What are the initial treatment recommendations, including doses and potential side effects, for an adult patient with rheumatoid arthritis?

Treatment Guidelines for Rheumatoid Arthritis

First-Line Treatment Strategy

Methotrexate should be initiated immediately upon diagnosis of rheumatoid arthritis as the anchor drug, combined with short-term low-dose glucocorticoids as bridging therapy. 1, 2

Methotrexate Dosing and Administration

• Initial dose: Start at 15 mg weekly, escalate to 25 mg weekly (oral or subcutaneous) within 4-8 weeks based on tolerability 3
• Folic acid supplementation: 1-5 mg daily or 5 mg weekly to reduce side effects 3
• Route: Subcutaneous administration may be more effective than oral if inadequate response 3
• Maximum dose: Do not exceed 25 mg weekly; doses above 5 mg/kg actual body weight increase retinopathy risk with hydroxychloroquine 4

Glucocorticoid Bridging Therapy

• Dose: Low-dose prednisone ≤10 mg/day (or equivalent) 1, 2
• Duration: Up to 6 months maximum 1, 2
• Tapering: Taper as rapidly as clinically feasible, ideally within 3 months 1, 2
• Rationale: Provides rapid symptom control while waiting 6-12 weeks for methotrexate to become effective 1, 2

Alternative First-Line Agents (When Methotrexate Contraindicated)

If methotrexate is contraindicated or not tolerated early, use sulfasalazine or leflunomide as the first-line DMARD. 1, 2

Sulfasalazine Dosing

• Initial dose: 500 mg daily
• Escalation: Increase by 500 mg weekly to target dose of 2000-3000 mg/day in divided doses 5

Leflunomide Dosing

• Loading dose: 100 mg daily for 3 days (optional, increases side effects)
• Maintenance dose: 10-20 mg daily 5

Hydroxychloroquine Dosing

• Dose for RA: 200-400 mg daily (single or divided doses) 4
• Maximum safe dose: Do not exceed 5 mg/kg actual body weight daily to minimize retinopathy risk 4
• Administration: Take with food or milk; do not crush tablets 4

Monitoring Requirements

Disease activity must be assessed every 1-3 months during active disease using validated composite measures (DAS28, SDAI, or CDAI). 1, 2

Treatment Adjustment Timeline

• At 3 months: If no improvement, therapy must be adjusted 1, 2
• At 6 months: If treatment target not reached, therapy must be escalated 1, 2
• Treatment target: Remission or low disease activity 1, 2

Laboratory Monitoring for Methotrexate

• Baseline: Complete blood count (CBC), liver function tests (AST, ALT), creatinine, hepatitis B and C screening 1
• Ongoing: CBC and liver function tests every 2-4 weeks for first 3 months, then every 8-12 weeks if stable 1

Treatment Escalation Strategy

For Patients Without Poor Prognostic Factors

If methotrexate monotherapy fails, switch to another conventional synthetic DMARD (sulfasalazine, leflunomide, or hydroxychloroquine) or add these to methotrexate as combination therapy. 1, 2

• Triple therapy option: Methotrexate + sulfasalazine + hydroxychloroquine has 61% probability of ACR50 response 6
• Dual therapy options: Methotrexate + leflunomide or methotrexate + hydroxychloroquine 1, 6

For Patients With Poor Prognostic Factors

Add a biologic DMARD to methotrexate if poor prognostic factors are present (high disease activity, positive rheumatoid factor/anti-CCP, early erosive disease). 1, 2

Biologic DMARD Options (All Combined with Methotrexate)

• TNF inhibitors: Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab 1
• Non-TNF biologics: Abatacept, tocilizumab, rituximab 1
• Probability of response: 56-70% ACR50 response with biologic + methotrexate combinations 6

Abatacept Dosing (Example Biologic)

• Intravenous: Weight-based dosing: <60 kg = 500 mg, 60-100 kg = 750 mg, >100 kg = 1000 mg 7
• Frequency: At weeks 0,2,4, then every 4 weeks 7
• Subcutaneous alternative: 125 mg weekly after optional IV loading dose 7

After First Biologic Failure

If the first biologic DMARD fails, switch to another biologic DMARD—either a different TNF inhibitor or a biologic with a different mechanism of action (abatacept, tocilizumab, rituximab). 1

After Biologic Failure

Tofacitinib (JAK inhibitor) may be considered after biologic treatment has failed. 1

• Dose: 5 mg twice daily 1
• Efficacy: ACR20 response odds ratio 2.44 vs placebo, 2.38 vs methotrexate 1

Major Side Effects and Monitoring

Methotrexate

• Common: Nausea, stomatitis, elevated liver enzymes, alopecia 3, 5
• Serious: Hepatotoxicity, bone marrow suppression, pneumonitis, teratogenicity 3, 5
• Monitoring: CBC and liver enzymes every 2-4 weeks initially, then every 8-12 weeks 1

