What is the recommended initial treatment for rheumatoid arthritis in an adult, including a conventional synthetic disease-modifying antirheumatic drug (DMARD), a nonsteroidal anti-inflammatory drug (NSAID), and low‑dose glucocorticoid, and how should therapy be escalated if disease activity remains high?

Rheumatoid Arthritis Treatment

Initial Treatment for DMARD-Naïve Patients with Moderate-to-High Disease Activity

Start methotrexate monotherapy immediately at 15 mg weekly, rapidly escalate to 25 mg weekly within 4–6 weeks, and add short-term low-dose glucocorticoids (≤10 mg/day prednisone-equivalent) for less than 3 months as bridging therapy. This approach is strongly recommended by the American College of Rheumatology over other conventional synthetic DMARDs, biologic monotherapy, or initial combination therapy. 1

Methotrexate Optimization

• Initiate methotrexate at 15–25 mg weekly with folic acid supplementation (1 mg daily or 5 mg weekly) and escalate to the optimal dose of 25–30 mg weekly within a few weeks. 1, 2
• Oral administration is conditionally recommended over subcutaneous for initial therapy. 1
• If oral methotrexate at 20–25 mg weekly is not tolerated or ineffective after 3 months, switch to subcutaneous administration before declaring treatment failure. 1, 2
• For patients experiencing gastrointestinal intolerance to oral methotrexate, consider split dosing over 24 hours or subcutaneous injection, and/or increase folic/folinic acid supplementation. 1

Glucocorticoid Bridging Strategy

• Add low-dose prednisone (≤10 mg/day or equivalent) at treatment initiation for rapid symptom control while methotrexate takes effect. 1, 2
• Use the lowest effective dose for the shortest duration—ideally less than 3 months—and taper as rapidly as clinically feasible. 1, 2
• Longer-term glucocorticoid use (≥3 months) is strongly discouraged; after 1–2 years, cumulative toxicities (osteoporosis, fractures, cataracts, cardiovascular disease) outweigh benefits. 1, 2
• Glucocorticoids provide symptomatic relief but are not disease-modifying and do not prevent radiographic progression when used alone. 2, 3

NSAIDs as Adjunctive Therapy

• NSAIDs may be continued for additional symptomatic relief after initiating methotrexate, but they provide only pain control and do not alter disease progression or prevent joint destruction. 2, 3
• Use NSAIDs at the minimum effective dose for the shortest time possible after evaluating gastrointestinal, renal, and cardiovascular risks. 4
• Continuing NSAID monotherapy beyond 1–2 months in patients with active arthritis is inappropriate because it fails to address the underlying autoimmune pathology. 2

Treatment Targets and Monitoring

The primary therapeutic goal is sustained clinical remission, defined by SDAI ≤3.3, CDAI ≤2.8, or ACR-EULAR Boolean criteria (≤1 tender joint, ≤1 swollen joint, CRP ≤1 mg/dL, patient global ≤1 on 0–10 scale). 2, 3

• If remission is not attainable, low disease activity (SDAI ≤11 or CDAI ≤10) is an acceptable alternative, particularly in patients with long-standing disease. 2, 3
• Assess disease activity every 1–3 months during active disease using validated composite measures (tender/swollen joint counts, patient and physician global assessments, ESR/CRP). 2, 3
• Expect at least 50% improvement in disease activity within the first 3 months of therapy; failure to achieve this warrants immediate escalation. 2, 3
• The treatment target must be reached within 6 months; if not, therapy must be escalated or modified. 1, 2, 3

Escalation Strategy for Inadequate Response

Patients Without Poor Prognostic Factors

If the treatment target is not reached with methotrexate monotherapy after 3–6 months and no poor prognostic factors are present, switch to an alternative conventional synthetic DMARD strategy before introducing biologic therapy. 1, 2

• Consider triple therapy (methotrexate + sulfasalazine + hydroxychloroquine) as a conventional DMARD combination option. 2, 3
• Under tight-control conditions, combination conventional DMARD therapy yields outcomes comparable to immediate biologic escalation in patients lacking poor prognostic markers. 1, 2

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 on imaging, or failure of two conventional synthetic DMARDs. 2, 3

Add a biologic DMARD or JAK inhibitor to methotrexate when an inadequate response persists after 3–6 months of optimized conventional DMARD therapy. 1, 2, 3

First-Line Biologic Selection

• TNF-α inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, and approved biosimilars) 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 anti-CD20 antibody (rituximab—after TNF inhibitor failure or in patients with prior lymphoproliferative disorder). 1, 2, 3
• JAK inhibitors (tofacitinib, baricitinib, upadacitinib) are acceptable options when biologics are unsuitable or after biologic failure; pooled analysis shows tofacitinib is more efficacious than placebo (ACR20 response OR 2.44) or methotrexate (ACR20 response OR 2.38). 1, 2
• Biologic agents and JAK inhibitors should be combined with methotrexate whenever possible because combination therapy demonstrates superior efficacy compared with biologic monotherapy. 1, 2, 3

After First Biologic Failure

• Switch to a biologic with a different mechanism of action if the initial biologic fails; registry and observational data show superior efficacy with a mechanism-switch. 2, 3
• After failure of a first TNF inhibitor, either another TNF inhibitor or a biologic from a different class may be used, though a mechanism-switch is now preferred. 1, 2, 3
• Allow 3–6 months to fully assess the efficacy of any newly introduced biologic or targeted synthetic DMARD before making further therapeutic changes. 2, 3

De-Escalation in Sustained Remission

When sustained remission (SDAI ≤3.3 or CDAI ≤2.8) is maintained for at least 6 months, cautious tapering of therapy can be considered. 1, 2

• Taper medications in the following sequence: first glucocorticoids, then biologics/JAK inhibitors, and finally conventional synthetic DMARDs. 2, 3
• Biologic or JAK inhibitor tapering (dose reduction or interval prolongation) may be attempted after glucocorticoid discontinuation and once remission is sustained, especially when combined with a conventional DMARD. 2
• Approximately 15–25% of patients may achieve sustained drug-free remission. 2, 3
• Tapering in low disease-activity states (rather than strict remission) carries a higher flare risk and is not advised. 2, 3

Critical Pitfalls to Avoid

• Delaying DMARD initiation leads to irreversible joint damage and poorer functional prognosis; treatment must commence immediately upon diagnosis. 2, 3, 5, 6
• Undertreating with suboptimal methotrexate doses (<25 mg weekly) prevents achieving treatment targets. 2, 3
• Not escalating therapy when <50% improvement is observed at 3 months or the target is not reached at 6 months permits unchecked irreversible joint damage. 2, 3
• Continuing systemic corticosteroids beyond 1–2 years leads to cumulative toxicity (fractures, cataracts, cardiovascular disease, osteoporosis) that outweighs symptomatic benefits. 2, 3
• Relying on NSAIDs or corticosteroids as sole therapy in established rheumatoid arthritis permits unchecked irreversible joint damage. 2, 3