Pharmacology of Antirheumatoid Drugs (DMARDs)

1. Introduction/Overview

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder characterized by persistent synovial inflammation, progressive joint destruction, and significant functional disability. The pharmacological management of RA has been fundamentally transformed by the development and clinical implementation of Disease-Modifying Antirheumatic Drugs (DMARDs). These agents are distinguished from purely symptomatic treatments, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, by their capacity to alter the underlying disease course, retard radiographic progression of joint damage, and improve long-term functional outcomes. The introduction of biologic and targeted synthetic DMARDs represents a pivotal advancement in rheumatologic therapeutics, enabling more precise targeting of specific immunologic pathways. A thorough understanding of the pharmacology of these agents is essential for clinicians to optimize therapeutic strategies, minimize toxicity, and improve patient prognosis in rheumatoid arthritis and other immune-mediated inflammatory diseases.

Learning Objectives

• Classify DMARDs into conventional synthetic, biologic, and targeted synthetic categories, and describe the defining characteristics of each class.
• Explain the molecular and cellular mechanisms of action for key DMARDs, including their specific targets within the immune-inflammatory cascade.
• Analyze the pharmacokinetic profiles of major DMARDs, including routes of administration, metabolism, elimination, and implications for dosing in special populations.
• Evaluate the spectrum of adverse effects and major drug interactions associated with DMARD therapy, and formulate appropriate monitoring plans.
• Integrate pharmacologic principles to develop rational treatment strategies for rheumatoid arthritis, considering factors such as disease activity, comorbidities, and patient-specific factors.

2. Classification

DMARDs are categorized based on their chemical nature, origin, and specificity of action. The traditional classification distinguishes between conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs). This framework reflects the evolution from broad-spectrum immunosuppressants to agents designed to inhibit specific molecular targets.

Conventional Synthetic DMARDs (csDMARDs)

These are typically small-molecule, orally administered agents with broad immunomodulatory effects. Their precise mechanisms were often elucidated after their clinical efficacy was established. Key members include:

• Methotrexate: A folate antagonist, considered the anchor drug and first-line therapy for most patients with RA.
• Leflunomide: A pyrimidine synthesis inhibitor.
• Sulfasalazine: A prodrug metabolized to 5-aminosalicylic acid and sulfapyridine.
• Hydroxychloroquine: An antimalarial agent with immunomodulatory properties.
• Gold salts (e.g., auranofin) and D-penicillamine: Older agents now rarely used due to toxicity and the availability of more effective alternatives.

Biologic DMARDs (bDMARDs)

These are large protein molecules, typically antibodies or receptor constructs, produced by recombinant DNA technology. They are designed to target specific cytokines or cell surface molecules involved in the immunopathogenesis of RA. They are generally administered via subcutaneous injection or intravenous infusion. Major subclasses include:

• Tumor Necrosis Factor-alpha (TNF-α) Inhibitors: Etanercept, infliximab, adalimumab, certolizumab pegol, golimumab.
• Interleukin-6 (IL-6) Receptor Antagonists: Tocilizumab, sarilumab.
• B-Cell Depleting Agents: Rituximab (anti-CD20 monoclonal antibody).
• T-Cell Costimulation Modulators: Abatacept (CTLA-4-Ig fusion protein).
• Interleukin-1 (IL-1) Inhibitors: Anakinra (IL-1 receptor antagonist), used less frequently in RA.

Targeted Synthetic DMARDs (tsDMARDs)

This class comprises small, orally bioavailable molecules that inhibit specific intracellular signaling enzymes involved in the immune response. The primary agents are Janus Kinase (JAK) inhibitors.

• JAK Inhibitors: Tofacitinib, baricitinib, upadacitinib, filgotinib. These inhibit one or more of the JAK enzymes (JAK1, JAK2, JAK3, TYK2).

