Drug treatment of rheumatoid arthritis


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Treatment of Rheumatoid arthritis

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Drug treatment of rheumatoid arthritis

  2. 2. INTRODUCTION • Chronic, systemic, inflammatory, autoimmune • Primary target is the synovial tissue • Characterized by joint erosions and destruction
  3. 3. EPIDEMIOLOGY • Commonest inflammatory joint disease seen in practice • Affects around .8% of world’s and about 1% of Indian population • Commoner in women by a ratio of 3:1 • Usually starts in 3rd to 5th decade of life • Associated mortality
  4. 4. AETIOLOGY • Multifactorial • Genetic predisposition and shared epitope hypothesis • Role of infections • Molecular mimicry
  5. 5. TREATMENT PARADIGMS PAST Traditional pyramidal approach;Go slow, go low (empirical) PRESENT Early and universal use of DMARDs (Disease modifying anti rheumatic drugs) often in combination (evidence based) FUTURE DMARDs + Biological agents (mechanism based)
  6. 6. IMPORTANCE OF EARLY DIAGNOSIS AND TREATMENT • Joint damage is an early phenomenon • It is largely irreversible • Duration of the disease is inversely proportional to outcome and response
  7. 7. ACR CRITERIA FOR DIAGNOSIS OF RHEUMATOID ARTHRITIS • Morning stiffness(lasting at least 1 hour) • Arthritis in 3 or more joint areas (soft tissue swelling or effusion observed by physician) • Arthritis of hand joints(wrist,PIP,MCP joints) • Symmetric arthritis • Rheumatoid nodules • Rheumatoid factors in serum • Radiological changes(erosions or periarticular bony calcifications on hand and wrist radiographs)
  8. 8. OTHER AIDS TO DIAGNOSIS • Elevated levels of serum rheumatoid factors • Radiographic changes • Serum antibodies like antibodies to CCP
  9. 9. SEVERITY ASSESSMENT • Duration of morning stiffness • Tender and swollen joint count • Observer and patient assessment • VAS for pain • Disease activity score (DAS)
  10. 10. SEVERITY ASSESSMENT DAS • Most widely employed • Requires 28 tender joint count, 28 swollen joint count, ESR and general health assessment by the patient • Can range from 0-9.4 • Remission • Meaningful change
  11. 11. POOR PROGNOSTIC FACTORS • High tender/swollen joint count • Early age of onset • High titres of RF, ESR and CRP • Erosions on hand X-rays • Presence of CCP antibodies
  12. 12. MEASUREMENTS OF RESPONSE ACR 20 Response : A decrease of at least 20% in both the number of tender and swollen joints along with 20% reduction in at least three of the following: , Patient s assessment of disease status , Patient s assessment of pain , Patient s assessment of physical function , Physician s assessment of disease status C-reactive protein level
  13. 13. CLASSIFICATION OF DRUGS • NSAIDs ( Non steroidal antiinflammatory drugs) • Corticosteroids • DMARDs • Biological response modifiers (BRMs)
  15. 15. Diagnosis establishment Assessment of baseline disease activity and damage Prognosis estimation NSAIDs DMARD as per severity Consider local or systemic corticosteroids Response-continue Response- continue No response Add Methotrexate if not already used Parenteral MTX if oral MTX used No response Add other DMARDs Add BRMs
  16. 16. NSAIDs IN RA • Integral part of initial therapy • Buy time and offer symptomatic benefit • ‘Adjuncts to’ and not ‘substitutes for’ DMARDs
  17. 17. NSAIDs IN RA • Combination of NSAIDs • Adverse effects • COX-2 inhibitors • Measures to control adverse effects
  18. 18. CORTICOSTEROIDS IN RA • Retard the rate of joint destruction and relieve synovitis in low doses • Mild disease modifying potential • Adverse effects and their prevention
  19. 19. CORTICOSTEROIDS IN RA • Bridge therapy for 8-12 weeks • Treatment of rheumatic flares • For rheumatic vasculitis and interstitial lung disease • Intra-articularly in recalcitrant joints
  20. 20. DMARDs IN RA • Step up approach • Step down approach • Saw tooth approach • Parallel approach
