Combined Etanercept, GAD-alum and vitamin D treatment: an open pilot trial to preserve beta cell function in recent onset type 1 diabetes.
C-peptide
Etanercept
GAD-alum
immune intervention
type 1 diabetes
vitamin D
Journal
Diabetes/metabolism research and reviews
ISSN: 1520-7560
Titre abrégé: Diabetes Metab Res Rev
Pays: England
ID NLM: 100883450
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
revised:
31
12
2020
received:
26
10
2020
accepted:
11
01
2021
pubmed:
25
1
2021
medline:
1
4
2022
entrez:
24
1
2021
Statut:
ppublish
Résumé
We aimed to study the feasibility and tolerability of a combination therapy consisting of glutamic acid decarboxylase (GAD-alum), Etanercept and vitamin D in children and adolescents with newly diagnosed with type 1 diabetes (T1D), and evaluate preservation of beta cell function. Etanercept Diamyd Combination Regimen is an open-labelled multi-centre study pilot trial which enrolled 20 GAD antibodies positive T1D patients (7 girls and 13 boys), aged (mean ±SD): 12.4 ± 2.3 (8.3-16.1) years, with a diabetes duration of 81.4 ± 22.1 days. Baseline fasting C-peptide was 0.24 ± 0.1 (0.10-0.35) nmol/l. The patients received Day 1-450 Vitamin D (Calciferol) 2000 U/d per os, Etanercept sc Day 1-90 0.8 mg/kg once a week and GAD-alum sc injections (20 μg, Diamyd™) Day 30 and 60. They were followed for 30 months. No treatment related serious adverse events were observed. After 6 months 90-min stimulated C-peptide had improved in 8/20 patients and C-peptide area under the curve (AUC) after Mixed Meal Tolerance Test in 5 patients, but declined thereafter, while HbA1c and insulin requirement remained close to baseline. Administration of Etanercept did not reduce tumour necrosis factor (TNF) spontaneous secretion from peripheral blood mononuclear cells, but rather GAD65-induced TNF-α increased. Spontaneous interleukin-17a secretion increased after the administration of Etanercept, and GAD65-induced cytokines and chemokines were also enhanced following 1 month of Etanercept administration. Combination therapy with parallel treatment with GAD-alum, Etanercept and vitamin D in children and adolescents with type 1 diabetes was feasible and tolerable but had no beneficial effects on the autoimmune process or beta cell function.
Substances chimiques
Alum Compounds
0
Insulin
0
Vitamin D
1406-16-2
aluminum sulfate
34S289N54E
Glutamate Decarboxylase
EC 4.1.1.15
Etanercept
OP401G7OJC
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3440Informations de copyright
© 2021 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.
Références
Bojestig M, Arnqvist HJ, Hermansson G, Karlberg BE, Ludvigsson J. Declining incidence of nephropathy in insulin-dependent diabetes mellitus. N Engl J Med. 1994;330(1):15-18. https://doi.org/10.1056/nejm.199401063300103.
Lind M, Svensson AM, Kosiborod M, et al. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med. 2014;371:1972-1982. https://doi.org/10.1056/NEJMoa1408214.
Madsbad S, Alberti KG, Binder C, et al. Role of residual insulin secretion in protecting against ketoacidosis in insulin-dependent diabetes. Br Med J. 1979;2:1257-1259. https://doi.org/10.1136/bmj.2.6200.1257.
Steffes MW, Sibley S, Jackson M, Thomas W. Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care. 2003;26(3):832-836. https://doi.org/10.2337/diacare.26.3.832.
Stiller CR, Laupacis A, Dupre J, et al. Cyclosporine for treatment of early type I diabetes: preliminary results. N Engl J Med. 1983;308(20):1226-1227.
Coutant R, Landais P, Rosilio M, et al. Low dose linomide in type I juvenile diabetes of recent onset: a randomized placebo-controlled double-blind trial. Diabetologia. 1998;41(9):1040-1046. https://doi.org/10.1007/s001250051028.
Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346(22):1692-1698. https://doi.org/10.1056/NEJMoa012864.
Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005;352(25):2598-2608. https://doi.org/10.1056/NEJMoa043980.
Sherry N, Hagopian W, Ludvigsson J, et al. Teplizumab for treatment of type 1 diabetes (Protege study): 1-year results from a randomized, placebo-controlled trial. Lancet. 2011;378(9790):487-497. https://doi.org/10.1016/S0140-6736(11)60931-8.