3. Mechanism of Action

The mechanisms of action of DMARDs are diverse, reflecting their different origins and targets. A unifying principle is their interference with the aberrant immune activation and inflammatory processes that characterize rheumatoid arthritis.

Mechanisms of Conventional Synthetic DMARDs

Methotrexate: At the low doses used in RA (typically 7.5-25 mg weekly), methotrexate’s anti-inflammatory effects are mediated through multiple pathways beyond simple folate antagonism. Intracellular methotrexate is polyglutamated (MTX-Glu_n), which enhances its retention. MTX-Glu_n inhibits several folate-dependent enzymes, including aminoimidazole carboxamide ribonucleotide (AICAR) transformylase. This inhibition leads to accumulation of AICAR, which subsequently increases extracellular adenosine release. Adenosine, a potent endogenous anti-inflammatory mediator, binds to A_2A receptors on neutrophils, macrophages, and lymphocytes, suppressing the production of pro-inflammatory cytokines like TNF-α and IL-6, and inhibiting neutrophil adhesion and oxidative burst. Methotrexate also inhibits T-cell activation and promotes apoptosis of activated T lymphocytes.

Leflunomide: It is a prodrug metabolized to its active form, teriflunomide. Teriflunomide non-competitively inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine synthesis pathway. Activated lymphocytes require this pathway for rapid proliferation. Inhibition of DHODH leads to a cytostatic arrest of the cell cycle in the G₁ phase, thereby suppressing clonal expansion of autoreactive T and B cells.

Sulfasalazine: This prodrug is cleaved by colonic bacteria into 5-aminosalicylic acid (5-ASA) and sulfapyridine. The immunomodulatory activity is primarily attributed to sulfapyridine, though 5-ASA may contribute locally in the gut. Its exact mechanism in RA is multifactorial and may include inhibition of nuclear factor kappa B (NF-κB) signaling, suppression of cytokine production (TNF-α, IL-1), and impairment of neutrophil chemotaxis and function.

Hydroxychloroquine: This weak base accumulates in acidic lysosomes, raising intralysosomal pH. This disrupts antigen processing and presentation by antigen-presenting cells (e.g., macrophages, dendritic cells) to CD4+ T cells. It may also inhibit Toll-like receptor (TLR) signaling, particularly TLR9, and reduce the production of cytokines like IL-1, IL-6, and TNF-α.

Mechanisms of Biologic DMARDs

TNF-α Inhibitors: TNF-α is a master pro-inflammatory cytokine pivotal in RA pathogenesis, driving synovitis, cartilage degradation, and bone erosion. Etanercept is a soluble TNF receptor-Fc fusion protein that binds soluble and membrane-bound TNF. Infliximab, adalimumab, golimumab, and certolizumab pegol are monoclonal antibodies (or antibody fragments) that bind TNF-α with high affinity, neutralizing its biological activity. Infliximab and adalimumab can also induce complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) against cells expressing membrane TNF.

IL-6 Receptor Antagonists: IL-6 is a pleiotropic cytokine involved in B-cell differentiation, T-cell activation, acute phase response (e.g., CRP production), and osteoclastogenesis. Tocilizumab and sarilumab are monoclonal antibodies that bind to the membrane-bound and soluble IL-6 receptor, blocking IL-6-mediated signal transduction via gp130, thereby inhibiting the downstream JAK-STAT pathway.

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

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

Mechanisms of Targeted Synthetic DMARDs (JAK Inhibitors)

JAK inhibitors interfere with intracellular signaling downstream of multiple cytokine receptors. Cytokine binding induces receptor dimerization and transphosphorylation of associated JAK proteins (JAK1, JAK2, JAK3, TYK2). Activated JAKs phosphorylate signal transducers and activators of transcription (STAT) proteins, which dimerize and translocate to the nucleus to regulate gene expression. Different JAK inhibitors have varying selectivity profiles. For example, tofacitinib preferentially inhibits JAK1 and JAK3, baricitinib inhibits JAK1 and JAK2, and upadacitinib is more selective for JAK1. By blocking this pathway, they inhibit the signaling of cytokines critical in RA, including IL-6, IL-2, IL-7, IL-15, IL-21, and interferons, thereby modulating both innate and adaptive immune responses.

