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  1. 1. DMARDS
  2. 2. Disease-modifying anti-rheumatic drugs  decrease pain and inflammation, reduce or prevent joint damage, and preserve the structure and function of the joints Previously RA – Pyramidal approach Now it is reversed. early use of DMARDs is recommended before radiologically damage develops.
  3. 3. Aim - aggressive approach is to limit inflammation and prevent joint damage and subsequent disability. firm diagnosis of rheumatoid arthritis predictors of poor outcome Positive RA factor, high disability scores and early involvement of large joints ACR-not to delay beyond 3 months
  4. 4. Rationale for DMARDs NSAIDS – offer symptomatic relief. No effect on cartilage or bone destruction. Inflammation is maximal at an early stage. If given early, DMARDs can stabilise joint function at a level which is near to normal, rather than preserving the joint in a state of disability
  5. 5. Traditional DMARDs HCQ Sulphasalazine Methotrexate Leflunomide Azothioprine Gold Minocycline Cyclosporin
  6. 6. Biologic response modifiers Etanercept Infliximab Adalimumab Rituximab Abatcept
  7. 7. Choice Empirical, Based on a balance between toxicity, efficacy & prescriber's preference
  8. 8. METHOTREXATE DMARD of choice. MOA: Inhibition of [AICAR] aminoimidazolecarboxamide transformylase & thymidylate synthetase. decrease the secretion of pro-inflammatory cytokines, such as TNF, while increasing the secretion of the inhibitory cytokine IL- 10. Decreases the rate of appearance of new erosions
  9. 9. Pharmacokinetics Bioavailability -70% Less active hydroxylated metabolite Polyglutamated with in cells. Serum T1/2 6-9 hrs Excreted principally in urine.
  10. 10. Dosage started at a dose of 7.5mg orally once weekly and this is increased slowly to a maximum of 20mg once weekly fail to respond to oral therapy - intramuscular route Indicated in RA, PA, JCA, polymyositis. onset of action: about one month
  11. 11. Adverse Effects Nausea and stomatitis hepatic toxicity pneumonitis teratogenic to ova and sperm Recommended- contraception is taken during therapy and that conception is avoided for at least six months after stopping methotrexate.
  12. 12. Interactions co-prescription of NSAIDs has been shown to increase the toxicity Conc increased by HCQ GI & liver A/E, - reduced with leucovorin 24 hrs after each wkly dose or folic acid daily. C/I in pregnancy
  13. 13. Monitoring FBC: Baseline, then fortnightly for one month (or until dose stable) then monthly RF:Baseline  LFT:Baseline, then fortnightly for one month (or until dose stable) then monthly  CXR:Baseline.
  14. 14. Hydroxychloroquine Antimalarials suppression of lysosomal enzymes and inhibition of IL-1 release. Suppression of T-cell lymphocyte response, leucocyte chemotaxis, trapping of free radicals. Clinical response 6 to 12 weeks.
  15. 15. Pharmacokinetics Rapidly absorbed Extensively tissue bound, esp melanin containing tissues- eyes. Eliminated in liver. DOSAGE: started at a dose of 400mg daily in two divided doses. The maintenance dose is usually between 200mg and 400mg daily .
  16. 16. Indications RA Not very effective. [bone damage] Restricted to patients with mild, non-erosive disease or to those in whom more powerful DMARD therapy is felt to be too risky used in combination with other agents
  17. 17. Adverse Effects irreversible retinopathy occurs rarely if daily dose of HCQ does not exceed 6.5mg/kg (or 400mg daily), the lifetime dose does not exceed 200g GI symptoms, rashes, nightmares blood disorders Relatively safe in pregnancy. Eye: Baseline & six monthly follow-up
  18. 18. GOLD Affect the function of B and T lymphocytes as well as PMN leucocyte function auranofin is less toxic but it is less efficacious Time to response,oral:3-6months Parentral: 2-4 months. Diarrhoea - frequent Oral – less frequently used.
  19. 19. DOSAGE: test dose of 10mg followed by weekly doses of 50mg until there is definite evidence of remission drug should be discontinued if no response after giving 1 gm of gold. Interval increased to 4 wks, continued up to 5 yrs after complete remission. Important to avoid complete relapse since second course of gold are not usually effective.
  20. 20. Adverse Effects Skin- eczematous reaction & M.U Kidney- proteinuria Blood: bone marrow suppression  lungs and liver limit the number of patients who can tolerate long-term parenteral gold Parenteral gold is still a useful option in patients who cannot tolerate sulphasalazine or methotrexate
  21. 21. SULPHASALAZINE anti-inflammatory (5aminosalicylic acid) and antibacterial (sulphapyridine) moieties onset of action 6 and 12 weeks IgA & IgM RA factors decreased. Suppresion of T-cell response to concanavalin. Only 10-20% is absorbed.
  22. 22. Indication Reduces the rate of new jt damage in RA JCA, AS & its associated uveitis. Dosage:starting dose of 500mg daily. Increased by 500mg at weekly intervals to a maintenance dose of between 2g and 3g daily in divided doses.
  23. 23. Adverse Effects GI intolerance Haematological abnormalities – serious reversible male infertility Not teratogenic FBC:Baseline, monthly for three months, then every three months  RF:Baseline  LFT:Baseline, monthly for three months, then every three months
  24. 24. PENCILLAMINE chelator of divalent cations structurally similar to cysteine impair antigen presentation, diminish globulin synthesis, to inhibit PMN leucocyte myeloperoxidase, Rarely used today because of toxicity.
