Inflammation: Drugs for Rheumatoid Arthritis

Introduction/Overview

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovial inflammation, progressive cartilage destruction, and bone erosions. The therapeutic landscape has expanded dramatically over the past decades, now encompassing non‑steroidal anti‑inflammatory drugs (NSAIDs), glucocorticoids, conventional synthetic disease‑modifying antirheumatic drugs (csDMARDs), biologic DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs). These agents differ markedly in their pharmacodynamic targets, clinical efficacy profiles, and safety considerations. A thorough understanding of these drugs is essential for optimizing disease control while minimizing adverse effects.

Learning Objectives

• Describe the pharmacological classes of anti‑inflammatory agents used in RA and their principal molecular targets.
• Explain the pharmacokinetic properties that influence dosing strategies for each drug class.
• Identify the key indications, contraindications, and off‑label uses for major RA therapeutics.
• Summarize the most common and serious adverse effect profiles associated with these agents.
• Discuss drug–drug interactions, special population considerations, and practical prescribing principles.

Classification

Non‑Steroidal Anti‑Inflammatory Drugs (NSAIDs)

NSAIDs constitute the first line for symptomatic pain and stiffness relief. They are classified by cyclo‑oxygenase (COX) selectivity: non‑selective agents (e.g., ibuprofen, naproxen) inhibit both COX‑1 and COX‑2, whereas selective COX‑2 inhibitors (e.g., celecoxib) preferentially block the pro‑inflammatory COX‑2 isoenzyme.

Glucocorticoids

Systemic and topical glucocorticoids (e.g., prednisone, methylprednisolone) act as potent anti‑inflammatory agents through genomic and non‑genomic pathways. Their classification is based on potency, half‑life, and route of administration.

Conventional Synthetic Disease‑Modifying Antirheumatic Drugs (csDMARDs)

CsDMARDs share a broad mechanism of immunomodulation and include methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, and azathioprine. Their chemical classification ranges from folate antagonists to pyrimidine analogs.

Biologic DMARDs (bDMARDs)

bDMARDs are monoclonal antibodies or fusion proteins targeting specific cytokines or cell surface molecules. Major subclasses include tumor necrosis factor (TNF) inhibitors (adalimumab, etanercept, infliximab, golimumab, certolizumab pegol), interleukin‑6 (IL‑6) receptor antagonist (tocilizumab), B‑cell depleting agent (rituximab), and T‑cell costimulation modulator (abatacept).

Targeted Synthetic DMARDs (tsDMARDs)

TsDMARDs are small‑molecule kinase inhibitors with selectivity for intracellular signaling pathways. Janus kinase (JAK) inhibitors (tofacitinib, baricitinib, upadacitinib) exemplify this class.

Mechanism of Action

NSAIDs

NSAIDs competitively inhibit cyclo‑oxygenase enzymes, thereby reducing prostaglandin synthesis. Non‑selective agents reduce both COX‑1–mediated gastric mucosal protection and COX‑2–mediated inflammatory prostaglandins, whereas COX‑2 selective agents spare gastric COX‑1 activity, potentially lowering gastrointestinal toxicity.

Glucocorticoids

Glucocorticoids bind cytoplasmic glucocorticoid receptors, translocate to the nucleus, and modulate transcription of anti‑inflammatory genes (e.g., lipocortin‑1) while down‑regulating pro‑inflammatory cytokines (IL‑1, IL‑6, TNF). Non‑genomic actions include rapid inhibition of phospholipase A2 and modulation of calcium signaling.

CsDMARDs

• Methotrexate: Inhibits dihydrofolate reductase, leading to depletion of tetrahydrofolate and suppression of DNA synthesis. In low doses, it enhances extracellular adenosine, exerting anti‑inflammatory effects.
• Leflunomide: Metabolized to teriflunomide, which irreversibly inhibits dihydroorotate dehydrogenase, blocking pyrimidine synthesis and lymphocyte proliferation.
• Sulfasalazine: Metabolized to sulfapyridine and 5‑aminosalicylic acid; the latter exerts anti‑inflammatory effects via cyclo‑oxygenase inhibition and free radical scavenging.
• Hydroxychloroquine: Interferes with lysosomal activity and toll‑like receptor signalling in dendritic cells.
• Azathioprine: Converted to 6‑mercaptopurine; inhibits purine synthesis, reducing lymphocyte proliferation.

bDMARDs

• TNF Inhibitors: Bind soluble or membrane‑bound TNF‑α, preventing interaction with TNF receptors and downstream NF‑κB activation.
• Tocilizumab: Blocks IL‑6 receptor, inhibiting IL‑6‑mediated STAT3 signalling.
• Rituximab: Targets CD20 on B‑cells, leading to complement‑mediated cytotoxicity and antibody‑dependent cellular cytotoxicity.
• Abatacept: Fusion protein comprising CTLA‑4 and IgG1 Fc; binds CD80/86 on antigen‑presenting cells, inhibiting CD28 co‑stimulation of T‑cells.

tsDMARDs

JAK inhibitors competitively bind the ATP pocket of JAK enzymes (JAK1, JAK2, JAK3, TYK2), blocking phosphorylation of STAT proteins and subsequent transcription of pro‑inflammatory cytokine genes.