  21. 21. DMARDs IN RA FREQUENTLY USED INFREQUENTLY USED • • Methotrexate • • Hydroxychloroquine • • Sulphasalazine • • Leflunomide • • Chloroquine Gold Cyclosporin A Levamisole D-penicillamine Minocycline
  22. 22. METHOTREXATE • Anchor of treatment • Acts by inhibiting dihydrofolate reductase, thymidylate synthetase and aminoimidazolecarboxamide • Most economical, best tolerated and with highest rate of retention
  23. 23. METHOTREXATE • Initial and maintenance dose • Duration of treatment • Treatment failure
  24. 24. METHOTREXATE • Adverse effects • Their prevention • Contraindication
  25. 25. HYDROXYCHLOROQUINE • Suggested mechanisms involve suppression of T lymphocyte responses to mitogens, reduced chemotaxis, free radical trapping • Extensively bound to tissues specially to melanin containing ones • Place in treatment of RA
  26. 26. HYDROXYCHLOROQUINE • Usual dosage • Adverse effects
  27. 27. SULFASALAZINE • Sulfapyridine is the active moiety • Acts by inhibition of proinflammatory cytokines and transcription factors • Usually used as an add on drug • Also useful in juvenile arthritis and ankylosing spondylitis
  28. 28. SULFASALAZINE • Adverse effects • Use in pregnancy
  29. 29. LEFLUNOMIDE • New DMARD • Isoxazole derivative • Acts by competitive inhibition of Dihydroorotate dehydrogenase
  30. 30. LEFLUNOMIDE Dihydroorotate Uridine monophosphate Orotate Early signals IL2, NFAT Ca influx + Go _ G1 Sensors of Ribon. Levels p53, cyclin D & E S G2 M
  31. 31. OTHER ACTIONS • Inhibition of Tyrosine kinase • Inhibition of NF-kB dependant transcription • Reduction in levels of IL-6, matrix metalloproteinases and prostaglandin E
  32. 32. PROPERTIES • Prodrug • Highly protein bound with long t ½ • Undergoes extensive enterohepatic circulation • Inhibits CYP2C9
  33. 33. USE IN RA • Found to be as efficacious as Sulfasalazine and MTX • Slows radiographic progression as compared to placebo • Alternative agent in face of MTX intolerance in the dose of 20 mg/day • Combination of MTX and Leflunomide
  34. 34. PREGNANCY PROTOCOL • Leflunomide in fetopathic and teratogenic • Should be discontinued before pregnancy • Emergency drug washout with oral Cholestyramine 8gm thrice daily for 11 days
  35. 35. ADVERSE EFFECTS • Reversible elevation in liver enzymes in 24% of patients • Risk of severe liver injury is small and acceptable • Weight loss • Diarrhea • Alopecia • Hypertension • others
  36. 36. COMBINATION OF DMARDs • Better than monotherapy in inducing remission • Cost effective in long term • Not necessarily more toxic • MTX +Leflunomide • MTX+Sulfasalazine +Hydroxychloroquine
  38. 38. Contraindicated Indicated Pregnancy MTX, Leflunomide Sulfasalazine,Steroids HCQS, NSAIDs Lactation do Cyclosporin do Gold salts Liver disease MTX, Leflunomide, NSAIDs, Sulfasalazine HCQS and Gold salts Renal disease NSAIDs, MTX- dose Gold HCQS, Sulafasalazine Lung disease MTX - caution Leflunomide, HCQS and Sulfasalazine
  39. 39. BRMs IN RA • Integration of molecular biology with bedside medicine • Genetically engineered products • Modulate a specific aspect of underlying autoimmune process • Therapeutic effect involves downregulation of proinflammatory cytokines and occupancy of their receptors
  40. 40. BRMs IN RA • Soluble TNF α receptor – Etanercept • Anti TNF α antibodies - Infliximab, Adalimumab • IL1 receptor antagonist – Anakinra
  41. 41. ETANERCEPT • Soluble TNF receptor fusion protein • Composed of soluble ligand binding portion of type2 TNF receptor linked to Fc portion of human IgG • Has affinity with both TNF α and β and binds to them before they can bind to their receptors
  42. 42. ETANERCEPT • Given by SC route • Dosage • Bioavailability-60% • t ½ - 50 hrs
  43. 43. ETANERCEPT IN RA • Better and faster ACR response rates as compared to placebo • Rapidity is dose dependent • Beneficial in patients who have an inadequate response to MTX • Approved for use as monotherapy
