Pharmacology of Antirheumatoid Drugs (DMARDs)

Introduction/Overview

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder characterized by persistent synovial inflammation, progressive joint destruction, and extra‑articular manifestations. The therapeutic goal is to halt disease progression, achieve remission or low disease activity, and preserve functional status. Disease‑modifying antirheumatic drugs (DMARDs) are the cornerstone of RA management, acting through a variety of immunomodulatory or anti‑inflammatory mechanisms. Their use has transformed the natural history of RA, yet their complex pharmacology necessitates careful consideration of efficacy, safety, and patient‑specific factors.

Learning objectives for this monograph include:

1. Identify the primary classes of DMARDs and their chemical characteristics.
2. Explain the principal mechanisms of action at the molecular and cellular levels.
3. Describe the pharmacokinetic properties that influence dosing regimens.
4. Summarize approved therapeutic indications and common off‑label applications.
5. Recognize major adverse effect profiles, drug interactions, and special population considerations.

Classification

Traditional (Non‑Biologic) DMARDs

Traditional DMARDs encompass a heterogeneous group of agents that were historically developed before the advent of biologic therapies. They are further divided into small‑molecule drugs and biologic‑derived compounds.

• Small‑molecule agents: methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, chloroquine, azathioprine, mycophenolate mofetil, cyclophosphamide.
• Biologic‑derived compounds: gold salts (e.g., auranofin), penicillamine, cyclosporine A.

Biologic DMARDs

Biologic agents are recombinant proteins or monoclonal antibodies engineered to target specific cytokines or cell surface receptors. They can be categorized by their molecular target:

• TNF‑α inhibitors: infliximab, adalimumab, certolizumab pegol, golimumab, etanercept.
• Interleukin‑6 (IL‑6) pathway inhibitors: tocilizumab, sarilumab.
• B‑cell depletion: rituximab.
• T‑cell costimulation blockade: abatacept.
• IL‑1 blockade: anakinra.
• Other targeted biologics: tofacitinib (though a small molecule, often grouped with biologics due to shared mechanism).

Targeted Synthetic DMARDs (tsDMARDs)

Targeted synthetic agents are small molecules that modulate intracellular signaling pathways. They are chemically distinct from traditional small‑molecule DMARDs and are often categorized by their primary target:

• Janus kinase (JAK) inhibitors: tofacitinib, baricitinib, upadacitinib, filgotinib.
• Other signal transduction inhibitors: none currently approved specifically for RA, but ongoing research explores PDE4 inhibitors and other kinase modulators.

Chemical Classification

Within each class, chemical structures vary. For example, methotrexate is a folate analogue; leflunomide is a pyrimidine synthesis inhibitor; sulfasalazine is a pro‑drug metabolized to sulfapyridine and 5‑aminosalicylic acid. Biologic agents are typically large proteins (~10–150 kDa) with complex tertiary structures, often glycosylated to enhance stability and reduce immunogenicity. tsDMARDs are small molecules (<500 Da) designed to traverse cell membranes and inhibit intracellular enzymes.

Mechanism of Action

Traditional DMARDs

Mechanisms are often pleiotropic and incompletely defined. Methotrexate, for instance, inhibits dihydrofolate reductase, reducing nucleotide synthesis, and increases adenosine levels, which exerts anti‑inflammatory effects. Leflunomide’s active metabolite, teriflunomide, inhibits dihydroorotate dehydrogenase, suppressing pyrimidine synthesis and thereby lymphocyte proliferation. Sulfasalazine is believed to modulate immune cell migration and cytokine production, while hydroxychloroquine interferes with lysosomal acidification, inhibiting antigen presentation and toll‑like receptor signaling. Azathioprine is metabolized to 6‑mercaptopurine, which integrates into DNA and disrupts purine metabolism, leading to impaired lymphocyte proliferation.

