Pharmacogenomic impact of methylenetetrahydrofolate reductase gene polymorphism in juvenile idiopathic arthritis: 322.01 Paediatrics and neonatology: Summary of the PhD thesis in medical sciences

Abstract

Children with juvenile idiopathic arthritis are treated and monitored throughout their lives [1]. This chronic disease has an unclear genesis and, despite new discoveries in disease pathogenesis, its course remains unpredictable. In the last decade, several molecular and genetic pathways have been investigated, which may provide the basis for a model to predict therapeutic success and long-term disease remission [2,3]. Changes in the osteoarticular and immune system under conditions of high disease activity cause sequelae and disability in the child's growth process [4]. JIA, with onset at any age and of any type, has consequences for the physical and psycho-emotional status of both the child and the family. At the same time, depending on the degree of disability confirmed, treatment of the disease involves additional costs for care and social integration [5]. At the onset and during the acute phase of juvenile idiopathic arthritis, locomotor and associated psychosomatic functions are compromised. With the initiation of stepped disease-modifying therapy, these functions partially recover, after which patients with difficulty accept continued administration of these medications. As a result, patients return to the rheumatology unit to associate or escalate treatment to the next step, over time, quality of life is reduced, some children remain disabled and require daily care and attention. The subsequent therapeutic step is inherently the introduction of steroidal anti-inflammatory medication, which also carries a dual character, on the one hand relieving systemic manifestations, and on the other inducing long-term side effects [6]. Recovery of musculoskeletal function depends on the degree of disease activity, the form of the disease and the patient's therapeutic compliance. At present, significant progress has been made in identifying the mechanisms, which have an impact on the onset of disease remission and restoration of locomotor function in JIA. These are biomolecular pathways and genetic susceptibility, which are target factors involved in the acute phase of the disease. The term "genetic susceptibility" refers to structural changes within the genome that have occurred in-vivo over the course of the child's development in response to internal and external factors. Susceptibility implies that the structure of a particular gene influences the function of the protein it encodes and phenotypically expresses the positive or negative character of a state or action. For JIA, this susceptibility favours the ability to tailor individual medication selection to follow the Treat-to-Target concept. Genetic variations would favour the explanation of some intolerance phenomena in the recovery of patients with JIA. Currently, expression of metabolic factor genes, especially mutant ones, is hypothesized as potential prognostic markers of nonresponders to disease-modifying therapy in JIA [7]. A wide spectrum of genes are associated with response to glucocorticosteroid, methotrexate and biologic therapy. Thus, methylenetetrahydrofolate reductase (MTHFR), being part of the metabolic cycle of the folates, is involved in modulating the response to initial therapy with methotrexate [8–10]. MTHFR is well known as a thrombophilia gene, and is implicated in causing adverse pregnancy outcomes [11–13], as well as cardiovascular risk, which has been investigated mainly in adults [14,15], and, last but not least, in neuropsychiatric pathology [16]. Furthermore, there is limited evidence that MTHFR is a maternal risk factor for chromosomal abnormalities in the fetus [17]. MTHFR is not directly affected by MTX, but displays the next step in the dysfunction of the folate cycle after MTX binding to dihydrofolate reductase. Indeed, mutations in the gene of this enzyme increase the risk of abolished protein synthesis and elevate serum homocysteine levels [18]. To date, determining whether patients with or without mutation for the rs1801133 and rs1801131 variants of the MTHFR gene combined would have a worse outcome following MTX administration remains a contradictory scientific pursuit [19]. New evidence has shown that treatment response and toxicity are multifactorial and require validation as a comprehensive predictive model. The aim of this study was to assess the role of MTHFR gene polymorphisms as predictors of methotrexate efficacy and toxicity in idiopathic juvenile arthritis in order to develop recommendations for optimizing methotrexate treatment. Study objectives: 1. Determining the presence of mutations in the MTHFR gene in juvenile idiopathic arthritis. 2. Clinical evaluation of disease activity scores and methotrexate intolerance in juvenile idiopathic arthritis. 3. Evaluation of methotrexate liver toxicity in relation to the presence of MTHFR gene mutation in juvenile idiopathic arthritis. 4. Functional assessment of methotrexate cardiac toxicity in relation to the presence of MTHFR gene mutation in juvenile idiopathic arthritis. 5. Development of recommendations for genetic polymorphism testing in JIA. [...]