4. Pharmacokinetics

The pharmacokinetic properties of DMARDs vary widely, influencing their routes of administration, dosing intervals, and need for therapeutic drug monitoring.

Conventional Synthetic DMARDs

Methotrexate: Oral bioavailability is approximately 70% at low doses but becomes variable and saturable at higher doses. Absorption occurs primarily in the proximal small intestine. It is often administered once weekly to enhance efficacy and reduce toxicity. Distribution is widespread, with a volume of distribution around 0.4-0.8 L/kg. Methotrexate undergoes minimal metabolism; it is primarily excreted unchanged in urine via glomerular filtration and active tubular secretion. Renal impairment significantly prolongs its half-life (t_1/2 ≈ 8-15 hours normally) and increases toxicity risk. Concomitant use of drugs like probenecid or penicillin that compete for tubular secretion can elevate methotrexate levels.

Leflunomide: Oral bioavailability of the prodrug is about 80%. It is rapidly converted in the gut wall and liver to the active metabolite, teriflunomide. Teriflunomide is highly protein-bound (>99%) and has a very long elimination half-life of approximately 2-3 weeks due to extensive enterolepatic recirculation. It undergoes biliary excretion and minimal renal excretion. An accelerated elimination procedure using cholestyramine or activated charcoal can be employed to rapidly reduce plasma levels if toxicity occurs.

Sulfasalazine: Only about 10-30% of the parent drug is absorbed in the small intestine. The majority reaches the colon, where bacterial azoreductases split it into sulfapyridine and 5-ASA. Sulfapyridine is well-absorbed, acetylated, and hydroxylated in the liver (subject to genetic polymorphism in acetylation), and excreted in urine. 5-ASA is largely excreted in feces. The half-life of sulfapyridine is 6-17 hours.

Hydroxychloroquine: It is well-absorbed orally, with a bioavailability of about 74%. It has a very large volume of distribution (600-1000 L/kg) due to extensive tissue sequestration, particularly in melanin-rich tissues (retina) and lymphoid organs. It is metabolized by cytochrome P450 enzymes (CYP2D6, CYP3A4, CYP2C8) to active metabolites. Elimination is complex and slow, with a terminal half-life of 40-50 days. Excretion is primarily renal (20-50%) and fecal.

Biologic DMARDs

As large proteins, bDMARDs are not absorbed orally and must be administered parenterally. They are typically degraded into peptides and amino acids by proteolytic enzymes throughout the body, with no hepatic metabolism via cytochrome P450 systems. Elimination occurs via proteolysis and, for some, target-mediated drug disposition (binding to and internalization with their target). Their pharmacokinetics often follow nonlinear patterns at lower doses due to saturable target binding. Clearance is generally slower, leading to longer dosing intervals (e.g., weekly to monthly).

• TNF Inhibitors: Subcutaneous agents (etanercept, adalimumab, golimumab, certolizumab) have absorption t_1/2 of 2-4 days. Their elimination half-lives range from approximately 2 weeks (etanercept) to 2-3 weeks (adalimumab, golimumab). Certolizumab pegol, a PEGylated Fab’ fragment, lacks an Fc region, resulting in a half-life of about 14 days and minimal placental transfer. Intravenous infliximab has a half-life of 8-10 days.
• Tocilizumab: Has a half-life of approximately 11-13 days when given subcutaneously and 6-7 days with IV administration, with clearance increasing with body weight.
• Abatacept: IV formulation half-life is 13-16 days; subcutaneous half-life is about 14.3 days.
• Rituximab: Pharmacokinetics are complex and influenced by the degree of B-cell depletion and anti-drug antibodies. The terminal half-life after the first infusion is about 20 days but increases with subsequent infusions as the number of CD20+ target cells decreases.

