What are the treatment options for rheumatoid arthritis (RA)?

Rheumatoid Arthritis Treatment

Start methotrexate immediately upon diagnosis at 15 mg weekly, rapidly escalate to 20-25 mg weekly within 4-6 weeks, and add short-term low-dose glucocorticoids (≤10 mg/day prednisone) as bridging therapy for the first 3 months. 1, 2, 3

First-Line Treatment Strategy

Methotrexate is the anchor drug for rheumatoid arthritis treatment and should be initiated as soon as the diagnosis is made to prevent irreversible joint damage. 4, 1

Methotrexate Dosing

• Start at 7.5-10 mg weekly and rapidly escalate to the optimal therapeutic dose of 20-25 mg weekly (or maximum tolerated dose) within 4-6 weeks. 1, 2
• If oral methotrexate at doses >15 mg/week causes gastrointestinal side effects or shows inadequate response, switch to subcutaneous methotrexate, which has superior bioavailability at higher doses and better tolerability. 5
• Always prescribe folic acid supplementation with methotrexate to reduce side effects. 6

Bridging Glucocorticoid Therapy

• Add low-dose glucocorticoids (≤10 mg/day prednisone equivalent) when starting methotrexate in patients with moderate or high disease activity to provide rapid symptomatic relief while waiting for DMARDs to take effect. 4, 1, 2
• Limit glucocorticoid duration to less than 3 months and taper as rapidly as clinically feasible to avoid long-term complications including cataracts, osteoporosis, and cardiovascular disease. 1, 2, 3

Alternative First-Line Agents

• For patients with contraindications to methotrexate (such as liver disease, significant alcohol use, or pregnancy), use leflunomide, sulfasalazine, or injectable gold as alternative first-line DMARDs. 4, 3

Treat-to-Target Monitoring

Monitor disease activity every 1-3 months using validated measures (SDAI, CDAI, or DAS28) and escalate therapy if remission or low disease activity is not achieved within 3-6 months. 4, 1, 2, 3

• The treatment target is clinical remission; if remission is not achievable, aim for at least low disease activity. 4
• If no improvement is seen within 3 months or the target is not reached by 6 months, therapy must be adjusted. 3

Treatment Escalation for Inadequate Methotrexate Response

Triple DMARD Therapy Option

• If methotrexate monotherapy fails after 3 months in patients without poor prognostic factors (absence of rheumatoid factor/anti-CCP antibodies, lower disease activity, no early erosions), consider adding sulfasalazine 500 mg twice daily and hydroxychloroquine 200 mg twice daily to methotrexate (triple therapy). 4, 1, 7
• Triple DMARD therapy achieved 77% response rates compared to 33% with methotrexate alone in a landmark trial. 7

Biologic DMARD or JAK Inhibitor Addition

• For patients with poor prognostic factors (presence of rheumatoid factor or anti-CCP antibodies, high disease activity, early erosions, or failure of two conventional synthetic DMARDs), add a biologic DMARD or JAK inhibitor to methotrexate. 4, 1, 2, 3

TNF inhibitors are the preferred first biologic agents and should be combined with methotrexate for optimal efficacy. 4, 1, 8

• Available TNF inhibitors include adalimumab, etanercept, infliximab, golimumab, and certolizumab pegol. 4, 1, 2, 8, 9
• Methotrexate reduces the apparent clearance of adalimumab and decreases immunogenicity, improving long-term efficacy. 9
• Concomitant methotrexate, glucocorticoids, salicylates, NSAIDs, or analgesics may be continued during treatment with etanercept. 8

Pre-Biologic Screening Requirements

• Screen for tuberculosis using TST or IGRA before initiating any biologic therapy, regardless of risk factors. 1, 2, 8
• Screen for hepatitis B and C before initiating biologics; do not use rituximab in untreated chronic hepatitis B. 1, 2
• Complete all age-appropriate vaccinations before starting biologics, and avoid live vaccines during biologic therapy. 8, 9

Management After First Biologic Failure

If the first TNF inhibitor fails, switch to either another TNF inhibitor (effective in 50-70% of cases) or a non-TNF biologic with a different mechanism of action. 4, 1

Non-TNF Biologic Options

• Abatacept (T-cell costimulation modulator): May be more effective in seronegative patients. 1
• Tocilizumab or sarilumab (IL-6 receptor antagonists): Effective as monotherapy and in combination with methotrexate; tocilizumab may be the most effective biologic as monotherapy. 1, 10
• Rituximab (anti-CD20 antibody): Particularly appropriate for rheumatoid factor-positive or anti-CCP-positive patients, and preferred in patients with history of lymphoproliferative malignancy or previously treated solid malignancy. 4, 1

JAK Inhibitor Option

• Tofacitinib and baricitinib are oral JAK inhibitors that have shown efficacy in patients with inadequate response to TNF inhibitors, though long-term safety data is limited. 1, 10

Contraindicated Combinations

• Do not combine TNF inhibitors with anakinra or abatacept due to increased risk of serious infections without added benefit. 9
• Do not use concomitant biologic DMARDs or multiple TNF blockers together. 9

Special Population Considerations

• For patients with heart failure (NYHA class III or IV), use non-TNF inhibitor biologics or JAK inhibitors instead of TNF inhibitors, as TNF inhibitors can worsen heart failure. 2
• For patients with hepatitis B infection who are hepatitis B core antibody positive, provide prophylactic antiviral therapy when initiating rituximab. 2
• For patients with liver disease, avoid methotrexate and consider leflunomide or sulfasalazine. 4

Treatment Tapering in Sustained Remission

• For patients in sustained remission for at least 6 months, consider cautious de-escalation of therapy through shared decision-making, typically tapering biologics first, then reducing conventional DMARDs. 4, 1, 2, 3
• Approximately 15-25% of patients may achieve sustained drug-free remission, particularly those with shorter symptom duration, absence of rheumatoid factor or anti-CCP antibodies, lower disease activity before remission, and less baseline disability. 1, 2, 3
• Most patients will require some ongoing DMARD therapy to maintain remission. 3

Common Pitfalls to Avoid

• Inadequate methotrexate dosing (using <15 mg/week) or failing to escalate to 20-25 mg/week before declaring treatment failure. 1, 5
• Not switching to subcutaneous methotrexate when oral methotrexate at higher doses causes side effects or shows suboptimal response. 5
• Prolonging glucocorticoid use beyond 3 months without appropriate monitoring for adverse effects including cataracts, osteoporosis, and cardiovascular disease. 1, 2
• Delaying DMARD initiation, which leads to irreversible joint damage and worse long-term outcomes. 6
• Failing to adjust therapy when treatment targets are not met within 3-6 months. 1, 2
• Not screening for tuberculosis and hepatitis before initiating biologic therapy. 1, 2, 8
• Using TNF inhibitors in patients with NYHA class III or IV heart failure. 2