  44. 44. INFLIXIMAB • Chimeric IgG anti-TNF-α antibody • Binds to both soluble and membrane bound TNF-α • First anti-TNF-α agent used
  45. 45. INFLIXIMAB- EFFECTS • Reduces serum conc. of IL6 • Reduces serum conc. of ICAM-1 and E selectin • Reduces vascular endothelial growth factor • Increases expression of TNF receptors
  46. 46. INFLIXIMAB • Half life about 9 days • 3 mg/kg by IV infusion at 0, 2 and 6 weeks followed by every 8 weeks • Single IV dose confers rapid improvement • Has been found to be effective as compared to placebo but monotherapy associated with loss of efficacy • Can only be used in combination with MTX • Other uses
  47. 47. ADALIMUMAB • Recombinant human IgG monoclonal antiTNF-α antibody (1330 amino acids) • Not only causes impaired cytokine binding but also lyses cells expressing surface TNF-α
  48. 48. ADALIMUMAB • Given by SC route . Dose 40 mg SC weekly • t ½ 2 weeks • Bioavailability 64%
  49. 49. ADALIMUMAB IN RA • Has shown better ACR response rates as compared to placebo • Appears to have additive effect with MTX • Inhibits progression of structural joint damage • Dose adjustment with MTX
  51. 51. INFECTIONS • Definite risk of opportunistic infections such as tuberculosis and histoplasmosis • Max risk with Infliximab • Tuberculosis occurs due to reactivation of old latent infection • Occurs within first 2-5 months of therapy • Importance of screening procedures
  52. 52. MALIGNANT DISEASES • Increased incidence of lymphoma but causal association lacking • No evidence of any other malignancy
  53. 53. INJECTION SITE AND INFUSION REACTIONS • Minor redness and itching for few days after receiving Etanercept and Adalimumab • Headache and nausea after Infliximab • Urticaria and anaphylaxis in 2% patients after Infliximab
  54. 54. IMMUNE RESPONSES • Etanercept is least immunogenic and antibodies found only in 3% patients • Human chimeric antibodies develop in a majority of patients taking Infliximab • Combination with MTX blunts the autoimmune response • Antibodies to Adalimumab found in 12% patients receiving monotherapy but only in 1% of those receiving MTX combinatuion
  55. 55. DEMYELINATING SYNDROMES • Reports of exacerbation of quiescent multiple sclerosis in patients taking Etanercept and Infliximab • Causal relationship not established
  56. 56. IL-1 AND RECEPTOR ANTAGONISTS • Role of IL-1 in immune and inflammatory process • IL-1 receptor antagonist(IL-1Ra) • Dynamic balance
  57. 57. ANAKINRA • It is recombinant IL-1Ra • Binds competitively to IL-R type 1 • Given 100 mg/day SC • Bioavailability-95% ; t ½ 4-6 hrs • Elimination by renal clearance
  58. 58. ANAKINRA • Has been found to be effective as compared to placebo both in monotherapy and combination with MTX • Slows the rate of joint damage • Useful in patients who have no response or fail to tolerate DMARDs and other BRMs
  59. 59. ANAKINRA • Theoritical possibility of synergistic action with TNF antagonists but not substantiated by studies • Well tolerated with MTX but a small fraction can develop reversible neutropenia • Contraindicated in presence of active infections • Daily injections have limited its role
  60. 60. BRMs IN RA • Indicated in resistant RA with active disease (DAS >5.1) • Defined as failure of response to at least 2 DMARDs ( one should be MTX) used in optimal doses for at least 6 months • Generally have rapid onset of response • Should be withdrawan in case of advent of adverse effects or lack of effect(DAS improvement <1.2 at >3 months) • Major deterrent to their use is cost
  61. 61. INITIAL TREATMENT Oral MTX 7.5-15mg per week +/- 5-7.5 mg Prednisone per day 5 mg increments in dose every month to a max of 20-30 mg per week Switch to subcutaneous injections DMARD combination New concept- Induction therapy with Etanercept which has been found to rapidly suppress disease activity
