What are the initial and subsequent treatment options for rheumatoid arthritis, including conventional synthetic Disease-Modifying Antirheumatic Drugs (DMARDs) and biologic DMARDs?

Rheumatoid Arthritis Drug Treatment

Start methotrexate immediately upon RA diagnosis, rapidly escalating to 20-25 mg weekly with folic acid supplementation, combined with low-dose glucocorticoids (≤10 mg/day prednisone) for up to 6 months as bridging therapy. 1, 2

Initial Treatment Strategy

First-Line Therapy: Methotrexate

• Methotrexate (MTX) is the anchor drug and must be part of the first treatment strategy for all patients with active RA 1, 2
• Start at 7.5-10 mg weekly and rapidly escalate to 20-25 mg weekly within 4-6 weeks 2
• Always prescribe folic acid supplementation to reduce side effects 2
• Consider subcutaneous administration if higher doses needed or gastrointestinal side effects occur (85% ACR20 response vs 77% oral) 2
• Maximum therapeutic effect achieved after 4-6 months 2

Alternative First-Line Options (MTX Contraindications/Intolerance)

• If MTX is contraindicated or not tolerated early, use leflunomide or sulfasalazine as the first-line csDMARD 1, 2

Glucocorticoid Bridging Therapy

• Add low-dose glucocorticoids (≤10 mg/day prednisone equivalent) for up to 6 months while awaiting DMARD effect 1, 2
• Taper glucocorticoids as rapidly as clinically feasible 1, 2
• Glucocorticoids retard radiographic progression but should never be used as monotherapy 2

Treatment Monitoring and Escalation Timeline

Monitoring Schedule

• Monitor disease activity every 1-3 months during active disease 1, 2
• If no improvement by 3 months, adjust therapy immediately 1, 2
• If treatment target not reached by 6 months, escalate therapy 1, 2

Treatment Target

• Aim for remission or low disease activity in every patient (treat-to-target approach) 1, 2

Treatment Escalation Algorithm

Step 2: After MTX Monotherapy Failure at 3-6 Months

Without Poor Prognostic Factors:

• Switch to another csDMARD strategy (leflunomide, sulfasalazine, or triple therapy: MTX + sulfasalazine + hydroxychloroquine) 1

With Poor Prognostic Factors (autoantibodies, high disease activity, early erosions):

• Add a biologic DMARD (bDMARD) or targeted synthetic DMARD (tsDMARD) to MTX 1, 2
• Poor prognostic factors include: RF or anti-CCP positivity, high disease activity, early erosions, or failure of two csDMARDs 1, 2

Step 3: Biologic DMARD Selection (First bDMARD)

First-line bDMARDs (all combined with MTX):

• TNF inhibitors: adalimumab, certolizumab pegol, etanercept, golimumab, infliximab (including biosimilars) 1, 2
• Non-TNF biologics: abatacept, tocilizumab, sarilumab 1
• Rituximab: under certain circumstances (history of lymphoma, demyelinating disease, or previous lymphoproliferative disorder) 1, 3
• JAK inhibitors (tsDMARDs): tofacitinib, baricitinib, filgotinib, upadacitinib 1, 2

All bDMARDs show comparable efficacy when combined with MTX 1, 4

Step 4: After First bDMARD Failure

• Switch to another bDMARD with a different or same mechanism of action 1
• If first TNF inhibitor fails, can use another TNF inhibitor or switch to different mechanism (abatacept, rituximab, tocilizumab, sarilumab) 1
• JAK inhibitors may be considered after biologic treatment failure 1

Special Population Considerations

Infection Risk

• Screen for tuberculosis before initiating any bDMARD or tsDMARD 2
• For serious infection within previous 12 months: prefer csDMARDs over bDMARDs/tsDMARDs 2
• For nontuberculous mycobacterial lung disease: use csDMARDs; if bDMARD needed, prefer abatacept over TNF inhibitors 2

Cardiovascular Disease

• For heart failure (NYHA class III or IV), avoid TNF inhibitors; use non-TNF bDMARDs or tsDMARDs instead 2

Hepatitis B

• For hepatitis B core antibody positive patients starting rituximab or other bDMARDs, provide prophylactic antiviral therapy 2, 3
• Rituximab carries risk of hepatitis B reactivation 3

Malignancy History

• For previous lymphoproliferative disorder, rituximab is preferred over other DMARDs 2

Tapering Strategy in Sustained Remission

Glucocorticoid Tapering

• Taper glucocorticoids first after achieving remission 1

bDMARD Tapering

• After persistent remission and glucocorticoid tapering, consider tapering bDMARDs (dose reduction or interval prolongation), especially when combined with csDMARD 1
• Most data available for TNF inhibitors, but applies to other biologics 1

csDMARD Tapering

• In sustained long-term remission, cautious reduction of csDMARD dose may be considered as shared decision with patient 1
• Never stop DMARDs completely even in sustained remission 1

Critical Pitfalls to Avoid

• Delaying DMARD initiation: Start immediately upon diagnosis to prevent irreversible joint damage 1, 2
• Inadequate MTX dosing: Failure to rapidly escalate to therapeutic doses (20-25 mg weekly) 2
• Omitting folic acid supplementation: Leads to unnecessary MTX side effects 2
• Prolonged glucocorticoid use: Taper as rapidly as possible due to cumulative toxicity 1, 2
• Insufficient monitoring: Must assess every 1-3 months and adjust therapy if no improvement by 3 months 1, 2
• Using bDMARDs without MTX backbone: Combination therapy superior to monotherapy for most biologics 1, 2, 4
• Ignoring comorbidities: Adjust DMARD selection based on infection history, heart failure, hepatitis B status 2