VIROPHARM IBSA. Immunoterapia del Diabete di Tipo I Stato dell arte Corrado Betterle

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1 Immunoterapia del Diabete di Tipo I Stato dell arte Corrado Betterle Ai sensi dell art. 3.3 del Regolamento applicativo dell Accordo Stato- Regioni , dichiaro che negli ultimi due anni ho avuto i seguenti rapporti anche di finanziamento con i seguenti soggetti portatori di interessi commerciali in campo sanitario: VIROPHARM IBSA Unità Operativa di Endocrinologia Dipartimento di Scienze Mediche e Chirurgiche Azienda Ospedaliera-Universitaria PADOVA In fede, Corrado Betterle NATURAL HISTORY OF AUTOIMMUNE TYPE 1 DM GENETIC SUSCEPTIBILITY: (DR3/DR4,DQB1-nonAsp 57,DQA1-Arg 52 Insulin gene) Fattori che Influenzano la Storia Naturale delle Malattie Autoimmuni Organo-Specifiche HORMONAL FACTORS BETA-CELL FUNCTION 100% 50% 0% ENVIRONMENTAL FACTORS (virus, infectious, drugs, gluten, beef milk) POTENTIAL ANTIBODIES TO ENDOCRINE PANCREAS (non pathogenic) ICA-IgG,,, b, ZnT8Ab INSULITIS Cytotoxic T lymphocytes Loss of First Phase Insulin Responce to IVGTT BETA-CELL DAMAGE ACTIVE INSULITIS Pathologic OGTT SUBCLINICAL PRECIPITATING EVENTS (infections, drugs, stress) OVERT DISEASE HONEY-MOON PERIOD PHASES OF AUTOIMMUNE TYPE 1 DM CLINICAL Tipo ed entità dei fenomeni autoimmuni Volume e riserva funzionale dell organo bersaglio Resistenza individuale Meccanismi di rigenerazione specifici (TSH, ACTH, FSH, LH) Meccanismi di rigenerazione aspecifici Aumento delle richieste ormonali (stress, infezioni, interventi) Altri ancora ignoti

2 DIABETE MELLITO TIPO 1: LE COMPONENTI CELLULARI DM TIPO 1 di recente insorgenza: anatomia patologica CELLULE β CELLULE α CELLULE δ CELLULE PP insulite CD8+ Insula di DM di Tipo 1 all esordio:cellule α Insula di DM di Tipo 1 all esordio:cellule β IL2+ Immunofenotipo dell insulite Islet-cell antibodies (ICA) DM di Tipo 1 autoimmune: SISTEMI ANTIGENE- ANTICORPO AUTOANTICORPI ANTIGENI TARGET METODI DI DOSAGGIO Anti-Insula pancreatica (ICA) Sconosciuto IFI Anti-GAD () Decarbossilasi acido RIA/ELISA glutammico Anti-2 antigene insulare () Tirosina fosfatasi Anti-Insulina Insulina RIA Anti-ZnT8 ZnT8 RIA RIA/ELISA

3 II International Standardization Meeting of ICA Rotorua, (New Zealand,1987) DIABETE DI TIPO 1 ALL ESORDIO (154 casi) ANTICORPI ANTI-PANCREAS (ICA,,, b) Helga Gleichman Corrado Betterle GianFranco Bottazzo George Eisenbarth % Casi Totali F M <20 >20 anni DIABETE DI TIPO 1 ALL ESORDIO ANTICORPI ANTI-PANCREAS % ICA ICA < 20 anni (97 casi) ICA IA2 ICA % > 20 anni (57 casi) 10 0 ICA ICA ICA ICA IA2 ICA were present in 45% of patients with IDDM during the first 6 months of disease ICA were present in 8,9 % of the patients with N-IDDM

