What are Disease-Modifying Antirheumatic Drugs (DMARDs)?

Disease-Modifying Antirheumatic Drugs (DMARDs)

Disease-modifying antirheumatic drugs (DMARDs) are medications that slow or halt the progression of rheumatoid arthritis and other inflammatory arthritis conditions by targeting the underlying disease process rather than just relieving symptoms. 1

Classification of DMARDs

DMARDs are classified into several categories:

• Conventional synthetic DMARDs (csDMARDs): These include methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, and azathioprine 2, 1

• Biologic DMARDs (bDMARDs): These are protein-based drugs that target specific components of the immune system, including:

  • TNF inhibitors (adalimumab, etanercept, infliximab, golimumab, certolizumab pegol) 2, 3
  • Other biologics targeting IL-1 receptor, IL-6 receptor, B lymphocytes, and T-cell costimulation 2

• Targeted synthetic DMARDs (tsDMARDs): These include Janus kinase (JAK) inhibitors, which are small molecule drugs that work intracellularly 2

Mechanism of Action

DMARDs work through various mechanisms to control inflammation and prevent joint damage:

• csDMARDs:

  • Methotrexate inhibits dihydrofolate reductase and adenosine release, affecting cytokine production 4
  • Hydroxychloroquine changes intracellular pH, downregulating immune functions 4
  • Sulfasalazine decreases cytokine production and lymphocyte proliferation 4
  • Leflunomide inhibits pyrimidine synthesis 5

• bDMARDs:

  • TNF inhibitors block the inflammatory cytokine TNF-α 2, 6
  • Other biologics target specific cytokines or immune cells involved in the inflammatory cascade 2

• tsDMARDs:

  • JAK inhibitors block intracellular signaling pathways involved in inflammation 2

Clinical Applications

DMARDs are primarily used in:

• Rheumatoid arthritis: The cornerstone of treatment, with methotrexate as the anchor drug 1, 2
• Psoriatic arthritis: Both csDMARDs and bDMARDs are effective 2, 5
• Ankylosing spondylitis: Particularly bDMARDs have shown efficacy 2
• Juvenile idiopathic arthritis: Various DMARDs are used based on subtype 5
• Other conditions: Including Crohn's disease, ulcerative colitis, and Behçet's disease 2, 5

Treatment Strategies

• First-line therapy: Methotrexate is strongly recommended as the first-line DMARD for most patients with RA due to its efficacy, safety profile, and cost-effectiveness 1, 7

• Combination therapy: Often more effective than monotherapy, particularly methotrexate combined with other csDMARDs or with a bDMARD 1, 8

• Treat-to-target approach: Adjusting therapy until reaching a predefined target (remission or low disease activity) 2, 8

• Tight control: Regular monitoring and prompt adjustment of therapy based on disease activity measures 8

Safety Considerations

• csDMARDs:

  • Methotrexate: Requires monitoring for hepatotoxicity, bone marrow suppression, and pulmonary toxicity 9
  • Hydroxychloroquine: Lowest toxicity profile but requires ophthalmologic monitoring 4
  • Sulfasalazine: Associated with gastrointestinal side effects, particularly in elderly patients 4
  • Leflunomide: Requires monitoring for hepatotoxicity and potential teratogenicity 9

• bDMARDs:

  • Increased risk of infections, particularly tuberculosis with TNF inhibitors 1
  • Require screening for tuberculosis and monitoring for infections 1

• Special populations:

  • Elderly patients may require dose adjustments and more careful monitoring 4
  • Patients with comorbidities like lung disease or liver disease may need alternative treatment strategies 2

Common Pitfalls and Caveats

• Delayed treatment: Delaying DMARD therapy beyond 3 months after symptom onset significantly reduces the chance of optimal outcomes 7

• Inadequate dosing: Suboptimal dosing of methotrexate (not reaching 25-30 mg weekly when needed) may lead to treatment failure 1

• Inappropriate use of biologics: Starting with biologics before trying methotrexate in DMARD-naive patients is not recommended and may expose patients to unnecessary risks and costs 7

• Poor monitoring: Inadequate monitoring for side effects can lead to preventable complications 9

• Premature discontinuation: DMARDs may take several months to reach full efficacy; premature discontinuation due to perceived lack of effect should be avoided 8

DMARDs have revolutionized the treatment of rheumatoid arthritis and other inflammatory arthritis conditions, shifting the focus from symptom control to disease modification and prevention of joint damage, ultimately improving long-term outcomes and quality of life for patients 2.