Immunosuppressive Therapy in the Comprehensive Treatment of Type 1 Diabetes Mellitus in Children

The dissertation addresses the problem of applying immunosuppressive therapy in the comprehensive treatment of type 1 diabetes mellitus in children. Type 1 diabetes mellitus is considered a chronic autoimmune disease in which the destruction of β-cells of the islets of Langerhans occurs. Replacement therapy with exogenous insulin is not a pathogenetic treatment method and does not allow the avoidance of specific complications, which substantiates the relevance of searching for methods to achieve controlled remission of the disease.

The study investigated the effect of isolated methotrexate therapy at a dose of 10 mg/m² and combined methotrexate therapy with monoclonal antibodies against tumor necrosis factor α (infliximab) on the course of type 1 diabetes mellitus in children. The dynamics of residual insulin secretion based on C-peptide levels, changes in insulin requirements, the degree of disease compensation based on glycated hemoglobin levels, and quality of life were assessed. Three observation groups included patients receiving methotrexate, combined methotrexate and infliximab therapy, and a control group.

Type 1 diabetes mellitus (T1DM) is one of the most prevalent chronic endocrine diseases of childhood and adolescence. Its prevalence, the "younging" of the disease, early disability, and high mortality render diabetes mellitus a social disease. Modern endocrinology adheres to the position of replacement therapy with exogenous insulin, which is not a pathogenetic method of treating T1DM and does not allow the avoidance of specific complications of this disease. Such an approach fundamentally excludes the possibility of curing or preventing the development of T1DM. [16].

At present, it is generally accepted that T1DM is a chronic autoimmune disease in which the destruction of insulin-producing β-cells of the islets of Langerhans occurs [18]. Repeated attempts have been made at therapy of autoimmune insulitis using antioxidants, cytostatics, and anti-inflammatory agents; however, there are no reports of proven efficacy and safety of these therapeutic approaches. [17]. Therefore, the search for methods to achieve and maintain controlled remission of T1DM is extremely relevant.

It is known that the "gold standard" of treatment for such an autoimmune disease as rheumatoid arthritis is methotrexate at a dose of 10-15 mg/m² once weekly. The inefficacy of methotrexate at a dose of 5 mg/m² weekly in the comprehensive treatment of T1DM has been previously demonstrated; however, the use of methotrexate at higher doses has not been studied. [47].

All current models of autoimmune insulitis point to the key role of pro-inflammatory cytokines, such as interleukin-1 (IL-1), tumor necrosis factor α (TNFα), and interferon γ (IFNγ), in the destruction of β-cells. For this reason, the use of drugs that affect their functional activity and thereby reduce the aggressiveness of the autoimmune process appears highly attractive.

In animal experiments, positive results have been obtained in the treatment of autoimmune insulitis with antibodies against pro-inflammatory cytokines. The high efficacy of monoclonal antibodies (mAbs) against TNFα has been proven in such autoimmune diseases as rheumatoid arthritis and Crohn's disease, providing grounds for employing this type of therapy in T1DM [83, 26].

The most extensive and longest (over 10 years) experience in the use of antibodies against pro-inflammatory cytokines for the therapy of rheumatoid arthritis, Crohn's disease, and psoriasis has been accumulated with respect to the drug infliximab (Remicade, Schering-Plough).

Infliximab is a chimeric IgG1 mAb, consisting of 75% human protein and 25% murine protein. [71]. Infliximab binds to both soluble and membrane-associated TNFα and also inhibits many of the biological effects of TNFβ. These genetically engineered antibodies bind human TNFα with high affinity, avidity, and specificity. High specificity reduces the possibility of non-specific effects on other immunological mechanisms. Furthermore, in in vitro studies, it has been demonstrated that infliximab induces lysis of TNF-producing cells through complement fixation or antibody-dependent cellular cytotoxicity (ADCC). [111].

Data from certain placebo-controlled studies indicate that infliximab in combination with methotrexate is more effective (e.g., in patients with rheumatoid arthritis) than infliximab without methotrexate (presumably because methotrexate potentiates the action of infliximab). Moreover, according to several authors, during combined use of methotrexate and infliximab, there is a decrease in the likelihood of production of anti-chimeric antibodies against infliximab.

The present study is devoted to investigating the effect of isolated methotrexate therapy at a dose of 10 mg/m² and therapy with mAbs against TNFα (infliximab) in combination with methotrexate on the course of T1DM in children.

The aim of the present study is to improve the effectiveness of the comprehensive treatment of type 1 diabetes mellitus in children through the use of various forms of immunosuppressive therapy.

The research objectives were as follows:

1. To assess the dynamics of residual insulin secretion by pancreatic β-cells based on C-peptide levels during isolated methotrexate therapy at a dose of 10 mg/m² and during combined therapy with infliximab and methotrexate.

2. To evaluate the effectiveness of methotrexate therapy at a dose of 10 mg/m² and infliximab therapy in combination with methotrexate for T1DM based on changes in patients' insulin requirements.

3. To determine the influence of these forms of therapy on the degree of compensation of T1DM based on glycated hemoglobin (HbA1c) levels.

4. To assess the influence of these forms of therapy on the quality of life of patients with T1DM.

5. Based on the obtained data, to determine indications and contraindications for immunosuppressive therapy of T1DM.