# Initial DMARD Therapy in Rheumatoid Arthritis — ACR 2021

## Guiding Principles

1. RA requires early evaluation, diagnosis, and management
2. Treatment decisions should follow a shared decision-making process
3. Treatment decisions should be reevaluated within a **minimum of 3 months** based on efficacy and tolerability of the DMARD(s) chosen
4. Recommendations are limited to DMARDs approved by the US FDA
5. Biosimilars are considered equivalent to FDA-approved originator bDMARDs

## DMARD-Naive Patients with Moderate-to-High Disease Activity

### Methotrexate Monotherapy (Preferred First-Line)

- **Methotrexate monotherapy is strongly recommended over hydroxychloroquine, sulfasalazine, or the combination of these csDMARDs** (Strong recommendation, Very low/Low certainty)
- **Methotrexate monotherapy is strongly recommended over biologic DMARD or targeted synthetic DMARD monotherapy** (Strong recommendation, Very low/Moderate certainty)
- **Methotrexate monotherapy is strongly recommended over methotrexate plus non-TNF inhibitor bDMARD or tsDMARD** (Strong recommendation, Very low certainty)
- Methotrexate monotherapy is conditionally recommended over leflunomide (Conditional, Low certainty)
- Methotrexate monotherapy is conditionally recommended over dual or triple csDMARD therapy (Conditional, Moderate certainty)
- Methotrexate monotherapy is conditionally recommended over methotrexate plus TNF inhibitor combination (Conditional, Low certainty)

### Methotrexate Dose Optimization

- **Oral methotrexate is conditionally recommended over subcutaneous** for initial administration (Conditional, Moderate certainty) — ease of oral administration preferred despite evidence of superior subcutaneous efficacy
- **Initiate and titrate to a weekly dose of >=15 mg within 4-6 weeks** conditionally recommended over <15 mg per week (Conditional, Moderate/Very low certainty) — this refers only to initial prescribing and is not meant to limit further dose escalation (typical target: 20-25 mg/week)
- Folic acid supplementation (at least 1 mg daily or 5 mg weekly) should be co-prescribed with methotrexate

### Managing Methotrexate Intolerance

For patients not tolerating oral weekly methotrexate:

1. **Split-dose oral methotrexate over 24 hours** (Conditional, Very low certainty)
2. **Switch to weekly subcutaneous injections** (Conditional, Very low certainty)
3. **Increase dose of folic acid or folinic acid** (Conditional, Very low certainty)

All three strategies are conditionally recommended **over switching to alternative DMARDs**, and may be tried in combination.

### Switching for Inadequate Response on Oral Methotrexate

- **Switching to subcutaneous methotrexate is conditionally recommended over addition of or switching to alternative DMARDs** for patients on oral methotrexate not at target (Conditional, Very low certainty) — subcutaneous route has higher bioavailability and may rescue oral non-responders

## DMARD-Naive Patients with Low Disease Activity

For patients presenting with low disease activity, the treatment approach differs:

- **Hydroxychloroquine is conditionally recommended over other csDMARDs** (Conditional, Very low certainty) — better tolerated and has a more favorable risk profile
- **Sulfasalazine is conditionally recommended over methotrexate** (Conditional, Very low certainty) — less immunosuppressive
- **Methotrexate is conditionally recommended over leflunomide** when methotrexate is selected (Conditional, Very low certainty)

## Decision Algorithm: DMARD-Naive RA

1. **Assess disease activity** using a validated measure (DAS28, CDAI, SDAI)
   - If **low disease activity** -> Start hydroxychloroquine or sulfasalazine
   - If **moderate-to-high disease activity** -> Start methotrexate monotherapy
2. **Initiate methotrexate** at oral dose, titrate to >=15 mg/week within 4-6 weeks
3. **Reassess at 3 months**
   - If **at target** (low disease activity or remission) -> Continue current therapy
   - If **not at target on oral methotrexate** -> Switch to subcutaneous methotrexate before adding/switching DMARD
   - If **intolerant** -> Split dose, switch route, or increase folic/folinic acid
4. **If still not at target** after optimizing methotrexate -> Escalate to bDMARD or tsDMARD (see biologic_targeted_dmards section)

> **OpenMedicine Calculator:** `calculate_das28` — available via MCP for automated DAS28-ESR and DAS28-CRP scoring.

## Triple Therapy

Triple therapy is defined as hydroxychloroquine + sulfasalazine + either methotrexate or leflunomide. The guideline conditionally recommends methotrexate monotherapy over triple therapy for initial treatment of moderate-to-high disease activity RA. Triple therapy remains a viable option when biologics are not accessible or are declined.

## Conventional Synthetic DMARDs Summary

| csDMARD | Role in 2021 ACR Guideline |
|---|---|
| **Methotrexate** | Preferred first-line for moderate-to-high disease activity |
| **Hydroxychloroquine** | Preferred first-line for low disease activity |
| **Sulfasalazine** | Alternative first-line for low disease activity |
| **Leflunomide** | Alternative to methotrexate (conditionally less preferred) |

## Limitations

- The guideline does not specify exact starting doses for each csDMARD beyond the methotrexate >=15 mg/week titration target
- 41% of the 81 PICO questions had no identified evidence, so many recommendations are based on very low certainty evidence
- Recommendations removed the prior distinction between early and established RA subgroups
- The guideline does not address nonpharmacologic treatment approaches
