1. Arthritis Medications Part II Dr. Sherry Rohekar June 24, 2010

2. Overview Acknowledgement: Dr. Andrew Thompson for his kind use of his slides! Wealth of information on his website (mentioned later in presentation) Acknowledgement: Dr. Andrew Thompson for his kind use of his slides! Wealth of information on his website (mentioned later in presentation) DMARDS DMARDS Traditional Traditional Methotrexate Methotrexate Sulfasalazine Sulfasalazine Plaquenil Plaquenil Leflunomide Leflunomide TNF Inhibitors (infliximab, adalimumab, etancercept) TNF Inhibitors (infliximab, adalimumab, etancercept) Newer biologics (abatacept, rituximab) Newer biologics (abatacept, rituximab)

3. Approach to Inflammatory Arthritis Paradigm shift in the treatment of inflammatory arthritis Paradigm shift in the treatment of inflammatory arthritis Rationale for Treatment Rationale for Treatment Large body of evidence which shows joint damage is an early phenomenon of rheumatoid arthritis Large body of evidence which shows joint damage is an early phenomenon of rheumatoid arthritis Joint erosions occur in up to 93% of patients with less than 2 years of disease activity Joint erosions occur in up to 93% of patients with less than 2 years of disease activity The rate of radiographic progression is greatest in the first two years The rate of radiographic progression is greatest in the first two years Disability occurs early – 50% of patients with RA will be work disabled at 10 years Disability occurs early – 50% of patients with RA will be work disabled at 10 years Severe disease is associated with increased mortality! Severe disease is associated with increased mortality!

4. It’s like an Iceberg

5. It’s what you don’t see!

6. Approach to Inflammatory Arthritis “Window of Opportunity” “Window of Opportunity” Early and aggressive treatment may have long-term benefits Early and aggressive treatment may have long-term benefits Principles of Treatment Principles of Treatment Treat Early Treat Early Treat Appropriately Treat Appropriately

7. A Fire in the Joints If there’s a fire in the kitchen do you wait until it spreads to the living room or do you try and put it out?

8. Therapeutic Strategies Use of early DMARDs Use of early DMARDs Combinations of Conventional DMARDs Combinations of Conventional DMARDs Three studies have confirmed the use of “triple therapy” in early RA is more effective than a single agent. (Clin Exp Rheumatol 17:699-704, 1999, Arthritis Rheum 50:2072-81, 2004, Arthritis Rheum 46:1164-70, 2002). Three studies have confirmed the use of “triple therapy” in early RA is more effective than a single agent. (Clin Exp Rheumatol 17:699-704, 1999, Arthritis Rheum 50:2072-81, 2004, Arthritis Rheum 46:1164-70, 2002). Combinations of Methotrexate plus Biologic agents Combinations of Methotrexate plus Biologic agents

9. What are DMARDs? Disease Modifying Anti-Rheumatic Drugs (DMARDs). Disease Modifying Anti-Rheumatic Drugs (DMARDs). Symptom Control Symptom Control Control current inflammatory features Control current inflammatory features Modify the course of disease Modify the course of disease Reduce joint damage and deformity Reduce joint damage and deformity Reduce radiographic progression Reduce radiographic progression Reduce long-term disability Reduce long-term disability

10. Available DMARDs Methotrexate Methotrexate Sulfasalazine (Salazopyrin®) Sulfasalazine (Salazopyrin®) Hydroxychloroquine (Plaquenil®) Hydroxychloroquine (Plaquenil®) Leflunomide (Arava®) Leflunomide (Arava®) Gold (Myochrisine®) Gold (Myochrisine®) Others Others Cyclosporine Cyclosporine Azathioprine Azathioprine Cyclophosphamide Cyclophosphamide

11. Common DMARD Combinations Triple Therapy Triple Therapy Methotrexate, Sulfasalazine, Hydroxychloroquine Methotrexate, Sulfasalazine, Hydroxychloroquine Double Therapy Double Therapy Methotrexate & Leflunomide Methotrexate & Leflunomide Methotrexate & Sulfasalazine Methotrexate & Sulfasalazine Methotrexate & Hydroxychloroquine Methotrexate & Hydroxychloroquine Methotrexate & Gold Methotrexate & Gold Sulfasalazine & Plaquenil Sulfasalazine & Plaquenil Monotherapy Monotherapy

