D2.363 - Immunologic Basis of Coexisting Slowly Progressive Insulin-Dependent Diabetes Mellitus (SPIDDM) and Generalized Myasthenia Gravis (MG)

     The coexistence of slowly progressive insulin-dependent diabetes mellitus (SPIDDM) and myasthenia gravis (MG) is extremely rare. Both conditions are autoimmune diseases, and overlapping HLA class II alleles together with Th1/Th17-dominant immune responses have been proposed as shared susceptibility factors［1,2,4].

     This descriptive study reports the clinical course of a 47-year-old male with concomitant SPIDDM and generalized MG. In March 2010, he presented with left ptosis and fatigue. Laboratory evaluation revealed marked hyperglycemia (plasma glucose 412 mg/dL, HbA1c 12%) and positive anti–glutamic acid decarboxylase antibodies (8.1 U/mL), leading to a diagnosis of SPIDDM [2]. Comorbidities included Helicobacter pylori–positive chronic atrophic gastritis, hyperuricemia, and visceral obesity. Basal–bolus insulin therapy was initiated.

     Subsequently, generalized MG was diagnosed based on elevated anti–acetylcholine receptor antibody titers (19 nmol/L) and electrophysiologic evidence of waning on repetitive nerve stimulation [1,3]. Immunosuppressive therapy with prednisolone and tacrolimus, in combination with pyridostigmine, was introduced, with careful insulin dose adjustment. Neuromuscular symptoms partially improved, while glycemic control was maintained using basal–bolus insulin and adjunctive oral therapy. During follow-up, anti-AChR antibody titers remained elevated (6–19 nmol/L), whereas GAD antibody titers stabilized around 8 U/mL.

     At the molecular level, MG is associated with specific HLA class II alleles, including DRB104–DQB103:02, DRB116–DQB105, and DRB103:01–DQB102:01, while SPIDDM  has been linked to DRB104:05–DQB104:01 and DRB109:01–DQB103:03. The partial overlap of these HLA class II susceptibility alleles suggests a shared autoimmune predisposition underlying the coexistence of both disorders [1][2]. In addition, Th1- and Th17-skewed immune responses have been implicated in the immunopathogenesis of both myasthenia gravis and autoimmune diabetes [4]. Experimental studies using Th17-deficient or combined Th1/Th17 knockout mouse models have demonstrated a marked reduction or delayed onset of experimental autoimmune myasthenia gravis and autoimmune diabetes, indicating that Th1/Th17-driven inflammation plays a critical role in the development and potential coexistence of these autoimmune conditions [5][6].

     This case demonstrates that SPIDDM and generalized MG can coexist in a middle-aged adult, likely mediated by overlapping HLA class II susceptibility and Th1/Th17-driven autoimmunity [1,2,4]. Recognition of this rare comorbidity is clinically important, as immunosuppressive therapy for MG may exacerbate hyperglycemia, requiring individualized and coordinated management strategies.

REFERENCES: 1)Ehsan S, et al. J Neurol Sci 2015;359:335–42. 2)Nishimura A. Diabetes Metab Syndr Obes 2019;12:2461–77. 3)Mishra AK, et al. Int J Mol Sci 2023;24:7670. 4)Li Y, et al. Mediators Inflamm 2015;2015:638470. 5)Madhok R, et al. Eur J Immunol 2015;45:1339–47. 6)Kuriya G, et al. Diabetes 2009;58:2060-8.