheumatoid arthritis are treated with the same biologic agents, though treatment selection may be guided by serostatus. 1

TNF-α Inhibitors

• Infliximab (chimeric monoclonal antibody) 1
• Adalimumab (fully human monoclonal antibody) 1
• Etanercept (fusion protein) 1
• Golimumab (monoclonal antibody) 1
• Certolizumab pegol (PEGylated antibody fragment) 1

Non-TNF Biologics

• Abatacept (CTLA4-Ig, T-cell costimulation modulator) 1
• Rituximab (anti-CD20 monoclonal antibody) 1
• Tocilizumab (anti-IL-6 receptor monoclonal antibody) 1
• Sarilumab (anti-IL-6 receptor monoclonal antibody) 1, 2
• Anakinra (IL-1 receptor antagonist) 1

JAK Inhibitors (Targeted Synthetic DMARDs)

• Tofacitinib 1, 2
• Baricitinib 1, 2

Serostatus-Guided Selection

For Seropositive RA (RF+ or Anti-CCP+)

• Rituximab is particularly appropriate as rheumatoid factor, anti-citrullinated protein antibodies, or elevated serum IgG predict favorable response 1, 2

For Seronegative RA (RF- and Anti-CCP-)

• Abatacept or tocilizumab are preferred over rituximab in seronegative patients with inadequate response to one or more anti-TNF drugs 1, 2

Direct Contraindications by Agent

All TNF-α Inhibitors (Infliximab, Adalimumab, Etanercept, Golimumab, Certolizumab)

• Active tuberculosis or untreated latent tuberculosis 2, 3
• Active serious infections (including sepsis, opportunistic infections) 4, 3, 5
• Moderate to severe heart failure (NYHA Class III/IV) 4, 3
• Demyelinating disorders (multiple sclerosis, optic neuritis) 4
• Hypersensitivity to the specific agent or its components 4

Etanercept (Specific Additional Considerations from FDA Label)

• Concurrent use with anakinra is contraindicated due to 7% rate of serious infections versus 0% with etanercept alone 4
• Concurrent use with abatacept is contraindicated due to increased serious adverse events without added benefit 4
• Concurrent cyclophosphamide therapy is not recommended 4
• Active inflammatory bowel disease (etanercept is not effective for IBD and rare cases have been reported) 4

Rituximab

• Active serious infections 2
• Untreated chronic hepatitis B 2
• Treated hepatitis B with Child-Pugh Class B or higher 2
• Should not be used in RA patients who have not had prior inadequate response to one or more TNF antagonists (per FDA label) 2
• History of progressive multifocal leukoencephalopathy 5

Abatacept

• Active serious infections 2, 6
• Concurrent use with TNF inhibitors is contraindicated due to increased serious adverse events 4
• Concurrent use with anakinra is not recommended 4
• Hypersensitivity to abatacept or its components 6

Tocilizumab and Sarilumab (IL-6 Receptor Antagonists)

• Active serious infections 2, 7
• Absolute neutrophil count <2000/mm³ 7
• Platelet count <100,000/mm³ 7
• ALT or AST >1.5 times upper limit of normal 7
• History of gastrointestinal perforation or diverticulitis 7
• Hypersensitivity to the agent 7

Anakinra (IL-1 Receptor Antagonist)

• Active serious infections 1, 4
• Concurrent use with TNF inhibitors is contraindicated due to 7% serious infection rate 4
• Neutropenia (ANC <1 × 10⁹/L) 4
• Hypersensitivity to E. coli-derived proteins 8

JAK Inhibitors (Tofacitinib, Baricitinib)

• Active serious infections including tuberculosis 1, 2
• Absolute lymphocyte count <500 cells/mm³ 1
• Hemoglobin <9 g/dL 1
• Absolute neutrophil count <1000 cells/mm³ 1
• Concurrent use with biologic DMARDs 1

Universal Screening Requirements Before Initiating Any Biologic

• Tuberculosis screening (TST or IGRA) is mandatory regardless of risk factors 2, 3
• Hepatitis B and C screening is required before starting any biologic 2, 3
• Pneumococcal, influenza, and hepatitis B vaccinations should be administered before biologic initiation 3
• Live vaccines are contraindicated during biologic therapy 4, 3

Special Population Considerations

Relative Contraindications Requiring Careful Assessment

• History of lymphoproliferative malignancy (rituximab may be preferred) 2
• Previously treated solid malignancy within 5 years (except non-melanoma skin cancer) 2
• Previously treated melanoma 2, 4
• Nontuberculous mycobacterial lung disease 2
• Liver disease (avoid tocilizumab/sarilumab if transaminases elevated) 2, 7

Pregnancy Considerations

• Certolizumab pegol has specific indication for pregnancy due to proven safety with low placental transfer 1, 4
• Etanercept shows low placental transfer in third trimester but theoretical risks exist for live vaccine administration to exposed infants 4

Critical Pitfalls to Avoid

• Never combine two biologic agents simultaneously due to dramatically increased infection risk without added benefit 4
• Do not use rituximab as first-line biologic - FDA label requires prior inadequate response to at least one TNF inhibitor 2
• Avoid long-term glucocorticoid use beyond 1-2 years due to risks of cataracts, osteoporosis, fractures, and cardiovascular disease 1, 2
• Screen for tuberculosis annually in all patients on biologics, not just at initiation 3
• Do not delay switching biologics - if no improvement by 3 months or inadequate response by 6 months, adjust therapy 2, 7
• Temporarily discontinue therapy with significant varicella exposure and consider varicella zoster immune globulin prophylaxis 4