1. Therapeutic Revolution in Rheumatoid Arthritis Brian J. Keroack, MD Rheumatology Associates Portland, Maine

2. Rheumatoid Arthritis Morning stiffness>1 hour Usually symmetric Parameters of systemic inflammation >6 weeks duration 70% +RF

3. Rheumatoid Arthritis Accepted Prevalence: 1- 1.5% (classic seropositive) 200,000 new cases annually 19.9 billion/year spent on RA. 9.5 billion dollars/million patients. This exceeds cost/patient in diabetes and cardiovascular disease. Rheumatoid Arthritis affects Survival:

4. Impact of RA Premature mortality Increased morbidity Significant impact on quality of life – Pain with associated functional disability – Fatigue 73% of patients 42% with severe fatigue – Depression Economic impact – Work dysfunction – Earnings loss of approximately 50%

5. Clinically Detectable Damage Occurs Early in RA MRI-detectable erosions are present within 4 months of symptom onset 1 Most patients (up to 93%) with RA of < 2 years’ duration show radiographic damage 2 Disease progression is more rapid during the first year than during the second and third years 3

7. Cartilage in RA: Target or Bystander? Early: – Cytokines (IL-1, TNF-  ): Macrophages – Catabolic Effects on Chondrocytes – Proteoglycan Depletion – Weakens ability to rebound from a load Next: – Induction of Metalloproteinases—Stromolysin, Collagenase Last: – Phagocytosis of Cartilage by Pannus

8. TNF-  is a pivotal cytokine in the pathogenesis of RA Mediates pathologic inflammation Mediates joint destruction Mediates systemic, extra-articular symptoms of inflammation Regulates levels of adhesion molecules responsible for leukocyte migration

9. Parameters of Inflammation

10. Approach to the Treatment of RA Try to figure out ‘what type’ of Rheumatoid Arthritis the patient has This is not a uniform disease – Young, Sero-positive patient vs. Older Sero- negative patient. – Abrupt vs gradual onset – Response to 10-15 mg prednisone (‘Lourdes’ response) Mild DMARDS vs Immunosuprssives

11. Approach to the Treatment of RA: Early Immunosupression Antiproliferative agents – More aggressive doses of methotrexate – Leflunomide Biologics – Infliximab/ Etanercept/Humira (TNF-  ) – Kineret (IL-1ra) – Orencia (abatacept) Rituxan (B-cell depletion) – MRA (IL-6 receptor) – Small Modular Immunopharmaceutical (SIMP) Combination therapy—sooner than ever before

12. Weinblatt Study

13. Methotrexate Multiple Trials Support Use DMARD of Choice (but there are challengers) Long Term Efficacy/Compliance Radiographic Data Relatively Rapid Onset of Action (4-8 weeks) Dosage 7.5-25mg/week (above 20 mg inject) I still try Methotrexate in Most RA patients before moving on to Newer DMARDS—but I move faster to Biologics in partial responders (2-3 months) —patience is NOT a virtue here. I would never give you a drug worse than your disease

15. Etanercept Activatedmacrophage Targetcell Signal sTNFR TNF TNFR Etanercept TNF Inhibition: Etanercept

16. Methotrexate Etanercept 25 mg Patients with baseline erosions 86%(25/29) 96%(24/25) 52%(98/188)72%(130/181) 57%(123/217) 75%(154/206) All patients P < 0.001 Patients With No New Erosions at 1 Year P < 0.001 P = 0.159 Patients with no baseline erosions Finck B. Arthritis Rheum. 1999.

17. Antibody Neutralization of TNF 

18. Infliximab in Active RA Despite MTX ATTRACT Improvement in Swollen Joints MTX Control 3 mg/kg q 8 wks 10 mg/kg q 8 wks MTX Control 3 mg/kg q 4 wks 10 mg/kg q 4 wks

19. Infliximab in Active RA Despite MTX ATTRACT Improvement in Tender Joints MTX Control 3 mg/kg q 8 wks 10 mg/kg q 8 wks MTX Control 3 mg/kg q 4 wks 10 mg/kg q 4 wks

20. Infliximab in Active RA Despite MTX ATTRACT Median C-reactive Protein (mg/dL)

21. *P<0.05 for HUMIRA + MTX vs MTX alone and HUMIRA alone † Normal CRP was defined as ≤ 0.5 mg/dL * * * * Percentage of Patients * TJC=0SJC=0HAQ=0Morning Stiffness=0 Normal CRP † PREMIER 2-Year Results of Selected Clinical Responses Emery P, et al. Presented at: EULAR; June 8-11, 2005; Vienna, Austria. Data on file, Abbott Laboratories. (n=268) (n=257) (n=274)

22. So What is the Catch? Cost = $17,000-25,000/year Injections or infusions Profound immunosupression – Careful who you put on the drug (Diabetes, COPD, Renal failure, etc) – When patients present with infection, they have more subtle complaints—fewer ‘systemic’ symptoms occur – Low threshold for antibiotics as most serious infections are ‘typical’ – Can you educate the patient?

23. The Other Biologics Orencia: Approved by FDA 2/2006—Role unclear—does work in TNF failures Rituxan: 2 doses can produce a protracted period of remission in refractory RA— Infusion reactions (1-2%)

24. Orencia—CTLA4-Ig

25. Rituxan

26. Bridge to the 21 st Century Early aggressive therapy especially in young seropositive patients—DMARDS within 3 months of diagnosis. Best chance for remission Methotrexate first—But in partial responders rapidly move to TNF-  blockers. The data suggest the they should be ADDED to Methotrexate. Biologics to induce early remissions for those with erosions at diagnosis. Try more than one TNF-  blocker (70% respond to a switch) Orencia/Rituxan in TNF-  Failures ?Low dose prednisone (5-10 mg) combined with osteoporosis protection—Many need it for symptoms NSAIDS/COX-2 as bridge therapy in mild Rheumatoid Arthritis (essentially worthless)

27. Future? MRA ?—IL-6 receptor antibody (+/- data to date and multiple problems—LFT’s, GI bleeding?) probably not a ‘player’ SIMP’s: these are single chain polypeptides with greater tissue penetration—high affinity --??greater efficacy We are in the ‘infancy’ of immune ‘manipulation’