12. Methotrexate Tetrahydrofolate is an important cofactor in the production of purines transferring a carbon atom.

13. Methotrexate

14. Methotrexate Substitutes as Folic Acid Substitutes as Folic Acid Interferes with the production of Tetrahydrofolate Interferes with the production of Tetrahydrofolate Interferes with the de novo synthesis of purines Interferes with the de novo synthesis of purines Affects cells that rapidly turn over Affects cells that rapidly turn over Immune cells Immune cells Mucosal cells Mucosal cells Hair follicles Hair follicles

15. Methotrexate – What to tell Patients Dose and Administration Dose and Administration Dose ranges from 7.5 to 25 mg Dose ranges from 7.5 to 25 mg ONLY GIVEN ONCE A WEEK ONLY GIVEN ONCE A WEEK 2.5 mg Tablets or Subcutaneous Injection 25 mg/mL 2.5 mg Tablets or Subcutaneous Injection 25 mg/mL Onset of Action Onset of Action 6-8 weeks 6-8 weeks Avoid Avoid Pregnancy – Teratogenic Pregnancy – Teratogenic Alcohol Alcohol Sulfa Antibiotics (Sulfasalazine is ok) Sulfa Antibiotics (Sulfasalazine is ok)

16. Methotrexate – What to Tell Patients Common S/E Common S/E Malaise, Nausea Malaise, Nausea Rise in Liver Enzymes Rise in Liver Enzymes Dose/Sensitivity Dose/Sensitivity Oral ulcers, alopecia, liver and bone marrow toxicity Oral ulcers, alopecia, liver and bone marrow toxicity Rare S/E Rare S/E Pulmonary: Fever, cough, SOB (early, old, lung disease) Pulmonary: Fever, cough, SOB (early, old, lung disease) Bone Marrow: Follow bloodwork – dose/sensitivity related Bone Marrow: Follow bloodwork – dose/sensitivity related Infection Infection Pregnancy Pregnancy Malignancy Malignancy

17. Methotrexate – What to give Patients Information Sheet – www.RheumInfo.com Information Sheet – www.RheumInfo.comwww.RheumInfo.com Folic Acid supplementation may help with nuisance side effects (nausea, mouth sores) Folic Acid supplementation may help with nuisance side effects (nausea, mouth sores) Lab Monitoring (monthly initially) Lab Monitoring (monthly initially) CBC, ESR, CRP CBC, ESR, CRP AST, ALT, ALP, Albumin AST, ALT, ALP, Albumin Cr Cr

18. MTX Dose Response in RA 39 53 47 23 41 15 8 29 Furst et al, J Rheum 11:313,1989 Percent of Patients with > 50 % Improvement 10 mg/ m 2 MTX 5 mg/m 2 MTX

19. Hydroxychloroquine (Plaquenil®) Anti-malarial medication found useful for the treatment of inflammatory arthritis Anti-malarial medication found useful for the treatment of inflammatory arthritis Highly concentrated within cells Highly concentrated within cells Increases intracellular pH Increases intracellular pH Interferes with cell’s ability to degrade and process proteins Interferes with cell’s ability to degrade and process proteins

20. Hydroxychloroquine (Plaquenil®) Dose & Administration Dose & Administration 200 mg tablets 200 mg tablets Dose ranges from 200 – 400 mg per day Dose ranges from 200 – 400 mg per day Onset Onset 6-12 weeks 6-12 weeks Avoid Avoid May increase sensitivity to the sun May increase sensitivity to the sun

21. Common S/E Common S/E Rash, nausea, diarrhea Rash, nausea, diarrhea Difficult with reading (affects accomodation) Difficult with reading (affects accomodation) Rare S/E Rare S/E Ocular, Skeletal muscle, heart Ocular, Skeletal muscle, heart Hydroxychloroquine (Plaquenil®)