4 The Lancet 350: ;1997 Curve di Morbilità nei Familiari di 1 Grado dei Diabetici di Tipo 1 Sopravvivenza senza DM di Tipo (1 Ab) (2 Ab) 35% 16% 11% 9% % 40 (3 Ab) 20 (4 Ab) Anni di Follow up Eisenbarth Cumulative risk of Type 1 DM (%) No. of patients CUMULATIVE RISK OF TYPE 1 DM IN PADOVA AND UK AUTOIMMUNE ENDOCRINE PROSPECTIVE STUDY (Betterle et al, Ann N Y Acad Sci 958:271;2002) 3 Abs vs 2 Abs = P < (Log-rank test) Years of follow-up Abs 2 Abs 1 Ab Terapia delle malattie autoimmuni organo-specifiche MALATTIA CLINICA: SOSTITUTIVA tiroidite cronica = ormoni tiroidei diabete mellito di tipo 1 = insulina morbo di Addison = idrocortisone + fludrocortisone gastrite cronica = ferro per os anemia perniciosa = vitamina B12 i.m. diabete insipido = ADH deficit ipofisari = ormoni sostitutivi menopausa precoce = estroprogestinici ipogonadismi maschili = testosterone ipoparatiroidismo = calcio + vitamina D Bloccante morbo di Graves = farmaci anti-tiroidei Radiante = 131 Iodio Chirurgica = tiroidectomia Immunosoppressiva oculopatia endocrina = cortisone+radioterapia miastenia gravis = cortisone+immonosop. epatiti autoimmuni = cortisone+immonosop. Immunomodulante sclerosi multipla = IFNbeta1a Trapianto d organo diabete mellito di tipo 1 = pancreas cirrosi biliare primitiva = fegato Eliminazione fattori esogeni morbo celiaco = dieta priva di glutine MALATTIA SUBCLINICA: BLOCCO IN FASE PRECOCE (PREDIABETE O LADA) MALATTIA POTENZIALE: ELIMINAZIONE DEI FATTORI ESOGENI SCATENANTI

5 TERAPIA DEL DIABETE MELLITO DI TIPO 1 MALATTIA CLINICA: DM-1 ESORDIO SOSTITUTIVA. MALATTIA SUBCLINICA: Insulina IMMUNOSOPPRESSIVA? PREDIABETE O LADA BLOCCO IN FASE PRECOCE SOSTITUTIVA Insulina IMMUNOSOPPRESSIVA?. MALATTIA POTENZIALE: ELIMINAZIONE DEI FATTORI ESOGENI SCATENANTI Abs-positivi con IVGTT patologico blocco della malattia DM-1 (alla diagnosi): con approcci immunsoppressivi non-antigene specifici Ciclosporina A -Stiller 1984: 30 patients treated within 6 weeks of diagnosis, 16 became insulin independent with concentrations of plasma C-peptide in the normal range and decreasing titers of islet cell antibodies. -Assan 1985: 4/12 patients had a complete remission and the insulin needs of 4/12 were cut by half. The other 4 did not have remissions. Initial basal and glucagon-stimulated C peptide were higher in those who went into remission than in those who did not; they rose during cyclosporin treatment in the former but not in the latter. -Martin 1991: treatment with cyclosporin A for a mean of 13.8 months had no long-lasting effect on the course of Type 1 diabetes persisting beyond drug discontinuation. Azatioprina+steroidi -Silverstein 1988:10/20 patients completing the one-year trial had satisfactory metabolic state (as compared with only 15 percent of the controls.) 3/20 immunosuppressed patients, were insulin-independent at 1yr. Micofenolato+Anti-CD25 (Daclizumab) -Gottlieb 2010: Neither MMF alone nor MMF in combination with daclizumab had an effect on the loss of C- peptide in subjects with new-onset type 1 diabetes. Higher doses or more targeted immunotherapies may be needed to affect the autoimmune process. Bacille Calmette-Guerrain Faustan 2012: BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes. -Bjork 1994, Elliott 1998, Allen 1999: No effects Anti-CD3 (Teplizumab=anti-T totali) (Herold 2002, 2005, Sherry 2011) Herold 2002: the mean the mean area under the curve (AUC) for C-peptide level fell in the placebo group from nmol per liter at baseline to 66.7 nmol per liter at 12 months, a decline of approximately 50% per year, whereas it rose slightly in the treatment group, from nmol per liter to nmol per liter. At 12 months, the level of C peptide was 71% higher in patients receiving treatment than in those receiving placebo. Keymeulen 2005 Anti-CD20 (Rituximab=anti-immature and mature B-cells) Pescovitz 2009: between 3 and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab. Anti-TNF (Etanercept) Mastrandrea 2009 In this small pilot study, treatment of pediatric patients with newly diagnosed DM-1 with etanercept resulted in lower A1C and increased endogenous insulin production, suggesting preservation of beta-cell function. A larger study is needed to further explore safety and efficacy. Anti-CTLA-4 (Abatacept) Orban 2011: in a multicenter double-blind randomized controlled trial with recent onset DM-1, the drug was used at 1,14,28 days followed by monthly injections for 2 years. The treatment resulted in a delay of in C-peptide reduction after 10 months. A long follow up is necessary to known the behaviuor after cessation of treatment. Anti-IL-1(Anakinra Canakinumab) (Sumpter 2011, Moran 2013) Moran 2013 two multicentre, randomised, double-blind, placebo-controlled trials demonstrated that Canakinumab and Anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset DM-1.

