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Tuesday, August 19, 2025

Antirheumatics


Introduction

Antirheumatics are a diverse group of medications used in the treatment of rheumatic diseases, including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), psoriatic arthritis, and other autoimmune or inflammatory musculoskeletal conditions. Their primary goal is to control inflammation, alleviate pain, reduce joint damage, and maintain function.

They include a wide range of drug classes:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs)

  • Glucocorticoids (corticosteroids)

  • Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)

  • Biologic DMARDs (bDMARDs)

  • Targeted synthetic DMARDs (tsDMARDs)

  • Adjunctive symptomatic agents

Classification of Antirheumatics

1. NSAIDs (Nonsteroidal Anti-inflammatory Drugs)

  • Generic names: Ibuprofen, naproxen, indomethacin, diclofenac, meloxicam, celecoxib, etoricoxib.

  • Mechanism: Inhibition of cyclooxygenase enzymes (COX-1 and COX-2), reducing prostaglandin synthesis, thereby decreasing inflammation, pain, and fever.

  • Role: Provide rapid relief of pain and stiffness in rheumatic diseases but do not alter disease progression.

2. Glucocorticoids (Corticosteroids)

  • Generic names: Prednisone, prednisolone, methylprednisolone, dexamethasone, triamcinolone (intra-articular).

  • Mechanism: Bind glucocorticoid receptors, altering gene transcription to suppress cytokine production and inflammatory pathways.

  • Role: Short-term use to control acute flares; may be used as bridging therapy while waiting for DMARDs to take effect.

3. Conventional Synthetic DMARDs (csDMARDs)

  • Methotrexate: First-line csDMARD for RA; folate antagonist reducing immune cell proliferation.

  • Leflunomide: Inhibits pyrimidine synthesis; reduces lymphocyte proliferation.

  • Sulfasalazine: Combines antibacterial and anti-inflammatory effects.

  • Hydroxychloroquine & Chloroquine: Antimalarial drugs with immunomodulatory properties; used in RA and lupus.

  • Azathioprine: Immunosuppressive purine analogue.

  • Cyclophosphamide: Alkylating agent, used in severe SLE or vasculitis.

  • Cyclosporine: Calcineurin inhibitor; reduces T-cell activation.

Role: Slow progression of disease, prevent joint damage, and preserve function.

4. Biologic DMARDs (bDMARDs)

a) TNF-α inhibitors

  • Etanercept

  • Infliximab

  • Adalimumab

  • Golimumab

  • Certolizumab pegol
    Mechanism: Block tumor necrosis factor-alpha, a key pro-inflammatory cytokine.

b) IL-6 receptor antagonists

  • Tocilizumab

  • Sarilumab
    Mechanism: Inhibit IL-6 signaling, reducing systemic and joint inflammation.

c) IL-1 inhibitors

  • Anakinra
    Mechanism: IL-1 receptor antagonist.

d) B-cell depleting therapy

  • Rituximab
    Mechanism: Anti-CD20 monoclonal antibody; depletes B lymphocytes.

e) T-cell co-stimulation modulators

  • Abatacept
    Mechanism: Fusion protein inhibiting T-cell activation.

5. Targeted Synthetic DMARDs (tsDMARDs)

  • Janus kinase (JAK) inhibitors: Tofacitinib, baricitinib, upadacitinib, filgotinib.

  • Mechanism: Inhibit JAK pathways, interfering with cytokine signaling inside immune cells.

6. Other Adjunctive Agents

  • Colchicine: Used in gout and certain inflammatory arthritis conditions.

  • Biologic agents for SLE: Belimumab (anti-BAFF antibody).

  • Other immunosuppressants: Mycophenolate mofetil (used in lupus nephritis).

Mechanisms of Action in Rheumatic Diseases

  • NSAIDs: Symptom control only (analgesic, anti-inflammatory).

  • Glucocorticoids: Broad immunosuppression by reducing cytokines (IL-1, TNF-α, IL-6).

  • csDMARDs: Reduce lymphocyte proliferation and inflammatory mediator production.

  • bDMARDs: Target specific immune pathways (e.g., TNF-α, IL-6, T-cell/B-cell activation).

  • tsDMARDs: Block intracellular signaling (JAK-STAT pathway), affecting multiple cytokines.

Clinical Uses

  • Rheumatoid arthritis (RA): Methotrexate (first-line), leflunomide, sulfasalazine, hydroxychloroquine, TNF inhibitors, JAK inhibitors.