22. Hydroxychloroquine – What to give Patients Information Sheet – www.RheumInfo.com Information Sheet – www.RheumInfo.comwww.RheumInfo.com Dose is based on lean body weight (6.5 mg/kg/day) Dose is based on lean body weight (6.5 mg/kg/day) Average Dose 300 (2 alt with 1 per day)– 400 (2 per day) mg per day Average Dose 300 (2 alt with 1 per day)– 400 (2 per day) mg per day No laboratory monitoring No laboratory monitoring Ophthalmologic screen for visual acuity, colour vision, and visual fields qyearly Ophthalmologic screen for visual acuity, colour vision, and visual fields qyearly

23. Sulfasalazine Developed in the late 1930s by Dr. Nana Svartz (Swedish Rheumatologist) for the treatment of “infective polyarthritis” Developed in the late 1930s by Dr. Nana Svartz (Swedish Rheumatologist) for the treatment of “infective polyarthritis” Anti-inflammatory: Salicylic Acid Anti-inflammatory: Salicylic Acid Antibiotic: Sulfapyridine Antibiotic: Sulfapyridine Sulfasalazine consists of salicylic acid and sulfapyridine joined by an azo bond. Sulfasalazine consists of salicylic acid and sulfapyridine joined by an azo bond. Sulfinpyradone is thought to be the active ingredient although, in RA, the mechanism of action is not understood Sulfinpyradone is thought to be the active ingredient although, in RA, the mechanism of action is not understood

24. Sulfasalazine Salicylate Sulfinpyradone

25. Sulfasalazine Pills taken twice daily (CPS and some pharmacists – QID!) Pills taken twice daily (CPS and some pharmacists – QID!) Start at a low dose 1 per day and gradually work up to 4 per day Start at a low dose 1 per day and gradually work up to 4 per day Takes 6-8 weeks to work Takes 6-8 weeks to work Common S/E: Malaise, Nausea, Abd pain, Rash, headaches, dizziness Common S/E: Malaise, Nausea, Abd pain, Rash, headaches, dizziness Rare S/E: Rare S/E: Hypersensitivity reaction Hypersensitivity reaction Liver: Follow enzymes – not usually a problem Liver: Follow enzymes – not usually a problem Bone Marrow: Follow bloodwork – dose/sensitivity related Bone Marrow: Follow bloodwork – dose/sensitivity related Renal: Very Rare Renal: Very Rare

26. Sulfasalazine – What to give Patients Information Sheet – www.RheumInfo.com Information Sheet – www.RheumInfo.comwww.RheumInfo.com Sulfasalazine 500 mg tablets Sulfasalazine 500 mg tablets Week 1: Take 1 tab PO qam Week 1: Take 1 tab PO qam Week 2: Take 1 tab PO BID Week 2: Take 1 tab PO BID Week 3: Take 2 tabs PO qam and 1 tab PO qpm Week 3: Take 2 tabs PO qam and 1 tab PO qpm Week 4 & therafter: Take 2 tabs PO BID Week 4 & therafter: Take 2 tabs PO BID Lab Monitoring (week 2, 4 and then monthly) Lab Monitoring (week 2, 4 and then monthly) CBC, ESR, CRP CBC, ESR, CRP AST, ALT, ALP, Albumin AST, ALT, ALP, Albumin Cr Cr

27. Leflunomide (Arava®) Newer DMARD Newer DMARD Inactive and converted to A177-1726 in the GI tract and liver Inactive and converted to A177-1726 in the GI tract and liver

28. Leflunomide (Arava®) A77-1726 inhibits the activity of dihydro-orotate dehydrogenase, an important enzyme in the de novo synthesis of pyrimidines. A77-1726 inhibits the activity of dihydro-orotate dehydrogenase, an important enzyme in the de novo synthesis of pyrimidines.

