What are the recommended treatments for rheumatoid arthritis, including disease-modifying antirheumatic drugs (DMARDs) and biologic agents?

Recommended Treatments for Rheumatoid Arthritis

Methotrexate is the anchor drug and first-line therapy for rheumatoid arthritis, started immediately upon diagnosis at 7.5-10 mg weekly and rapidly escalated to 20-25 mg weekly within 4-6 weeks, combined with folic acid supplementation and short-term low-dose glucocorticoids (≤10 mg/day prednisone equivalent) as bridging therapy. 1

Initial Treatment Strategy

First-Line DMARD Therapy

• Start methotrexate immediately upon RA diagnosis to prevent joint damage and disability, as therapy with DMARDs should be initiated without delay 1
• Rapidly escalate methotrexate from 7.5-10 mg weekly to 20-25 mg weekly (or 16 mg in Asian populations) within 4-6 weeks to achieve optimal dosing 1
• Always prescribe folic acid supplementation with methotrexate to reduce side effects—this is a critical step that should never be omitted 1
• Consider subcutaneous administration if higher doses are needed or gastrointestinal side effects occur, as it shows higher ACR20 response rates (85%) compared to oral administration (77%) 1

Adjunctive Glucocorticoid Therapy

• Add low-dose glucocorticoids (≤10 mg/day prednisone equivalent) as temporary bridging therapy for up to 6 months while waiting for DMARD effect, then taper as rapidly as clinically feasible 2, 1
• Glucocorticoids should never be used as monotherapy for disease modification—they serve only as adjunctive therapy 1

Alternative First-Line Options

• For patients with contraindications or early intolerance to methotrexate, use leflunomide or sulfasalazine as alternative first-line csDMARDs 2, 1

Treatment Monitoring and Escalation Algorithm

Monitoring Schedule

• Monitor disease activity every 1-3 months during active disease using composite measures 2, 1
• If no improvement by 3 months or target not reached by 6 months, therapy must be adjusted 2, 1
• The treatment target is clinical remission or, if remission is unlikely to be achievable, at least low disease activity 2

Phase II: Adding Biologic or Targeted Synthetic DMARDs

When to escalate:

• Inadequate response to methotrexate monotherapy after 3 months in patients with poor prognostic factors (RF/ACPA positive, especially at high levels; very high disease activity; early joint damage) 2, 1

Biologic DMARD options (preferably with methotrexate):

• TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab or FDA/EMA approved biosimilars) are the preferred first biologic agents 2, 1
• Alternative biologics include abatacept (T-cell costimulation blocker), tocilizumab (IL-6 receptor inhibitor), or rituximab (B-cell depleting agent) 2
• JAK inhibitors (tsDMARDs) can be used after failure of biologics, though efficacy and safety after tofacitinib failure was not sufficiently studied at the time of the 2013 EULAR update 2

Phase III: Switching Biologic Therapy

After failure of first biologic DMARD:

• Switch to a second TNF inhibitor with methotrexate, OR 2
• Switch to a different mechanism of action: abatacept, rituximab, or tocilizumab (all combined with methotrexate) 2, 1
• After failure of two biologics, JAK inhibitors can be considered, though data on their use after failure of abatacept, rituximab, and tocilizumab was limited 2

Special Population Considerations

Patients with Comorbidities

• Serious infection within previous 12 months: Addition of/switching to DMARDs is preferred over glucocorticoid escalation 1
• Heart failure (NYHA class III or IV): Use non-TNF inhibitor biologics or tsDMARDs instead of TNF inhibitors 1
• Hepatitis B infection: Prophylactic antiviral therapy is strongly recommended when initiating rituximab or other biologics in hepatitis B core antibody positive patients 3
• Previous lymphoproliferative disorder: Rituximab is conditionally recommended over other DMARDs 1
• Nontuberculous mycobacterial lung disease: Add csDMARDs over biologics/tsDMARDs; if biologics needed, abatacept is preferred 1

Important Safety Considerations

• Screen for tuberculosis before initiating TNF inhibitors and monitor for infections during therapy 1
• Avoid live vaccines during biologic DMARD therapy; patients should be brought up-to-date with non-live vaccines at least 4 weeks prior to initiating biologics 4, 3
• Do not combine biologics with other biologic DMARDs (e.g., anakinra, abatacept) or other TNF blockers due to increased risk of serious infections without added benefit 4, 3
• Methotrexate reduces apparent adalimumab clearance but does not require dose adjustment, and actually enhances TNF inhibitor efficacy while reducing neutralizing antibody development 1, 4

Common Pitfalls to Avoid

• Failing to rapidly escalate methotrexate to therapeutic doses (20-25 mg weekly) within 4-6 weeks—underdosing is a frequent cause of apparent treatment failure 1
• Neglecting folic acid supplementation with methotrexate, leading to unnecessary side effects and discontinuation 1
• Using glucocorticoids as monotherapy or continuing them beyond 6 months—they should only serve as temporary bridging therapy 1
• Delaying treatment escalation beyond 3 months without improvement or 6 months without reaching target—early aggressive treatment prevents irreversible joint damage 2, 1
• Inadequate monitoring frequency—active disease requires assessment every 1-3 months, not every 6-12 months 2, 1