Hagopian W, Ferry RJ, Jr, Sherry N, et al. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled. Protégé Trial. Diabetes. 2013;62(11):3901-3908. https://doi.org/10.2337/db13-0236.
Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, et al. Type 1 diabetes trial Net anti-CD20 study group. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med. 2009;361(22):2143-2152. https://doi.org/10.1056/NEJMoa0904452.
Rigby MR, Harris KM, Pinckney A, et al. Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. J Clin Invest. 2015;125(8):3285-3296. https://doi.org/10.1172/JCI81722.
Haller MJ, Gitelman SE, Gottlieb PA, et al. Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes. J Clin Invest. 2015;125(1):448-455. https://doi.org/10.1172/JCI78492.
Ludvigsson J, Faresjo M, Hjorth M, et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med. 2008;359(18):1909-1920. https://doi.org/10.1056/NEJMoa0804328.
Wherrett DK, Bundy B, Becker DJ, et al. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet. 2011;378(9788):319-327. https://doi.org/10.1016/S0140-6736(11)60895-7.
Ludvigsson J, Krisky D, Casas R, et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med. 2012;366(5):433-442. https://doi.org/10.1056/nejm.oa1107096.
Tavira B, Cheramy M, Axelsson S, Åkerman L, Ludvigsson J, Casas R. Effect of simultaneous vaccination with H1N1 and GAD-alum on GAD65-induced immune response. Diabetologia. 2017;60:1276-1283. https://doi.org/10.1007/s00125-017-4263-x.
Ludvigsson J, Chéramy M, Axelsson S, Phil M, Åkerman L, Casas R. GAD-treatment of children and adolescents with recent-onset type 1 diabetes preserves residual insulin secretion after 30 months. Diabetes Metab Res Rev. 2013;30(5):405-414. https://doi.org/10.1002/dmrr.2503.
Beam CA, MacCallum C, Herold KC, Wherrett DK, Palmer J, Ludvigsson J. Type 1 Diabetes TrialNet Study Group. GAD vaccine reduces insulin loss in recently diagnosed type 1 diabetes: findings from a Bayesian meta-analysis. Diabetologia. 2017;60(1):43-49. https://doi.org/10.1007/s00125-016-4122-1.
Ludvigsson J, Routray I, Elluru S, et al. Combined vitamin D, ibuprofen and glutamic acid decarboxylase-alum treatment in recent onset Type I diabetes: lessons from the DIABGAD randomized pilot trial. Future Sce OA. 2020;6(7):FSO604. https://doi.org/10.2144/fsoa-2020-0078.
Piemonti L, Monti P, Sironi M, et al. Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol. 2000;164(9):4443-4451. https://doi.org/10.4049/jimmunol.164.9.4443.
Mathieu C, Gysemans C, Giulietti A, Bouillon R. Vitamin D and diabetes. Diabetologia. 2005;48:1247-1257. https://doi.org/10.1007/s00125-005-1802-7.
Mandrup-Poulsen T, Zumsteg U, Reimers J, et al. Involvement of interleukin 1 and interleukin 1 antagonist in pancreatic β- cell destruction in insulin-dependent diabetes mellitus. Cytokine. 1993;5(3):185-191. https://doi.org/10.1016/1043-4666(93)90003-N.
Argiles JM, Lopez-Soriano J, Lopez-Soriano FJ. Cytokines and diabetes: the final step? Involvement of TNF-α in both type I and II diabetes mellitus. Horm Metab Res. 1994;26(10):447-449. https://doi.org/10.1055/s-2007-1001730.
Weisman MH, Paulus HE, Burch FX, et al. A placebo-controlled, randomized, double-blinded study evaluating the safety of etanercept in patients with rheumatoid arthritis and concomitant comorbid diseases. Rheumatology. 2007;46(7):1122-1125. https://doi.org/10.1093/rheumatology/kem033.
Braun J, McHugh N, Singh A, Wajdula JS, Sato R. Improvement in patient-reported outcomes for patients with ankylosing spondylitis treated with etanercept 50 mg once- weekly and 25 mg twice-weekly. Rheumatology. 2007;46(6):999-1004. https://doi.org/10.1093/rheumatology/kem069.
Mastrandrea L, Yu J, Behrens T, et al. Etanercept treatment in children with new-onset type 1 diabetes: pilot randomized, placebo- controlled, double-blind study. Diabetes Care. 2009;32(7):1244-1249. https://doi.org/10.2337/dc09-0054.