6 Anti-CD3 (Teplizumab=anti-T totali)(herold 2002, 2005, Keymeulen 2005,Sherry 2011) Anti-CD20 (Rituximab=anti-immature and mature B-cells) Anti-TNF (Etanercept) Mastrandrea 2009 In this small pilot study, treatment of pediatric patients with newly diagnosed DM-1 with etanercept resulted in lower A1C and increased endogenous insulin production, suggesting preservation of beta-cell function. A larger study is needed to further explore safety and efficacy. Anti-CTLA-4 (Abatacept) Orban 2011: in a multicenter double-blind randomized controlled trial with recent onset DM-1, the drug was used at 1,14,28 days followed by monthly injections for 2 years. The treatment resulted in a delay of in C-peptide reduction after 10 months. A long follow up is necessary to known the behaviour after cessation of treatment. Anti-IL-1(Anakinra Canakinumab) (Sumpter 2011, Moran 2013) Moran 2013 two multicentre, randomised, double-blind, placebo-controlled trials demonstrated that Canakinumab and Anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset DM-1. DM-1 (alla diagnosi): con approcci immunsoppressivi antigene-specifici NICOTINAMIDE O NICOTINAMIDE + CICLOSPORINA Pozzilli 1994 One year after diagnosis 4/27 NCT treated, 2/25 NCT+CyA but 0/28 of the control patients were in remission (NCT vs control p= 0.05). Clinical remission lasted longer (7 +/- 3 SD months) in NCT treated patients than in NCT+CyA treated or control patients (p < 0.02). NICOTINAMIDE O NICOTINAMIDE + CORTISONE Pozzilli 1994 Group A (n = 18) received NCT for 1 year (25 mg.kg-1.day-1) plus deflazacort (DFL) for 3 months. Group B (n = 18) received NCT for 1 year (25 mg.kg-1.day-1) plus placebo for the first 3 months. All patients were treated with intensified insulin therapy. At the end of a 1-year follow-up, basal C-peptide did not differ between the two groups, although stimulated C-peptide was still significantly higher in patients of group A compared with group B (P < 0.05). Finally, insulin requirement did not differ between the two groups. VITAMIN D Gabbay subjects with DM-1 within 6 months from diagnosis and with preserved C-peptide were treated with Cholecalciferol 2,000 IU or placebo day for 18 months. In the treated group stimulated C-Peptide was better and the progression to undetectable C peptide was less as respect to controls. Cholecalciferol in addition to insulin is safe and associated with a protective immunological effect and a slow decline of residual B-cell function in patients with recent-onset DM-1. Anti-CD3 + insulina nasale Bresson 2006 in 2 murine diabetes models combining a systemic immune modulator with antigen-specific Treg induction is more efficacious in reverting diabetes. Since Tregs act site-specifically, this strategy should also be expected to reduce the potential for systemic side effects. GAD-Alume (Sottocute) (Ludvigsson 2008) vedi sotto

