1 / 38

unibas.ch/itpbasel

Israel 2006. Update on Immunopathology, Immunomodulation and Clinical Research of Idiopathic Thrombocytopenic Purpura. Paul Imbach, University Children‘s Hospital Basel and Aarau, Switzerland. www.unibas.ch/itpbasel. 05/06 Imb. Idiopathic Thrombocytopenic Purpura ITP. Main Characteristics

gala
Download Presentation

unibas.ch/itpbasel

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Israel 2006 Update on Immunopathology, Immunomodulation and Clinical Research of Idiopathic Thrombocytopenic Purpura Paul Imbach, University Children‘s Hospital Basel and Aarau, Switzerland www.unibas.ch/itpbasel 05/06 Imb

  2. Idiopathic Thrombocytopenic Purpura ITP Main Characteristics Facts of Autoimmunity Model for Targeted Immunomodulation Clinical Presentation and Management Research 05/06 Imb

  3. Severe Bleeding Definition / Diagnosis of ITP • Bleeding • Isolated thrombocytopeniaplatelets < 150 x 109/L) • Otherwise healthy individual Partial recovery: No bleeding, platelet count > 10-30 x 109/L Animated 05/06 Imb

  4. Etiology of ITP Idiopathic … Etiology unknown - Research in Genetics Effect of single base change in regulatory region of a cytokine expression TGCATCGC or Alteration in Immune Response TGCGTCGC expression Cytokine promoter Chanock 2001;113:596 - Polymorphism of FcGammaRIIIB is high in children with chronic ITP Foster CB et al. Br J Haematol. 2001 Jun;113(3):596-9. - Inhibitory cytokine IL-4 and IL-10 polymorphisms are associated with chronic ITP. Wu KH et al.Br J Haematol. 2005 Mar;128(6):849-52. Animated 05/06 Imb

  5. Autoimmunity = Disturbances of the immune response Antigen Binding T-cell activation and cytokine signaling B-cell expansion and autoantibody production Activation of Phagocytosis/Complement Disregulation of Apoptosis Pathophysiology of ITP Immune response APC T B RES Animated 05/06 Imb

  6. IgG -Subclasses Facts of Autoimmunity in ITP 1950 Harrington et al 1965 Shulman et al ITP plasma factor is an IgG antibody Transient ITP after applications of ITP plasma to volunteers Animated 05/06 Imb

  7. 1987 McMillan et al Müller-E. et alAntigen-Antibody specific assays for platelet associated IgG Specificity 78-95% Sensitivity 46-66% Today: Flowcytometric, specific antibody measurement Facts of Autoimmunity in ITP 1982 Van Leeuwen et al.Autoantibodies against platelet specific glycoproteins 1975 Dixon et al IgG associated with platelet Animated 05/06 Imb

  8. Summary of Pathophysiology Immune response involvement APC T B RES Facts of Autoimmunity in ITP 1991 Semple et al CD-4+ T helper cell defect 05/06 Imb (modified from Semple W et al: Blood 78, 1991)

  9. Pilot study Increase of platelet count after pooled IgG transfusion from blood donors: key observation Imbach et al., Lancet 1981;1:1228-31 Randomised study Imbach et al., Lancet 1985;2:464-68 ITP as a model of targeted immunomodulation Animated 05/06 Imb

  10. 1984 Kazatchkine et al Disease-associated autoantibodies inhibited by IVIG 1989 Berchtold et al Anti-idiotypic antibodies in IVIG inhibit auto-antibody binding to platelet‘s glycoptoteins 2001 Stasi et al Platelet increase after B-cell depletion by monoclonal CD-20 antibody Summary of treatment experiences with rituximabin children and adults with refractory ITP Authors Number of patients Response rate n of patients Phase I/II Studies 85 56%* Wang et al. J Pediatr 2005 24 62%1 Bennet et alBlood 2006 36 31%*1,2 * Inclusion of patients with Evans Syndrome 1 Main side effect: Serum sickness 2 Initial response/primary outcome only Immunomodulation on B-cells and Autoantibodies Animated 05/06 Imb

  11. Clarkson et al Platelet increase after monoclonal anti-FcGammaR-antibodies 2001 Samuelsson et al Anti-inflammatory activity of IVIG mediated through inhibitory FcGammaRIIB Immunomodulation on Fc-Receptors 1982 Fehr et al1983 Salama et al Competitive inhibition of FcGamma receptors by Anti-D-loaded erythrocytes Animated 05/06 Imb