29. Leflunomide (Arava®) Dose and Administration Dose and Administration 10 & 20 mg Tablets 10 & 20 mg Tablets Given daily – ranges from 10-20 mg per day Given daily – ranges from 10-20 mg per day Onset of Action Onset of Action 6-8 weeks 6-8 weeks Avoid Avoid Pregnancy – Teratogenic Pregnancy – Teratogenic Alcohol Alcohol

30. Leflunomide (Arava®) Common S/E Common S/E Diarrhea, nausea, malaise, hypertension, alopecia, rash Diarrhea, nausea, malaise, hypertension, alopecia, rash Rare S/E Rare S/E Liver: Follow enzymes – not usually a problem Liver: Follow enzymes – not usually a problem Bone Marrow: Follow bloodwork – dose/sensitivity related Bone Marrow: Follow bloodwork – dose/sensitivity related Infection Infection Pregnancy Pregnancy Malignancy Malignancy

31. Leflunomide (Arava®) Information Sheet – www.RheumInfo.com Information Sheet – www.RheumInfo.comwww.RheumInfo.com Leflunomide 20 mg tablet PO OD – If side effects can: Leflunomide 20 mg tablet PO OD – If side effects can: Reduce to 10 mg PO OD or Reduce to 10 mg PO OD or Reduce to 20 mg every other day (Cheaper) Reduce to 20 mg every other day (Cheaper) Lab Monitoring (monthly initially) Lab Monitoring (monthly initially) CBC, ESR, CRP CBC, ESR, CRP AST, ALT, ALP, Albumin AST, ALT, ALP, Albumin Cr Cr

32. Common Strategies Triple therapy for 3-6 months Triple therapy for 3-6 months Optimize dose and route of medications Optimize dose and route of medications Incomplete Response Incomplete Response Changing to sc methotrexate Changing to sc methotrexate Adding Leflunomide Adding Leflunomide Adding a Biologic Agent Adding a Biologic Agent

33. Biologics Specially designed to treat inflammatory types of arthritis such as rheumatoid and psoriatic arthritis. Specially designed to treat inflammatory types of arthritis such as rheumatoid and psoriatic arthritis. Six biologics currently available (and more coming) Six biologics currently available (and more coming) Work by different mechanisms. Work by different mechanisms. Like DMARDs, biologics are used to suppress inflammation and help prevent damage to the joint. Like DMARDs, biologics are used to suppress inflammation and help prevent damage to the joint.

34. Current Available Biologics TNF Inhibitors TNF Inhibitors Adalimumab Adalimumab Etanercept Etanercept Infliximab (Remicade) Infliximab (Remicade) IL-1 Inhibitors IL-1 Inhibitors Anakinra (Kineret) Anakinra (Kineret) T-Cell Co-Stimulatory Blockade T-Cell Co-Stimulatory Blockade Abatacept (Orencia) Abatacept (Orencia) B-Cell Depletion B-Cell Depletion Rituximab (Rituxan) Rituximab (Rituxan)

35. Available Biologics

36. TNF Inhibitors In some people with arthritis, a protein called Tumour Necrosis Factor (TNF) is present in the blood and joints in excessive amounts where it increases inflammation (pain & swelling). In some people with arthritis, a protein called Tumour Necrosis Factor (TNF) is present in the blood and joints in excessive amounts where it increases inflammation (pain & swelling).

38. TNF SIGNAL Monoclonal Antibody directed against TNF-alpha: Infliximab (Remicade ®), Adalimumab (Humira®) Soluble TNF-Receptors serve as a balance to TNF Engineered Soluble TNF Receptor Etanercept (Enbrel®)

39. TNF-Inhibitors Mechanism of Action Mechanism of Action Infliximab and Adalimumab are antibodies directed against TNF Infliximab and Adalimumab are antibodies directed against TNF Etanercept is a soluble receptor decoy Etanercept is a soluble receptor decoy Administration Administration Infliximab is given intravenously Infliximab is given intravenously Etanercept and Adalimumab are given by subcutaneous injection Etanercept and Adalimumab are given by subcutaneous injection