7 The Diabetes Prevention Trials type 1 (DPT-1) 1) NICOTINAMIDE 2) INSULINA 3) GAD-Alum 4) Anti-CD3 (Teplizumab) 5) Anti-CTLA4 (Abatacept) The Diabetes Prevention Trials type 1 (DPT-1) NICOTINAMIDE Elliott 1991: The selection criteria were age less than 16 years, islet cell antibody greater than or equal to 80 IUs, and first phase insulin release less than 5th percentile. All of eight untreated control subjects have developed diabetes, whereas only 1 of 14 treated children has diabetes to date. These data suggests that NCT has an effect in preventing Type 1 diabetes and that randomized controlled studies are now indicated. Deutche Nicotinamide intervention Trial (DENIT) Lampeter 1998: Individuals at high risk for developing IDDM by screening the siblings of patients with IDDM for the presence of high titer (>20 [JDF] U) islet cell antibodies. Treatment did not cause a major decrease or delay of diabetes development. The Diabetes Prevention Trials type 1 (DPT-1) INSULINA -SOTTOCUTE E POI E.V. (Skyler 2002) European Nicotinamide Diabetes Intervention Trial (ENDIT) Gale 2004 A double-blind placebo-controlled trial of NCT in 552 relatives with ICA levels of 20 JDF/U or more, and a non-diabetic oral glucose tolerance test. Participants were recruited from 18 European countries, Canada, and the USA, with nicotinamide (1.2 g/m2) or placebo for 5 years. There was no difference in the development of diabetes between the treatment groups. Of 159 participants who developed diabetes in the course of the trial, 82 were taking nicotinamide and 77 were on placebo. -

8 Skyler et al. N. Engl. J. Med. 346: ;2002 casi (testati x ICA) (ICA + >10 U/JDF) (3.7%) (sottoposti ad IVGTT) 339 (deficit della I A fase insulinica) Casi 169 Casi 170 Insulina sottocute 2 volte al dì (0,25U/Kg/dì) + e.v. 1 volta all anno (infusione continua per 4 dì) DM Tipo 1= 69 casi Osservazione senza terapia DM Tipo 1= 70 casi The Diabetes Prevention Trials type 1 (DPT-1) INSULINA -ORALE Skyler 2005: Annualized rate of diabetes was 6.4% with oral insulin and 8.2% with placebo (hazard ratio 0.764, P = 0.189). In a hypothesis-generating analysis of a subgroup with insulin autoantibody () levels confirmed (on two occasions) > or =80 nu/ml (n = 263), there was the suggestion of benefit: annualized diabetes rate 6.2% with oral insulin and 10.4% with placebo (0.566, P = 0.015). Oral insulin did not delay or prevent type 1 diabetes. -INTRANASALE Harrison individuals, median age 10.8 years, with to one or more antibodies pancreatic (insulin, GAD65, or IA2) were randomized to treatment with intranasal insulin (1.6 mg) or a carrier solution, daily for 10 days and then 2 days a week for 6 months, before crossover. Diabetes developed in 12 /38 (30%) participants with negligible-cell function at entry after a median of 1.1 year. Nanto-Salonen 2008: in a double-blind trial, we randomly assigned 224 infants and 40 siblings positive for two or more autoantibodies, in consecutive samples, to receive short-acting human insulin (1 unit/kg; n=115) or placebo (n=109) once a day intranasally. Diabetes was diagnosed in 49 index children receiving insulin, and in 47 with placebo (hazard ratio [HR] 1.14; 95% CI ). DIAPREV-IT with GAD-alum: Ongoing in children with multiple pancreatic autoantibodies ( PRIMARY PREVENTION Hydrolized cow s milk Trial to Reduce IDDM in the Genetically at Risk (TRIGR) Knipp 2010: demonstrated that supplementing breast milk with highly hydrolyzed milk formula reduces the appearance of the cumulative incidence of diabetes-associated autoantibodies in children but not the incidence of DM-1 at 10 years of follow-up. Removal of bovine Insulin from cow s milk Finnish Intervention Trial for the Prevention of Type 1 Diabetes (FINDIA) Ilonen 2011: demonstrated that weaning to an insulin-free formula reduced the cumulative incidence of autoantibodies by age three in children at genetic risk of DM-1. Vitamin D Wicklow 2006: Recent epidemiologic, immunologic, and NOD mouse studies suggest that intervention in the vitamin D system may be a successful method to prevent type 1 diabetes. Newborns at increased HLA risk are randomized to receive either 400 or 2000 IU vitamin D3 by 1 month of age. We show that recruitment of babies from the general population for identification of HLA-associated risk status followed by enrollment to a randomized controlled prevention trial is feasible in Canada. Gluten free diet in infancy (BABYDIET) Hummel 2011: Delaying gluten exposure until the age of 12 months is safe but does not substantially reduce the risk for islet autoimmunity in genetically at-risk children.

