Rheumatoid Arthritis (RA) - Treatment

Overarching Principle: Treat-to-Target

• Early, accurate diagnosis
• Early DMARD therapy (essentially all RA patients should receive a DMARD)
• Strive for remission in all patients
• Monitor carefully for treatment toxicities
• Address comorbid conditions (cardiovascular disease, infection risk, osteoporosis)

1. NSAIDs

• Should never be used as sole therapy without a concurrent DMARD
• COX-2 selective agents (e.g., celecoxib) are preferred for GI safety but carry cardiovascular risk - use at the lowest effective dose
• A proton pump inhibitor should be co-prescribed in all RA patients on NSAIDs
• Watch for renal effects and blood pressure elevation

2. Glucocorticoids

• Prednisone is most commonly used; rarely exceed 10 mg/day for articular disease
• At ≤5 mg/day of prednisolone, add-on therapy is appropriate in patients >65 years
• Slowly taper to the lowest effective dose; the ultimate goal is to discontinue
• Intra-articular glucocorticoid injections are useful for individual inflamed joints (ultrasound guidance helps)
• Intramuscular depot injections are used to manage flares or during initial DMARD escalation
• Higher doses may be needed for extra-articular manifestations (vasculitis, scleritis)

3. Conventional Synthetic DMARDs (csDMARDs)

Methotrexate (MTX) - Anchor Drug

• Drug of choice and benchmark for all RA therapies
• Dose: 7.5-25 mg/week orally or subcutaneously (SQ preferred for better bioavailability)
• Mechanism at RA doses: stimulates adenosine release → anti-inflammatory effect
• Folic acid 1 mg/day must be co-prescribed to reduce toxicities
• Monitoring: CBC, LFTs, creatinine every 2-3 months; chest X-ray at baseline

Hydroxychloroquine (HCQ)

• Dose: 200-400 mg/day (max 5 mg/kg/day to reduce retinal risk)
• Does not delay radiographic progression - not a true DMARD in the strictest sense
• Used for early/mild disease or as adjunct in combination regimens
• Key toxicity: irreversible retinal damage - monitor with OCT and visual fields annually
• Also: cardiotoxicity (QT prolongation), blood dyscrasia

Sulfasalazine (SSZ)

• Dose: Start 500 mg twice daily, maintenance 1000-1500 mg twice daily (2-3 g/day total)
• Shown to reduce joint inflammation and radiographic progression in RCTs
• Monitoring: CBC every 2-4 weeks for first 3 months, then every 3 months; check G6PD level

Leflunomide

• Dose: 10-20 mg/day
• Inhibitor of pyrimidine synthesis; efficacy similar to methotrexate
• Effective as monotherapy or in combination with MTX
• Serious toxicities: hepatotoxicity, myelosuppression, teratogenicity (Category X - requires cholestyramine washout before conception)

Triple Therapy

Other Conventional DMARDs

• Azathioprine: 1-2.5 mg/kg/day; generally second-line
• Minocycline: 100 mg twice daily; modest effect, used in mild/seropositive disease

4. Biologic DMARDs (bDMARDs)

Anti-TNF Agents (First-line biologics)

• TB screening (PPD or IGRA) is mandatory before initiating any TNF inhibitor
• If latent TB is found, treat with isoniazid for at least 4 weeks before starting biologic

Abatacept (T-cell co-stimulation blocker)

• Mechanism: blocks CD80/CD86-CD28 interaction (CTLA4-Ig fusion protein), preventing T-cell activation
• Dose: 500-1000 mg IV at weeks 0, 2, 4, then every 4 weeks (also available SQ)
• Effective in patients who failed MTX or anti-TNF therapy
• Generally better tolerated in terms of infection risk vs. TNF inhibitors

Rituximab (Anti-CD20, B-cell depletion)

• Mechanism: depletes CD20+ B cells
• Dose: Two 1000 mg IV infusions, 2 weeks apart (one course), every 16-24 weeks; used with MTX
• Preferred in patients with prior lymphoma, latent TB concerns, or anti-TNF failure
• Requires hepatitis B screening before use (risk of reactivation)

IL-6 Receptor Inhibitors

• Tocilizumab: 4 mg/kg IV every 4 weeks, increased to 8 mg/kg; also available SQ
• Sarilumab: SQ every 2 weeks
• Can be used as monotherapy (unlike most other biologics which work best with MTX)
• Monitor: LFTs, lipids, neutrophil count; risk of bowel perforation

IL-1 Inhibitor

• Anakinra (IL-1Ra): 100 mg SQ daily; less commonly used for RA today

5. Targeted Synthetic DMARDs (tsDMARDs) - JAK Inhibitors

• Effective in MTX-inadequate responders and biologic-inadequate responders
• Important safety note: JAK inhibitors carry boxed warnings for serious infections (including TB and herpes zoster), major adverse cardiovascular events (MACE), venous thromboembolism, and malignancy risk - particularly in patients >50 years with cardiovascular risk factors. Use with caution in this population.

6. Step-up Treatment Algorithm

Step 1: Newly diagnosed RA
   → Start Methotrexate ± short-term bridging glucocorticoid
   → Reassess in 3-6 months

Step 2: Inadequate response to MTX monotherapy
   → Add HCQ + SSZ (Triple therapy), OR
   → Add a biologic DMARD (anti-TNF preferred first-line), OR
   → Add a JAK inhibitor

Step 3: Inadequate response to first biologic/JAK inhibitor
   → Switch to different mechanism biologic (e.g., anti-TNF → abatacept or rituximab or IL-6i), OR
   → Switch within the same class (different anti-TNF)

Step 4: Refractory RA
   → Combination strategies, clinical trials, specialist referral

7. Non-Pharmacological Measures

• Physical therapy: Range-of-motion exercises, strengthening
• Occupational therapy: Joint protection techniques, assistive devices
• Patient education: Disease self-management, smoking cessation (smoking worsens RA)
• Orthopedic surgery: Synovectomy, tendon repair, joint replacement for refractory joint damage

8. Monitoring & Comorbidity Management

Recent Evidence Update