Abstract
Cyclosporin and methotrexate administration induces remission of type 1 diabetes mellitus. Administration of high-dose cyclosporin (cyclo) has been demonstrated to induce remission of type 1 diabetes mellitus (T1D). Its usefulness was limited by its toxicity. Since methotrexate (mtx) and cyclo synergistically inhibit autoimmune processes, we postulated that low doses of cyclo and mtx could safely induce remission of T1D. In a pilot study, insulin dose requirements and glycemic control were compared in 10 new onset T1D control children with seven children who were administered cyclo at 7.5 mg/kg/day for 6 weeks and then 4 mg/kg/day in addition to mtx 5 mg/kg/wk for 1 year. After 6 weeks, cyclo doses were adjusted to maintain blood cyclo levels 110–220 ng/ml. All children were treated with two daily injections of insulin. Clinical and biochemical toxicity of drug therapy was assessed. There were only very minor adverse effects and no drug induced biochemical test abnormalities. Mean HbA1c levels were similar in the experimental and control groups at baseline and at 3, 6, and 9 months but was lower in the cyclo + mtx group at 12 months. Daily insulin requirements of the groups were similar at baseline but lower in the cyclo + mtx group at 3, 6, 9, and 12 months. Although no control subjects became non-insulin requiring, four of seven cyclo + mtx-treated subjects were entirely off insulin therapy for 2.5, 4.5, 8, and 12 months. Low-dose cyclo and mtx treatment of subjects with new onset T1D can safely induce remission of disease and decrease the amount of required insulin.
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References
Rabinowe SL, Eisenbarth GS (1984) Type I diabetes mellitus: a chronic autoimmune disease? Pediatr Clin North Am 31:531–543
Machnica L, Osior A, Jarosz-Chobot P, Deja G, Polanska J, Otto-Buczkowska E (2008) An analysis of the prevalence of thyroid autoantibodies:thyroid peroxidase and thyroglobulin antibodies in children with newly diagnosed diabetes mellitus type 1 during 20000–2004 in Upper Silesia region, Poland. Acta Diabetol 45:37–40
Elliott RB, Crossley JR, Berryman CC, James AG (1981) Partial preservation of pancreatic beta-cell function in children with diabetes. Lancet 2:1–4
Harrison LC, Colman PG, Dean B, Baxter R, Martin FIR (1985) Increase in remission rate in newly diagnosed type I diabetic subjects treated with azathioprine. Diabetes 34:1306–1308
Ludvigsson J, Heding L, Liedén G, Marner B, Lernmark A (1983) Plasmapharesis in the initial treatment of insulin-dependent diabetes mellitus in children. Br Med J 286:176–178
Jackson RA, Morris MA, Haynes BF, Eise nbarth GS (1974) Increased circulating Ia antigen-bearing T cells in type 1 diabetes mellitus. N Engl Med 306:785–788
Al-Kassab AS, Raziuddin S (1990) Immune activation and T cell subset abnormalities in circulation of patients with recently diagnosed type 1 diabetes mellitus. Clin Exp Imunol 81:267–271
Roep BO (2003) The role of T cells in the pathogenesis of type 1 diabetes from cause to cure. Diabetologia 46:305–321
Keymeulen B, Vandemeulebroucke E, Zieler A et al (2005) Insulin needs after CD3-antibody therapy in New-Onset Type 1 diabetes. New Eng J Med 352:2598–2608
Herold KC, Hagopian W, Auger JA et al (2002) Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346:1692–1698
Hollander GA, Bierer BE, Burakoff SJ (1994) Molecular and biological actions of cyclosporin A and FK506 on T cell development and function. Transfus Sci 15:207–220
Laupacis A, Gardell C, Dupre J et al (1983) Cyclosporin prevents diabetes in BB Wistar rats. Lancet 1:8314–8315
