What is a DMARD (Disease-Modifying Antirheumatic Drug)?

Disease-Modifying Antirheumatic Drugs (DMARDs)

DMARDs are medications that modify the disease process in rheumatoid arthritis and other inflammatory conditions by slowing joint damage and improving long-term outcomes, unlike symptom-relieving treatments such as NSAIDs. 1

Classification of DMARDs

DMARDs are classified into three main categories:

• Conventional synthetic DMARDs (csDMARDs): Traditional medications including methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, and azathioprine 1, 2
• Biologic DMARDs (bDMARDs): Protein-based drugs targeting specific components of the immune system 1, 2
  • Biological original DMARDs (boDMARDs): Original biologic agents 2
  • Biosimilar DMARDs (bsDMARDs): Biosimilar versions of original biologics 2
• Targeted synthetic DMARDs (tsDMARDs): Small molecule drugs specifically developed to target particular molecular structures, such as JAK inhibitors 1, 2

Mechanism of Action

• csDMARDs work through various mechanisms to modify the disease process, including:
  • Methotrexate: Inhibits dihydrofolate reductase and adenosine release 3
  • Hydroxychloroquine: Changes intracellular pH to downregulate immune functions 3
  • Sulfasalazine: Decreases cytokine production and lymphocyte proliferation 3
• bDMARDs target specific components of the immune system:
  • TNF inhibitors (adalimumab, etanercept, infliximab, golimumab, certolizumab pegol): Block inflammatory cytokine TNF-α 1, 4
  • Other biologics target IL-1 receptor, IL-6 receptor, B lymphocytes, and T-cell costimulation 1
• tsDMARDs block intracellular signaling pathways:
  • JAK inhibitors (tofacitinib, baricitinib): Inhibit Janus kinase enzymes involved in inflammation 1, 2

Clinical Applications

DMARDs are primarily used in:

• Rheumatoid arthritis: Methotrexate is the anchor drug and first-line therapy 1, 5
• Psoriatic arthritis: Both csDMARDs and bDMARDs are effective 1
• Ankylosing spondylitis: bDMARDs show efficacy, particularly in patients who haven't responded to csDMARDs 1
• Juvenile idiopathic arthritis: DMARDs are recommended over NSAID monotherapy 5
• Other inflammatory conditions: Various autoimmune and inflammatory disorders 4

Treatment Strategies

• Early intervention: Early and continuous use of DMARDs is necessary to slow joint damage and improve long-term outcomes 6
• Treat-to-target approach: Adjusting therapy until reaching remission or low disease activity 1, 5
• Combination therapy: Often more effective than monotherapy, particularly in moderate to high disease activity 5, 1
• Step-up approach: Starting with methotrexate monotherapy and adding other DMARDs or biologics if response is inadequate 5

Common Treatment Algorithm for Rheumatoid Arthritis

1. Initial therapy: Methotrexate (rapid escalation to 25 mg/week) plus short-term glucocorticoids 5
2. If inadequate response after 3-6 months:
   • Without poor prognostic factors: Switch to or add another csDMARD 5
   • With poor prognostic factors (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs): Add bDMARD or tsDMARD 5
3. If still inadequate response: Switch to another bDMARD or tsDMARD 5
4. If sustained remission: Consider tapering bDMARDs 5

Limitations and Considerations

• Long-term treatment with DMARDs is frequently limited by loss of response and/or onset of serious adverse events 6
• TNF inhibitors require screening for tuberculosis and monitoring for infections 1
• Patients with comorbidities may require alternative treatment strategies, including dose adjustments and more careful monitoring 1
• Cost considerations may limit access to bDMARDs despite their efficacy and potentially fewer side effects compared to csDMARDs 4

Recent Developments

• The introduction of biosimilars has increased access to biologic therapies 2
• New tsDMARDs offer additional treatment options with different mechanisms of action 1, 2
• Combination DMARD strategies continue to be studied to optimize outcomes while minimizing side effects 7