Rheumatoid arthritis management


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Rheumatoid arthritis management

  3. 3. Dr .Augustin Jacob Landré-Beauvais documented first case of r.a.<br />SUFFERED FROM R.A.<br />PETER PAUL RUBENS<br />DOROTHY MARY HODGKIN<br />CHRISTIAAN BERNARD<br />ALFRED BARING GARROD<br />
  4. 4. RHEUMATOID ARTHRITIS<br />Chronic inflammatory autoimmune and systemic disease. <br />Target tissue is SYNOVIAL TISSUE. <br />PREVALENCE -0.8% adult population worldwide. <br />Age 4th -5th decades (80% 35-50 yrs ).<br />
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  6. 6. GENARAL PRINCIPLES <br />Pain relief <br />Reduce inflammation <br />Protection of articular surfaces <br />Maintenance of function <br />Control of systemic involvement <br />
  7. 7. MANAGEMENT OF R.A.<br />Medications are divided into three main classes<br />1.NSAIDs<br />2.corticosteroids<br />3.DMARDs <br />4.BIOLOGICS <br />5.Surgery <br />
  8. 8. Outline of current management of RA<br />Non biologics <br />biologics<br />
  14. 14. MINOCYCLINE ,DOXYCYCLINE. </li></li></ul><li>
  15. 15. TYPES OF COMBINATION THERAPYOF DMARDS<br />STEP –UP <br />TICORAtrial-SSZ ESCALATING MTX ,HCQ if it fails cycloph and MTX NEXT LEF ,INJ GOLD <br />STEP-DOWN: 3or 4DMARDS deescalated to 1 DMARD <br />COBRAtrial –SSZ+MTX+prednisoloneonly SSZ <br />PARALLEL :multiple DMARDS continued on long term basis <br />FINRACO TRIAL –SSZ+MTX+HCQ+low dose prednisolone for 2yrs<br />
  16. 16. DISEASE ACTIVITY SCORE (DAS)<br />Is a composite score <br />Tender and swollen joint count <br />ESR<br />PATIENT global assessment of disease activity using a 100 mm visual analogue scale.<br />Assessess suitability for biological therapies and response to treatment.<br />DAS28 = 0.56  (number of tender joints )+ 0.28 (number of swollen joints ) + 0.70 In (ESR)+0.014 global assessment in mm<br />
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  18. 18. METHOTREXATE<br />gold std of treatment<br />7.5 to 25 mg orally, IM, or SC per week given at least 3-6 months<br />One to two months<br />Nausea, diarrhea; fatigue; mouth ulcers; rash, alopecia; abnormal LFTsRare: low WBC and platelets; pneumonitis; sepsis; liver disease; Epstein-Barr virus–related lymphoma; nodulosis<br />CBC, creatinine, and LFTs monthly for six months, then every one to two months; repeat AST or ALT in two to four weeks if initially elevated, and adjust dose as needed; liver biopsy if no resolution on discontinuation.<br />Rapid onset (six to 10 weeks); tends to produce more sustained results over time than other DMARDs and lowers all-cause mortality; can be used when cause of polyarthritis uncertain; often combined with newer DMARDs.<br />
  19. 19. HYDROXYCHLOROQUINE (Plaquenil)<br />200 to 400 mg orally per day(6.5mg/kg) <br />Immunomodulatory effect<br />Two to six months<br />Nausea; headachesRare: abdominal pain; myopathy; retinal toxicity<br />Eye examinations every 12 months in patients older than 40 years and those with previous eye disease<br />In combination with MTX ,SSZ,corticosteroids.<br />
  20. 20. SULFASALAZINE(Azulfidine)<br />2 to 3 g orally per day in divided doses<br />48 (14 to 31)<br />One to three months<br />Nausea, diarrhea; headache; mouth ulcers; rash, alopecia; contact lens staining; reversible oligospermia; abnormal LFTsRare: leukopenia<br />CBC every two to four weeks for three months, then every three months<br />Rapid onset (eight to 13 weeks); enteric, coated forms available; can be used when diagnosis uncertain; modest effects compared with other medications.<br />
  21. 21. LEFLUNOMIDE (Arava)<br />(100 mg orally per day for three days loading dose earlier) 10 to 20 mg orally per day<br />Four to 12 weeks (tending toward four)<br />Nausea, diarrhea; rash; alopecia; highly teratogenic, even after discontinuationRare: leukopenia; hepatitis; thrombocytopenia<br />Hepatitis B and C serology in high-risk patients; CBC, creatinine, and LFTs monthly for six months, then every one to two months; repeat AST or ALT in two to four weeks if initially elevated, and adjust dose as needed.<br />Inhibits pyrimidine synthesis and may suppress T-cell activation; <br />LEF toxicity ;cholestyramine 8gms -11days or activated charcoal 50gm qid-11days<br />