Biologic DMARDs

These agents exhibit high specificity for their targets:

• TNF‑α inhibitors: bind soluble and membrane‑bound TNF‑α, preventing interaction with TNF receptors and subsequent NF‑κB activation, cytokine cascade, and leukocyte recruitment.
• IL‑6 pathway inhibitors: tocilizumab and sarilumab competitively inhibit IL‑6 receptor binding, blocking downstream JAK/STAT signaling and acute‑phase protein production.
• Rituximab: targets CD20 on B‑cells, inducing complement‑mediated cytotoxicity and apoptosis, thereby reducing autoantibody production.
• Abatacept: a fusion protein comprising CTLA‑4 and Fc portions, binds CD80/86 on antigen‑presenting cells, inhibiting costimulatory signaling required for T‑cell activation.
• Anakinra: an IL‑1 receptor antagonist that competitively inhibits IL‑1 binding, reducing inflammatory mediator release.

Targeted Synthetic DMARDs

JAK inhibitors block intracellular kinase activity critical for cytokine signaling. Tofacitinib preferentially inhibits JAK1 and JAK3, modulating signaling of IL‑2, IL‑4, IL‑7, IL‑9, IL‑15, and IL‑21, which are vital for lymphocyte activation. Baricitinib and upadacitinib inhibit JAK1 and JAK2, affecting erythropoietin and growth hormone signaling in addition to cytokine pathways. Filgotinib is a JAK1‑selective inhibitor, potentially offering a favorable safety profile. By impeding JAK-STAT signaling, these agents reduce pro‑inflammatory cytokine production, cell proliferation, and adhesion molecule expression.

Pharmacokinetics

Absorption

Traditional small‑molecule DMARDs are typically administered orally, with variable bioavailability. Methotrexate absorption is concentration‑dependent, with a maximum bioavailability of ~50 % at doses ≤10 mg. Leflunomide shows >80 % oral bioavailability, with a lag phase due to enterohepatic recirculation. Sulfasalazine’s absorption is incomplete, as it is a pro‑drug requiring colonic bacterial reduction. Hydroxychloroquine is well absorbed, with a volume of distribution (V_d) of ~150 L, indicating extensive tissue penetration.

Biologic agents are generally administered parenterally (intravenous or subcutaneous). Infliximab and adalimumab are given IV or SC, respectively, with bioavailability ranging from 50–70 % SC. Etanercept, an Fc‑fusion protein, is given subcutaneously, with a half‑life (t_1/2) of ~3–5 days. Tocilizumab is available IV or SC, with t_1/2 of ~8 days IV and ~12 days SC. Rituximab is given IV, with a t_1/2 of ~12–21 days depending on infusion schedule. Abatacept, an Fc‑fusion protein, is administered IV or SC, with a t_1/2 of ~12 days SC.

Targeted synthetic agents are orally bioavailable. Tofacitinib has a C_max within 1 hour of dosing, with a t_1/2 of ~3 hours. Baricitinib shows a t_1/2 of ~12 hours. Upadacitinib has a t_1/2 of ~9 hours. Filgotinib reaches C_max at ~2 hours, with a t_1/2 of ~12 hours.

Distribution

Small‑molecule DMARDs exhibit varying degrees of plasma protein binding. Methotrexate is highly protein‑bound (~90 %), reducing free fraction. Leflunomide’s metabolite teriflunomide demonstrates ~99 % binding. Hydroxychloroquine shows extensive tissue distribution, with a V_d exceeding 100 L, reflecting accumulation in reticuloendothelial cells and lysosomes. Biologic agents, due to their size and glycosylation, primarily distribute within the vascular and interstitial spaces, with limited penetration into the central nervous system. tsDMARDs show moderate protein binding (toxicology data suggest ~20–40 % bound for tofacitinib).

Metabolism

Metabolic pathways differ across agents. Methotrexate is primarily excreted unchanged by the kidneys, with minimal hepatic metabolism. Leflunomide undergoes hepatic oxidation to teriflunomide via CYP2C9; teriflunomide is further metabolized by CYP3A4. Sulfasalazine is hydrolyzed to sulfapyridine and 5‑ASA, with sulfapyridine undergoing glucuronidation. Hydroxychloroquine is metabolized by CYP2D6, CYP3A4, and CYP2C8 to active metabolites. Biologic agents are degraded via proteolytic pathways, with minimal hepatic metabolism. tsDMARDs are primarily metabolized by CYP3A4 (tofacitinib, baricitinib) and are substrates for CYP2C19 (upadacitinib). Filgotinib is metabolized by CYP3A4 and UGT1A9.

