Disease-Modifying Antirheumatic Drugs

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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) DMARD Classifications and FDA-Approved Drugs for RA

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

csDMARDs - Old Guard Allies

Methotrexate structure and mechanism

  • 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

FeatureMethotrexateLeflunomideSulfasalazineHydroxychloroquine
MoADHFR inhibitor, ↑adenosineDihydroorotate dehydrogenase inhibitorProdrug (5-ASA + sulfapyridine)↑lysosomal pH, ↓TLR signaling
Key ADRsMyelosuppression, hepatotoxicity, oral ulcersHepatotoxicity, teratogenicity, diarrheaGI upset, rash, oligospermiaRetinal toxicity, GI upset
MonitoringCBC, LFTs, renal functionLFTs, BPCBC, LFTsOphthalmologic exam
PregnancyCategory XCategory XCategory B (folate needed)Generally considered safe (Cat C debated)

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.

Biologic DMARDs mechanisms of action

tsDMARDs & Combos - Tiny Targets, Team Tactics

JAK-STAT signaling pathways

  • 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_._
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Practice Questions: Disease-Modifying Antirheumatic Drugs

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Drug X is useful in the treatment of rheumatoid arthritis. It is available only in the parenteral formulation and its mechanism of action is antagonism of tumor necrosis factor. Which of the following can be X?

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Flashcards: Disease-Modifying Antirheumatic Drugs

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_____ may be contraindicated during the 3rd trimester of pregnancy due to risk of premature closure of the ductus arteriosus

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_____ may be contraindicated during the 3rd trimester of pregnancy due to risk of premature closure of the ductus arteriosus

NSAIDs

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Disease-Modifying Antirheumatic ... - Free Indian Medical PG