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NSAIDs

NSAIDs. 1 st line of therapy in the medical management of RA. Control the symptoms and signs of local inflammatory process Minimal effect on the progression of the disease i.e. Diclofenac sodium, naproxen sodium, etc. COX-2 inhibitors Suppresses COX that is involved in inflammation

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NSAIDs

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  1. NSAIDs 1st line of therapy in the medical management of RA

  2. Control the symptoms and signs of local inflammatory process • Minimal effect on the progression of the disease • i.e. Diclofenac sodium, naproxen sodium, etc.

  3. COX-2 inhibitors • Suppresses COX that is involved in inflammation • Less damaging to the stomach • Associated with increased risk of cardiovascular events

  4. GLUCOCORTICOIDS 2nd line of therapy

  5. Systemic GC therapy • Provide effective symptomatic therapy in patients with RA • Low dose PREDNISONE (<7.5 mg/dl) • Useful additive therapy to control symptoms • May retard the progression of bone erosions • Initial course of low dose GC may have a long term protective effect against bone damage • LOW DOSE GC + DMARD therapy (i.e. Methotrexate) can be beneficial in controlling sins and symptoms rapidly and affording long term retardation of bone erosion Source: Harrison’s Principles of Internal Medicine 17th ed.

  6. DMARDS(Disease-Modifying Anti-rheumatic Drugs) 3rd line of therapy

  7. Slows down the progression of joint destruction • Slow acting because it may take 6 weeks to 6 months for it to become evident • Methotrexate, azathioprine, penicillamine, hydroxychloroquine and chloroquine, organic gold compounds, sulfasalazine

  8. Methotrexate • DMARD of FIRST choice to treat RA • Individuals with RF for development of bone erosions or persistent synovitis or >3months

  9. MOA: • Inhibition of aminoimidazolecarboxamideribonucleotide (AICAR) transformylase and thymidylatesynthetase, with secondary effects on polymorphonuclearchemotaxis

  10. Pharmacokinetics • 70% absorbed after oral administration • Metabolized to a less active hydroxylated metabolite and both the parent compound and the metabolite are polyglutamated within cells where they stay for prolonged periods • Half-life: 6-9 hours • Increased in the presence of hydroxychloroquine • Excreted primarily in the urine

  11. Indications • Dosing regimen: 15-25 mg weekly, 30 or 35 mg weekly has an increased effect • Decreases the rate of appearance of new erosions • Juvenile chronic arthritis, ankylosingspondylitis, polymyositis, dermatomyositis, Wegener’s granulomatosis, giant cell arteritis, SLE and vasculitis • Maximal improvement is observed after 6 months of therapy

  12. Adverse Effects • Nausea and mucosal ulcers – most common • GI upset • Progressive dose-related hepatotoxicity (enzyme elevation) occurs frequently • Contraindicated in pregnancy Source: Basic and Clinical Pharmacology 10th edition, 2007 by Katzung

  13. BIOLOGICS 4th line of therapy

  14. Slows down progression of damage to articular structures • Major impact on the signs and symptoms of RA

  15. TNG-neutralizing agents • Infliximab, etanercept and adalimumab • IL-1 neutralizing agents • Anakinra • B-cell inhibitors • Rituximab • Inhibition of T cell activation • Abatacept

  16. ABATACEPT

  17. MOA: • Costimulation modulator that inhibits the activation of T cells.

  18. Pharmacokinetics • IV infusion • 3 doses (day 0, week 2 and week 4) initially • Followed by monthly infusions • Dose is based on body weight • <60kg – 500mg • 60-100kg – 750mg • >100kg – 1000g • Half-life: 13-16 days • Coadministration with methotrexate, NSAIDs and corticosteroids does not influence clearance of abatacept

  19. Indications • Can be used as monotherapy or in combination with other DMARDs in patients with moderate to severe rheumatoid arthritis who have had an inadequate response to DMARDs or TNF antagonists. • Reduces the clinical signs and symptoms of rhematoid arthritis, slows the progression of damage to the joints, and improves the physical function of patients

  20. Adverse Effects • Increased risk of upper respiratory tract • concomitant use with TNF antagonists is NOT recommended due to increased risk of infection Source: Basic and Clinical Pharmacology 10th edition, 2007 by Katzung

  21. IMMUNOSUPPRESSIVE THERAPY 5th line of therapy

  22. Azathioprine, leflunomide, cyclosporine and cyclophosphamide • Effective in the treatment of RA and exerts therapeutic effects similar to DMARDs • DMARDs > immunosuppressive agents • Increase toxicities • Reserved for patients who have failed DMARDs and biologics therapy Source: Harrison’s Principles of Internal Medicine 17th ed.

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