Excretion

Renal excretion is the main elimination route for many traditional DMARDs. Methotrexate is excreted unchanged via glomerular filtration and tubular secretion, with a t_1/2 of ~3–10 hours, extended in renal impairment. Leflunomide’s metabolite teriflunomide has a prolonged t_1/2 of ~18 days due to enterohepatic recycling. Sulfasalazine’s metabolites are excreted renally. Hydroxychloroquine is eliminated slowly, with a t_1/2 of ~20–30 days. Biologic agents are cleared by proteolysis and reticuloendothelial uptake; their t_1/2 ranges from days to weeks. tsDMARDs are primarily renally excreted (tofacitinib ~60 % renal), with hepatic metabolism contributing to the remainder. Dose adjustments are often required in renal or hepatic dysfunction.

Half‑Life and Dosing Considerations

Traditional DMARDs generally require weekly or monthly dosing, reflecting their pharmacokinetic profiles (e.g., methotrexate 7–14 days t_1/2). Biologics are dosed every 1–4 weeks, based on their t_1/2 and formulation. tsDMARDs are typically dosed once or twice daily, aligning with their shorter t_1/2 and oral administration. Dose individualization is guided by therapeutic drug monitoring (especially for methotrexate and leflunomide), renal/hepatic function, and patient-specific factors such as age, weight, and comorbidities.

Therapeutic Uses/Clinical Applications

Approved Indications

DMARDs are indicated for the treatment of moderate to severe RA, with the following approvals:

• Traditional DMARDs: methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, azathioprine (in certain refractory cases), mycophenolate mofetil (off‑label for RA, but approved for lupus).
• Biologic DMARDs: TNF‑α inhibitors (infliximab, adalimumab, certolizumab pegol, golimumab, etanercept) for RA, psoriatic arthritis, ankylosing spondylitis; IL‑6 inhibitors (tocilizumab, sarilumab) for RA; rituximab for RA refractory to other biologics; abatacept for RA; anakinra for RA.
• Targeted synthetic DMARDs: tofacitinib, baricitinib, upadacitinib, filgotinib for moderate to severe RA, with or without methotrexate.

Off‑Label and Emerging Uses

Common off‑label applications include:

• Hydroxychloroquine for systemic lupus erythematosus (SLE) and dermatomyositis.
• Azathioprine for refractory RA and systemic vasculitis.
• Mycophenolate mofetil for RA-associated interstitial lung disease.
• JAK inhibitors for psoriatic arthritis, ankylosing spondylitis, and Crohn’s disease.
• Abatacept for juvenile idiopathic arthritis (JIA) and non‑steroidal anti‑inflammatory drug‑resistant RA.

Adverse Effects

Common Side Effects

Adverse effects vary by class but frequently include:

• Traditional DMARDs: gastrointestinal upset (nausea, vomiting), hepatotoxicity (elevated transaminases), cytopenias (anemia, neutropenia), hypersensitivity reactions (rash). Methotrexate may cause mucositis and stomatitis.
• Biologic DMARDs: injection site reactions (pain, erythema), nasopharyngitis, upper respiratory infections. TNF inhibitors increase the risk of tuberculosis reactivation.
• tsDMARDs: upper respiratory tract infections, anemia, neutropenia, increased serum creatinine, lipid abnormalities, and rare thromboembolic events.

Serious / Rare Adverse Reactions

Serious complications include:

• Infections: opportunistic infections (TB, fungal, viral reactivation) are more pronounced with biologics and JAK inhibitors.
• Malignancy: increased non‑melanoma skin cancer risk with methotrexate and biologics; lymphoma risk remains a concern, particularly in biologic‑treated patients.
• Hepatotoxicity: severe hepatic injury with methotrexate, leflunomide, and sulfasalazine.
• Gastrointestinal perforation: increased risk with NSAIDs plus TNF inhibitors.
• Thromboembolic events: reported with JAK inhibitors, particularly in patients with cardiovascular risk factors.

Black Box Warnings

Several agents carry black box warnings:

• JAK inhibitors: risk of serious cardiovascular events, malignancies, and death.
• TNF inhibitors: risk of serious infections and malignancy.
• Rituximab: risk of progressive multifocal leukoencephalopathy (PML).

