Disease-Modifying Antirheumatic Drugs

DMARDs Overview - RheumaRiders Kickoff

• DMARDs: Disease-Modifying Antirheumatic Drugs; aim to alter the underlying rheumatic disease process.
• Goals of Therapy:
  • Achieve remission or low disease activity.
  • Prevent structural joint damage & long-term disability.
  • Improve Quality of Life (QoL).
• General Principles:
  • Early diagnosis and prompt initiation.
  • Treat-to-target strategy.
  • Regular monitoring for efficacy and adverse effects.
• Broad Classification:
  • csDMARDs (Conventional Synthetic)
  • bDMARDs (Biologic: original & biosimilars)
  • tsDMARDs (Targeted Synthetic)

⭐ Methotrexate is the cornerstone DMARD for most Rheumatoid Arthritis patients, often initiated first-line unless contraindicated.

csDMARDs - Old Guard Allies

• Methotrexate (MTX): 📌 'Mother Of All DMARDs'
  • MoA: Inhibits DHFR, AICAR transformylase → ↑adenosine.
  • Dose: Weekly.
  • Supplement: Folic acid (reduces ADRs).
  • ADRs: Oral ulcers, hepatotoxicity, myelosuppression, pneumonitis.
  • Contra: Pregnancy, liver disease.
• Leflunomide:
  • MoA: Inhibits dihydroorotate dehydrogenase → ↓pyrimidine synthesis.
  • ADRs: Hepatotoxicity, teratogenicity, diarrhea.
  • Elimination: Cholestyramine wash-out.
• Sulfasalazine (SSZ):
  • MoA: Prodrug → 5-ASA (anti-inflammatory) + sulfapyridine (antibacterial/immunomodulatory).
  • ADRs: GI upset, rash, oligospermia (reversible), yellow-orange skin/urine.
• Hydroxychloroquine (HCQ):
  • MoA: ↑lysosomal pH, ↓TLR signaling.
  • ADRs: Retinal toxicity ('bull's eye maculopathy'), GI upset, skin pigmentation.
  • Monitor: Regular ophthalmologic exam.

⭐ MTX is the anchor drug for rheumatoid arthritis and is often the first csDMARD prescribed.

Table: Comparative Overview of csDMARDs

bDMARDs - BioLogic Blockers

• Anti-TNF-α Agents: Infliximab (chimeric mAb), Etanercept (fusion protein), Adalimumab (human mAb), Golimumab (human mAb), Certolizumab pegol (pegylated Fab' fragment).
  • MoA: Neutralize TNF-α.
  • ADRs: Injection site/infusion reactions, ↑risk of infections (esp. TB reactivation, fungal), demyelination, worsening HF, drug-induced lupus.
  • Screening: TB, HBV, HCV.

  ⭐ Pre-treatment screening for TB (latent & active), HBV, and HCV is crucial before starting anti-TNF-α therapy due to risk of reactivation.

• Rituximab (Anti-CD20 mAb):
  • MoA: Depletes B-cells.
  • Uses: RA refractory to anti-TNF agents.
  • ADRs: Infusion reactions, PML, HBV reactivation.
• Abatacept (CTLA4-Ig):
  • MoA: T-cell co-stimulation modulator.
  • ADRs: ↑infections; ⚠️ avoid with TNF-α inhibitors.
• Tocilizumab/Sarilumab (Anti-IL-6R mAb):
  • MoA: Block IL-6 receptor.
  • ADRs: ↑infections, dyslipidemia, ↑LFTs, neutropenia, GI perforation.
• Anakinra (IL-1 receptor antagonist):
  • Less commonly used in RA.

tsDMARDs & Combos - Tiny Targets, Team Tactics

• JAK Inhibitors (tsDMARDs)
  • Oral: Tofacitinib, Baricitinib, Upadacitinib.
  • MoA: Inhibit Janus kinases (JAKs) → ↓cytokine signaling.
  • ADRs: ⚠️ ↑Serious infections (Herpes Zoster, TB), hyperlipidemia, cytopenias, ↑thrombosis, malignancy. FDA Boxed Warnings.
  • Monitoring: Lipids, CBC, LFTs (baseline & periodic).
• Combination DMARDs
  • Strategy: MTX + bDMARD or MTX + other csDMARDs.
  • ⚠️ Avoid combining two bDMARDs (↑immunosuppression).
• General DMARD Monitoring
  • Baseline: CBC, LFTs, renal fx, ESR/CRP, viral (HBV/HCV/TB) screen.
  • Periodic: For efficacy & toxicity.
• DMARDs in Special Populations
  • Pregnancy:
    • Safer: HCQ, SSZ.
    • Contraindicated: MTX, Leflunomide.
  • Breastfeeding:
    • Generally compatible: HCQ, SSZ.
    • Avoid: MTX, Leflunomide.

⭐ Tofacitinib (a JAK inhibitor) carries FDA Boxed Warnings for serious infections, MACE, malignancy, and thrombosis.

High‑Yield Points - ⚡ Biggest Takeaways

• Methotrexate (MTX): first-line DMARD for RA; folic acid supplementation is crucial.
• Leflunomide: inhibits dihydroorotate dehydrogenase; an alternative to MTX.
• Hydroxychloroquine (HCQ): monitor for retinal toxicity (bull's eye maculopathy).
• Sulfasalazine: used in RA and IBD; side effects include hemolysis in G6PD deficiency.
• TNF-α inhibitors (e.g., Infliximab, Adalimumab): screen for latent TB before starting.
• Tofacitinib: an oral JAK inhibitor, for RA refractory to other DMARDs_._