Pharmacology of Antirheumatoid Drugs (DMARDs)

1. Introduction/Overview

The management of rheumatoid arthritis (RA) and related autoimmune inflammatory arthropathies represents a cornerstone of clinical rheumatology and pharmacotherapy. Disease-modifying antirheumatic drugs (DMARDs) constitute the primary pharmacological intervention aimed not merely at symptom palliation but at altering the underlying disease course. The introduction of these agents has fundamentally transformed RA from a condition often leading to severe disability into a manageable chronic disease. This chapter provides a systematic examination of the pharmacology of DMARDs, encompassing traditional synthetic agents, targeted synthetic drugs, and biologic response modifiers.

The clinical relevance of DMARDs is profound, as they form the backbone of treat-to-target strategies in RA. Early and aggressive intervention with these drugs is associated with significant reductions in joint damage, preservation of physical function, and improved long-term patient outcomes. Their use has expanded beyond RA to include other systemic autoimmune and inflammatory conditions, underscoring their broad immunomodulatory potential.

Learning Objectives

• Classify DMARDs into their major categories: conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs).
• Explain the molecular and cellular mechanisms of action for representative drugs from each major class, linking pharmacodynamics to clinical effects.
• Analyze the key pharmacokinetic properties, including routes of administration, metabolism, and elimination, that influence dosing regimens and monitoring requirements.
• Evaluate the spectrum of therapeutic applications, major adverse effect profiles, and significant drug interactions for commonly used DMARDs.
• Apply knowledge of special considerations, such as use in organ impairment or pregnancy, to develop rational and safe treatment plans.

2. Classification

Antirheumatoid drugs are systematically categorized based on their chemical nature, origin, and mechanism of action. The prevailing classification system distinguishes three principal groups.

Conventional Synthetic DMARDs (csDMARDs)

These are typically small-molecule, orally administered agents with broad immunosuppressive or immunomodulatory actions. Their precise mechanisms were often elucidated after their clinical efficacy was established.

• Antimetabolites: Methotrexate (a folate antagonist), Leflunomide (a pyrimidine synthesis inhibitor), Sulfasalazine.
• Alkylating Agents: Cyclophosphamide (used in severe, systemic disease).
• Other Immunomodulators: Hydroxychloroquine (an antimalarial), Gold salts (now rarely used), Minocycline.

Biologic DMARDs (bDMARDs)

This class comprises proteins, usually antibodies or receptor constructs, produced by recombinant DNA technology. They are designed to target specific components of the immune system involved in the inflammatory cascade.

• Tumor Necrosis Factor-alpha (TNF-α) Inhibitors: Etanercept, Infliximab, Adalimumab, Certolizumab pegol, Golimumab.
• Interleukin Inhibitors:
  • IL-1 inhibitor: Anakinra.
  • IL-6 receptor inhibitors: Tocilizumab, Sarilumab.
  • IL-17A inhibitor: Secukinumab (used in psoriatic arthritis and ankylosing spondylitis).
  • IL-12/23 inhibitor: Ustekinumab (used in psoriatic arthritis).
• B-Cell Depleting Agent: Rituximab (anti-CD20 monoclonal antibody).
• T-Cell Co-stimulation Modulator: Abatacept (CTLA4-Ig fusion protein).

Targeted Synthetic DMARDs (tsDMARDs)

These are orally active, small-molecule drugs designed to inhibit specific intracellular signaling kinases involved in immune cell activation and cytokine signaling.

• Janus Kinase (JAK) Inhibitors: Tofacitinib, Baricitinib, Upadacitinib, Filgotinib.

3. Mechanism of Action

The mechanisms of DMARDs are diverse, reflecting the complexity of the immunopathogenesis of rheumatoid arthritis. A common endpoint is the suppression of the aberrant immune response that leads to synovial inflammation, pannus formation, and subsequent cartilage and bone destruction.

Mechanisms of Conventional Synthetic DMARDs

Methotrexate: At the low doses used in rheumatology, methotrexate’s primary action is attributed to the inhibition of aminoimidazole carboxamide ribonucleotide (AICAR) transformylase. This leads to accumulation of AICAR and subsequent increased release of extracellular adenosine, a potent endogenous anti-inflammatory mediator. Adenosine binds to receptors on neutrophils, macrophages, and lymphocytes, inhibiting their pro-inflammatory functions and cytokine production (e.g., TNF-α, IL-6). A secondary, folate-antagonist effect contributes to immunosuppression by impairing lymphocyte proliferation.

