What are examples of Disease-Modifying Antirheumatic Drugs (DMARDs) and how do they work in treating rheumatoid arthritis?

Disease-Modifying Antirheumatic Drugs (DMARDs) for Rheumatoid Arthritis

DMARDs are the cornerstone of rheumatoid arthritis treatment, with methotrexate being the first-line agent due to its established efficacy in reducing disease activity, preventing joint damage, and improving physical function in patients with RA. 1

Classification of DMARDs

DMARDs are categorized into three main groups:

1. Conventional Synthetic DMARDs (csDMARDs)

   • Methotrexate (MTX): First-line therapy, inhibits dihydrofolate reductase and promotes adenosine release, which has anti-inflammatory effects
   • Leflunomide: Inhibits pyrimidine synthesis
   • Sulfasalazine: Anti-inflammatory effects through inhibition of NF-κB
   • Hydroxychloroquine: Interferes with antigen processing and toll-like receptor signaling
   • Gold compounds: Inhibit lysosomal enzymes and decrease cytokine production
   • D-penicillamine: Mechanism involves immunomodulation and free radical scavenging

2. Biological DMARDs (bDMARDs)

   • TNF inhibitors:
     • Adalimumab: Fully human monoclonal antibody against TNF-α 2
     • Certolizumab pegol: PEGylated Fab' fragment of anti-TNF-α antibody
     • Etanercept: Soluble TNF receptor fusion protein
     • Golimumab: Human monoclonal antibody against TNF-α
     • Infliximab: Chimeric monoclonal antibody against TNF-α
   • IL-6 pathway inhibitors:
     • Tocilizumab and sarilumab: Target IL-6 receptor
   • T-cell co-stimulation modulator:
     • Abatacept: CTLA-4-Ig fusion protein
   • B-cell depleting agent:
     • Rituximab: Anti-CD20 monoclonal antibody

3. Targeted Synthetic DMARDs (tsDMARDs)

   • JAK inhibitors:
     • Tofacitinib: Inhibits JAK1/JAK3
     • Baricitinib: Inhibits JAK1/JAK2
     • Upadacitinib: Selective JAK1 inhibitor
     • Filgotinib: Selective JAK1 inhibitor
     • Peficitinib: Pan-JAK inhibitor 3, 4

Mechanisms of Action

Conventional Synthetic DMARDs

• Methotrexate: The cornerstone DMARD that works by:

  • Inhibiting dihydrofolate reductase
  • Promoting adenosine release (anti-inflammatory)
  • Reducing cell proliferation
  • Inducing apoptosis of activated T-cells 3, 5

• Leflunomide: Inhibits dihydroorotate dehydrogenase, an enzyme involved in pyrimidine synthesis, thereby reducing T-cell proliferation 5

• Sulfasalazine: Anti-inflammatory effects through inhibition of NF-κB pathway and prostaglandin synthesis 5

• Hydroxychloroquine: Interferes with antigen processing and presentation, inhibits toll-like receptor signaling 5, 6

Biological DMARDs

• TNF inhibitors: Block the pro-inflammatory cytokine TNF-α, which plays a central role in joint inflammation and destruction in RA 2

• IL-6 pathway inhibitors: Block IL-6 signaling, reducing acute phase reactants, synovitis, and systemic inflammation 3

• Abatacept: Prevents T-cell activation by blocking co-stimulatory signals between T-cells and antigen-presenting cells 3

• Rituximab: Depletes CD20+ B-cells, reducing autoantibody production and antigen presentation 3, 7

Targeted Synthetic DMARDs

• JAK inhibitors: Block intracellular signaling pathways (Janus kinase-signal transducer and activator of transcription pathway) that are crucial for cytokine signaling in RA pathogenesis 3, 4

Treatment Strategy and Efficacy

1. First-line therapy:

   • Methotrexate is recommended as first-line therapy at 10-15 mg/week with rapid escalation to 20-25 mg/week within 4-6 weeks 1
   • Can be combined with short-term glucocorticoids to bridge until DMARDs take effect 3

2. Inadequate response to MTX:

   • Add other csDMARDs (triple therapy with MTX, sulfasalazine, and hydroxychloroquine) 1
   • Or add a bDMARD (TNF inhibitor, IL-6 inhibitor, abatacept) or tsDMARD (JAK inhibitor) 3

3. Treatment failure with first bDMARD:

   • Switch to another bDMARD (same or different class) or tsDMARD 3

Safety Considerations

• csDMARDs: Regular monitoring of blood counts, liver function, and renal function is required 1

• bDMARDs: Increased risk of serious infections, including tuberculosis reactivation; screening for latent TB is mandatory before initiation 3, 2

• JAK inhibitors: Associated with increased risk of herpes zoster and potentially venous thromboembolism 3

• Combination therapy: Higher efficacy but potentially increased risk of adverse events, particularly infections 3

Clinical Pearls

1. Early treatment is crucial: The "window of opportunity" for optimal treatment is within the first year of disease onset 1, 8

2. Treat-to-target strategy: Aim for remission or low disease activity with regular monitoring every 1-3 months and treatment adjustment if targets are not met 3, 1

3. Tapering: Consider tapering DMARDs in patients who achieve sustained remission, but complete discontinuation is not recommended due to high risk of flare 3

4. Combination therapy: Often more effective than monotherapy, particularly in patients with high disease activity or poor prognostic factors 3, 1

5. Personalized approach: Consider comorbidities, pregnancy plans, and patient preferences when selecting DMARDs 3, 1

By targeting different pathways in the immune system, DMARDs effectively reduce inflammation, prevent joint damage, and improve long-term outcomes in patients with rheumatoid arthritis. The development of newer DMARDs, particularly biologics and JAK inhibitors, has revolutionized RA treatment, making remission an achievable goal for many patients.