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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 & prescribers 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 blockingagents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 medicationrecommendations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