Leflunomide: The active metabolite, teriflunomide, reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). DHODH is critical for the de novo synthesis of pyrimidine ribonucleotides. Inhibition preferentially affects rapidly proliferating lymphocytes, leading to a cytostatic reduction in activated T-cell and B-cell clones. This results in decreased autoantibody production and modulation of cell-mediated immunity.

Sulfasalazine: This prodrug is split by colonic bacteria into 5-aminosalicylic acid (5-ASA) and sulfapyridine. The anti-inflammatory activity in RA is primarily attributed to sulfapyridine, though the exact mechanism remains incompletely defined. Proposed actions include inhibition of nuclear factor kappa B (NF-κB) signaling, scavenging of reactive oxygen species, and impairment of folate metabolism, collectively leading to reduced cytokine production and lymphocyte function.

Hydroxychloroquine: This weak base accumulates in acidic lysosomes, raising intralysosomal pH and interfering with antigen processing and presentation by macrophages and other antigen-presenting cells. It also inhibits Toll-like receptor (TLR) signaling, particularly TLR9, which reduces the activation of plasmacytoid dendritic cells and production of type I interferons and other cytokines.

Mechanisms of Biologic DMARDs

TNF-α Inhibitors: These agents neutralize the pro-inflammatory cytokine TNF-α, a master regulator of the inflammatory cascade. TNF-α promotes synovitis, stimulates osteoclast-mediated bone resorption, and inhibits cartilage synthesis. Etanercept is a soluble TNF receptor fusion protein that binds TNF. Infliximab, adalimumab, golimumab, and certolizumab are monoclonal antibodies or antibody fragments that bind and neutralize soluble and membrane-bound TNF-α, potentially also inducing antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) against TNF-expressing cells.

IL-6 Receptor Inhibitors (Tocilizumab, Sarilumab): These monoclonal antibodies bind to the membrane-bound and soluble IL-6 receptor, blocking IL-6-mediated signaling. IL-6 is a pleiotropic cytokine that drives B-cell differentiation, acute phase response (e.g., CRP production), and Th17 cell differentiation, while also contributing to anemia of chronic disease.

B-Cell Depleting Therapy (Rituximab): This chimeric monoclonal antibody targets the CD20 antigen expressed on pre-B and mature B lymphocytes, but not on stem cells or plasma cells. Binding leads to B-cell depletion via ADCC, CDC, and induction of apoptosis. This reduces autoantibody production (including rheumatoid factor and anti-CCP antibodies), antigen presentation, and cytokine production.

T-Cell Co-stimulation Modulator (Abatacept): Abatacept is a fusion protein of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the Fc portion of IgG1. It binds to CD80/CD86 on antigen-presenting cells, blocking their interaction with CD28 on T cells. This prevents the necessary “second signal” for full T-cell activation, leading to T-cell anergy and reduced downstream inflammatory cytokine production.

Mechanisms of Targeted Synthetic DMARDs (JAK Inhibitors)

Janus kinases (JAK1, JAK2, JAK3, TYK2) are intracellular tyrosine kinases associated with cytokine receptor subunits. Upon cytokine binding, JAKs phosphorylate each other and the receptor, creating docking sites for Signal Transducers and Activators of Transcription (STAT) proteins. Phosphorylated STATs dimerize and translocate to the nucleus to regulate gene transcription. JAK inhibitors are small molecules that competitively bind to the ATP-binding site of one or more JAK enzymes, blocking this signaling pathway. Different agents have varying selectivity profiles:

• Tofacitinib: Inhibits JAK1 and JAK3 preferentially, affecting cytokines using the common gamma chain (e.g., IL-2, IL-4, IL-7, IL-15, IL-21) and JAK1-dependent cytokines (e.g., IL-6, interferons).
• Baricitinib: Preferentially inhibits JAK1 and JAK2, impacting signaling of IL-6, interferons, and granulocyte-macrophage colony-stimulating factor (GM-CSF).
• Upadacitinib: Designed as a JAK1-selective inhibitor to potentially improve the safety profile by sparing JAK2-mediated effects like erythropoiesis.

4. Pharmacokinetics

Pharmacokinetic properties vary dramatically across DMARD classes, influencing their routes of administration, dosing frequency, and monitoring needs.

Conventional Synthetic DMARDs

Methotrexate: Oral bioavailability is approximately 70% at low doses but becomes variable and saturable at higher doses. Absorption can be reduced by food. It is distributed widely, with a volume of distribution around 0.4-0.8 L/kg. Minimal metabolism occurs to a polyglutamated active form intracellularly. Renal excretion of unchanged drug is the primary elimination pathway (80-90%), with a terminal half-life of 6-9 hours for the parent drug, though intracellular polyglutamates persist for weeks. Impaired renal function significantly increases toxicity risk.

