Summary

The 2021 ACR guideline updates pharmacologic management of rheumatoid arthritis, covering csDMARDs, bDMARDs, tsDMARDs, glucocorticoids, and DMARD use in high-risk populations (liver disease, heart failure, lymphoproliferative disorder, prior serious infection, NTM lung disease). It includes 44 recommendations (7 strong, 37 conditional). Key changes from 2015 include initial hydroxychloroquine/sulfasalazine for low disease activity, removal of early-vs-established RA subgroups, and a strong push to minimize glucocorticoid exposure.

Key Recommendations

Methotrexate monotherapy is strongly recommended over hydroxychloroquine, sulfasalazine, bDMARD/tsDMARD monotherapy, or combination methotrexate plus a non-TNFi bDMARD/tsDMARD for DMARD-naive patients with moderate-to-high disease activity.
For DMARD-naive patients with low disease activity, hydroxychloroquine is preferred over other csDMARDs, sulfasalazine over methotrexate, and methotrexate over leflunomide.
Initiation of a csDMARD without longer-term (≥3 months) glucocorticoids is strongly recommended; short-term glucocorticoids should be limited to the lowest effective dose for the shortest duration.
Oral methotrexate is preferred initially over subcutaneous, with titration to ≥15 mg weekly within 4–6 weeks; switch to subcutaneous or split dosing (with increased folate) before changing DMARDs for intolerance.
A treat-to-target approach is strongly recommended over usual care in bDMARD/tsDMARD-naive patients; initial goal of low disease activity is preferred over remission.
For patients on maximally tolerated methotrexate not at target, add a bDMARD or tsDMARD (conditionally preferred over triple therapy); when switching for inadequate response, switch to a different class.
Before tapering, patients must be at target (low disease activity/remission) for ≥6 months; continue all DMARDs at current dose conditionally preferred over dose reduction, and dose reduction preferred over gradual discontinuation.
When tapering combination therapy, gradually discontinue methotrexate rather than the bDMARD/tsDMARD, and discontinue sulfasalazine rather than hydroxychloroquine in triple therapy.
In NYHA class III/IV heart failure, prefer a non-TNFi bDMARD or tsDMARD over a TNF inhibitor; switch off TNFi if heart failure develops.
Rituximab is preferred for patients with prior lymphoproliferative disorder for which rituximab is approved; prophylactic antiviral therapy is strongly recommended for HBcAb-positive patients starting rituximab (any HBsAg status) or any bDMARD/tsDMARD if also HBsAg-positive.
For prior serious infection within 12 months or NTM lung disease with inadequate csDMARD response, add csDMARDs rather than bDMARD/tsDMARD; if biologic needed in NTM, prefer abatacept and avoid TNF inhibitors.
Methotrexate is conditionally recommended in mild/stable lung disease and in NAFLD with normal LFTs and no advanced fibrosis (stage 3–4), with more frequent (every 4–8 weeks) monitoring.

Thresholds & Doses

Methotrexate target dose: ≥15 mg weekly, titrated within 4–6 weeks of initiation.
Short-term glucocorticoids defined as <3 months; longer-term as ≥3 months (strongly discouraged).
Treat-to-target reassessment: minimum every 3 months based on efficacy/tolerability.
Minimum duration at target (low disease activity or remission) before considering DMARD taper: 6 months.
Serious infection lookback window influencing DMARD choice: previous 12 months.
LFT monitoring interval for methotrexate in NAFLD patients: every 4–8 weeks.
Heart failure threshold for avoiding TNF inhibitors: NYHA class III or IV.
Hepatitis B prophylactic antiviral therapy indicated for HBcAb+ patients starting rituximab (regardless of HBsAg) or HBcAb+/HBsAg+ patients starting any bDMARD/tsDMARD.

Citations

Table 2 (DMARD initiation) — methotrexate monotherapy preference and glucocorticoid recommendations in DMARD-naive patients.
Table 3 (Methotrexate administration) — oral vs SC route, titration to ≥15 mg/week, strategies for intolerance.
Table 4 (Treat-to-target and treatment modification) — TTT strongly recommended, switch class for inadequate response, low disease activity as initial target.
Table 5 (Tapering/discontinuing DMARDs) — 6-month at-target rule, preferred tapering sequences.
Table 6 (Specific patient populations) — heart failure, lymphoproliferative disorder, hepatitis B, NAFLD, prior serious infection, NTM lung disease.
Table 1 (Guiding principles) — definitions of csDMARDs, bDMARDs, tsDMARDs, triple therapy, treat-to-target, serious infection.
Discussion section — rationale for bDMARD/tsDMARD over triple therapy after methotrexate failure and emphasis on minimizing glucocorticoids.
Table 7 — key clinical questions requiring further research (knowledge gaps in tapering, comorbidities, comparative bDMARD/tsDMARD safety).