NLP SNP

Multiple Sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS), which is highly heterogeneous in terms of clinical symptoms, MS subtypes and treatment response. In each patient with MS, inflammatory, neurodegenerative and reparative processes are intermingled in different proportions, making the disease course unpredictable and the treatment approach challenging. Although MS etiology is still unclear, many studies have demonstrated that T and B cells are crucial cellular determinants of MS pathophysiological processes. Auto-reactive T lymphocytes have been also implicated in excitotoxic synaptopathy, an early hallmark of MS recently emerged to link inflammation and neurodegeneration in a complex and inter-regulated circuit. In addition, several reports published in the last few years show the presence of a link between metabolism and immune responses. Indeed, it is now clear that cell metabolism is able to control T cell survival, growth, activation and differentiation. It has been reported that distinct metabolic pathways are able to support specific T cell activities suggesting that the delicate balance among glycolysis, fatty acid oxidation (FAO) and mitochondrial respiration drives specific effector (Tconv) and regulatory T cell (Treg) differentiation and functions. The individual response to treatment varies widely and their use may be burdened by side effects and major adverse events. An explanation of the clinical and pharmacological individual variability can be sought in the pathological heterogeneity and in different genetic, immunological and metabolomics profiles. With this perspective, the lack of a single predictive or diagnostic test remains a great obstacle in the management of MS at most stages and in the choice of the therapy. Consequently, the availability of biomarkers that reliably capture the different aspects of the disease could be extremely useful.

NCT04121065 Relapsing Multiple Sclerosis Procedure: Blood withdrawal

MeSH:Multiple Sclerosis Sclerosis

In line with this, it has been recently identified an ADA genetic variant (rs244072, non-risk/risk allele: T/C) linked to brain inflammation and MS disease severity (article in preparation), by screening more than 50 SNPs in MS-related genes of 514 MS patients and looking for association with clinical and biochemical parameters.

The primary objective of the study is to evaluate the influence of the ADA SNP rs244072 (non-risk/risk allele: T/C) on lymphopenia induced by Cladribine (2-CdA) in real world setting in patients with relapsing multiple sclerosis (RMS).

Primary Outcomes

Description: Assessment of lymphopenia induced by oral Cladribine (2-CdA) treatment comparing the change in the number of pre-post treatment lymphocytes after oral Cladribine treatment at month 12 (compared with month 0), between two groups (associated with the genetic polymorphism of ADA). Changein the number of lymphocytes measured as number of cells per cubic millimeter (mm3), grades of lymphopenia will be assigned according to the common terminology criteria for adverse events: grade 1 (mild lymphopenia) ALC < lower limit of normal to 800/mm3, grade 2 (moderate lymphopenia) ALC < 800-500/mm3, and grade 3 (severe lymphopenia) ALC < 500-200/mm3.

Measure: 1. Evaluation of lymphopenia, measured by the number of lymphocytes per cubic millimeter (mm3) and associated to ADA polymorphism

Time: Month 0 enrollment compared to month 12; RMS patients

Secondary Outcomes

Description: To investigate the association between SNPs, gene expression and clinical parameters (Expanded Disability Status Score (EDSS), Kurtzke Functional System Score (KFS), 9-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW), Symbol Digit Modality Test (SDMT), Annualized Relapses Rate (ARR) and the Percentage of "No Evidence of Disease acitivity (NEDA)) at months 0, 6, 12 and 24. Statistical correlations of minor allele presence of each screened SNP with gene expression and/or the clinical parameters. The significance level is established at p<0.05.

Measure: Genotyping of SNPs and gene expression for correlation analysis with disease effectiveness of Cladribine treatment