  12. Summary of Immunomodulation Immune response Examples Immunomodulation APC Antibiotics, Virostatics, IVIG Antigen suppression Inhibition of T cells and signaling Cyclosporin A, tacrolimus, IVIG T B Regulation of autoreactive B cells and antiidiotype network Anti-CD20/-CD52Antiidiotypic antibodies, IVIG Modulation of • Phagocytosis • Complement • Apoptosis Anti-D IgG, IVIG RES Animated 05/06 Imb

  13. 3 1 2 1 ITP, Kawasaki Syndrome, aGVHD, anti HLA 2 AIHA, ITP, ALPS • 3 Neuropathies: e.g. GBS, MS • Dermatologic disorderse.g. SJS, Pemphigus, … Documented Immunomodulation APC Regulation of Ag binding Inhibition of T-cells and signalling T B Regulation of autoreactive B-cells and antiidiotype network Modulation of • Phagocytosis • Complement • Apoptosis RES Animated 05/06 Imb

  14. Worldwide demand for polyvalent IVIG (tons) 1980-2005 provided by ZLB Behring, Bern • Today: • Plasmaproducts are safer (GMP) • Mechanism of action unclear • Lack of systematic dose finding studies 05/06 Imb

  15. Idiopathic Thrombocytopenic Purpura ITP Clinical Presentation and Management • Bleeding is fearful • Platelet counts tyrannize the patient 05/06 Imb

  16. Registry I, n = 2‘031 05/06 Imb

  17. Idiopathic Thrombocytopenic Purpura ITP Initial Bleeding ASPHO Abstract 2005

  18. Follow-up of ITP

  19. Idiopathic Thrombocytopenic Purpura ITP Registry I: Follow-up 6-12 months of 308 of 2‘031 children with ongoing ITP Percentage of platelet counts Pediatric Blood Cancer 2006;46:351-356.

  20. Management Staging and management recommendation of patients with ITP * modified from P Bolton-Maggs et al and G Buchanan et al Animated 05/06 Imb

  21. Management Treatment options in ITP • Standard treatment of ITP • Immunoglobulin: IV 0.4 – 0.8 g/kg bodyweight once • Anti-D-RhO-immunoglobulin: IV 0.5 µg/kg bodyweight per dose; maximum every 14 days • Corticosteroids: 4 mg/kg bodyweight/ d x 4 05/06 Imb

  22. Management 05/06 Imb

  23. Intercontinental Childhood ITP Study Group ICIS Mean plt ct x 109/L 26.6 8.0 13.3 8.1 Lancet 2001;358:2122-25 05/06 Imb

  24. Management Treatment options in ITP 05/06 Imb

  25. Management Treatment options in ITP 05/06 Imb

  26. Idiopathic Thrombocytopenic Purpura ITP Clinical Research Animated 05/06 Imb

  27. Retrospective Analyses in ITP Eden OB et al. Guidelines for management of idiopathic thrombocytopenic purpura: the British Paediatric Haematology Group. Arch Dis Child 1992;67:1056-58. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for The American Society of Hematology. Blood 1996;88:3-40. Bolton-Maggs P, Moon I. Assessment of UK practice for management of acute childhood idiopathic thrombocytopenic purpura against published guidelines. Lancet 1997;350:620-23. Vesely S, Buchanan GR, Cohen Am et al. Self-reported diagnostic and management strategies in childhood idiopathic thrombocytopenic purpura: results of a survey of practicing pediatric hematology/ oncology specialists. J Pediatr Hematol Oncol 2000;22:55-61. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in Adults, Children and in Pregnancy. BJ Haem 2003;120:574-596. 05/06 Imb

  28. Intercontinental Childhood ITP Study Group ICISwww.unibas.ch/itpbasel Prospective Analyses Registry I(closed) Registry II (closed) Splenectomy Registry(open) PARC-ITP Registry(open) 05/06 Imb

  29. Intercontinental Childhood ITP Study Group ICISwww.unibas.ch/itpbasel Cooperation of 219 physicians and 42 countries 05/06 Imb

