State of Lupus Treatment: New Therapeutics


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State of Lupus Treatment: New Therapeutics

  1. 1. State of Lupus Treatment: New Therapeutics Richard Furie, MD Chief, Division of Rheumatology Professor of MedicineHofstra North Shore-LIJ School of Medicine New York
  2. 2. Like Snowflakes No Two Cases Are Alike• Case 1: 22 y/o Caucasian female with fatigue, photosensitive malar rash, arthralgias, adenopathy, ANA 1/320 (Sp), SS-A Ab; better with NSAIDs and hydroxychloroquine• Case 2: 22 y/o African American female with fatigue, alopecia, scarring rash in the scalp and ears, hypertension, arthritis, nephritis, ANA 1/1280 (H), high DNA Ab, low C’, anemia, and thrombocytopenia; refractory to high doses of steroids and MMF; dialysis in the near future
  3. 3. Goals of Therapy: Back to Basics• Do Good • Control disease activity • Prevent damage from disease • Prevent flares• Do No Harm • Prevent damage from treatment • Do not treat damage with agents intended for active disease
  4. 4. Principles of Treatment Design• Identify disease manifestations• Distinguish activity from chronicity – Does rash represent active disease or scar? – Does proteinuria represent active nephritis or previous damage?• Prioritize active disease manifestations
  5. 5. Principles of Treatment Design• Disease activity is a continuum• Use the least toxic medicine and lowest dose to treat the most concerning disease manifestation (and hope the less concerning manifestations come under control)• Treatment rules would not be an issue if it were not for the toxicities of our most potent agents
  6. 6. Drugs1. Analgesics2. Topicals3. NSAID’s4. Antimalarials5. Corticosteroids6. Antimetabolites7. Chemotherapy8. Biologics
  7. 7. Specificity and Safety of Therapeutic Interventions Normal Tissues Pathologic Process (lupus)Immunosuppressives DesiredSteroids Therapy
  8. 8. Corticosteroids: ToxicitiesHypertension HirsuitismCushingoid appearance OsteoporosisOsteonecrosis Fluid retentionGlucose intolerance Skin fragilityIncreased infection risk Cataracts• Side effects are related to dose and duration• Use the lowest dose that does the job
  9. 9. Antimetabolites: Toxicities1. Azathioprine cytopenias, lymphoma2. Methotrexate hepatotoxicity3. Mycophenolate mofetil GI symptoms; skin ca. lymphoma4. Leflunomide hypertension, hepatotoxicity
  10. 10. Cyclophosphamide: Toxicities1. Cytopenias2. Infection3. Hemorrhagic cystitis4. Sterility (risk related to dose and age)5. Cancer (bladder cancer; leukemia)
  11. 11. A Case: Rank the Disease Manifestations• Swollen and painful finger joints (arthritis):• Pain in right hip (osteonecrosis)• Hematuria/proteinuria/high DNA Ab/low C’ (nephritis)• Hair loss (alopecia)• Platelet count low (thrombocytopenia)• Fatigue
  12. 12. A Case: Rank the Disease Manifestations (Patient)1. Swollen and painful finger joints (arthritis)2. Hair loss (alopecia)3. Fatigue4. Pain in right hip (osteonecrosis)5. Platelet count low (thrombocytopenia)6. Hematuria/proteinuria/high DNA Ab/low C’
  13. 13. A Case: Rank the Disease Manifestations (Physician)1. Platelet count low (thrombocytopenia)2. Hematuria/proteinuria/high DNA Ab/low C’3. Swollen and painful finger joints (arthritis)4. Hair loss (alopecia)5. Fatigue6. Pain in right hip (osteonecrosis)
  14. 14. Treating the Disease Manifestations:1. Thrombocytopenia high dose prednisone2. Nephritis cyclophosphamide; MMF3. Arthritis4. Alopecia5. Fatigue6. Osteonecrosis Analgesics
  15. 15. What Does One Follow?:1. Symptoms (pain, fatigue)2. Signs (joint swelling, rash)3. Laboratory values (cell counts, kidney function, DNA Ab, C’)4. SLEDAI or BILAG (in studies) Much of this is art and not science
  16. 16. What if Conventional Therapy Fails?:1. “Pulse” steroids2. Bone marrow transplantation3. Other chemotherapy/IS (calcineurin inhibitors)4. TNF inhibitors5. Biologics: belimumab6. Off-label biologics: rituximab, abatacept7. Experimental medicine
  17. 17. Probability of Survival Survival in SLE 100 80 Cytotoxic Agents 60 Glucocorticoids 40 Pre-Glucocorticoids 20 0 0 1 5 10 Years After Diagnosis
  18. 18. Driving Forces Behind SLE Drug Development• Need for more efficacious therapies – Lupus nephritis – Severe extra-renal lupus – Flare prevention – Remission induction• Safer therapies – Replace steroids & cyclophosphamide
  19. 19. SLE Clinical Trial Challenges • Heterogeneity of manifestations – Complicates entry criteria, trial design, and endpoints • Confounding by background meds • Trial endpoints
  20. 20. Innate DNA FcR SunAdaptive TLR 9 IL 6 pDendritic Cell mDC IL 12 CXCL10 IFNγ IL 10 IFNα CD28 - CD80/86 TCR - MHC T Cell B Cell APRIL CD40L - CD40 C’ PMN ICOS - ICOS-L BLyS/BAFF Ab Plasma Cell DNA Macrophage IC
  21. 21. B Cell-Directed Therapies: Extracellular Targets Ab CD 20 Ab CD 80CTLA4 Ig BLyS R CD 86 BLyS B TACIAb CD 19 TACI MHC II APRIL Ag BCMAAb CD40 LFA-3 ICOS L CD 22 Ab Ab
  22. 22. Biologic Rationale for Targeting BLyS • Crucial to B cells – Maturation – Differentiation – Survival (anti-apoptotic [overrides Bcl-2]) • Murine models – Transgenic mice develop SLE-like disease – TACI-Ig ameliorates murine lupus activity • Human SLE – Elevated levels (predictive of flare)
  23. 23. Novel Response Endpoint (SLE Responder Index: SRI)• Index generated from belimumab phase II• Responder index composed of: – > 4 point improvement in SS score – No BILAG worsening (new A or 2 B flares) – No worsening in PGA (< 0.3 point increase) Furie RA et al. Arthritis Care and Research. 2009;61:1143-51
  24. 24. BLISS Phase III Summary • Primary endpoint was met in both phase 3 studies – Significant improvement in SRI at wk 52 BLISS-52 BLISS-76 p = 0.013 • Belimumab plus current routine therapy was generally well tolerated, with a safety profile comparable to that ofa placebo plus current routine therapya Nov 9, 2010, Poster 1172. Wallace et al. Presented at the American College of Rheumatology Annual Meeting,
  25. 25. Belimumab– Who should be treated?– What manifestations respond best?– When is a response expected?– When should failure be declared?– If successful, how long should it be used?– How clinically significant is the SRI?
  26. 26. Lessons Learned: SLE Clinical TrialsThe recent past – Developing drugs in SLE is humbling – Surprising failures: rituximab – Successful failures: MMF – Sucesses: belimumab – An endpoint that worked
  27. 27. Lessons Learned: SLE Clinical TrialsThe future – Unprecedented trials activity now – Challenges • Not enough patients to fill studies • Trial design challenges remain
  28. 28. Move over ACR 20 (and DAS),make room for SLEDAI and BILAG Thank you