  25. 25. CYCLOSPORIN Fungal peptide-impairs the function of B and T lymphocytes by suppressing the synthesis and release of IL-1 & IL-2 Started at a dose of 2.5mg/kg daily in two divided doses. Increased gradually after six weeks to a maximum of 4mg/kg daily Full response will take 12 wks.
  26. 26. Good efficiency Less well tolerated because of hypertension and nephrotoxicity which are common and dose related. used in patients with severe disease who failed on other treatments or unsuitable for other DMARDs valuable when used together with methotrexate in patients with very active early disease.
  27. 27. AZATHIOPRINE oral purine analogue inhibits lymphocyte proliferation, by disrupting the incorporation of adenosine and guanine in DNA synthesis. becomes biologically active after metabolism in the liver to 6-thioinosinic acid and 6-thioguanylic acid. renally excreted
  28. 28. dose of 1.5 to 2.5mg/kg daily in divided doses efficacy comparable to that of gold but greater toxicity. potential for lymphoproliferative cancers Used for progressive disease which is refractory to other DMARDs of comparable potency or as a steroid-sparing agent
  29. 29. LEFLUNOMIDE immunomodulatory DMARD Rapid conversion in to active metabolite A77-1726, Isoxazole derivative. Inhibit the dihydrooratate dehydrogenase  decrease in RNA synthesis & arrest the stimulated cells in G1 phase of cell growth. Inhibit T cell proliferation & production of antibodies by B- cells.
  30. 30. Increases IL-10 receptor m RNA Decreases IL-8 receptor type A m RNA P.Kinetics: completely absorbed. Enterohepatic circulation. Indicated in RA for inhibition of bone damage.
  31. 31. diarrhoea reversible alopecia, hypertension, dizziness teratogenic in mammals and is therefore not recommended in women of childbearing age in the absence of reliable contraception Liver function should be monitored
  32. 32. Dosage Daily dose of 10-20 mg Loading dose of 100 mg once weekly for 3 wks in addition to daily dose. Complete effect takes 6-12 wks.
  33. 33. BIOLOGICALS – TNF-alpha blocking agents Cytokines –central role in immune response in RA. TNF – alpha  heart of inflammatory process. Two different approaches are available to decrease TNF activity
  34. 34. anti-TNF alpha antibodies which cross link with TNF receptor inhibit the endogenous cytokine soluble TNF receptors – combining soluble TNF alpha. Inhibit T –cell & macrophage function. Avoid live vaccines
  35. 35. ADALIMUMAB Recombinant human anti TNF monoclonal antibody. Adm: subcutaneously, T ½ 9-14 days Dose: 40 mg once in 2 wks. With Mtx it is action potentiated – 30% reduced clearance, decreased formation of antibodies.
  36. 36. Reduces the formation of new erosions. Monotherapy or in combination. Indicated: RA, AS, PA,JCA. Adv effects: risk macrophage dependent infections. Screening for latent TB to be done before therapy.
  37. 37. INFLIXIMAB Chimeric monoclonal antibody [25% mouse, 75% human] Binds with both soluble & membrane bound TNF IV infusions 3-5 mg/kg every 8 wks. Antichimeric AB – 62% pts Concurrent MTx adm, reduces.
  38. 38. Recommended to give along with MTx Can be given with other DMARDs. UTI ,opportunistic infections. ANA & DS DNA antibodies occur but frank SLE rare. Infusion site reaction.
  39. 39. ETANERCEPT Recombinant fusion protein consists of two soluble TNF P75 receptor moieties linked to Fc portion of human IgG1. Binds TNF & inhibits lymphotoxin alpha. Adm: SC 25 mg twice wkly or 50 mg once wkly. Peak conc 72 hrs after administration. Used along with MTx
  40. 40. Incidence of inf is lower Injection site reaction- 20-40% Antibodies appear in 16% of Pts.
  41. 41. Newer biologicals Rituximab –depletes B –cells by binding to cell surface marker CD-20. Abatecept – inhibits co-stimulatory molecule. Anakinra -recombinant form of the naturally occurring human IL-1 receptor antagonist.
  42. 42. Combination therapy Complementry MOA Non-overlapping pharmacokinetics Non-overlapping toxicity. With MTx back ground therapy, cyclosporin, HCQ, LFN, infliximab adalimumab, etanercept shows improves efficiency. With auronofin, azothioprine, SS- no additional benefit.
  43. 43. Triple drug regimen: MTx, SS, HCQ. Disadv: more toxicity [mostly not occurs] C.T is becoming a rule for those not responding to monotherapy.
  44. 44. Perioperative medication recommendations NSAIDS: Discontinue 5 half-lives before surgery. Aspirin: discontinue 7-10 days before surgery. Corticosteroids:Perioperative use depends on level of potential surgical stress MTx:Continue perioperatively for all procedures.
  45. 45. withholding 1 to 2 doses of MTx for patients with poorly controlled diabetes; the elderly; and those with liver, kidney, or lung disease Leflunomide:Continue for minor procedures. Withhold 1-2 days before moderate and intensive procedures and restart 1- 2 weeks later. Sulfasalazine, HCQ - Continue for all procedures
  46. 46. TNF antagonists:Continue for minor procedures. For moderate to intensive procedures, withhold etanercept for1 week, and plan surgery for the end of the dosing interval for adalumimab and infliximab. Restart 10-14 days Postoperatively. IL-1 antagonist:Continue for minor procedures. Withhold 1- 2 days before surgery and restart 10 days postoperatively for moderate to intensive procedures
  47. 47. Suggestions More aggressive therapy Early institution of DMARDs with in 3 months Consider NSAIDS Consider local or low dose systemic steroids as bridge therapy. Maximization of MTx therapy. Addition of TNF inhibitors for persistent activity.
  48. 48. THANK YOU