Brain Salivary, Parotid glands Thyroid Heart, Lungs Serous linings of Heart, Lungs, GI tract Kidneys Special Complications of Pregnancy Joints Blood Vessels and Blood Proteins Inflammation vs Coagulation Skin LUPUS Variable from patient to patient Waxing and Waning Unpredictable Chronic Illness and Disability
Prevalence of Lupus vs Other Diseases JDRF Society Nat Inst Neur Dis and Stroke Lupus Foundation of America Susan Komen Foundation ( in USA x 1000)
Disease-Specific Funding per year by NIH (normalized to patient numbers) Millions/year/pt www.nih.gov.news
Wallace in Arthr and Allied Cond , 13 th Ed V2, p1319 Koopman, ed % YEARS IMPROVED SURVIVAL IN SLE: 1955-1990 Epidemiologic Data Based on SLE Cause of Death The Major Difference has been due to Steroids
Many Faceted Disorders Many Causes for Each Symptom Unpredictable Flares of Disease Waxing and Waning Activity Problems: Treatment Selection Optimizing the Dose Outcome Measurement Impediments to Drug Development In the 21 st Century
Lupus <ul><li>Not an Infection </li></ul><ul><li>Disorder of the Immune System </li></ul><ul><li>Inflammation in Various Organs </li></ul><ul><li>Complicated Causes and Course </li></ul><ul><li>Like the others even more so….. </li></ul><ul><li>No new Treatment Approved in > 40 years </li></ul><ul><li>But there is one small population with lupus we can cure </li></ul>
Bioplex Units Six Lupus Patients with “Arthritis” IL10 IL8 IFN ALPHA TNF ALPHA HUMANS ARE NOT MICE
Adapted from: Ramanujam M, Davidson A. Arthritis Research and Therapy 2004; 197 Make inflammatory Proteins Activate other cells B IFN- T M Make antibodies D B1 INF alpha
Adapted from: Ramanujam M, Davidson A. Arthritis Research and Therapy 2004; 197 B IFN- T M Rituximab Ocrelizumab Epratuzumab Abatacept Lymphostat B, TACI Ig Riquent, Edritide TLR inhibitors INF alpha inhibitors D TNF inhibitors Cellcept, Aslera Anti IL6 IDEC 131 Biogen
T cell activation and decreased apoptosis Congenic Dissection of Lupus Pathogenesis B cell hyperactivity NZM2410 Lupus-prone Loss in immune tolerance to chromatin Mohan C, et al. J Clin Invest. 1998;101:1362-1372. Mohan et al., J. Immunology, 1998 NZM2410 B6 2 B6. Sle2 B6 strain Lupus-resistant 1 3 2 3 B6. Sle3 1 B6. Sle1
Re-assembly of Lupus Pathogenesis by various combinations of congenic intervals Re-assembly of congenic intervals >90% Fatal lupus ~ 15% Fatal lupus ~50% Fatal lupus 0% Fatal lupus Morel et al. PNAS 97:6670-6675, 2000 2 3 B6. Sle2 B6. Sle3 1 B6. Sle1 1 3 2 B6. Sle1,2,3 1 2 B6. Sle1,2 1 3 B6. Sle1,3 2 3 B6. Sle2,3
Lupus in People From Different Genetic Backgrounds: Risk is not Destiny
SLE Genes: Ethnic Differences GENE CAUC AFR references TNF alpha X Hum Immunol 65:622 16q12-13 X E J Hum Gen 12:668 12q24 X Am J Hum Gen 74:73 FcgRIIIa X Rheum (Ox) 42:446 FcgRIIa X J Clin Invest 95:1348 11p13 (discoid) X J Inv Derm Sym 9:64 NO synth prom X J Rheum 30:60 FasL 1q23 X J Immun 170:132
2008: From Genome to Gene Harley JB…. Langefeld CD Nature Genetics 40:152, 2008 ITGAM PXK KIAA1542 Whole Genome Scanning Hom G….Behrens T New England J of Med 358:900, 2008 C8orf13-BLK and ITGAM -ITGAX Whole Genome Scanning Nath S….Harley JB Nature Genetics 40:152, 2008 ITGAM Functional variant in integrin CR3 identified Kelly JA….Edberg JC IRF5 African Americans Kawasaki A…. Behrens T Arthritis Rheumatism 58:826, 2008 IRF5 Japanese Population
Pharmacogentics of Cyclophosphamide <ul><li>Cyclophosphamide is activated by cytochrome P450 (CYP) enzymes (genetic variants) </li></ul><ul><li>62 patients with proliferative nephritis </li></ul><ul><li>Relative risk of ovarian failure 0.10 with CYP2C19*2 (combined hetero/homozygous) </li></ul><ul><li>Increased risk of ESRF or doubled serum creat. </li></ul><ul><li>with CYP2B6*5 or CYP2C19*2 </li></ul>Takadak Arth Rheum 2004;50:2202
AZATHIOPRINE OPTIMIZATION <ul><li>Imuran (AZA) - derivative of 6-mercaptopurine </li></ul><ul><li>AZA metabolized in cells by thiopurine S-methyltransferase (TPMT) to active thiopurine nucleotides: genetic variants of TPMT differentiate response </li></ul><ul><ul><li>6-thioguanine ( 6-TG) (too low: AZA ineffective, too high: bone marrow suppression) </li></ul></ul><ul><ul><li>6-methylmercaptopurine ( 6-MMP) too high: hepatotoxicity </li></ul></ul><ul><ul><li>Appropriate level of 6-TG is associated with therapeutic effects in Inflammatory bowel disease </li></ul></ul><ul><li>Dubinsky. Gastroenterology 2000; 118:705 </li></ul>
Were any of these concepts applied to the clinical trials? Will the new biologic trials be more focused and strategic?
Many Faceted Disorder (even more than most) Many Causes for Each Symptom (more than most) Unpredictable Flares of Disease (more than most) Waxing and Waning Activity (more than most) Problems: Treatment Selection/Patient Selection/Timing of Selection Optimizing the Dose/Earlier Outcome Measures No approved treatments in > 40 years Outcome Measurement IS A CRISIS!!!! Poorly trained clinical trialists and we need MORE!!!! Impediments to Drug Development Specifically for Lupus
Focus on practical Need, based on a multi-disciplinary perspective from biotech, IT, academic, foundation partners Bring Basic Science Down the Hall to the Clinic Develop a More Sophisticated Immune Pharmacology Develop Individualized Medicine for a multi-faceted disease Pave the way for new approaches to other such diseases Bringing Down the Barriers to Treatment Development for Lupus
LFA PROGRAM Lupus Biomarkers Clinical Consortium Industry- Sponsored Trials Pharmaco- genomics Shared Community Data/Sample Resource SLICC and FLARE Biomarkers Lupus Foundation of America Bedside to Bench Patient Selection New Drugs Optimize Rx P t selection, guide Rx objective outcomes Improve Clinical Tools Education, International Site Development, Public Awareness, FDA, Govt Agencies,
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