What is the recommended treatment for rheumatoid arthritis?

Treatment for Rheumatoid Arthritis

Start methotrexate 15–25 mg weekly with folic acid immediately upon diagnosis, rapidly escalate to 25–30 mg weekly within a few weeks, add low-dose prednisone ≤10 mg daily for less than 3 months as a bridge, and reassess every 3 months to escalate therapy if remission or low disease activity is not achieved within 6 months. 1, 2, 3

Initial Disease-Modifying Therapy

Methotrexate is the anchor DMARD for all patients with active rheumatoid arthritis and must be initiated as soon as the diagnosis is confirmed; delays lead to irreversible joint damage. 1, 2, 3

• Start methotrexate at 15–25 mg weekly with folic acid 1 mg daily supplementation 1, 2, 3
• Rapidly titrate to the optimal dose of 25–30 mg weekly within a few weeks to maximize disease-modifying effect 1, 2, 3
• If oral methotrexate is not tolerated or ineffective after 3 months at 20–25 mg weekly, switch to subcutaneous administration before declaring treatment failure 1, 4
• When methotrexate is contraindicated, use leflunomide or sulfasalazine as first-line alternatives 1, 2, 3

Glucocorticoid Bridge Therapy

• Add low-dose oral prednisone ≤10 mg daily (or equivalent) for rapid symptom control while methotrexate takes effect 1, 2, 3
• Limit glucocorticoid duration to less than 3 months and use the lowest effective dose 1, 2, 3
• Taper prednisone as soon as disease control is achieved with DMARD optimization 1
• After 1–2 years, long-term corticosteroid risks (osteoporosis, fractures, cataracts, cardiovascular disease) outweigh benefits 1

High-dose corticosteroids alone are not disease-modifying therapy and do not prevent radiographic progression; NSAIDs provide only symptomatic relief without disease modification. 1

Treatment Targets and Monitoring Schedule

The primary therapeutic goal is clinical remission, defined as SDAI ≤3.3, CDAI ≤2.8, or ACR-EULAR Boolean criteria (≤1 tender joint, ≤1 swollen joint, CRP ≤1 mg/dL, patient global ≤1/10). 1, 2, 3

• If remission is unattainable, low disease activity (SDAI ≤11 or CDAI ≤10) is an acceptable alternative 1, 2, 3
• Assess disease activity every 1–3 months during active disease using composite measures (joint counts, patient/physician global assessments, ESR or CRP) 1, 2, 3
• Expect ≥50% improvement in disease activity within the first 3 months of therapy 1, 2, 3
• The treatment target must be reached within 6 months; failure mandates immediate escalation 1, 2, 3

Escalation Strategy for Inadequate Response

Patients Without Poor Prognostic Factors

• Add combination conventional synthetic DMARDs (triple therapy: methotrexate + sulfasalazine 500 mg twice daily titrated to 1000 mg twice daily + hydroxychloroquine 400 mg daily) 1, 2, 3
• Triple-DMARD therapy is particularly effective in patients with poor prognostic factors, yielding sustained improvement rates of approximately 77% versus 33% with methotrexate alone 1

Patients With Poor Prognostic Factors

Poor prognostic factors include high rheumatoid factor or anti-CCP titers, high baseline disease activity (DAS28 >5.1), early erosive changes, or failure of two conventional synthetic DMARDs. 1, 2

• Add a biologic DMARD or JAK inhibitor to methotrexate when inadequate response persists after 3–6 months of optimized conventional DMARD therapy 1, 2, 3
• TNF-α inhibitors (adalimumab, etanercept, infliximab, certolizumab pegol, golimumab) are the preferred first-line biologic agents 1, 2, 3
• Alternative biologic classes include IL-6 receptor antagonists (tocilizumab, sarilumab), T-cell costimulation modulators (abatacept), and rituximab (particularly for seropositive patients or those with prior lymphoma) 1, 2, 3
• JAK inhibitors (tofacitinib, baricitinib, upadacitinib) are appropriate when biologics are unsuitable or after biologic failure 1, 2, 3
• Biologic agents should be combined with methotrexate whenever possible because combination therapy demonstrates superior efficacy compared with biologic monotherapy 1, 2

Management After First Biologic Failure

• Switch to a biologic with a different mechanism of action rather than a second agent from the same class; registry and observational data show superior efficacy with a mechanism-switch 1, 2
• After failure of a first TNF inhibitor, either another TNF inhibitor or a biologic from a different class may be used, but a mechanism-switch is now preferred 1, 2
• Allow 3–6 months to fully assess the efficacy of any newly introduced biologic or targeted synthetic DMARD before making further therapeutic changes 1, 2
• Non-TNF biologics typically require up to 6 months to achieve maximal therapeutic effect 1

Mandatory Safety Screening Before Biologics

• Screen for tuberculosis (TST or IGRA such as QuantiFERON-TB Gold) before initiating any biologic DMARD 1, 2
• Screen for hepatitis B surface antigen, surface antibody, and core antibody; if core antibody is positive, initiate prophylactic antiviral therapy 1
• Administer age-appropriate vaccines, including recombinant herpes zoster vaccine, at least 2–4 weeks before the first biologic infusion; live vaccines are contraindicated after B-cell depletion 1, 2
• Assess for active infections, congestive heart failure (NYHA Class III-IV), and history of malignancy 2
• Rituximab may be preferred in patients with a history of lymphoproliferative malignancy 1, 2

Baseline Laboratory Assessment

• Obtain complete blood count with differential and platelet counts, hepatic enzymes, renal function tests, and chest X-ray before starting methotrexate 4
• During therapy, monitor hematology at least monthly and renal/liver function every 1–2 months 4
• Obtain baseline serum immunoglobulin levels (IgG, IgM, IgA) before rituximab to enable monitoring for hypogammaglobulinemia 1

De-Escalation in Sustained Remission

• When sustained remission is maintained for ≥1 year, cautious tapering of therapy can be considered, beginning with prednisone discontinuation followed by gradual reduction of DMARD dose 1, 2, 3
• Approximately 15–25% of patients may achieve sustained drug-free remission 1, 2, 3
• Factors associated with sustained drug-free remission include shorter symptom duration before treatment, absence of rheumatoid factor or anti-CCP antibodies, lower disease activity before achieving remission, and less baseline disability 2

Critical Pitfalls to Avoid

• Delaying DMARD initiation leads to irreversible joint damage—start treatment immediately upon diagnosis 1, 2, 3
• Using NSAIDs or corticosteroids alone provides only symptomatic relief without disease modification 1
• Undertreating with suboptimal methotrexate doses (<25 mg weekly) prevents achieving treatment targets 1
• Not escalating therapy when <50% improvement at 3 months or target not reached at 6 months allows ongoing joint damage to become irreversible 1, 2
• Continuing systemic corticosteroids beyond 1–2 years because cumulative adverse effects (fractures, cataracts, cardiovascular disease, osteoporosis) outweigh symptomatic benefits 1