Targeted Synthetic DMARDs (JAK Inhibitors)

These are small molecules with good oral bioavailability (tofacitinib ~74%, baricitinib ~79%, upadacitinib ~88%). They are rapidly absorbed, with time to maximum concentration (T_max) within 0.5-2 hours. Protein binding varies (tofacitinib ~40%, baricitinib ~50%, upadacitinib ~52%). They are metabolized extensively in the liver, primarily by CYP3A4 (tofacitinib, upadacitinib) and to a lesser extent by CYP2C19. Baricitinib is minimally metabolized, with renal excretion of the unchanged drug being the major route of elimination. Elimination half-lives are relatively short: tofacitinib ~3 hours, baricitinib ~12 hours, upadacitinib ~8-14 hours. Despite short half-lives, sustained target inhibition allows for twice-daily or once-daily dosing.

5. Therapeutic Uses/Clinical Applications

The primary indication for DMARDs is the treatment of moderate-to-severe active rheumatoid arthritis. Treatment paradigms, such as the “treat-to-target” strategy, emphasize early, aggressive intervention to achieve clinical remission or low disease activity.

Approved Indications

First-Line Therapy: Methotrexate is universally regarded as the first-line csDMARD and the anchor therapy for RA. It is often initiated as monotherapy or in combination with other agents. Other csDMARDs like leflunomide or sulfasalazine may be used as monotherapy if methotrexate is contraindicated or not tolerated.

Combination csDMARD Therapy: Combinations such as methotrexate plus sulfasalazine plus hydroxychloroquine (“triple therapy”) can be as effective as methotrexate plus a biologic agent in some patients.

Biologic and Targeted Synthetic DMARDs: These are typically reserved for patients with an inadequate response to one or more csDMARDs, often methotrexate. They are almost always used in combination with a csDMARD (most commonly methotrexate) to enhance efficacy and reduce immunogenicity. Specific scenarios may guide choice:

• TNF Inhibitors: First-line biologic class for most patients without specific contraindications. Also used in other spondyloarthropathies (psoriatic arthritis, ankylosing spondylitis) and inflammatory bowel disease.
• Rituximab: Particularly effective in seropositive (RF+ and/or anti-CCP+) RA. Often considered after failure of TNF inhibitors or in patients with specific contraindications to TNF inhibition (e.g., history of lymphoma, demyelinating disease).
• Abatacept: Used after inadequate response to csDMARDs or other biologics. Its mechanism may be favorable in patients with high T-cell activity.
• Tocilizumab/Sarilumab: Effective as monotherapy or in combination. May be preferred in patients with systemic features (elevated acute phase reactants) or anemia of chronic disease.
• JAK Inhibitors: Used after inadequate response to csDMARDs or other biologics. Their oral administration is an advantage. Recent safety data have led to recommendations for their use typically after failure of at least one TNF inhibitor, especially in patients with cardiovascular risk factors.

Off-Label Uses

Many DMARDs are used off-label for other autoimmune and inflammatory conditions, reflecting shared pathogenic pathways. Examples include:

• Methotrexate: Psoriasis, psoriatic arthritis, inflammatory myopathies, vasculitis (e.g., giant cell arteritis).
• Leflunomide: Psoriatic arthritis.
• Hydroxychloroquine: Systemic lupus erythematosus (SLE), Sjögren’s syndrome.
• TNF Inhibitors: Crohn’s disease, ulcerative colitis, uveitis, hidradenitis suppurativa.
• Rituximab: ANCA-associated vasculitis, SLE, pemphigus vulgaris.
• Tocilizumab: Giant cell arteritis, cytokine release syndrome.

6. Adverse Effects

The adverse effect profiles of DMARDs are diverse and can be serious, necessitating vigilant patient education and monitoring.