Leflunomide: Orally bioavailable (>80%) and rapidly converted to its active metabolite, teriflunomide, in the gut wall and liver. Teriflunomide is highly protein-bound (>99%) and has a very long elimination half-life (approximately 2 weeks) due to extensive enterolepatic recirculation. Elimination is primarily via biliary excretion and direct intestinal secretion, with renal clearance being minor. This prolonged half-life necessitates a washout procedure with cholestyramine if rapid elimination is required.

Sulfasalazine: Poorly absorbed from the small intestine. Colonic bacterial azoreductases cleave it into sulfapyridine (well-absorbed) and 5-ASA (poorly absorbed). Sulfapyridine undergoes hepatic acetylation (subject to genetic polymorphism) and renal excretion. Its half-life is about 6-17 hours. 5-ASA is largely excreted in feces.

Hydroxychloroquine: Excellent oral bioavailability (~75%). It has a very large volume of distribution (600-1000 L/kg) due to extensive tissue sequestration, particularly in melanin-rich tissues and leukocytes. Hepatic metabolism by CYP enzymes (CYP2D6, CYP3A4, CYP2C8) generates active and inactive metabolites. Elimination is complex, with a multiexponential decay; the terminal half-life is extremely long (40-50 days). Renal excretion accounts for a minor fraction of elimination.

Biologic DMARDs

All bDMARDs are proteins, necessitating parenteral administration (subcutaneous or intravenous). Oral bioavailability is negligible due to gastrointestinal proteolysis. Their distribution is largely confined to the plasma and extracellular fluid, with volumes of distribution often approximating the plasma volume. Clearance occurs via proteolytic catabolism throughout the body. A significant pathway for monoclonal antibodies is target-mediated drug disposition (TMDD), where binding to the soluble or membrane-bound target leads to internalization and degradation. When target saturation is achieved, clearance slows, leading to nonlinear pharmacokinetics for some agents. Half-lives range from several days (e.g., anakinra, ~4-6 hours) to approximately 2-3 weeks for most monoclonal antibodies (e.g., adalimumab t_1/2 ~2 weeks). Anti-drug antibodies can increase clearance and reduce efficacy.

Targeted Synthetic DMARDs (JAK Inhibitors)

JAK inhibitors are orally bioavailable small molecules. Tofacitinib has rapid oral absorption (C_max in 0.5-1 hour) with ~74% bioavailability. It is approximately 40% protein-bound. Metabolism is primarily hepatic via CYP3A4, with minor contribution from CYP2C19. Renal excretion of unchanged drug accounts for about 30% of elimination. Its half-life is around 3 hours, necessitating twice-daily dosing. Baricitinib has good oral bioavailability (~79%). It is not extensively metabolized, with ~75% excreted unchanged in urine. Its half-life is approximately 12-14 hours, allowing once-daily dosing. Upadacitinib is extensively metabolized by CYP3A4. Its effective half-life supports once-daily dosing.

5. Therapeutic Uses/Clinical Applications

Approved Indications

The primary indication for DMARDs is rheumatoid arthritis, typically in patients with moderate to severe disease activity. Methotrexate is universally regarded as the first-line anchor drug, often used in combination with other agents. DMARDs are also approved for a spectrum of other immune-mediated conditions, reflecting shared pathogenic pathways.

• Psoriatic Arthritis: Methotrexate, Leflunomide, TNF inhibitors, IL-12/23 inhibitors (ustekinumab), IL-17 inhibitors (secukinumab), JAK inhibitors.
• Ankylosing Spondylitis and Axial Spondyloarthritis: TNF inhibitors, IL-17 inhibitors, JAK inhibitors.
• Juvenile Idiopathic Arthritis (JIA): Methotrexate, Etanercept, Adalimumab, Abatacept, Tocilizumab.
• Systemic Lupus Erythematosus (SLE): Hydroxychloroquine is foundational; Mycophenolate mofetil and Cyclophosphamide for severe organ involvement; Belimumab (a B-lymphocyte stimulator inhibitor) is a targeted biologic.
• Inflammatory Bowel Disease (IBD): Several TNF inhibitors (infliximab, adalimumab, certolizumab, golimumab) and the anti-integrin vedolizumab are used, though sulfasalazine is more specific for ulcerative colitis.
• Other: Vasculitides (cyclophosphamide, rituximab), Adult-onset Still’s disease (IL-1 or IL-6 inhibitors).

Off-Label Uses

Common off-label applications exist, often based on robust clinical evidence. These include the use of rituximab in refractory SLE or autoimmune blistering diseases, methotrexate in chronic uveitis or sarcoidosis, and TNF inhibitors in Behçet’s disease or non-infectious uveitis. Treatment decisions in these contexts are typically guided by specialist consensus and emerging trial data.

