Disease-Modifying Antirheumatic Drugs (DMARDs)
Definition:
DMARDs are a group of drugs used primarily to slow down the progression of autoimmune
diseases, particularly rheumatoid arthritis (RA), by modifying the underlying disease process
rather than just treating symptoms.
1. Mechanism of Action (General Overview):
• DMARDs work by suppressing the overactive immune response seen in
autoimmune diseases.
• They reduce inflammation, prevent joint and tissue damage, and slow disease
progression.
• The exact mechanisms vary depending on the specific drug.
2. Classification of DMARDs:
A. Conventional Synthetic DMARDs (csDMARDs)
These are older, chemically synthesized drugs.
Examples:
1. Methotrexate (First-line DMARD for RA)
• Mechanism: Inhibits dihydrofolate reductase (DHFR), reducing DNA synthesis
and cell proliferation.
• Uses: Rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD).
• Side effects: Hepatotoxicity, myelosuppression, mucositis, pulmonary fibrosis,
teratogenicity.
• Monitoring: Regular liver function tests and CBC.
2. Sulfasalazine
• Mechanism: Metabolized into 5-aminosalicylic acid (5-ASA) and sulfapyridine,
which reduce inflammation.
• Uses: RA, ulcerative colitis.
• Side effects: GI distress, rash, hepatotoxicity, hemolytic anemia (in G6PD
deficiency).
3. Leflunomide
• Mechanism: Inhibits dihydroorotate dehydrogenase, blocking pyrimidine
synthesis, reducing T-cell proliferation.
• Uses: RA.
• Side effects: Hepatotoxicity, diarrhea, alopecia, teratogenicity.
4. Hydroxychloroquine
• Mechanism: Inhibits antigen presentation and reduces cytokine production.
• Uses: RA, systemic lupus erythematosus (SLE).
• Side effects: Retinopathy (irreversible), GI upset, skin pigmentation changes.
• Monitoring: Regular eye exams.
B. Biologic DMARDs (bDMARDs)
These are genetically engineered proteins targeting specific immune system components.
They are usually given parenterally (IV or subcutaneously).
Examples:
1. Tumor Necrosis Factor-alpha (TNF-α) Inhibitors:
• Infliximab (IV)
• Etanercept (Subcutaneous)
• Adalimumab (Subcutaneous)
• Mechanism: Neutralize TNF-α, a pro-inflammatory cytokine.
• Side effects: Increased risk of infections (e.g., TB reactivation), malignancies.
• Screening: TB screening before initiation.
2. Interleukin Inhibitors:
• Anakinra: IL-1 receptor antagonist.
• Tocilizumab: IL-6 receptor antagonist.
• Side effects: Infections, elevated liver enzymes.
3. B-cell Depleting Agents:
• Rituximab: Monoclonal antibody against CD20 on B-cells.
• Uses: RA, lymphoma.
• Side effects: Infusion reactions, increased risk of infections.
4. T-cell Co-stimulation Modulators:
• Abatacept: Inhibits T-cell activation.
• Side effects: Increased infection risk.
C. Targeted Synthetic DMARDs (tsDMARDs)
These are small molecule inhibitors designed to target intracellular signaling pathways.
Examples:
1. Tofacitinib
• Mechanism: Inhibits Janus Kinase (JAK) pathway.
• Uses: Moderate to severe RA.
• Side effects: Infections, increased cholesterol levels.
2. Baricitinib
• Similar to Tofacitinib, inhibits JAK-STAT pathway.
• Uses: RA.
3. Indications for DMARDs:
• Rheumatoid Arthritis (RA) (Primary indication)
• Psoriatic arthritis
• Systemic lupus erythematosus (SLE)
• Ankylosing spondylitis
• Inflammatory bowel disease (IBD)
4. Adverse Effects of DMARDs (General):
• Myelosuppression: Risk of anemia, leukopenia, thrombocytopenia.
• Hepatotoxicity: Regular liver function monitoring is essential.
• Increased infection risk: Due to immunosuppressive effects.
• Teratogenicity: Especially Methotrexate and Leflunomide.
• GI disturbances: Nausea, diarrhea.
• Specific risks: Retinopathy (Hydroxychloroquine), TB reactivation (TNF
inhibitors).
5. Monitoring Requirements for DMARDs:
• CBC: To monitor for myelosuppression.
• Liver function tests (LFTs): To check for hepatotoxicity.
• Kidney function tests: Especially for drugs with renal clearance.
• TB Screening: Before starting TNF-α inhibitors.
• Ophthalmologic exams: For Hydroxychloroquine.
6. Key Points to Remember:
• Methotrexate is the first-line DMARD for RA.
• Biologic DMARDs are often used in methotrexate-resistant cases.
• Hydroxychloroquine is safer in pregnancy.
• Screening for TB is essential before starting biologics.
• Combination therapy (e.g., Methotrexate + Biologic DMARD) is common in
severe cases.
DMARDs require careful monitoring and long-term management, as they are not quick-acting
drugs—it can take weeks to months for full therapeutic effects to be observed.
