Disease Modifying Antirheumatic Drugs Mechanism Of Action

Disease-modifying antirheumatic drugs (DMARDs) represent a cornerstone in the management of rheumatic diseases, particularly rheumatoid arthritis (RA). These medications are distinguished by their ability to alter the course of the disease, not merely treat its symptoms. Understanding their mechanisms of action is critical for appreciating their therapeutic potential and optimizing their use in clinical practice.

Introduction to DMARDs

Rheumatic diseases, such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, are characterized by chronic inflammation that leads to joint damage, pain, and disability. Traditional analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) can alleviate symptoms but do not halt the progression of the underlying disease. DMARDs, on the other hand, aim to modify the disease process itself, thereby preventing or slowing down joint destruction and improving long-term outcomes.

DMARDs are typically categorized into two main groups: conventional synthetic DMARDs (csDMARDs) and biologic DMARDs (bDMARDs). More recently, targeted synthetic DMARDs (tsDMARDs) have emerged, offering a third category with unique mechanisms of action.

• csDMARDs: These are small-molecule drugs that have been used for decades and include methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine.
• bDMARDs: These are larger, more complex molecules, usually proteins, that target specific components of the immune system. Examples include TNF inhibitors (e.g., etanercept, infliximab, adalimumab), IL-6 inhibitors (e.g., tocilizumab), and B-cell depleting agents (e.g., rituximab).
• tsDMARDs: These are small-molecule drugs designed to selectively inhibit intracellular signaling pathways, such as JAK inhibitors (e.g., tofacitinib, baricitinib).

The mechanisms of action of DMARDs are diverse and often not fully understood. However, they generally involve modulation of the immune system, reduction of inflammation, and protection against joint damage.

Mechanisms of Action of Conventional Synthetic DMARDs (csDMARDs)

Methotrexate

Methotrexate is often the first-line DMARD used in the treatment of rheumatoid arthritis and other rheumatic diseases. Its mechanism of action is complex and involves multiple pathways.

• Folate Antagonism: Methotrexate is an analog of folic acid and acts as an antimetabolite by inhibiting dihydrofolate reductase (DHFR). DHFR is an enzyme crucial for the synthesis of tetrahydrofolate, a coenzyme required for the production of purines and pyrimidines, which are essential building blocks for DNA and RNA. By inhibiting DHFR, methotrexate reduces the availability of these building blocks, thereby suppressing cell proliferation, particularly in rapidly dividing cells such as immune cells.
• Adenosine Release: Methotrexate increases intracellular adenosine levels. Adenosine is an endogenous purine nucleoside with anti-inflammatory properties. It binds to adenosine receptors on immune cells, inhibiting their activation and suppressing the release of inflammatory cytokines.
• Inhibition of Enzymes Involved in Inflammation: Methotrexate inhibits several enzymes involved in inflammation, including aminoimidazolecarboxamide ribonucleotide transformylase (AICAR transformylase) and thymidylate synthase. Inhibition of AICAR transformylase leads to the accumulation of AICAR, which inhibits adenosine monophosphate (AMP) deaminase, further increasing adenosine levels.

The overall effect of methotrexate is to suppress immune cell proliferation and reduce inflammation, thereby slowing down the progression of rheumatic diseases.

Sulfasalazine

Sulfasalazine is a combination drug consisting of sulfapyridine and 5-aminosalicylic acid (5-ASA). It is used to treat rheumatoid arthritis, ulcerative colitis, and Crohn's disease. The exact mechanism of action in rheumatic diseases is not fully understood, but several mechanisms have been proposed.

• Anti-inflammatory Effects: Sulfasalazine and its metabolites (sulfapyridine and 5-ASA) have anti-inflammatory properties. They can inhibit the production of inflammatory mediators such as prostaglandins and leukotrienes.
• Inhibition of Cytokine Production: Sulfasalazine can suppress the production of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6. It also modulates the activity of immune cells, including T cells and B cells.
• Antioxidant Effects: Sulfasalazine has antioxidant properties, which may contribute to its anti-inflammatory effects. It can scavenge free radicals and reduce oxidative stress in the joints.
• Modulation of Gut Microbiota: Sulfasalazine can alter the composition of the gut microbiota, which may influence the immune system and contribute to its therapeutic effects in rheumatic diseases.

The combination of these mechanisms contributes to the anti-inflammatory and disease-modifying effects of sulfasalazine in rheumatic diseases.

Leflunomide

Leflunomide is a DMARD that inhibits pyrimidine synthesis. It is used to treat rheumatoid arthritis and psoriatic arthritis.