Mori Y, Suko M, Okudaira H et al (1986) Preventive effects of cyclosporin on diabetes in NOD mice. Diabetologia 29:244–247
Stiller CR, Dupré J, Gent M, Jenner MR, Keown PA, Laupacis A, Martell R, Rodger NW, Graffenried BV, Wolfe BMJ (1984) Effects of cyclosporin immunosuppression in insulin-dependent diabetes mellitus of recent onset. Science 223:1362–1367
Assan R, Debray-Sachs M, Laborie C, Chatenoud L, Feutren G, Quiniou-Debrie MC, Thomas G, Bach JF (1985) Metabolic and immunologic effects of cyclosporin in recently diagnosed type 1 diabetes mellitus. Lancet 1:67–71
The Canadian-European Randomized Control Trial Group (1988) Cyclosporin-induced remission of IDDM after early intervention. Association of 1 year of cyclosporin treatment with enhanced insulin secretion. Diabetes 37:1575–1582
Graeb C, Arbogast H, Guba M, Jauch KW, Land W (2004) Cyclosporine: 20 years of experience at the University of Munich. Transplant Proc 36(2 suppl):125S–129S
Cattaneo D, Perico N, Gaspari F, Remuzzi G (2004) Nephrotoxic aspects of cyclosporine. Transplant Proc 36:234S–239S
Weinblatt ME (1985) Toxicity of low dose methotrexate in rheumatoid arthritis. J Rheumatol 12(Suppl 2):35–39
Aydin F, Canturk T, Turanli AY (2006) Methotrexate and cyclosporin combination for the treatment of severe psoriasis. Clin Exp Dermatol 31:520–524
Sorror ML, Leisenring W, Deeg HJ, Martin PJ, Storb R (2005) Twenty-year follow-up in patients with aplastic anemia given marrow rafts from HLA-identical siblings and randomized to received methotrexate/cyclosporine or methotrexate alone for prevention of graft-versus-host disease (letter). Biol Blood Marrow Transplant 11:567–568
Tugwell P, Pincus T, Yocum D et al (1995) Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. Methotrexate-cyclosporin combination study group. N Engl J Med 33:137–141
Berth-Jones J (2005) The use of ciclosporin in psoriasis. J Dermatolog Treat 16:258–277
Walker SE, Ranatunga SK (2006) Rheumatoid arthritis: a review. Mo Med 103:539–544
Giannini EH, Brewer EJ, Kuzmina N, Shaikov A, Maximov A, Vorontsov I, Fink CW, Newman AJ, Cassidy JT, Zemel LS (1992) Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind, placebo-controlled trial. The pediatric rheumatology collaborative study group and the cooperative children’s study group. N Engl Med 326:1043–1049
Naldi L, Griffiths CE (2005) Traditional therapies in the management of moderate to severe chronic plaque psoriasis: an assessment of the benefit and risks. Br J Dermatol 152:597–615
Bougneres P-F, Landais P, Boisson C, Carel J-C, Frament N, Boitard C, Chaussain J-L, Bach J-F (1990) Limited duration of remission of insulin dependency in children with recent overt type 1 diabetes treated with low-dose cyclosporin. Diabetes 39:1264–1272
Stiller CR, Dupre J, Gent M, Heinrichs D, Jenner MR, Keown PA, Laupacis A, Martell R, Rodger NW, Wolfe BMJ, Mahon J (1987) Effects of cyclosporin in recent-onset juvenile type 1 diabetes: impact of age and duration of disease. J Pediatr 111:1069–1072
Rodriguez E, Delucci MA, Cano F, Valdebenito S, Castillo MC, Villegas R (2005) Comparison of cyclosporin concentrations 2 hours post-dose determined using 3 different methods and trough level in pediatric renal transplantation. Transplant Proc 37:3354–3357
Bergan S, Rugstad HE, Stokke O, Bentdal O, Froysaker T, Bergan A (1993) Cyclosporine A monitoring in patients with renal, cardiac, and liver transplants: a comparison between fluorescence polarization immunoassay and two different RIA methods. Scand J Clin Lab Invest 53:471–477
