Combined immunosuppressive therapy induces remission in patients with severe type B insulin resistance – a prospective cohort study

Objective: Type B insulin resistance due to autoantibodies against the insulin receptor is characterized by diabetes refractory to massive doses of insulin, severe hypercatabolism, hyperandrogenism and high mortality rate. We analyzed the efficacy of combined immunosuppressive therapy in the management of this extreme form of diabetes.
Research design and methods: We performed a prospective cohort study including patients with confirmed insulin receptor autoantibodies, followed for median 72 months (25th-75thIQR 25-88), treated with rituximab, high-dose pulsed steroids, and cyclophosphamide until remission, followed by maintenance therapy with azathioprine. Remission was defined as the amelioration of the hyperglycemia and discontinuation of insulin and/or normalization of hyperandrogenemia.
Results: All data are given as median [25th,75th centile]. Twenty-two patients aged 42 [25,57] years, 86.4% female, fulfilled inclusion criteria. At baseline, fasting glucose was 307 [203,398] mg/dl, HbA1c 11.8 [9.7,13.6] %, total testosterone (women) 126 [57,571] ng/dl (normal 8-60), daily insulin requirements 1775 [863,2700] units. After 5 [4,6.3] months, 86.4% of patients (19/22) achieved remission, documented by discontinuation of insulin in all patients, normal fasting glucose of 80 [76,92] mg/dl, HbA1c 5.5% [5.2,6] %, testosterone (women) 28 [20,47] ng/dl. During follow-up of 72 [25,88] months, 13.6% (3/22) of patients developed disease recurrence, occurring 24 [22,36] months after initial remission, which responded to repeated therapy. None of the patients died.
Conclusions: Combined immunosuppressive therapy has changed the natural history of this disease, from 54% mortality to a curable form of diabetes, and as such should be recommended in patients with type B insulin resistance