9 CONSIDERAZIONI FINALI 1 IL DM-1 è una malattia autoimmune T-mediata: All ESORDIO DELLA MALATTIA CLINICA: Molti degli approcci immunosoppressivi hanno sortito un certo effetto ma uno degli elementi fondamentali per la risposta si è dimostrato essere una discreta secrezione residua di peptide C. I trattamenti che hanno avuto un risultato debbono essere continuati a tempo indeterminato, perché altrimenti la malattia si ripresenta. Non ci sono vantaggi a diventare immunosoppressori-dipendenti rispetto ad essere insulino-dipendenti (anzi ci sono molti svantaggi). Per quanto riguarda la terapia con antigeni specifici, non ci sono stati risultati importanti né con l insulina (somministrata per varie vie) né con la GAD. D altro canto sinora per indurre una tolleranza immunitaria si sono utilizzati gli antigeni riconosciuti dagli autoanticorpi, ma noi non conosciamo ancora quali siano gli antigeni riconosciuti dai linfociti T infiltranti l insula. La loro identificazione potrebbe portarci a cercare di indurre una immunosoppressione specifica. CONSIDERAZIONI FINALI 2 PER QUANTI RIGURDA I SOGGETTI A RISCHIO: Siamo in grado oggi di predire con altissima probabilità la malattia nei famigliari di DM-1, nella popolazione scolare o nei pazienti con endocrinopatie autoimmuni mediante valutazioni immunologiche (ICA, GADab,, ) associate a test funzionali (IVGTT). Tuttavia non siamo in grado ancora di modificare la storia naturale della malattia né mediante l uso di immunosoppressori, di vitamine (Nicotinamide, Vitamina D) o di antigeni specifici (GAD, insulina). PER QUANTI RIGUARDA LA PREVENZIONE PRIMARIA Non sono stati identificati ad oggi fattori esogeni patogenetici capaci di indurre l inizio del processo autoimmune (e l eliminazione di quelli sospettati non ha dimostrato efficacia). IN CONCLUSIONE There is a cure and we will find it JDF Grazie per l attenzione

10 Pazienti con DM di di Tipo 1 Ciclosporina A (Stiller 1984, Feutren 1996) di recente insorgenza Azatioprina + steroidi (Silverstein 1988) Anti-CD3 (Herold 2002, Keymeulen 2005) Anti-CD3 + insulina nasale (Bresson 2006) Anti-CD3 + Glucagon-like peptide (Wajchenberg 2007) Decarbossilasi acido glutamico(gad)(ludvigsson 2008) Anti-CD20 (Rituximab) (Pescovitz 2009) Soggetti ad alto rischio Terapia intensiva insulina sottocute + insulina e.v. (Skyler 2002) Insulina per via nasale (Nanto-Salonen 2008) Nicotinamide (Gale 2004) Eliminazione del latte di mucca