  30. Intercontinental Childhood ITP Study GroupICIS Registry I: Participants Argentina:Blanca Diez, Hugo Donato, Regina Kohan, Armando Oscar Picon, Gabriela Sciuccati, Aurora Feliu Torres, Ana Maria de Galvagni, Cristin Rapetti, Buenos Aires. Monica Matus, Rosario. Australia:Chris Munt, Michael Rice, Harry Burnell, Richard Couper, Phil Egan, Ping Han, David Ketteridge, Richard Power, Ben Saxon, Heather Tapp, Geoff Thompson, Ian Toogood, Adelaide. Lydia Pitcher, Brisbane. Tony Israel, Modbury. Peter Downie, Henry Ekert, Parkville Victoria. Catherine Cole, Perth. Claire Dooley, Pt Augusta. Austria:Sonja Shukry-Schulz, Wien. Belarus:Tatjana Uglova, Minsk. Brazil:Liane Daudt, PortoAlegre. Bulgaria:Ilia Kalev, Kenderova Vesselina, Sofia. Canada:Mohan Pai, Hamilton. Michèle David, Montreal. Koon-Hung Luke, Ottawa. Victor Blanchette, Toronto. Bonnie Cham, David Eisenstat, Sara Israels, Patricia McCusker, Kent Stobart, Rochelle Yanofsky, Winnipeg. China:Jing Chen, Shanghai. Ren Chi Yang, Tianjin. Croatia:Miljenka Smokvina, Rijeka. Srdjana Culic, Split. Josip Konja, Zagreb. Czech Republic:Dagmar Pospisilova, Olomouc. Petr Smisek, Praha.Egypt:Mohsen Elalfy, Cairo. Germany:Ursula Schulte Overberg, Berlin. Carola Hasan, Bonn.Markus Roehnelt, Dominik Schneider, Düsseldorf. Charlotte Niemeyer, Freiburg. Thorsten Faust, Köln. Harald Schönhofen, Neunkirchen. Ruth Reil, Paderborn. Peters Ove, Regensburg. Greece:Sophie Aronis, Helen Platokouki, Athinai. Fany Athanassiadou, Thessaloniki. Hongkong:Godfrey Chan, Hongkong. Hungary:Pal Kajtar, Pecs. India:Gauri Kapoor, New Delhi. Iran:Mardawig Alebouyeh, Parvaneh Vossough, Tehran-Tajrish. Israel:Ariel Koren, Afula.Arnaldo Ducach, Ashkelon. Ayelet Ben-Barak, Ronit Elhasid, Sergey Postovsky, Evelyne Shabad, Haifa. Ami Ballin, Holon. Hannah Tamary, Petah Tikva.Dalia Sthoeger, Rehovot. Bella Bielorat, Hana Golan, Chaim Kaplinsky, Tel Hashomer. Italy:Giovanni Amendola, Castellamare. Elio Boeri, Giorgio Mori, Genova. Momcilo Jankovic, Monza. Luigi Esposito, Bruno Nobili, Napoli. Carlo Baronci, Giulio de Rossi, Roma. Ugo Ramenghi, Torino. Jamaica:Joye Taylor-Houston, Jennifer Thame, Gilian Wharfe, Kingston. Japan:Jun-ichi Akatsuka, Chiba. Haruhiko Eguchi, Toshiro Hara, Kamizono Junti, Fukuoka. Misako Iga, Rie Kanai, Izumo. Shoichi Koizumi, Kanazawa. Akira Shirahata, Kitakyusyu. Yoshiyuki Kosaka, Kobe. Kanako Arzie, Kohji Fujisawa, Yokho Takano, Komae. Hideaki Iyori, Mizuhiki Atsugi.Kojima Seiji, Nagoya. Takashi Arayama, Noda. Hiroshi Miyata, Osaka. Sumio Miyazaki, Saga. Isao Sekine, Seiichiro Takeshita, Saitama.Shigeru Tsuchiya, Sendai.Toshiji Shitara, Seta Gunma. Yoshifumi Kashii, Tochigi. Kensuke Aoki, Fumio Bessho, Kohmei Ida, Kyoko Iwasawa, Tsutoshi Morimoto, Tomohiro Morio, Hideo Mugishima, Hiroji Okawa, Naoya Sakaguchi, Hiroaki Shiihara, Tokyo. Nariyuki Aoyagi, Wakayama. Tetsuo Kawakami, Yonago. Korea:Chin Moo Kang, Heungsik Kim, Taegu.Sang Wook Choi, Seoul. Kyrgyztan:Chinara Mambetova, Bishkek. Malta:Simon Attard Montalto, Cecil Vella, Malta. Nigeria:Norah Olubunmi Akinola, Ile-Ilfe. Poland:Hanna Gazda, Krenke Katarzyna, Michal Matysiak, Edyta Niewiadomska, Warszawa.Grazyna Wrobel, Wroclaw. Portugal:Isabel Soares, Almada. Russia:Xenia Pshenichnaya, St. Petersburg. Slovakia:Elena Hostynova, Bratislava. Kamila Trebunova, Kosice. South Africa, Cyril Karabus, Rondebosch. Linda Wainwright, Soweto. Sweden:Per Bolme, Norrköping. Anders Aklin, Göran Elinder, Catharina Hanngren, Joachim Kramer, Stockholm. Switzerland:Regula Angst, Franziska Scherer, Aarau.Brigitte Scharrer, Chur. James Humbert, Pierre Wacker, Genève. Markus Schmugge, Zürich. The Netherlands:Rienk Tamminga, Groningen. Turkey:Mehmet Ertem, Ankara.Leyla Agaoglu, Capo Istanbul.Tung Bahattin, Isparta. UnitedKingdom:David Bareford, Birmingham. David Fielding, Chester. Elizabeth Chalmers, Brenda Gibson, Glasgow. Paula Bolton-Maggs, Liverpool. Irene Roberts, London. Carol Barton, Reading. Paul Revell, Stafford. Howard Davis, Welwyn Garden City.Rasieka Jayatunga, West Midlands. Dan Thompson, Luton Beds. USA:Laurence Boxer,Raymond Hutchinson, Laurence Boxer, Ann Arbor.Nejeme Alter, Judith Mullins, Michael Rytting, Corpus Christi. George Buchanan, Dallas. Narayan Shah, Darwille. Emmett Broxson, Mukund Dole, Leticia Valdez, Dayton. Kanta Bhambhani, Merlin Hamre, Adonis Lorenzana, Jeanne Lusher, Yaddanapudi Ravindranath, Hadi Sawaf, Indira Warrier, Detroit. Charles Brickner, Fairchild. Paul Bowman, Gretchen Eames, Timothy Griffin, Jeffrey Murray, Joann Sanders, Ami Shah, Fort Worth. Desiree Medeiros, Honolulu. Sharon Castellino, Johnson City. Michael Jeng, Memphis. Diane J. Nugent, Orange. Frank Shafer, Philadelphia.Judy Felgenhauer, Spokane. Dagmar Stein, Roger Vega, Toledo. Vietnam:Tran van Be, Ho Chi Minh City. Yugoslavia:Lidija Dokmanovic, Petar Ivanovski, Dragana Janic, Nada Jovanovic, Dejan Skoric, Branka Vasiljevic, Belgrade. Pediatric Blood Cancer 2006;46:354-356 05/06 Imb