  22. 22. AZATHIOPRINE (Imuran)<br />50 to 150 mg orally per d<br />Two to three months<br />NauseaRare: leukopenia; sepsis; lymphoma<br />CBC every one to two weeks until dose is stable, then every one to three months<br />Has greater toxicity and is used less commonly than other DMARDs<br />
  23. 23. CYCLOSPORINE (Gengraf, Neoral, generic)<br />2.5 to 5 mg per kgorally per day<br />Two to four months<br />Nausea; paresthesias, tremor; headaches; gingival hypertrophy; hypertrichosisRare: hypertension; renal disease; sepsis<br />Creatinine every two weeks until dose is stable, then monthly; consider CBC, LFTs, and potassium level tests<br />Significant clinical benefit up to one year; adverse effects limit use.<br />
  24. 24. D-PENICILLAMINE<br />D-Penicillamine (Cuprimine)<br />250 to 750 mg orally per day<br />Three to six months<br />Nausea; loss of taste; rash; reversible platelet decreaseRare: proteinuria; late autoimmune disease<br />CBC and urinary protein by dipstick every two weeks until dose is stable, then every one to three months<br />Used less commonly than other DMARDs.<br />
  25. 25. AURANOFIN<br />Auranofin (Ridaura)<br />3 mg orally twice per day or 6 mg orally per day<br />Four to six months<br />ADV :DiarrheaRare: leukopenia<br />Monitor ---CBC and urine protein (by dipstick) every one to three months<br />Has modest effects compared with other DMARDs.<br />
  26. 26. IM GOLD<br />Gold sodium thiomalate (Myochrysine)Aurothioglucose (Solganal)<br />25 to 50 mg IM every two to four weeks<br />Six to eight weeks<br />Mouth ulcers; rash; vasomotor symptoms after injectionRare: leukopenia; thrombocytopenia; proteinuria; colitis<br />CBC and urinary protein by dipstick every two weeks until dose is stable, then with each injection<br />Has significant withdrawal rate in trials because of toxicity.<br />
  27. 27. MINOCYCLINE (Minocin)<br />100 mg orally twice per day<br />One to three months<br />Dizziness; skin pigmentation<br />None needed<br />Effective in combination with prednisone for management of new-onset rheumatoid arthritis.<br />
  28. 28. GUIDELINES FOR USE OF BIOLOGICS <br />Must have failed to response with atleast two DMARDs including MTx (20-25mg/wk)<br />Must have ACTIVE disease.<br />Have no major infections in the preceding six months.<br />Have no malignancies<br />Non pregnant,non breast feeding women <br />
  29. 29. INFLIXIMAB<br />Infliximab(Remicade)<br />3 mg per kg IV at weeks zero, 2, and 6, then every eight weeks<br />A few days to four months<br />Infusion reactions; increased infection risk, including TB reactivationRare: demyelinating disorders<br />Monitor for TB, histoplasmosis, and other infections; CBC and ALT at baseline and monthly until dose is stable; may continue every two to three months thereafter.<br />A chimeric(mouse and human) monoclonal antibody to TNF-3; reduces disease activity with acceptable safety.<br />Always used n conjunction w MTX 10-25mg/wk<br />
  30. 30. Chimeric monoclonal antibody against TNFα<br />
  31. 31. Monoclonal antibody against TNFα<br />
  32. 32. ETARNERCEPT<br />Etanercept (Enbrel)<br />25 mg SC twice per week or 50 mg SC per <br />A few days to 12 weeks<br />Contraindicated in infection; mild injection site reactionsRare: demyelination<br />CBC and ALT at baseline and monthly until dose is stable; may continue every two to three months thereafter.<br />Combination fusion protein of TNF receptor and portion of IgG1; inhibits TNF-3; slows joint damage.<br />
  33. 33. ADALIMUMAB<br />DMARDs for Treatment of Rheumatoid Arthritis<br />Adalimumab (Humira)<br />40 mg SC every two weeks<br />A few days to four months<br />Adv reactions :Infusion reactions; increased infection risk, including TB reactivationRare: demyelinating disorders<br />Monitor for TB, histoplasmosis, and other infections; CBC and ALT at baseline and monthly until dose is stable; may continue every two to three months thereafter.<br />Recombinant monoclonal antibody to TNF-3; shown to reduce disease activity with acceptable safety.<br />