Mortensen HB, Hougaard P, Swift P, et al. New definition for the partial remission in children and adolescents with type 1 diabetes. Diabetes Care. 2009;31(8):1384-1390. https://doi.org/10.2337/dc08-1987.
Tavira B, Barcenilla H, Wahlberg J, Achenbach P, Ludvigsson J, Casas R. Intralymphatic glutamic acid decarboxylase-alum administration induced Th2-like-spe cific immunomodulation in responder patients: a pilot clinical trial in type 1 diabetes. J Diabetes Res. 2018;2018:9391845. https://doi.org/10.1155/2018/9391845.
Zaba LC, Cardinale I, Gilleaudeau P, et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med. 2007;204(13):3183-3194. https://doi.org/10.1084/jem.20071094.
Aerts NE, De Knop KJ, Leysen J, et al. Increased IL-17 production by peripheral T helper cells after tumour necrosis factor blockade in rheumatoid arthritis is accompanied by inhibition of migration associated chemokine receptor expression. Rheumatology. 2010;49(12):2264-2272. https://doi.org/10.1093/rheumatology/keq224.
Bellemore SM, Nikoopour E, Krougly O, Lee-Chan E, Fouser LA, Singh B. Pathogenic T helper type 17 cells contribute to type 1 diabetes independently of interleukin-22. Clin Exp Immunol. 2015;183(3):380-388. https://doi.org/10.1111/cei.12735.
Abdel-Moneim A, Bakery HH, Allam G. The potential pathogenic role of IL-17/Th17 cells in both type 1 and type 2 diabetes mellitus. Biomed Pharmacother. 2018;101:287-292. https://doi.org/10.1016/j.biopha.2018.02.103.
Bradshaw EM, Raddassi K, Elyaman W, et al. Monocytes from patients with type 1 diabetes spontaneously secrete proinflammatory cytokines inducing Th17 cells. J Immunol. 2009;183(7):4432-4439. https://doi.org/10.4049/jimmunol.0900576.
Arif S, Moore F, Marks K, et al. Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated beta-cell death. Diabetes. 2011;60(8):2112-2119. https://doi.org/10.2337/db10-1643.
Kumar P, Natarajan K, Shanmugam N. High glucose driven expression of pro-inflammatory cytokine and chemokine genes in lymphocytes: molecular mechanisms of IL-17 family gene expression. Cell Signal. 2014;26(3):528-539. https://doi.org/10.1016/j.cellsig.2013.11.031.
Katz Y, Nadiv O, Beer Y. Interleukin-17 enhances tumor necrosis factor α-induced synthesis of interleukins 1, 6, and 8 in skin and synovial fibroblasts : a possible role as a “fine-tuning cytokine” in inflammation processes. Arthritis Rheum 2001;44(9):2176-2184. https://doi.org/10.1002/1529-0131(200109)44:9<2176::AID-ART371>3.0.CO;2-4.
Li Y, Liu Y, Chu CQ. Th17 cells in Type 1 diabetes: role in the pathogenesis and regulation by gut microbiome. Mediat Inflamm. 2015;2015:638470. https://doi.org/10.1155/2015/638470.
Axelsson S, Cheramy M, Åkerman L, Pihl M, Ludvigsson J, Casas R. Cellular and humoral immune responses in type 1 diabetic patients participating in a phase III GAD-alum intervention trial. Diabetes Care. 2013;36(11):3418-3424. https://doi.org/10.2337/dc12-2251.
Ludvigsson J, Carlsson A, Deli A, et al. Decline of C-peptide during the first year after diagnosis of Type 1 diabetes in children and adolescents. Diabetes Res Clin Pract. 2013;100(2):203-209. https://doi.org10.1016/j.diabres.2013.03.003.
Haller MJ, Wasserfall CH, McGrail KM, et al. Autologous umbilical cord blood transfusion in very young children with type 1 diabetes. Diabetes Care. 2009;32(11):2041-2046. https://doi.org/10.2337/dc09-0967.
Ludvigsson J, Tavira B, Casas R. More on intralymphatic injection of autoantigen in type 1 diabetes. N Engl J Med. 2017;377(4):403-405. https://doi.org/10.1056/nejm.c1703468.
Leslie RD, Jerram ST. Looking back and looking forward: a brief history of research into type 1 diabetes. Diabetes Metab Res Rev. 2019 Sep;35(6):e3196. https://doi.org/10.1002/dmrr.3196.