  31. Intercontinental Childhood ITP Study Group ICIS: Registry I (n=2‘031) Lancet 2003 05/06 Imb

  32. Intercontinental Childhood ITP Study Group ICIS PARC-ITP Study Pediatric and Adult Intercontinental Registry on Chronic ITP Worldwide database - Prospective multicenter studywith side studies 05/06 Imb

  33. Intercontinental Childhood ITP Study Group ICIS Secondary ITP/other disorders Children and Adults with newly diagnosed ITP Long-term follow-up yearly Remission (plt ct > 150 x 109/L) Forms: • Initial form (initial diagnosis) • Follow-up form (6 months, 1 year, 2 years, etc.) On-line PARC database at www.parc-itp.net 05/06 Imb

  34. Intercontinental Childhood ITP Study Group ICIS PARC-ITP: Accruel June 2006

  35. Genetics / Single Nucleotide Polymorphisms Severe Bleeding HrQoL Refractory ITP Secondary ITP ITP during Pregnancy Intercontinental Childhood ITP Study Group ICIS PARC-ITP Study: Genetics Trees in the PARC Animated 05/06 Imb

  36. Intercontinental Childhood ITP Study Group ICIS PARC-ITP Study: Genetics • Aims • Identification of new genomic regions predisposing to or influencing the course of ITP • Analysis of genotype in a wide range of immune response genes www.unibas.ch/itpbasel 05/06 Imb

  37. Intercontinental Childhood ITP Study Group ICIS • The etiology of ITP is unknown. • The pathogenesis of ITP is autoimmune. • Since 1980 ITP serves as a model of therapeutic immunomodulation: firstly by the human IgG concentrate IVIG, later by T-, B-, FcR-modifiers. • Management according to staging of quality of life and bleeding • Global cooperation is necessary for evidence-based research as examplified by ICIS. • Genetic analysis may • - indicate predispositions- be a tool for prognosis and targeted management Summary 05/06 Imb

  38. ICIS Office Baselwww.unibas.ch/itpbasel P Imbach, J Rischewski, J Fong, C Martin, T Kühne

More Related