Refractory severe type B insulin resistance treated with daratumumab

Type B insulin resistance syndrome (TBIRS) is a rare autoimmune condition characterized by insulin receptor autoantibodies, often in association with systemic lupus erythematosus (SLE). It can cause extreme insulin resistance, with fewer than 200 cases described worldwide. A 24-year-old man with no prior autoimmune history presented with diabetic ketoacidosis and severe insulin resistance, requiring up to 215 000 units of insulin daily. Laboratory studies revealed high-titer antinuclear antibodies, hypocomplementemia, lupus-specific autoantibodies, and mesangial proliferative lupus nephritis, confirming new-onset SLE. His management was complicated by latent tuberculosis, neutropenia, and cyclophosphamide-induced hearing loss. Despite intensive therapy with corticosteroids, rituximab, cyclophosphamide, obinutuzumab, plasmapheresis, and intravenous immunoglobulin, he remained profoundly insulin resistant, requiring very high daily insulin doses, with persistently elevated insulin receptor antibody titers. Initiation of daratumumab, a CD38 monoclonal antibody, resulted in marked clinical improvement, with progressive decline in insulin requirements and eventual discontinuation of insulin 17 months after presentation. He achieved durable remission with normalization of hemoglobin A1c. This unusually severe case of TBIRS highlights the limitations of conventional B-cell-directed therapies, where long-lived plasma cells sustain pathogenic autoantibodies. Plasma cell-targeted strategies such as daratumumab may represent an effective therapeutic option in refractory cases.