New Therapeutic Perspectives in Type B Insulin Resistance Syndrome: Efficacy of a Multitarget Therapy With Obinutuzumab and Mycophenolate Mofetil in Two Patients With Insulin Receptor Autoantibodies and Systemic Lupus Erythematosus Free

Type B insulin resistance syndrome (TBIRS) is a rare autoimmune syndrome caused by anti–insulin receptor autoantibodies (AIRAs), typically leading to refractory hyperglycemia (1). With <200 reported cases, TBIRS is predominantly reported to affect middle-aged women of African descent and is associated with autoimmune disorders in half of the cases, most frequently systemic lupus erythematosus (SLE) (2). Typical clinical features include severe hyperglycemia requiring extremely high insulin doses as well as widespread acanthosis nigricans, weight loss, and hyperandrogenism, but hypoglycemia may also occur. While high-dose insulin therapy is needed as a symptomatic treatment, the curative approach relies on immunosuppressive treatments with variable effectiveness.

We report the efficacy of multitarget therapy using obinutuzumab (a humanized type II anti-CD20 monoclonal antibody) and mycophenolate mofetil (MMF) in two patients with SLE-associated TBIRS resistant to multiple immunosuppressive treatments.

An 18-year-old woman (patient 1 [P1]) and a 49-year-old man (patient 2 [P2]) were referred for newly diagnosed diabetes, with major hyperglycemia and ketosis resistant to high-dose insulin therapy, severe weight loss, and acanthosis nigricans. In both patients, type 1 diabetes–related autoantibodies and anti-insulin autoantibodies were negative and insulin secretion was increased (high C-peptide levels). Cortisol and insulin growth factor 1 levels were normal. The absence of lipoatrophy and the presence of signs indicating insulin receptor pathology (i.e., absence of hepatic steatosis, low-to-normal triglycerides, and normal adiponectin levels) ruled out the diagnosis of lipodystrophic syndrome (1). Concurrently, active SLE was diagnosed with the following symptoms: in P1, joint and hematological involvement, hypocomplementemia, and anti-nuclear, anti-Sm, and anti-RNP antibodies; in P2, skin (discoid lupus), joint, and hematological involvement, hypocomplementemia, and anti-nuclear, anti–double-stranded DNA (dsDNA), and anti-SSA antibodies. AIRAs were identified by demonstrating the ability of the serum of both patients to immunoprecipitate recombinant human insulin receptors (1). Major hyperglycemia persisted after 3 months of high-dose insulin therapy and combined immunosuppressive treatments: glucocorticoids 10–20 mg/day, hydroxychloroquine 400 mg/day, i.v. immunoglobulins 2 g/kg monthly, and then rituximab 1 g twice (day 1 and day 15) and MMF 2 g/day (Fig. 1). Due to incomplete B-cell depletion (P1 and P2) and immunization against rituximab documented in P1 by the presence of antidrug antibodies, treatment with obinutuzumab 1 g twice (day 1 and day 15) was added to MMF and hydroxychloroquine in both patients. Standard anti-infectious prophylaxis, including cotrimoxazole, vaccinations, and viral hepatitis screening, with corticosteroid premedication, antihistamines, and paracetamol plus close monitoring during administration to prevent adverse events, were implemented. This combination of treatments led to major metabolic efficacy, allowing cessation of insulin therapy within 4 and 1 months (P1 and P2, respectively), weight regain, major reduction in acanthosis nigricans, normalization of glucose and C-peptide levels, decrease in AIRAs and CD19 lymphocyte levels, and improvement of SLE biological markers, namely, C3 complement fraction (P1 and P2) and anti-dsDNA antibodies (P2) (Fig. 1). The clinical and biological benefit remained at 21 (P1) and 20 (P2) months of follow-up.

TBIRS is caused by polyclonal autoantibodies targeting the insulin receptor, which leads to insulin resistance with severe hyperglycemia and/or hypoglycemia due to dysregulation of insulin signaling (1). Several therapeutic options have been reported in the literature, each with varying efficacy, onset of action, and safety, including glucocorticoids, cyclophosphamide, plasmapheresis, azathioprine, rituximab, i.v. immunoglobulins, MMF, and cyclosporine (2,3). Spontaneous remission may occur, but a study of 22 patients showed that immunosuppressive combination therapy, compared with plasmapheresis or single-agent therapy, had higher remission rates, shorter remission time, and reduced mortality (2). Several cases reported MMF use with other drugs and additional therapy influenced by organ involvement, such as lupus nephritis. However, the effectiveness of MMF-based therapies for TBIRS remained unclear due to the use of variable strategies.

The choice of obinutuzumab for our two patients was justified by the presence of active systemic lupus, refractory hyperglycemia, and catabolic state despite high-dose insulin and a combination of immunosuppressants and documented immunization against rituximab in P1. In a randomized, placebo-controlled, phase 2 trial for lupus nephritis patients, obinutuzumab showed rapid and potent depletion of peripheral B cells without increasing serious adverse events (4). Moreover, obinutuzumab exhibited greater B-cell cytotoxicity and better natural killer cell activation than rituximab in SLE patients, and it was more effective in treating murine lupus nephritis (5). Although remission may occur spontaneously in 30% of TBIRS patients, the concurrence of a favorable metabolic response, decreased levels of SLE markers, and B-cell depletion supports the efficacy of obinutuzumab combined with MMF in our patients.

In conclusion, these observations illustrate, in two patients with refractory TBIRS associated with SLE, the effectiveness of obinutuzumab and MMF with a follow-up of 20 months. This could offer a therapeutic prospect in this rare but severe disease after further validation in a larger population.