Although, high doses of cyclosporine (cyclo)has been demonstrated to inhibit the development of type 1diabetes mellitus (T1D), its usefulness was limited by its toxicity. Since methotrexate (Mtx) and cyclo have been shown to synergistically act in other disease processes, we determined if low dose cyclo and Mtx therapy could inhibit the development of diabetes and reduce or eliminate the need for insulin therapy in a pilot study.
Methods: Insulin dose and glycemic control were compared in 7 children (mean age 13.7 year) with new onset T1D who were administered cyclo at 7.5 mg/kg/day for 6 weeks and then 4 mg/kg/day and Mtx 5 mg/kg/day for one year and in 10 newly diagnosed diabetic control children (mean age 12.5 year). After 6 weeks, cyclo doses were adjusted to maintain blood cyclo levels 100200 ng/ml. All children were treated with two daily doses of NPH and fast acting insulin. Clinical and biochemical toxicity of drug therapy was assessed. The study was approved by the Institutional Review Board.
Results: There were two episodes of mild mucositis which required transient lowering of the Mtx dose and one case of transient mild elevation of bilirubin. There were no abnormalities in other liver function tests, creatinine, BUN, or CBC. Mean HbA1c levels were similar in the experimental and control groups at baseline (12.6% vs 11.5%) and at 3, 6, 9, and 12 months. Daily Insulin requirements of the groups were similar at baseline. However the mean insulin dose (u/kg) at 3, 6, 9, and 12 months were significantly (P<0.001) lower in the experimental group (0.14 vs 0.56 at 3 months, 0.12 vs 0.61 at 6 months, 0.16 vs 0.55 at 9 months, and 0.22 vs 0.71 at 12 months). No control subjects became non-insulin requiring. However 4 of 7 experimental drug treated subjects were entirely off insulin therapy for 2.5, 4.5, 7 and 12 months. While off insulin therapy, the HbA1c levels of 3 of the 4 subjects were normal. The other subjects HbA1c was only mildly elevated at 6.7%. In conclusion. low dose cyclosporine and MTX treatment of subjects with new onset T1D can safely induce remission of disease and decrease the amount of required insulin.