  • Juvenile idiopathic arthritis (JIA): Methotrexate, TNF inhibitors, abatacept.

  • Systemic lupus erythematosus (SLE): Hydroxychloroquine, corticosteroids, mycophenolate, azathioprine, belimumab.

  • Psoriatic arthritis (PsA): Methotrexate, leflunomide, TNF inhibitors, IL-17 inhibitors (secukinumab, ixekizumab).

  • Ankylosing spondylitis (AS): NSAIDs, TNF inhibitors, IL-17 inhibitors.

  • Vasculitis (e.g., GPA, MPA): Cyclophosphamide, rituximab, corticosteroids.

Dosage Examples

  • Methotrexate: 7.5–25 mg orally or subcutaneously once weekly (with folic acid supplementation).

  • Leflunomide: 10–20 mg orally daily.

  • Sulfasalazine: 1–3 g/day orally in divided doses.

  • Hydroxychloroquine: 200–400 mg orally daily.

  • Prednisone: 5–20 mg/day orally for maintenance; higher doses for acute flares.

  • Etanercept: 50 mg subcutaneously once weekly.

  • Adalimumab: 40 mg subcutaneously every 2 weeks.

  • Tofacitinib: 5 mg orally twice daily (or extended-release 11 mg once daily).

Contraindications

  • Methotrexate: Pregnancy, severe hepatic impairment, chronic alcoholism.

  • Leflunomide: Pregnancy (teratogenic), severe liver disease.

  • Sulfasalazine: Sulfa allergy, G6PD deficiency.

  • Hydroxychloroquine: Pre-existing retinopathy.

  • Biologics: Active or chronic infections (e.g., tuberculosis, hepatitis B).

  • JAK inhibitors: Severe infections, history of thromboembolic disease.

Side Effects

  • NSAIDs: Gastric irritation, peptic ulcers, renal impairment, cardiovascular risks.

  • Glucocorticoids: Weight gain, osteoporosis, diabetes, hypertension, infection risk, adrenal suppression.

  • Methotrexate: Hepatotoxicity, bone marrow suppression, pulmonary toxicity, mucositis.

  • Leflunomide: Hepatotoxicity, gastrointestinal upset, alopecia.

  • Sulfasalazine: Rash, hemolysis in G6PD deficiency, gastrointestinal intolerance.

  • Hydroxychloroquine: Retinopathy, GI upset, skin hyperpigmentation.

  • Biologics: Infusion reactions, infections (TB, fungal, viral reactivation), malignancy risk (lymphoma).

  • JAK inhibitors: Increased risk of infections, thrombosis, elevated liver enzymes, lipid abnormalities.

Precautions

  • Screening before biologics and JAK inhibitors: TB, hepatitis B/C, HIV testing.

  • Vaccinations: Avoid live vaccines while on biologics or immunosuppressants.

  • Monitoring:

    • Methotrexate, leflunomide: Regular liver function tests and CBC.

    • Hydroxychloroquine: Annual ophthalmic exams.

    • Biologics: Monitor for infections and malignancies.

    • JAK inhibitors: Monitor blood counts, liver function, and lipids.

Drug Interactions

  • Methotrexate: Increased toxicity with NSAIDs, trimethoprim, sulfonamides.

  • Leflunomide: Interacts with hepatotoxic drugs (e.g., isoniazid).

  • Sulfasalazine: Reduced absorption with antibiotics.

  • Hydroxychloroquine: May increase risk of arrhythmia with QT-prolonging drugs.

  • Biologics: Avoid combining multiple biologics due to infection risk.

  • JAK inhibitors: Additive immunosuppression with biologics or strong immunosuppressants.

Role in Modern Therapy

  • Methotrexate remains the anchor drug in RA and is often combined with biologics.

  • Biologics and JAK inhibitors have revolutionized rheumatology, offering targeted therapy for refractory disease.

  • Combination therapy (e.g., methotrexate + biologic) is common for enhanced efficacy.

  • Glucocorticoids are increasingly limited to short-term use due to long-term adverse effects.

Resistance and Limitations

  • Some patients are non-responders to methotrexate or biologics.

  • Secondary loss of response can occur (e.g., development of anti-drug antibodies against biologics).

  • High costs of biologics and JAK inhibitors limit access in many settings.



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