40. Side Effects of TNF Inhibition Infusion Reactions with Infliximab, Injection Site Reactions with Adalimumab and Etanercept Infusion Reactions with Infliximab, Injection Site Reactions with Adalimumab and Etanercept Infection Infection Tuberculosis Tuberculosis Serious resulting in death Serious resulting in death Malignancy Malignancy Increased risk of lymphoma – early data Increased risk of lymphoma – early data Solid tumors? Solid tumors? Neurologic Neurologic Multiple Sclerosis, seizures, inflammation of the ocular nerve Multiple Sclerosis, seizures, inflammation of the ocular nerve Autoimmune Autoimmune Antibody formation – SLE like illness Antibody formation – SLE like illness Worsening of Congestive Heart Failure Worsening of Congestive Heart Failure

41. When to Stop TNF-Inhibitors STOP if develop a fever, have an infection, or have been prescribed antibiotics STOP if develop a fever, have an infection, or have been prescribed antibiotics Tell your doctor about any upcoming surgeries Tell your doctor about any upcoming surgeries

42. T-Cell Co-Stimulatory Blockade (Abatacept)

45. Practical Aspects Given on week 0, 2, and 4 then every 4 weeks Given on week 0, 2, and 4 then every 4 weeks Quick infusions over 30 minutes Quick infusions over 30 minutes Well tolerated Well tolerated Home infusion program Home infusion program

46. Practical Aspects Side Effects Side Effects INFECTION INFECTION COPD Exacerbation COPD Exacerbation MALIGNANCY – Lung Cancer MALIGNANCY – Lung Cancer Infusion Reactions – Rare Infusion Reactions – Rare

47. B-Cell Depletion (Rituximab)

48. Rheumatoid Arthritis (RA) RA was thought to be T-Cell mediated RA was thought to be T-Cell mediated Most widely accepted hypothesis: Most widely accepted hypothesis: Professional Antigen Presenting Cell encounters some “unknown” antigen Professional Antigen Presenting Cell encounters some “unknown” antigen It presents this “unknown” antigen to a CD4 T-helper Cell It presents this “unknown” antigen to a CD4 T-helper Cell In a genetically predisposed individual, this starts an immune chain reaction In a genetically predisposed individual, this starts an immune chain reaction Immune system is confused and targets healthy tissue Immune system is confused and targets healthy tissue

49. B-Cell can serve role as Antigen Presenting Cell and Antibody Producing Cell Immune Reaction Autoantibody Cytokines Antigen Presenting Cell CD4 T-Cell Antigen B-Cell

50. Rheumatoid Arthritis Autoantibody B-CellCD4 T-Cell Auto- Antigen B-Cell

51. B-Cell Depletion Therapy in RA How does B-Cell Depletion work? How does B-Cell Depletion work? B-Cells cannot act as antigen presenting cells to activate T-Cells B-Cells cannot act as antigen presenting cells to activate T-Cells B-Cells cannot produce Rheumatoid Factor B-Cells cannot produce Rheumatoid Factor B-Cells cannot release cytokines B-Cells cannot release cytokines B-Cell Plasma Cell Antibodies Rheumatoid Factor

52. Rituximab

53. Rituximab in RA B-Cell CD-20 Rituximab: anti-CD-20

54. Initial Studies Professor J.C. Edwards at University College in London England Professor J.C. Edwards at University College in London England Treated 5 patients with Rituximab Treated 5 patients with Rituximab Based on the premise of reducing auto- antibodies Based on the premise of reducing auto- antibodies All 5 responded All 5 responded Since then multiple large trials have confirmed these results Since then multiple large trials have confirmed these results

55. Practical Aspects Given as two (2) infusions of 1000mg spaced two weeks apart Given as two (2) infusions of 1000mg spaced two weeks apart All patients given 100 mg of solumedrol with each infusion All patients given 100 mg of solumedrol with each infusion Takes about 3-4 months to kick in Takes about 3-4 months to kick in Time to re-treatment – 6 to 9 months Time to re-treatment – 6 to 9 months

56. Practical Aspects Side Effects Side Effects INFECTION INFECTION INFUSION REACTIONS INFUSION REACTIONS Other rare things – severe skin reactions, arrhythmia, drop in blood counts Other rare things – severe skin reactions, arrhythmia, drop in blood counts

57. Any questions?