Conventional Synthetic DMARDs

Methotrexate:

• Common: Nausea, oral stomatitis, fatigue, alopecia, elevated liver transaminases (dose-related).
• Serious: Myelosuppression (leukopenia, thrombocytopenia), hepatotoxicity (fibrosis, cirrhosis—risk increased with alcohol, obesity, diabetes), interstitial pneumonitis (acute onset of cough, dyspnea), severe mucositis. Renal impairment drastically increases toxicity risk.
• Mitigation: Concomitant folic acid (1-5 mg daily or weekly) significantly reduces gastrointestinal and mucosal toxicity without compromising efficacy.

Leflunomide:

• Common: Diarrhea, nausea, alopecia, rash, elevated liver enzymes.
• Serious: Hepatotoxicity, myelosuppression, peripheral neuropathy, interstitial lung disease (rare). Its long half-life poses a challenge in managing toxicity.

Sulfasalazine:

• Common: Gastrointestinal upset (nausea, anorexia), headache, rash, orange discoloration of urine and sweat.
• Serious: Myelosuppression (agranulocytosis), hepatotoxicity, severe cutaneous reactions (Stevens-Johnson syndrome), oligospermia (reversible).

Hydroxychloroquine:

• Common: Generally well-tolerated. Nausea, diarrhea, skin rash, headache.
• Serious: Retinopathy is the most significant concern, leading to irreversible vision loss. Risk is dose-dependent (based on real body weight and duration of use). Regular ophthalmologic screening (e.g., spectral-domain optical coherence tomography) is mandatory. Rarely, cardiomyopathy and skeletal myopathy can occur.

Biologic and Targeted Synthetic DMARDs

Injection/Infusion Reactions: Common with parenteral bDMARDs. Subcutaneous agents can cause local injection site reactions (erythema, pain, itching). IV agents like infliximab and rituximab can cause acute infusion reactions (fever, chills, urticaria, hypotension) during or shortly after administration, often managed by slowing the infusion rate and premedication with antihistamines, acetaminophen, or corticosteroids.

Infections: All biologic DMARDs and JAK inhibitors carry a black box warning for increased risk of serious and sometimes fatal infections. This includes bacterial (e.g., pneumonia, cellulitis), viral (herpes zoster reactivation—particularly high with JAK inhibitors), fungal, and opportunistic infections (e.g., tuberculosis, histoplasmosis, pneumocystosis). TNF inhibitors are specifically associated with a heightened risk of reactivating latent tuberculosis; screening with tuberculin skin test or interferon-gamma release assay is required prior to initiation.

Malignancy: There is a theoretical and observed increased risk of certain malignancies, particularly lymphoma and non-melanoma skin cancer. The risk appears to be elevated in patients with severe, active RA itself, making causality difficult to establish. JAK inhibitors carry a black box warning for an increased risk of major adverse cardiovascular events (MACE), malignancy, thrombosis, and all-cause mortality based on a post-marketing safety trial (ORAL Surveillance).

Other Class-Specific Effects:

• TNF Inhibitors: Can induce or exacerbate demyelinating disorders (e.g., multiple sclerosis), worsen congestive heart failure (NYHA Class III/IV), and cause drug-induced lupus. They may also cause psoriasis-like skin lesions.
• IL-6 Inhibitors: Commonly cause neutropenia and elevated cholesterol (increased LDL and HDL), which usually does not require discontinuation. Can cause gastrointestinal perforation, particularly in patients with diverticulitis.
• Rituximab: Associated with reactivation of hepatitis B virus. Can cause severe mucocutaneous reactions and progressive multifocal leukoencephalopathy (PML), a rare, fatal brain infection caused by JC virus.
• JAK Inhibitors: Increased risk of herpes zoster, venous thromboembolism (DVT, PE), elevated liver enzymes, and lipid elevations (LDL, HDL).

7. Drug Interactions

Significant drug interactions can alter the efficacy and toxicity profiles of DMARDs.