• Inhibition of Dihydroorotate Dehydrogenase (DHODH): Leflunomide is a prodrug that is converted to its active metabolite, teriflunomide. Teriflunomide inhibits DHODH, an enzyme required for the de novo synthesis of pyrimidines. By inhibiting DHODH, leflunomide reduces the availability of pyrimidines, which are essential for DNA and RNA synthesis. This leads to suppression of cell proliferation, particularly in rapidly dividing immune cells.
• Reduction of Inflammation: Leflunomide reduces the production of inflammatory cytokines such as TNF-α, IL-1β, and IL-6. It also inhibits the activation of T cells and B cells, thereby modulating the immune response.
• Other Effects: Leflunomide may have other effects, such as inhibiting tyrosine kinase activity and modulating the production of prostaglandins and leukotrienes.

The primary mechanism of action of leflunomide is the inhibition of pyrimidine synthesis, which leads to suppression of immune cell proliferation and reduction of inflammation.

Hydroxychloroquine

Hydroxychloroquine is an antimalarial drug that is also used to treat rheumatoid arthritis, lupus, and other autoimmune diseases. Its mechanism of action is not fully understood, but several mechanisms have been proposed.

• Lysosomal Inhibition: Hydroxychloroquine accumulates in lysosomes, which are cellular organelles responsible for degrading cellular waste. By accumulating in lysosomes, hydroxychloroquine increases the pH within these organelles, thereby inhibiting their function. This can interfere with antigen processing and presentation to T cells, reducing the activation of the immune system.
• Inhibition of Toll-Like Receptors (TLRs): Hydroxychloroquine inhibits TLRs, which are receptors on immune cells that recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). By inhibiting TLRs, hydroxychloroquine reduces the activation of the immune system in response to these stimuli.
• Reduction of Cytokine Production: Hydroxychloroquine can reduce the production of inflammatory cytokines such as TNF-α, IL-1β, and IL-6.
• Other Effects: Hydroxychloroquine may have other effects, such as inhibiting the migration of immune cells and reducing the production of autoantibodies.

The combined effects of lysosomal inhibition, TLR inhibition, and cytokine reduction contribute to the anti-inflammatory and immunomodulatory effects of hydroxychloroquine in rheumatic diseases.

Mechanisms of Action of Biologic DMARDs (bDMARDs)

Biologic DMARDs are genetically engineered proteins that target specific components of the immune system. They are generally used in patients who have not responded adequately to csDMARDs.

TNF Inhibitors

TNF inhibitors are among the most widely used bDMARDs. They target tumor necrosis factor-alpha (TNF-α), a key pro-inflammatory cytokine involved in the pathogenesis of rheumatoid arthritis and other rheumatic diseases.

• Neutralization of TNF-α: TNF inhibitors bind to TNF-α, preventing it from binding to its receptors on immune cells and other cells. This neutralizes the activity of TNF-α, reducing inflammation and preventing joint damage.
• Types of TNF Inhibitors:
  • Etanercept: A fusion protein consisting of the TNF receptor linked to the Fc portion of human IgG1. It acts as a decoy receptor, binding to TNF-α and preventing it from binding to its natural receptors.
  • Infliximab: A chimeric monoclonal antibody that binds to TNF-α. It neutralizes TNF-α and can also induce complement-mediated lysis of TNF-α-producing cells.
  • Adalimumab: A fully human monoclonal antibody that binds to TNF-α. It neutralizes TNF-α and has similar effects to infliximab.
  • Certolizumab pegol: A PEGylated Fab' fragment of a humanized antibody that binds to TNF-α. The PEGylation increases its half-life and allows for less frequent dosing.
  • Golimumab: A fully human monoclonal antibody that binds to TNF-α.

By neutralizing TNF-α, these agents reduce inflammation, pain, and joint damage in patients with rheumatic diseases.

IL-6 Inhibitors

IL-6 inhibitors target interleukin-6 (IL-6), another key pro-inflammatory cytokine involved in the pathogenesis of rheumatoid arthritis.

• Inhibition of IL-6 Signaling: IL-6 inhibitors bind to the IL-6 receptor, preventing IL-6 from binding and activating its signaling pathway. This reduces the production of inflammatory mediators and suppresses the immune response.
• Tocilizumab: A humanized monoclonal antibody that binds to the IL-6 receptor. It inhibits IL-6 signaling and reduces inflammation.
• Sarilumab: Another humanized monoclonal antibody that binds to the IL-6 receptor with high affinity.

IL-6 inhibitors are effective in reducing inflammation and improving symptoms in patients with rheumatoid arthritis who have not responded adequately to other DMARDs.

B-Cell Depleting Agents

B-cell depleting agents target B cells, which are immune cells responsible for producing antibodies and contributing to the pathogenesis of rheumatoid arthritis.