  34. 34. Recombinant TNFα Soluble Receptor<br />
  35. 35. ANAKINRA<br />100 to 150 mg SCper day<br />Within 12 weeks; lasting effects by 24 weeks<br />ADV REACTIONS :Infections and decreased neutrophil counts; headaches, dizziness; nauseaRare: hypersensitivity<br />MONITOR :CBC at baseline, monthly for three months, then every three months<br />Interleukin-1 receptor antagonist; used when treatment with another DMARD has failed.<br />
  36. 36. TNFα and it’s Receptor<br />
  37. 37. TOCLIZUMAB<br />First IL-6receptor inhibiting monoclonal antibody. <br />Dose :8mg/kg i.v. every 4wks given as i. v. infusion over an hour. <br />Moderate to severe RA <br />CONTRA INDICATIONS :infusion reactions,active infections.<br />
  38. 38. RITUXIMAB(anti CD20 therapy)<br />Genetically engineered human mouse chimeric monoclonal antibody. <br />CD 20 antagonist and B cell ACTION depletor<br />Dose:1000mg /infusion on days 1 and 15(over sevaeral hrs ) with 100mg i.v. methyl prednisolone. <br />Contraindications :hypersensitivity,activeinfection,severe HF.<br />
  39. 39. ABATACEPT (T cells CTLV-4 Ig)<br />Prevents co-stimulatory binding of CD28 on naïve T-cells and attenuating T-cell function. <br />Dose:10mg/kg i.v. every 2wkly for 3 doses ,followed by every 4wkly. <br />Contraindications: hypersensitivity,activeinfections,COPD.<br />
  40. 40. ADVERSE REACTIONS OF BRMs<br />1.injection site/infusion reactions<br />2.infections (activation of latent TB or new TB)<br />3.neutropenia,aplastic anemia<br />4.mild reversible lupus like syndrome<br />5.CCF<br />6.malignancy<br />7.ANA postivity<br />8.demyelinating neurological diseases <br />
  41. 41. PARADIGM SHIFT<br />1.early use of DMARDs --initiated early within 3months-3yrs. <br /> -- to avail window of oppurtunity,replacing’ Go low,go slow. <br /> --’inverting pyramid’ concept <br />2.REMISSION :instead of relief. <br /> 3.MTX :anchor drug -as monotherapy or combination therapy. <br />
  42. 42. Contd….<br />4.Combination therapy—DMARD combination <br /> triple therapy-of MTX+SSZ+HCQ <br />MTX+biologicals --better outcome <br />5.Reappraisal of glucocorticoids:low dose+DMARDS<br />6.Evolution of strategy trials :like COBRA,CAMERA,FINRACO,TICORA. <br /> Sub group of Best trails.<br />
  43. 43. When to start DMARD therapy <br />Before onset of erosion by US/MRI <br />Within 3-6 months<br />
  44. 44. Who to Treat?<br />Consider DMARD therapy for all patients with early inflammatory polyarthritis where persistent disease is likely<br />Most important determinant of chronicity is disease duration > 12 weeks. <br />
  45. 45. Whom to treat with DMARDS?<br />Early n severe synovitis<br />Strogly +ve ACPA and RF <br />Extra articular features <br />Joint erosion –US/MRI <br />Functional impairment <br />Lower educational status<br />
  46. 46. How to initiate DMARD therapy?<br />SSZ,HCQ -in mild cases <br />MTX,LEF OR cyclosporine-in severe cases <br />MTX +biologicals –very severe cases <br />
  47. 47. In pregnancy DMARDS ?<br />SSZ ,HCQ are safe<br />
  48. 48. Follow up?<br />Every6 wks or earlier.<br />
  49. 49. Combination DMARD therapy<br />MTX + SSZ + OH-Chloroquine<br /> O’Dell 1995<br />MTX + CSA <br />Tugwell 1995<br />MTX + Etanercept<br />MTX + Remicade<br />MTX + Adalimumab<br />MTX + Leflunomide<br />excellent safety & improved efficacy over MTX alone<br />
  50. 50. Rationale for TNFα Blockade<br />Cytokines are small molecules whose function is to communicate between cells<br />Tumor necrosis factor α = gatekeeper of inflammatory cascade<br />Cytokines can be either pro-inflammatory or anti-inflammatory<br />
  51. 51. Mechanisms in Rheumatology ©2001<br />Proinflammatory and anti-inflammatory cytokines in RA<br />
  52. 52. Matrix metalloproteinases in RA<br />Mechanisms in Rheumatology ©2001<br />