Major Drug-Drug Interactions

Methotrexate:

• NSAIDs, Salicylates, Proton Pump Inhibitors: May compete for renal tubular secretion, potentially increasing methotrexate levels and toxicity.
• Trimethoprim-Sulfamethoxazole: Synergistic antifolate effect; increases risk of myelosuppression.
• Probenecid, Penicillins: Reduce renal clearance of methotrexate.
• Hepatotoxic drugs (e.g., high-dose acetaminophen, leflunomide): Increased risk of liver injury.

Leflunomide:

• Other hepatotoxic drugs: Increased risk of liver injury. Concurrent use with methotrexate requires careful monitoring of liver function.
• Live vaccines: Contraindicated due to immunosuppression.
• Warfarin: Teriflunomide may increase INR by inhibiting CYP2C9.

Biologic DMARDs:

• Other immunosuppressants: Combination with other potent immunosuppressants (e.g., high-dose corticosteroids, azathioprine) may excessively increase infection risk, though combination with csDMARDs like methotrexate is standard.
• Live vaccines: Generally contraindicated during therapy. Inactivated vaccines are safe but may have diminished immunogenicity.
• Abatacept with TNF inhibitors: Concurrent use is not recommended due to increased infection risk without added efficacy.

JAK Inhibitors:

• Strong CYP3A4 Inducers (e.g., rifampin, carbamazepine): May decrease concentrations of tofacitinib and upadacitinib, reducing efficacy.
• Strong CYP3A4 Inhibitors (e.g., ketoconazole) or Drugs that inhibit both CYP3A4 and CYP2C19 (e.g., fluconazole): May increase concentrations of JAK inhibitors, potentially increasing toxicity. Dose adjustments are often required.
• Other immunosuppressants: Increased risk of infection and possibly malignancy.

Contraindications

Absolute contraindications vary by agent but commonly include:

• Active, serious infection (for all immunosuppressive DMARDs).
• Severe hepatic impairment (for methotrexate, leflunomide).
• Severe renal impairment (for methotrexate, requires dose adjustment or avoidance; caution with JAK inhibitors excreted renally).
• Pregnancy (for methotrexate, leflunomide—Category X; mycophenolate, if used). Many biologics (except certolizumab pegol) and JAK inhibitors are Category B or C but used with caution.
• History of demyelinating disease (for TNF inhibitors).
• NYHA Class III/IV heart failure (for TNF inhibitors).
• History of lymphoproliferative disorder (relative contraindication for many, especially TNF inhibitors).

8. Special Considerations

Pregnancy and Lactation

Pregnancy Planning and Management is critical. Methotrexate and leflunomide are teratogenic (Category X) and must be discontinued well before conception (methotrexate: ≥3 months; leflunomide: requires accelerated elimination procedure and confirmation of low plasma levels). Sulfasalazine and hydroxychloroquine are considered safe and are often continued to maintain disease control. Among bDMARDs, most IgG1-based agents (adalimumab, infliximab, etanercept, golimumab) actively cross the placenta in the second and third trimesters. Certolizumab pegol, due to its lack of an Fc region, shows minimal to no placental transfer, making it a preferred option. JAK inhibitors are generally avoided due to limited safety data. A multidisciplinary approach involving rheumatology and obstetrics is essential.

Lactation: Methotrexate and leflunomide are contraindicated. Sulfasalazine, hydroxychloroquine, and most biologic agents are considered compatible with breastfeeding as minimal amounts are excreted in breast milk and are likely degraded in the infant’s gut.

Pediatric Considerations

Polyarticular juvenile idiopathic arthritis (JIA) is the primary pediatric indication. Methotrexate is the cornerstone csDMARD. Etanercept, adalimumab, abatacept, and tocilizumab are approved for pediatric use. Dosing is typically based on body surface area or weight. Live vaccines should be administered prior to starting immunosuppressive therapy if possible. Monitoring for growth and development is important.