6. Adverse Effects

The adverse effect profiles of DMARDs are class- and agent-specific, ranging from mild and common to severe and life-threatening.

Conventional Synthetic DMARDs

Methotrexate: Common side effects include oral ulcers, nausea, and fatigue. Myelosuppression, hepatotoxicity (elevated transaminases, fibrosis), and interstitial pneumonitis are serious but often dose-related. Concomitant folic acid supplementation reduces mucosal and gastrointestinal toxicity. Renal impairment dramatically increases the risk of myelosuppression.

Leflunomide: Diarrhea, alopecia, and elevated liver enzymes are frequent. Hypertension and peripheral neuropathy may occur. Its teratogenic potential is a major concern, requiring verified contraception and a washout protocol.

Sulfasalazine: Gastrointestinal upset (nausea, anorexia), headache, and rash are common. Reversible oligospermia, hemolytic anemia in G6PD-deficient patients, and rarely, severe cutaneous reactions or agranulocytosis can occur.

Hydroxychloroquine: Generally well-tolerated. Gastrointestinal symptoms and skin rashes are most common. The most significant toxicity is retinal damage, which is dose- and duration-dependent, necessitating regular ophthalmologic screening. Rarely, cardiomyopathy and myopathy may develop.

Biologic DMARDs

Infections: All bDMARDs carry an increased risk of infections, particularly reactivation of latent tuberculosis (highest with TNF inhibitors), fungal infections, and opportunistic pathogens. Screening for latent TB is mandatory prior to initiation.

Infusion/Injection Reactions: Acute hypersensitivity reactions can occur, more commonly with intravenous agents like infliximab. Subcutaneous agents may cause local injection site reactions.

Malignancy: A potential increased risk of lymphoma and non-melanoma skin cancer has been observed, though disentangling this risk from the underlying inflammatory disease and concomitant immunosuppressants is complex.

Class-Specific Effects:

• TNF Inhibitors: May induce or exacerbate demyelinating disorders, worsen congestive heart failure (NYHA Class III/IV), and cause lupus-like syndromes.
• IL-6 Inhibitors: Can cause neutropenia, elevated cholesterol levels, and gastrointestinal perforation (rare).
• Rituximab: Associated with increased risk of severe viral infections (e.g., hepatitis B reactivation, progressive multifocal leukoencephalopathy from JC virus), and hypogammaglobulinemia with prolonged use.

Targeted Synthetic DMARDs (JAK Inhibitors)

Class-wide safety concerns have emerged from post-marketing studies, leading to Black Box Warnings for serious infections, malignancy, major adverse cardiovascular events (MACE), and thrombosis. Common adverse effects include upper respiratory tract infections, headache, and elevated creatine phosphokinase (CPK). Herpes zoster reactivation occurs at a significantly higher rate compared to other DMARDs. Laboratory abnormalities may include increased lipid parameters (LDL, HDL, triglycerides), anemia, neutropenia, and elevated liver enzymes.

7. Drug Interactions

Major Drug-Drug Interactions

Methotrexate: Concurrent use with other antifolate drugs (e.g., trimethoprim-sulfamethoxazole) increases the risk of myelosuppression. Nephrotoxic drugs (e.g., NSAIDs, aminoglycosides) can reduce methotrexate clearance, leading to toxicity. Probenecid inhibits renal tubular secretion of methotrexate.

Leflunomide: Cholestyramine and activated charcoal enhance elimination via interruption of enterolepatic recirculation. Concurrent use with other hepatotoxic drugs (e.g., methotrexate, high-dose paracetamol) may increase liver injury risk.

Biologics: Combining multiple biologic DMARDs or combining a biologic with a potent immunosuppressant like cyclophosphamide is generally avoided due to an unacceptable increase in infection risk without proven additive efficacy. An exception is the common use of methotrexate concomitantly with TNF inhibitors to reduce immunogenicity and potentially enhance efficacy.

JAK Inhibitors: Strong CYP3A4 inducers (e.g., rifampin) can significantly reduce concentrations of JAK inhibitors like tofacitinib and upadacitinib. Concurrent use with other potent immunosuppressants may increase infection risk. Coadministration with therapeutic doses of methotrexate does not appear to cause significant pharmacokinetic interactions.

Contraindications

• Absolute Contraindications: Active, untreated infection (for all immunosuppressive DMARDs); severe, uncontrolled heart failure (for TNF inhibitors); pregnancy (for methotrexate, leflunomide, mycophenolate); hypersensitivity to the drug or its components.
• Relative Contraindications: Pre-existing significant cytopenias, moderate-to-severe hepatic or renal impairment (depending on the drug’s elimination pathway), history of malignancy, demyelinating disease (for TNF inhibitors), and untreated latent tuberculosis.