  62. 62. ESTABLISHED RA Maximal MTX dose 2-3 months Add Sulfasalazine, Hydroxychloroquine or both but not Cyclosporin 3 months Add Leflunomide to MTX 1 year after diagnosis TNF inhibitors
  63. 63. COEXISTING ILLNESSES • Infections • Osteoporosis • Cardiovascular disease
  64. 64. INFECTIONS • Doubling of the risk of infection and degree of increase correlates with severity • Possible role of corticosteroids and TNF inhibitors • Regular Influenza and Pneumococcal vaccination ( start before DMARD) • Prescreen and follow up for TB
  65. 65. OSTEOPOROSIS • Incidence of osteoporosis is doubled • Base line bone density studies • Bisphosphonate therapy
  66. 66. FUTURE STRATEGIES • B cell depletion therapy using Rituximab • Inhibition of IL-6 • Inhibition of IL-18 • Costimulation block
  67. 67. RITUXIMAB • Chimeric monoclonal IgG anti CD20 antibody • Has shown significant efficacy comparable to TNF inhibitors
  68. 68. RITUXIMAB-DOSAGE • Given by slow infusion • Two doses of 1 gm each 1 week apart • Methyl Prednisolone as premedication on the day of dosing • Effects last at least 6 weeks • Monotherapy in RF +ve patients • No benefit of combining with MTX
  69. 69. ADVERSE EFFECTS • Pricking sensation in the throat at the time of first infusion • Increased risk of lower airway infections • Transfusion reactions
  70. 70. IL-6 • Pleiotropic cytokine, glycoprotein in nature • Various names • Produced by a variety of immunocytes and mesenchymal cells • Binds to cell surface or soluble receptor • IL-6/IL-6R complex binds to gp 130 on cell surface and leads to effects
  71. 71. FUNCTIONS OF IL-6 • Stimulation of B cells • Proliferation and differentiation of T cells • Differentiation of osteoclasts and increased proteoglycan breakdown • Pyrogenic and weight loss • Paradoxically suppresses IL-1 and TNF-α
  72. 72. IL-6 IN RA • Implicated in joint damage and systemic manifestations of disease • IL-6 knockout mice • Results of SC IL-6
  73. 73. ANTAGONISTS OF IL-6 •In animal models •In human studies Rapid improvement with 10 days treatment in initial studies (10 mg/kg IV OD) In subsequent studies, found to be effective after 1 wk and sustained effect till 8 wks Optimum dose- 8 mg/kg Combination with MTX found to be better than monotherapy with either drug
  74. 74. INTERLEUKIN - 18 • Belongs to IL1 superfamily • Major function is induction of INF-γ • Also induces T- helper cells as also other inflammatory cytokines • Increased levels are seen in patients of RA • IL-18BP is produced endogenously and counters IL-18
  75. 75. ROLE OF IL-18 AND ITS ANTIBODY Antimurine IL-18 antibody Suppresses swelling by 60% and reduces TNFα and IL-1 levels when given to Rabbits with Streptococcal cell wall induced arthritis IL-18 when given to Mice immunized with type II collagen, increases the erosive and inflammatory component of arthritis
  76. 76. ROLE OF IL-18BP Reduces the clinical severity of the disease in Mice having CIA and causes a reduction in the levels of circulating cartilage matrix protein Murine IL-18BP fused with Fc portion of murine IgG Has been found to reduce histological severity
  77. 77. COSTIMULATION BLOCKERS • Requirement of dual signal for T-cell activation • CTLA4 – constitutively expressed protein on T cell surface
  78. 78. CTLA4-Ig • It is a soluble antigen immunoglobulin fusion protein • Consists of extracellular domain of human CTLA4 and Fc portion of human IgG
  79. 79. CTLA4-Ig IN RA • Found to induce long term graft survival in rodent models • In phase-II trails – combination of CTLA4Ig and MTX compared with MTX monotherapy • Combination showed ACR 20 response in 60% patients as compared to 35.3% in monotherapy group
  80. 80. OTHER AGENTS • Pegylated soluble TNF-α receptor antagonist • Agents that trap cytokines • Interleukin 15 blockers • Agents that prevent the cleavage of human compliment component C5 • Agents that inhibit adhesion molecules