Geriatric Considerations

Elderly patients often have comorbidities (renal/hepatic impairment, cardiovascular disease, frailty) and polypharmacy, increasing the risk of adverse events and drug interactions. Renal function must be assessed carefully for dose adjustment of renally excreted drugs (methotrexate, some JAK inhibitors). Increased susceptibility to infections, myelosuppression, and falls (from dizziness, myelosuppression) necessitates cautious dosing and vigilant monitoring. The cardiovascular and thromboembolic risks associated with JAK inhibitors require careful assessment in this population.

Renal and Hepatic Impairment

Renal Impairment:

• Methotrexate: Contraindicated in severe impairment. Requires dose reduction and close monitoring in moderate impairment due to drastically reduced clearance.
• Leflunomide: Dose adjustment not typically required as renal excretion is minimal, but caution is advised due to risk of other toxicities.
• Biologics: No dose adjustment generally needed.
• JAK Inhibitors: Baricitinib requires dose reduction in moderate-to-severe renal impairment. Tofacitinib and upadacitinib may also require adjustment.

Hepatic Impairment:

• Methotrexate & Leflunomide: Contraindicated in significant liver disease due to hepatotoxicity risk.
• Hydroxychloroquine: Use with caution; metabolism may be impaired.
• Most Biologics: No dose adjustment.
• JAK Inhibitors: Tofacitinib and upadacitinib require dose reduction in moderate-to-severe hepatic impairment.

9. Summary/Key Points

• DMARDs are the cornerstone of RA management, with the goal of modifying the disease course, preventing joint damage, and preserving function. They are classified into conventional synthetic (csDMARDs), biologic (bDMARDs), and targeted synthetic (tsDMARDs) agents.
• Methotrexate remains the first-line anchor therapy, with its anti-inflammatory effects mediated largely through adenosine release. Biologics target specific cytokines (TNF-α, IL-6) or cells (B cells, T cells), while JAK inhibitors block intracellular signaling pathways.
• Pharmacokinetics vary dramatically: csDMARDs are generally oral with variable metabolism; bDMARDs are parenteral proteins degraded by proteolysis; tsDMARDs are oral small molecules metabolized by CYP enzymes.
• Therapeutic use follows a treat-to-target strategy, with methotrexate as first-line. Biologics and JAK inhibitors are added or switched in cases of inadequate response, often in combination with a csDMARD.
• Adverse effects are a major concern. All immunosuppressive DMARDs increase infection risk. csDMARDs have organ-specific toxicities (hepatic, pulmonary, hematologic). Biologics carry risks of infusion reactions, specific infections (e.g., TB), and demyelination. JAK inhibitors have black box warnings for cardiovascular events, thrombosis, malignancy, and serious infections.
• Significant drug interactions exist, particularly for methotrexate (with NSAIDs, trimethoprim) and JAK inhibitors (with CYP modulators). Live vaccines are generally contraindicated.
• Special populations require tailored approaches: teratogenic drugs must be avoided before/during pregnancy; renal/hepatic function dictates dosing for many agents; and elderly patients need careful risk-benefit assessment due to comorbidities.

Clinical Pearls

• Folic acid supplementation is mandatory with methotrexate to reduce mucosal and GI toxicity.
• Screen for latent tuberculosis and hepatitis B prior to initiating any biologic or JAK inhibitor.
• Regular monitoring (CBC, liver function tests, creatinine) is essential for patients on csDMARDs and JAK inhibitors.
• Certolizumab pegol may be the biologic of choice in women planning pregnancy due to minimal placental transfer.
• The choice of a specific advanced therapy (biologic or JAK inhibitor) should be individualized based on disease factors, comorbidities (e.g., heart failure, demyelination, hepatitis B), patient preference (oral vs. injectable), and cost/access.
• Never stop DMARD therapy abruptly during an active infection; temporary withholding may be necessary, with decisions made in consultation with a specialist.

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