8. Special Considerations

Use in Pregnancy and Lactation

Pregnancy: Methotrexate and leflunomide are potent teratogens (Category X) and must be discontinued well before conception, with a leflunomide washout confirmed by plasma level. Many bDMARDs (e.g., certolizumab pegol, etanercept, infliximab, adalimumab) and some tsDMARDs may be used cautiously during pregnancy if needed, as they do not cross the placenta in significant amounts until the late second/third trimester due to their large size. However, the last dose is often timed to minimize neonatal exposure. Hydroxychloroquine is considered safe and is often continued. A multidisciplinary approach is essential.

Lactation: Methotrexate and cyclophosphamide are contraindicated. Small amounts of biologics are excreted in breast milk, but they are likely degraded in the infant’s gut; their use is often considered compatible with breastfeeding. Hydroxychloroquine is considered safe. Data on JAK inhibitors are limited, and their use is generally not recommended.

Pediatric and Geriatric Considerations

Pediatrics: Dosing is typically based on body surface area or weight. Methotrexate and etanercept are mainstays in JIA. Live vaccines are contraindicated in patients on most immunosuppressive DMARDs. Long-term effects on growth, development, and fertility require monitoring.

Geriatrics: Age-related declines in renal and hepatic function necessitate dose adjustments for renally/hepatically cleared drugs like methotrexate. Increased comorbidity burden and polypharmacy elevate the risks of drug interactions and infections. The increased baseline risk of cardiovascular disease and malignancy must be weighed carefully when considering agents like JAK inhibitors.

Renal and Hepatic Impairment

Renal Impairment: Methotrexate, cyclophosphamide, and baricitinib require significant dose reduction or avoidance in moderate-to-severe impairment due to predominant renal excretion. Biologics, which are not renally cleared, typically do not require dose adjustment.

Hepatic Impairment: Methotrexate, leflunomide, and JAK inhibitors metabolized by CYP450 systems (tofacitinib, upadacitinib) may require caution or dose modification in significant liver disease. Hydroxychloroquine is contraindicated in pre-existing retinopathy or severe hepatic impairment.

9. Summary/Key Points

Bullet Point Summary

• DMARDs are categorized into conventional synthetic (csDMARDs), biologic (bDMARDs), and targeted synthetic (tsDMARDs) agents, each with distinct mechanisms, pharmacokinetics, and safety profiles.
• Methotrexate remains the first-line anchor therapy in RA, with its anti-inflammatory effects largely mediated through increased adenosine release.
• Biologic DMARDs target specific cytokines (TNF-α, IL-6) or immune cells (B-cells, T-cells), offering high efficacy but carrying class-specific risks, notably serious infections.
• JAK inhibitors block intracellular cytokine signaling pathways and provide oral efficacy, but are associated with Black Box Warnings for serious infections, cardiovascular events, malignancy, and thrombosis.
• The pharmacokinetics of DMARDs vary from oral absorption with hepatic/renal elimination (csDMARDs, tsDMARDs) to parenteral administration with proteolytic clearance (bDMARDs).
• Adverse effect management requires vigilant monitoring, including regular blood counts, liver function tests, infection screening (especially for TB), and, for specific drugs, ophthalmologic or lipid monitoring.
• Significant drug interactions exist, particularly for metabolized agents and those with overlapping toxicities (e.g., myelosuppression, hepatotoxicity).
• Special population management demands careful planning regarding teratogenicity, vaccine administration, and dose adjustment in organ impairment.

Clinical Pearls

• The choice of DMARD is guided by disease activity, prognostic factors, patient comorbidities, cost, and patient preference. Methotrexate is the usual first step.
• Combination therapy, often “triple therapy” with methotrexate, sulfasalazine, and hydroxychloroquine, or methotrexate with a biologic/JAK inhibitor, is employed for inadequate response to monotherapy.
• The presence of anti-drug antibodies can lead to secondary failure to biologic agents; strategies to address this include dose escalation, switching to another agent within the same class, or switching to a different mechanism of action.
• Pre-treatment screening for latent tuberculosis, hepatitis B and C, and assessment of vaccination status (administering non-live vaccines prior to immunosuppression) are critical safety measures.
• Treatment should be aligned with a treat-to-target strategy, with regular assessment of disease activity and adjustment of therapy to achieve a defined goal, such as low disease activity or remission.

References

1. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
4. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
5. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
6. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
7. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.