Drug Interactions

Major Drug-Drug Interactions

Interaction profiles differ across classes:

• Traditional DMARDs: methotrexate is contraindicated with trimethoprim–sulfamethoxazole (SMX/TMP), NSAIDs (increased nephrotoxicity), and proton pump inhibitors (decreased absorption). Leflunomide interacts with potent CYP3A4 inhibitors (ketoconazole) and inducers (rifampin).
• Biologic DMARDs: concomitant use of TNF inhibitors with interferon‑α may increase risk of infections. Rituximab can potentiate the effects of chemotherapy agents and immunosuppressants, raising infection risk.
• tsDMARDs: JAK inhibitors inhibit CYP3A4, leading to increased plasma concentrations of CYP3A4 substrates (e.g., statins). They also inhibit CYP2C19, affecting metabolism of clopidogrel. P-glycoprotein inhibitors (e.g., verapamil) can increase JAK inhibitor levels.

Contraindications

Contraindications include:

• Active tuberculosis or latent TB infection untreated with appropriate therapy for biologics and JAK inhibitors.
• Severe hepatic impairment for methotrexate, leflunomide, and biologics.
• Severe renal impairment for methotrexate and leflunomide (dose adjustments required).
• Pregnancy for most biologics and methotrexate, with limited data for tsDMARDs.

Special Considerations

Pregnancy and Lactation

Most DMARDs are contraindicated during pregnancy due to teratogenicity or potential fetal harm. Methotrexate is a known teratogen. TNF inhibitors are generally avoided, though etanercept and adalimumab have limited data suggesting relative safety after the first trimester. JAK inhibitors are contraindicated. Hydroxychloroquine is considered safe and is often continued in SLE during pregnancy. Lactation is generally discouraged with biologics due to potential transfer into breast milk, but hydroxychloroquine is acceptable.

Pediatric Considerations

In children with juvenile idiopathic arthritis (JIA), methotrexate remains a first‑line agent. Biologics such as etanercept, adalimumab, and abatacept have specific pediatric formulations and dosing schedules. JAK inhibitors are under investigation in pediatric populations; safety data are limited. Growth and bone health must be monitored due to potential effects on the skeleton.

Geriatric Considerations

Older adults are at increased risk for adverse events due to polypharmacy and comorbidities. Renal and hepatic function decline with age, necessitating dose adjustments. The risk of infection and malignancy is higher in this group, warranting careful monitoring and judicious use of biologics and JAK inhibitors.

Renal and Hepatic Impairment

Renal dose adjustments are required for methotrexate (≤30 mL/min GFR) and leflunomide (≤30 mL/min). Hepatic impairment reduces clearance of methotrexate and leflunomide; dose reductions or avoidance may be necessary. JAK inhibitors require dose adjustment in moderate hepatic impairment; severe hepatic disease is a contraindication. Biologics are generally safe in mild to moderate hepatic impairment but should be used cautiously in severe disease.

Summary/Key Points

• DMARDs encompass traditional small‑molecule agents, biologics, and targeted synthetic drugs, each with distinct mechanisms and pharmacokinetic profiles.
• Mechanisms range from broad immunosuppression (methotrexate) to targeted cytokine inhibition (TNF, IL‑6) and intracellular kinase blockade (JAK inhibitors).
• Pharmacokinetics influence dosing schedules: weekly to monthly for traditional DMARDs, biweekly to monthly for biologics, and once or twice daily for tsDMARDs.
• Therapeutic indications include RA and related inflammatory arthritides, with extensive off‑label use in autoimmune diseases.
• Adverse effects span mild (GI upset) to serious (infections, malignancy, hepatotoxicity), with black box warnings for several agents.
• Drug interactions are common, particularly with CYP3A4 substrates and inhibitors; careful medication reconciliation is essential.
• Special populations (pregnancy, pediatrics, geriatrics, renal/hepatic impairment) require individualized dosing and monitoring.
• Clinical decision‑making should balance efficacy, safety, and patient preferences, guided by up‑to‑date guidelines and pharmacovigilance data.

Understanding the pharmacology of DMARDs is fundamental for optimizing therapeutic outcomes while minimizing risks in patients with rheumatoid arthritis and related disorders.

References

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