Pharmacokinetics

NSAIDs

Oral absorption is rapid, with peak plasma concentrations reached within 1–2 h. Distribution is extensive; lipophilicity varies among agents. Metabolism occurs primarily in the liver via CYP450 (e.g., ibuprofen CYP2C9, naproxen CYP1A2). Excretion is mainly renal. Half‑lives range from 1–4 h (short‑acting) to 12 h (long‑acting). Dosage adjustments are required in hepatic or renal impairment, particularly for agents with significant renal clearance.

Glucocorticoids

Systemic glucocorticoids exhibit rapid absorption (prednisone: T_max ≈ 1 h). Bioavailability is high for oral forms. Distribution is widespread, with high protein binding. Metabolism occurs via hepatic CYP3A4; metabolites are excreted renally. Half‑life varies: prednisone ≈ 3 h, methylprednisolone ≈ 12 h. Dosing schedules (daily vs. intermittent) influence receptor occupancy and side‑effect profiles.

CsDMARDs

• Methotrexate: Oral absorption is dose‑dependent (≈ 50 % at 10 mg). Renal excretion is predominant; accumulation occurs in renal impairment. Half‑life: 3–10 h.
• Leflunomide: Bioavailability ~ 50 %. Metabolized to teriflunomide (half‑life ≈ 18 days); prolonged exposure necessitates a cholestyramine washout. Renal excretion accounts for 60–80 % of drug elimination.
• Sulfasalazine: Rapid absorption; metabolized by gut flora to sulfapyridine and 5‑ASA. Sulfapyridine cleared renally; half‑life ≈ 12 h.
• Hydroxychloroquine: Slower absorption (T_max ≈ 6 h). Long half‑life (~ 20–30 days) due to extensive tissue distribution. Renal excretion of metabolites.
• Azathioprine: Metabolized to 6‐mercaptopurine; half‑life ≈ 2 h. Hepatic metabolism via TPMT; renal excretion of 6‑MP metabolites.

bDMARDs

Monoclonal antibodies and fusion proteins are administered parenterally (intravenous or subcutaneous). Absorption is slow; bioavailability for subcutaneous routes is 70–80 %. Distribution is primarily intravascular and interstitial; limited penetration into solid tissues. Metabolism follows proteolytic catabolism; no hepatic or renal clearance. Clearance is linear and dose‑dependent. Dosing intervals range from weekly to monthly, depending on the agent.

tsDMARDs

Orally administered JAK inhibitors exhibit rapid absorption (T_max ≈ 1–2 h). Distribution is extensive across tissues, with plasma protein binding 90–95 %. Metabolism is predominantly hepatic via CYP3A4 (upadacitinib) or CYP2C19 (tofacitinib). Renal excretion of metabolites is significant. Half‑lives: tofacitinib ≈ 9 h; baricitinib ≈ 12 h; upadacitinib ≈ 9 h. Dose modifications are necessary in hepatic or renal dysfunction.

Therapeutic Uses/Clinical Applications

NSAIDs

Primarily provide symptomatic relief of pain and stiffness. They are used as adjuncts to csDMARDs or biologics, especially in early disease or during flare management. Off‑label use includes management of osteoarthritis symptoms.

Glucocorticoids

Serve as bridging therapy while csDMARDs or biologics take effect. They are employed during acute flares, for patients requiring rapid control, and in cases of contraindication to other DMARDs. Long‑term systemic use is generally avoided due to cumulative toxicity.

CsDMARDs

• Methotrexate is the anchor drug for RA; it is first‑line for disease control and is commonly combined with biologics. Off‑label uses include psoriasis and inflammatory bowel disease.
• Leflunomide is an alternative for patients intolerant of methotrexate; it is also used in psoriatic arthritis.
• Sulfasalazine is indicated for mild to moderate disease and is frequently combined with methotrexate.
• Hydroxychloroquine is reserved for patients with low disease activity and is often used in combination therapy.
• Azathioprine is employed as a steroid‑sparing agent or in combination with methotrexate in select cases.

bDMARDs

Indicated for patients with inadequate response to csDMARDs, especially methotrexate. TNF inhibitors are first‑line biologics; IL‑6 receptor antagonists, B‑cell depleting agents, and T‑cell costimulation modulators are used in refractory disease or specific clinical scenarios (e.g., concomitant systemic vasculitis).

tsDMARDs

JAK inhibitors are indicated for patients with inadequate response or intolerance to csDMARDs and biologics. They are also employed as monotherapy or in combination with methotrexate for moderate to severe disease.

Adverse Effects

NSAIDs

• Gastrointestinal mucosal damage, including dyspepsia, ulceration, and bleeding.
• Renal impairment, especially in volume‑depleted states.
• Cardiovascular risk elevation (hypertension, thromboembolic events).
• Allergic reactions (rash, anaphylaxis).

Glucocorticoids

• Metabolic derangements: hyperglycemia, osteoporosis, dyslipidemia.
• Endocrine suppression: adrenal insufficiency, Cushingoid features.
• Infections: opportunistic pathogens, reactivation of latent TB.
• Psychiatric effects: mood swings, insomnia.
• Chronic use may precipitate avascular necrosis and cataracts.