• Depletion of B Cells: These agents bind to B cells, leading to their depletion from the circulation and lymphoid tissues. This reduces the production of autoantibodies and modulates the immune response.
• Rituximab: A chimeric monoclonal antibody that binds to the CD20 protein on B cells. It induces complement-mediated lysis and antibody-dependent cellular cytotoxicity, leading to B-cell depletion.

Rituximab is used to treat rheumatoid arthritis and other autoimmune diseases in patients who have not responded adequately to TNF inhibitors.

T-Cell Co-stimulation Inhibitors

T-cell co-stimulation inhibitors target the co-stimulatory signals required for T-cell activation.

• Inhibition of T-Cell Activation: These agents interfere with the interaction between T cells and antigen-presenting cells, preventing the co-stimulation signals required for T-cell activation. This reduces T-cell activation and modulates the immune response.
• Abatacept: A fusion protein consisting of the extracellular domain of CTLA-4 linked to the Fc portion of human IgG1. CTLA-4 binds to CD80 and CD86 on antigen-presenting cells, preventing them from binding to CD28 on T cells. This inhibits the co-stimulatory signal required for T-cell activation.

Abatacept is used to treat rheumatoid arthritis in patients who have not responded adequately to other DMARDs.

Mechanisms of Action of Targeted Synthetic DMARDs (tsDMARDs)

Targeted synthetic DMARDs are small-molecule drugs that selectively inhibit intracellular signaling pathways involved in the pathogenesis of rheumatic diseases.

JAK Inhibitors

JAK inhibitors target Janus kinases (JAKs), which are intracellular enzymes that play a key role in signaling downstream of cytokine receptors.

• Inhibition of JAK-STAT Pathway: JAK inhibitors block the activity of JAKs, preventing the phosphorylation and activation of STATs (signal transducers and activators of transcription). STATs are transcription factors that regulate the expression of genes involved in inflammation and immune responses. By inhibiting the JAK-STAT pathway, JAK inhibitors reduce the production of inflammatory mediators and modulate the immune response.
• Types of JAK Inhibitors:
  • Tofacitinib: A selective inhibitor of JAK1 and JAK3.
  • Baricitinib: A selective inhibitor of JAK1 and JAK2.
  • Upadacitinib: A selective inhibitor of JAK1.
  • Filgotinib: A selective inhibitor of JAK1.

JAK inhibitors are effective in reducing inflammation and improving symptoms in patients with rheumatoid arthritis and other rheumatic diseases.

Combination Therapies

In clinical practice, DMARDs are often used in combination to achieve better control of rheumatic diseases. Combination therapies can involve:

• csDMARDs: Combining methotrexate with other csDMARDs such as sulfasalazine and hydroxychloroquine.
• csDMARDs and bDMARDs: Combining methotrexate with a TNF inhibitor or another bDMARD.
• csDMARDs and tsDMARDs: Combining methotrexate with a JAK inhibitor.

The rationale for combination therapies is to target multiple pathways involved in the pathogenesis of rheumatic diseases, thereby achieving a more comprehensive and effective treatment.

Adverse Effects and Monitoring

DMARDs can cause a variety of adverse effects, ranging from mild to severe. Common adverse effects include:

• Gastrointestinal symptoms: Nausea, vomiting, diarrhea, and abdominal pain.
• Liver toxicity: Elevated liver enzymes.
• Bone marrow suppression: Anemia, leukopenia, and thrombocytopenia.
• Infections: Increased risk of bacterial, viral, and fungal infections.
• Skin reactions: Rash, itching, and photosensitivity.

Due to the potential for adverse effects, patients receiving DMARDs require regular monitoring, including blood tests to assess liver function, kidney function, and blood counts. Patients should also be monitored for signs and symptoms of infection.

Conclusion

Disease-modifying antirheumatic drugs (DMARDs) are essential medications for the management of rheumatic diseases. They work by modulating the immune system, reducing inflammation, and protecting against joint damage. Understanding the mechanisms of action of DMARDs is crucial for optimizing their use in clinical practice.

• csDMARDs such as methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine have been used for decades and have diverse mechanisms of action.
• bDMARDs such as TNF inhibitors, IL-6 inhibitors, B-cell depleting agents, and T-cell co-stimulation inhibitors target specific components of the immune system.
• tsDMARDs such as JAK inhibitors selectively inhibit intracellular signaling pathways.

DMARDs can cause adverse effects, and patients require regular monitoring. Combination therapies are often used to achieve better control of rheumatic diseases. The choice of DMARDs and treatment strategy should be individualized based on the patient's disease activity, risk factors, and preferences. With appropriate use and monitoring, DMARDs can significantly improve the outcomes for patients with rheumatic diseases.