  53. 53. TNF inhibitors and TB<br />Mycobacterium tuberculosis currently infects approximately one third of the world's population (close to 2 billion people). <br />Approximately 2 million people die of TB each year and there are 8 million new cases reported annually. <br />TNF is essential for formation and sustainment of granuloma, which sequester mycobacteria and prevent their dissemination.<br />The calculated risk ratio of TB in infliximab-treated patients with RA versus patients with RA not exposed to this agent was 19.9 (95% confidence interval [CI], 16.2–24.8) in the year 2000 and 11.7 (95% CI, 9.5–14.6) in the year 2001. <br />Screening has almost eliminated this increased risk in Spain and Germany<br />
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  55. 55. Quality of Life in Rheumatoid Arthritis<br />
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  66. 66. SURGERY IN RA<br />Tenosynovectomy. <br />Decompression of carpal tunnel <br />Reconstructive arthroplasty<br />Corrective artrotomies of matatarsals<br />Stabilization of cervical spine <br />Tendon release and transfer <br />Arthrodesis of ankle<br />
  67. 67. CORTICOSTEROIDS IN RA<br />ACCORDING TO EULAR COMMITTEE RECOMMONDATIONS <br />NOMENCLATURE OF CORTICOSTEROID DOSING : <br />Low dose:<7.5mg prednisolone/day <br />Medium dose:>7.5 but <30mg /day <br />High dose:.>30 but <100mg/day <br />Very high dose:>100mg/day <br />Pulse therapy:>250mg/day for 1 or few days<br />
  68. 68. corticosteroids<br />Current indications are--- <br />1.bridge therapy inacute cases <br />2.acute ocular emergencies <br />3.rheumatoid vasculitis<br />4.combin therapy with DMARDs <br />5.active disease in pregnancy <br />6.intra articular use in monosynovitis<br />
  69. 69. Modes of use of CS<br />Oral prednisolone 10mg/d with tapering to 2.5-5mg/d over few months. <br />Inj.methylprednisolone acetate 80-120mg i.m. every 4 wks for 2-3 months. <br />Intra articular steroids in monosynovitis<br />
  70. 70. RECENT ADVANCES CS<br />NOVEL MODIFIED RELEASE( MR) prednisolone formulation given at bedtime -better clinical effects <br /> CAPRA -1(circadian administration ofpradnisolone in RA trail). <br />SEGRAs :Selective glucocorticoid receptor agonists (NEW CLASS OF STEROIDS) <br /> Compound A(CpdA) <br />Botschanzev<br />
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  72. 72. TARGETS OF TREATMENT IN RA.<br />Biological agents are divided into -- <br />monoclonal ab<br />small molecules <br />
  73. 73. MONOCLONAL AB s<br /> FUNCTION BY neutralizing target cytokine/receptor blocking co stimulation moleculescytolysis depletion of target cell molecule or apoptosis.<br />
  74. 74. TNF ALPHA INHIBITORS<br />Infliximab,etanercept,adalimumab –being used. <br />Golimumab ;certolizumab likely to be approved<br />
  75. 75. IL -1 INHIBITORS<br />ANAKINRA <br />Canakinumab is on clinical trails<br />
  76. 76. IL -6 inhibitors<br />Tocilizumab now approved for the mod to severe RA.<br />
  77. 77. IL-15 INHIBITOR :HUMANISED MONOCLONAL AB AGAINST IL-15(HuMaxIL-15) proved <br />IL-17 inhibitor :clinical trial in progress. <br />IL-12/IL-23 inhibitor :ustekinumab–on going trails. <br />Inhibitors of osteoclastogenesis :Danosumab in phase 3 clnical trail. <br />Inhibitors of TNF superfamily members :baminercept,belimubab ,atacicept –in trails<br />
  78. 78. Inhibitors of chemokines and angiogenesis :bevacizumab –ab against VEGF. <br />APOPTOSIS regulators :anti FAS IgMab under trails. <br />T-cell inhibitors :alemtuzumab ,keliximab,clinoliximab --discontinued trails due to lymphopenia and skin rash. <br />B-cell inhibitors :RITUXIMAB approved ;clinical trails in progress by ocrelizumab,ofatumumab. <br />
  79. 79. SMALL MOLECULES<br />Molecular wts do not exceed 1kDa. <br />GOAL is to develop orally effective agents and increased selectivity.<br />
  80. 80. INHIBITORS OF<br /> 1. intracellular signalling molecules <br /> 2. mitogen activated protein (MAP)<br /> 3. transcription factors <br /> 4. cytokines/chemokines<br /> 5. cell surface markers<br />
  81. 81. OTHER TARGET FUTURE Rx of RA<br />Regulatory t cells (treg cells) <br />Toll like receptors <br />RNA epigenetic alterations <br />Gene therapy <br /> UNDER TRIALS.<br />
  82. 82. With the help of these newer drugs,the future may well see rheumatologists talking not about symptomatic relief but potencial cure for RA.<br />
  83. 83. Aim of management of r.a .case<br />
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  85. 85. THANK YOU<br />