Hydroxychloroquine

• Serious: Retinopathy (dose-dependent), cardiomyopathy, QT prolongation 4
• Monitoring: Baseline ophthalmologic exam, then annually after 5 years of use 4
• Cardiac monitoring: ECG if cardiac risk factors present 4

Sulfasalazine

• Common: Gastrointestinal upset, rash 5
• Serious: Bone marrow suppression, hepatotoxicity 5
• Monitoring: CBC and liver enzymes every 2-4 weeks for 3 months, then every 3 months 1

Leflunomide

• Common: Diarrhea, elevated liver enzymes, alopecia 5
• Serious: Hepatotoxicity, bone marrow suppression, teratogenicity 5
• Monitoring: CBC and liver enzymes every 2-4 weeks for 6 months, then every 8 weeks 1

Glucocorticoids

• Short-term: Hyperglycemia, hypertension, mood changes, insomnia 1
• Long-term: Osteoporosis, cataracts, weight gain, increased infection risk, cardiovascular disease 1, 2
• Avoidance strategy: Taper and discontinue within 6 months to minimize cumulative toxicity 1, 2

Biologic DMARDs

• Serious infections: Increased risk of bacterial, viral, fungal, and opportunistic infections 1
• Tuberculosis reactivation: Screen all patients before initiating biologics 1
• Malignancy: Possible increased risk of lymphoma with TNF inhibitors 1
• Infusion/injection reactions: Common with IV biologics 1

Contraindications

Methotrexate Absolute Contraindications

• Pregnancy or breastfeeding 3
• Chronic liver disease or excessive alcohol use 3
• Immunodeficiency syndromes 3
• Pre-existing blood dyscrasias 3
• Severe renal impairment (GFR <30 mL/min) 3

Hydroxychloroquine Contraindications

• Known hypersensitivity to 4-aminoquinoline compounds 4
• Pre-existing retinopathy 4
• Congenital or acquired QT prolongation 4
• Uncorrected hypokalemia or hypomagnesemia 4

Biologic DMARD Contraindications

• Active serious infections 1
• Untreated latent tuberculosis 1
• Active hepatitis B or C (relative contraindication, requires specialist management) 1
• Severe congestive heart failure (NYHA class III/IV) for TNF inhibitors 1
• Recent malignancy (within 5 years, except non-melanoma skin cancer) 1
• Demyelinating disease for TNF inhibitors 1

Special Populations

Hepatitis B or C

• Screening required: Test all patients for hepatitis B surface antigen, core antibody, and hepatitis C antibody before starting DMARDs or biologics 1
• Management: Hepatitis B carriers require antiviral prophylaxis before biologic therapy; hepatitis C patients may use biologics with specialist consultation 1

Tuberculosis Screening

• Required before biologics: Tuberculin skin test or interferon-gamma release assay, chest X-ray 1
• Latent TB treatment: Complete at least 1 month of isoniazid therapy before starting biologics 1

Vaccination

• Live vaccines: Contraindicated during biologic or tofacitinib therapy 1
• Inactivated vaccines: Pneumococcal, influenza, hepatitis B recommended before starting immunosuppressive therapy 1
• Timing: Administer vaccines at least 2-4 weeks before starting biologics when possible 1

Tapering and Discontinuation

Prerequisites for Tapering

Tapering should only be considered after achieving persistent remission or low disease activity for at least 6 months. 8, 2

Tapering Sequence

1. First: Taper and discontinue glucocorticoids completely 8, 2
2. Second: Taper biologic DMARDs before conventional synthetic DMARDs 8, 2
3. Third: Consider tapering methotrexate only after biologics discontinued and remission sustained 8, 2

Methotrexate Tapering Approach

• Method: Reduce dose by 50% initially rather than stopping completely 8
• Monitoring: Assess disease activity every 1-3 months during tapering 8
• If flare occurs: Immediately return to previous effective dose 8

Common Pitfalls and Caveats

• Delayed treatment initiation: Starting DMARDs within 3 months of symptom onset is critical for preventing irreversible joint damage 1, 2
• Inadequate methotrexate dosing: Many patients receive suboptimal doses; escalate to 25 mg weekly before declaring treatment failure 3
• Prolonged glucocorticoid use: Never continue glucocorticoids beyond 6 months due to cumulative toxicity; taper aggressively 1, 2
• Combining biologics: Never combine two biologic DMARDs due to excessive infection risk without added benefit 1, 9
• Ignoring treat-to-target: Failure to monitor disease activity every 1-3 months and adjust therapy leads to poor outcomes 1, 2
• NSAIDs as monotherapy: NSAIDs only control symptoms and do not prevent joint damage; always use DMARDs as primary therapy 2, 5
• Premature tapering: Attempting to reduce DMARDs before achieving 6 months of sustained remission increases flare risk 8, 2