CsDMARDs

• Methotrexate: Hepatotoxicity, pulmonary fibrosis, myelosuppression, mucositis.
• Leflunomide: Hepatotoxicity, hyperuricemia, cholestatic jaundice.
• Sulfasalazine: Hemolytic anemia, agranulocytosis, photosensitivity.
• Hydroxychloroquine: Retinal toxicity (maculopathy), cardiotoxicity.
• Azathioprine: Myelosuppression, hepatotoxicity, increased infection risk.

bDMARDs

• Increased susceptibility to infections, particularly tuberculosis and opportunistic organisms.
• Injection site reactions, hypersensitivity.
• Hematologic abnormalities: neutropenia, thrombocytopenia.
• Potential for malignancy (lymphoma, skin cancers) with long‑term use.
• Specific agents: rituximab may cause infusion reactions; abatacept may lead to increased viral reactivation.

tsDMARDs

• Herpes zoster reactivation is notably higher with JAK inhibitors.
• Elevated liver enzymes, cytopenias.
• Risk of thromboembolic events increases with age and comorbidities.
• Potential for serious infections, including opportunistic pathogens.
• Black box warning for increased risk of serious infections, malignancy, and death with tofacitinib.

Drug Interactions

NSAIDs

• Concurrent use with anticoagulants (warfarin, DOACs) amplifies bleeding risk.
• NSAIDs reduce the antihypertensive efficacy of ACE inhibitors, ARBs, and diuretics.
• COX‑2 inhibitors may interfere with aspirin’s antiplatelet effect.

Glucocorticoids

• Co‑administration with CYP3A4 inhibitors (ketoconazole, ritonavir) elevates glucocorticoid exposure.
• Glucocorticoids increase serum glucose, potentially worsening diabetes management.
• Stimulants such as caffeine can accentuate adrenal suppression.

CsDMARDs

• Methotrexate interacts with NSAIDs, penicillins, and rifampin, increasing hepatotoxic risk.
• Leflunomide is contraindicated with CYP3A4 inhibitors (ketoconazole, itraconazole).
• Azathioprine may potentiate myelosuppression when combined with other myelosuppressants (cyclophosphamide).

bDMARDs

• Biologics may interfere with live vaccines; timing of administration relative to vaccination is crucial.
• TNF inhibitors may interact with TB screening agents; interferon‑γ release assays may be altered.
• Abatacept may reduce serological responses to vaccines.

tsDMARDs

• JAK inhibitors are contraindicated with strong CYP3A4 inhibitors (ketoconazole, itraconazole) or inducer (rifampin).
• Co‑administration with strong CYP3A4 inhibitors increases serum concentrations, heightening infection risk.
• Use with antiplatelet agents (clopidogrel, aspirin) may elevate bleeding risk.

Special Considerations

Pregnancy and Lactation

NSAIDs and glucocorticoids are generally avoided in the third trimester due to fetal renal suppression and ductus arteriosus closure. Methotrexate is teratogenic and contraindicated. Leflunomide requires a washout procedure. Biologics vary: TNF inhibitors are considered relatively safe in early pregnancy with low risk of fetal immunosuppression; IL‑6 inhibitors and JAK inhibitors are contraindicated. Lactation is discouraged with biologics due to potential neonatal immunosuppression.

Pediatric Considerations

Children with juvenile idiopathic arthritis may tolerate lower doses of methotrexate and NSAIDs. Glucocorticoid dosing requires careful monitoring to prevent growth suppression. Biologics are approved for certain pediatric subtypes; safety data are limited for tsDMARDs in this population.

Geriatric Considerations

Older adults exhibit increased sensitivity to NSAID–induced gastrointestinal bleeding and renal dysfunction. Dose adjustments for methotrexate and leflunomide are often necessary. JAK inhibitors carry an elevated thromboembolic risk in patients over 65.

Renal and Hepatic Impairment

Renal insufficiency requires dose reduction for methotrexate, leflunomide, and NSAIDs. Hepatic dysfunction mandates monitoring of transaminases and potential discontinuation of hepatotoxic agents. JAK inhibitors require graded dose reductions based on creatinine clearance and liver enzyme levels.

Summary/Key Points

• NSAIDs and glucocorticoids provide symptomatic relief but are limited by GI, renal, and systemic toxicity.
• CsDMARDs constitute disease‑modifying therapy; methotrexate remains the cornerstone, with leflunomide and sulfasalazine as alternatives.
• bDMARDs target specific cytokines or immune cells, offering superior disease control in refractory cases.
• tsDMARDs, particularly JAK inhibitors, provide oral options with rapid onset but carry infection and thrombosis risks.
• Therapeutic decisions should balance efficacy, safety, patient comorbidities, and pharmacokinetic profiles.
• Regular monitoring of laboratory parameters, infection screening, and vaccination status is essential across all drug classes.
• Special populations—pregnant patients, the elderly, and those with organ impairment—require individualized dosing and vigilant surveillance.

References

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