Similarities and differences between multiple sclerosis and type 1 diabetes

Abstract Multiple sclerosis (MS) and type 1 diabetes (T1D) are chronic conditions that result from dysfunction of the immune system. Their common root in autoimmunity stimulates interest in the exploration of similarities and differences between the two diseases. Genetic susceptibility is relevant, creating a substrate, on which environmental factors act as a trigger of an aberrant immune response. Despite being both T‐cell mediated disorders with a strong involvement of the humoral arm, immunomodulation is a mainstay of MS management, whereas hormone replacement therapy remains the principal approach for T1D. T1D is usually diagnosed in children and adolescents, while MS is typical of young adults. This difference has implications for disease progression and treatment. The SARS‐CoV‐2 pandemic and its effect on immunity may affect the prevalence of these conditions, as well as their clinical manifestation.

DRB1*0405-DQA1*0501-DQB1*0301 and DRB1*0301-DQA1* 0501-DQB1*0201 haplotypes, which were found to increase the risk for both conditions. 4 Additionally, single nucleotide polymorphisms (SNPs) are believed to contribute to the genetic susceptibility for both diseases and an overlap between SNPs has been described.
Indeed, evidence from loci of susceptibility suggest that two out of seven SNPs (rs12708716 from the CLEC16A gene and rs763361 from the CD226 gene) known to be associated with T1D are also associated with MS (Table 1). These findings prove, on one hand, the polygenic modality of inheritance for both conditions and, on the other, suggest a common root for MS and T1D. 5 The genotype variability only partially explains the co-occurrence of MS and T1D, suggesting that other factors are also at play. 6 In fact, MS and T1D share some environmental factors that are thought to be involved in their pathogeneses. A latitudinal gradient is present for both conditions. Their increased prevalence away from the equator 7 suggests that vitamin D may be involved. 8,9 Viruses, such as Enterovirus (e.g., Coxsackievirus) in T1D and EBV in MS, are considered a possible trigger, leading to molecular mimicry in both conditions. 10

| IMMUNE PATHOPHYSIOLOGY AND TREATMENT
Regardless of the specific predisposing or triggering factors inducing the immune response, both MS and T1D are T-cell mediated F I G U R E 1 Similarities and differences between type 1 diabetes and multiple sclerosis. The middle row shows commonalities between the two conditions; differences or characteristics specific to one condition only are reported in the rows close to the each of the conditions. CSF, cerebrospinal fluid; CT, computed tomography; EBV, Epstein-Barr virus; GADA, glutamic acid decarboxylase antibody; HLA, human leucocyte antigen; IA-2A, islet antigen 2 autoantibody; IAA, insulin autoantibodies; MRI, magnetic resonance imaging; PP, primary progressive; RR, relapsing remitting; SP, secondary progressive; ZnT8A, zinc transporter 8 autoantibody T A B L E 1 Similarities and differences between MS and T1D in age, genetic loci, autoimmunity and treatment targets

Autoimmunity involvement T cells and oligoclonal bands (13) T cells and autoantibodies
are the staple of MS treatment, with several medications used to modulate the immune system by targeting its adaptive and humoral branches ( Table 1). A similar approach is being evaluated for the treatment of T1D. 15 For example, the CTLA4-Ig Abatacept, used in rheumatological conditions, 16 can preserve C-peptide levels and improve insulin sensitivity for a limited interval of time (i.e., 48 months). 17 Evidence from targeting B cells with an anti CD20 monoclonal antibody showed that a course of treatment can delay the fall of C-peptide by months. 18 Whereas anti CD 20 monoclonal antibodies are not commonly used in T1D, they are used in MS to achieve a reduction of disease activity and a delay of disease progression. 19

| AGE OF ONSET AND ITS IMPLICATIONS
The age of onset of T1D is normally earlier than MS and, in both conditions, can affect sex differences in the prevalence, disease course and prognosis. 20 whereas the incidence of T1D stabilises. 22 Unlike the female preponderance typical of adult onset MS, 23 in T1D, there is a slightly higher prevalence of males. 22 In POMS, the co-occurrence of the two diseases may have therapeutic implications for a personalised approach to therapy.
Indeed, POMS tends be actively inflamed, when compared to adult onset MS, and thus requires more aggressive immunotherapy 24 that may influence the immunological mechanisms contributing to T1D.
Currently, there are only a few immunomodulatory treatments approved for paediatric-onset MS 25 and thus the therapeutic implications of T1D and MS comorbidity remain to be explored.
Age has important implications also for the clinical evolution and therapeutic management of both conditions. An earlier age of MS onset is typically associated with a relapsing course and longer time to conversion to secondary progression. 26 In T1D, instead, an earlier diagnosis is associated with a higher risk of clinical progression 27  The immune response is an age dependent process that can affect response to treatment in both T1D and MS. A younger age at MS onset is associated with better response to immunomodulation because of a higher inflammatory activity. 23 Similarly, in newly diagnosed T1D, a short course with the anti-CD3 Teplizumab, leads to a preservation in C-peptide levels in the medium term and this effect is greater in younger patients. 29 Recent studies have shown that Teplizumab can improve and stabilise β cell function in antibody-positive high-risk individuals, therefore delaying the onset of T1D. 30

| MS AND T1D IN THE ERA OF THE SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-CoV-2) PANDEMIC
The

CONFLICTS OF INTEREST
The authors have no conflict of interest to report.

ETHICAL APPROVAL
For this article, Ethical Committee approval was not required.

AUTHOR CONTRIBUTION
Valeria Pozzilli, Eleonora Agata Grasso and Valentina Tomassini all contributed to manuscript preparation.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article, as no datasets were generated or analysed for this work.