Feutren G, Assan R, Karsenty G, DuRostu H, Sirmai J, Papoz L, Vialettes B, Vexiau P, Rodier M, Lallemand A, Bach J-F (1986) Cyclosporine increases the rate and length of remissions in insulin-dependent diabetes of recent onset. Results of a multicentre double-blind trial. Lancet 2:119–123
Bougneres PF, Carel JC, Castano L, Boitard C, Gardin JP, Landais P, Hors J, Mihatsch MJ, Paillard M, Chaussain JL, Bach JF (1988) Factors associated with early remission of type 1 diabetes in children treated with cyclosporine. N Engl J Med 318:663–670
Feutren G (1988) Functional consequences of risk factors of chronic cyclosporine nephrotoxicity in type I diabetes trials. Transplant Proc 20:356–366
Mihatsch MJ, Belghiti D, Bohman SO, Porter K, Dubertret L, Fry L, Juhlin L, Zachariae H, Feutren G (1990) Kidney biopsies in control or cyclosporin A-treated psoriatic patients. Br J Dermatol 122(36):95–100
Miescher PA, Favre H, Chatelanat F, Mihatsch MJ (1987) Combined steroid-cyclosporin treatment of chronic autoimmune disease. Klin Wochenschr 65:727–736
Svarstad E, Helland S, Morken T, Bostad L, Myking A, Iversen BM, Ofstad J (1994) Renal effects of maintenance low-dose cyclosporin A treatment in psoriasis. Nephrol Dial Transplant 9:1462–1467
Anonymous (1987) The DCCT research group. Effects of age, duration and treatment of insulin-dependent diabetes mellitus on residual beta-cell function: observations during eligibility testing for the diabetes control and complications trial (DCCT). J Clin Endo Metab 65:30–36
Sherry NA, Tsai EB, Herold KC (2005) Natural history of β-cell function in type 1 diabetes. Diabetes 54:532–539
Assan R, Feutren G, Sirmai J, Laborie C, Boitard C, Vexiau P, Du Rostu H, Rodier M, Figoni M, Vague P et al (1990) Plasma C-peptide levels and clinical remissions in recent-onset type I diabetic patients treated with cyclosporin A and insulin. Diabetes 27:768–774
Dupre J, Stiller CR, Gent M, Donner A, von Graffenreid B, Murphy G, Heinrichs D, Jenner MR, Keown PA, Laupacis A, Mahon J, Martell R, Rodger NW, Wolfe BW (1988) Effects of immunosuppression with cyclosporine in insulin-dependent diabetes mellitus of recent onset. The Canadian open study of 44 months. Transplant Proceed 20(Suppl 4):184–192
Wahlstrom HE, Akimoto R, Endres D, Kolterman O, Moossa AR (1992) Recovery and hypersecretion of insulin and reversal of insulin resistance after withdrawal of short-term cyclosporine treatment. Transplantation 53:1190–1195
Assan R, Timsit J, Feutren G, Bougneres P, Czernichow P, Hannedouche T, Boitard C, Noel L-H, Mihatsch MJ, Bach J-F (1994) The kidney in cyclosporin A-treated diabetic patients: a long-term clinicopathological study. Clin Neph 41:41–49
Stiller personal communication
Buckingham BA, Sandborg CI (2000) A randomized trial of Methotrexate in newly diagnosed patients with type 1 diabetes mellitus. Clin Immunol 96:88–90
Acknowledgments
We wish to thank Nandita Mani and Larry Mitnaul for their technical assistance and Barbara Runner for her secretarial support. This work was funded, in part, by the Diabetes Research and Education Program at Georgetown University. This work was in part presented at the European Endocrinology Society in Budapest, Hungary 2007.
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Sobel, D.O., Henzke, A. & Abbassi, V. Cyclosporin and methotrexate therapy induces remission in type 1 diabetes mellitus. Acta Diabetol 47, 243–250 (2010). https://doi.org/10.1007/s00592-010-0188-2
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DOI: https://doi.org/10.1007/s00592-010-0188-2