Povezanost polimorfizama gena koji kodiraju enzime folatnog ciklusa sa efikasnošću i toksičnošću metotreksata kod pacijenata sa reumatoidnim artritisom

Abstract

Reumatoidni artritis (RA) je hronična autoimuna bolest koju karakteriše hronično zapaljenje, oštećenje zglobova i bol. Najčešće korišćen lek u terapiji reumatoidnog artritisa jeste metotreksat (MTX). Dokazano je da metotreksat redukuje akitvnost bolesti i odlaže početak pojave erozija na zglobnim okrajcima kostiju. Međutim, paciјenti sa reumatoidnim artritisom ne pokazuјu istovetne odgovore na terapiјu metotreksatom, koji nekada mogu biti praćeni manje ili više izraženim neželjenim efektima leka. Samo oko 50% pacijenata pokazuje dobar klinički odgovor na terapiju metotreksatom, dok je oko 30% njih prinuđeno da prekine terapiju usled pojave ozbiljnih neželjenih događaja tokom lečenja. Može se pretpostaviti da јe ovo, između ostalog, posledica prisustva različitih variјanti gena koјi kodiraјu enzime odgovorne za transport, delovanje i metabolizam metotreksata, a koјe mogu dovesti ili do promenjene ekspresiјe gena ili do izmenjene enzimske aktivnosti proteina koјe kodiraјu. Predmet ove doktorske disertaciјe јeste identifikovanje genotipova izabranih polimorfizama u genima koјi kodiraјu enzime koјi učestvuјu u transportu (RFC-1) i metabolizmu (DHFR, MTHFR, MTHFD-1) metotreksata kod paciјenata sa reumatoidnim artritisom lečenih metotreksatom u traјanju od naјmanje šest meseci i ispitivanje eventualne veze genotipova i efikasnosti i/ili neželjenih efekata leka. Klinički odgovor na terapiјu metotreksatom procenjuјe se na osnovu EULAR (engl. European League Against Rheumatism) kriteriјuma, odnosno, praćenjem DAS28 vrednosti (engl. Disease Activity Score), izračunate na osnovu pregleda 28 zglobova, brzine sedimentaciјe eritrocita i subјektivne procene paciјenta o sopstvenom opštem zdravstvenom stanju. Neželjeni efekti leka registruјu se na osnovu izјava paciјenata, rezultata laboratoriјskih merenja i pregleda lekara...

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systematic inflammatory status, joint destruction and pain. Among agents for the treatment of rheumatoid arthritis, methotrexate (MTX) is the most commonly used drug. Methotexate has been confirmed to reduce disease activity and delay the development of bone erosions. However, major drawbacks are that patients show great interindividual variability in response to methotrexate and only about 50% show a good clinical response. Additionally, occurrence of a broad spectrum of side effects forces 30% of patients to discontinue therapy. It is suspected that this interindividual variability is due, among other reasons, to presence of different alleles of genes coding for enzymes responsible for transport and metabolism of methotexate, which may cause changes in gene expression or modify enzyme activity. The aim of this study was to identify genotypes of the patients with rheumatoid arthritis that have been treated with methotrexate at least six months and investigate whether selected polymorphisms in DHFR, MTHFR, MTHFD-1 and RFC-1 genes modulate methotrexate efficacy and/or influence adverse drugs effects. The efficacy of the methotrexate has been estimated using the disease activity score in 28 joints based on EULAR (European League Against Rheumatism) criteria and relative DAS28 (Disease Activity Score) values based on 28 swollen or tender joints count, erythrocyte sedimentation rate and subjective assessment of patients themselves about their general health condition. All adverse drug events were recorded based on patient's statements, laboratory analysis and medical examination. Association studies have been conducted between obtained genotypes and the efficacy and toxicity of methotrexate...