Title (srp)

Uticaj polimorfizama gena koji kodiraju adenozinske receptore na efikasnost i toksičnost monoterapije metotreksatom kod pacijenata sa reumatoidnim artritisom: doktorska disertacija

Author

Grk, Milka, 1987-, 23884391

Contributor

Jekić, Biljana, 1973-, 12858471
Cvjetićanin, Suzana, 1965-, 12682855
Ostojić, Predrag, 1973-, 7308647
Šupić, Gordana, 11972967

Description (eng)

Rheumatoid arthritis (RA) is a chronic, autoimmune disease that primarily affects synovial joints, leading to disability and premature death. Methotrexate (MTX) is the anchor treatment in RA. Via adenosine cycle enzymes inhibition, MTX leads to increased production and excretion of adenosine. Adenosine mediates its antiinflammatory effects by binding to adenosine receptors (ADOR). Polymorphisms within genes coding for adenosine pathway enzymes and ADOR could affect their expression and function, and consequently the outcome of MTX therapy. The aim of this doctoral dissertation was to assess the frequency of alleles and genotypes within ADORA2A (rs2298383, rs2236624, rs5751876, rs17004921), ADORA3 (rs2298191, rs1544223, rs3393) and ITPA (rs1127354) gene polymorphisms and their association with efficacy and toxicity of MTX monotherapy. Method: Our study included 127 RA patients on MTX monotherapy. MTX efficacy estimation was based on the changes in Disease activity score (DAS28) after 6 months of therapy, according to EULAR response criteria. Patients with good and moderate response were classified as ''responders'', while the patients with poor response were classified as ''nonresponders''. Adverse effects (AE) were collected during the six months follow-up period. Radiographic progression was based on the appearance of erosions on standard radiographic images of the hands and feet. Genotyping was performed using the KASP assays. Results: Among patients 112 (88.2%) were responders. We observed bone erosions in 82 (64.6%) of our patients. AE were reported in 31 patients (24.4%). We observed no association between analyzed individual polymorphisms and efficacy and toxicity of MTX. ADORA3 TAA haplotype was more frequent in patients with bone erosions (29% vs 15.6% p = 0.023), as well as in patients with hepatotoxicity (51.3% vs 21.6% p = 0.013). Conclusion: The results of our study suggest that haplotypes, rather than individual polymorphisms, could represent potential predictive biomarkers for response to MTX monotherapy in RA patients.

Description (srp)

Reumatoidni artritis (RA) je hronično, autoimunsko oboljenje sinovijalnih zglobova koje dovodi do invalidnosti i prerane smrti. Metotreksat (MTX) je zlatni standard u terapiji RA. Inhibicijom enzima adenozinskog ciklusa MTX povećava akumulaciju i izlučivanje adenozina, koji svoje antiinflamatorno dejstvo ostvaruje vezivanjem za adenozinske receptore (ADOR). Polimorfizmi u genima koji kodiraju enzime adenozinskog puta kao i ADOR mogli bi uticati na njihovu ekspresiju i funkciju, a posledično i na sam ishod terapije. Cilj ove doktorske disertacije bio je ispitivanje učestalost alala i genotipova polimorfizama ADORA2A gena (rs2298383, rs2236624, rs5751876, rs17004921), ADORA3 gena (rs2298191, rs1544223, rs3393) i ITPA gena (rs1127354), kao i njihove povezanosti sa efikasnošću i toksičnošću monoterapije MTXom. Metod: Naša studija je uključila 127 bolesnika sa RA koji su bili na monoterapiji MTXom. Efikasnost MTXa je procenjivana na osnovu EULAR kriteijuma koji se baziraju na promeni aktivnosti bolesti merene DAS28 indeksom nakon 6 meseci monoterapije. Oboleli sa dobrim i umerenim odgovorom su klasifikovani kao grupa bolesnika koja ,,pokazuju odgovor na terapiju’’, dok su oboleli bez odgovora činili grupu koja ,,ne pokazuju odgovor na terapiju’’. Neželjeni efekti (NE) su prikupljani tokom šestomesečnog praćenja bolesnika. Radiografska progresija bolesti se bazirala na praćenju pojave erozija na standardnim radiografskim snimcima šaka i stopala. Genotipizacija je izvedena primenom KASP eseja. Rezultati: Na terapiju je odgovor pokazalo 112 (88,2%) bolesnika. Erozije je razvilo 82 (64,6%) bolesnika. NE su bile prijavljene kod 31 (24,4%) bolesnika. Pojedinačni polimorfizmi nisu povezani sa efikasnošću i toksičnošću MTXa. ADORA3 TAA haplotip bio je češći kod obolelih sa erozijama kostiju (29% prema 15,6%, p = 0,023), kao i kod bolesnika sa hepatotoksičnošću (51,3% prema 21,6%, p = 0,013). Zaključak: Rezultati naše studije ukazuju da bi haplotipovi, pre nego pojedinačni polimorfizmi, mogli predstavljati potencijalne prediktivne biomarkere za odgovor na monoterapiju MTXom kod bolesnika sa RA.

Description (srp)

Medicina - Molekularna medicina / Medicine- Molecular medicine Datum odbrane: 05.07.2021.

Object languages

Serbian

Date

2021

Rights

Creative Commons License
This work is licensed under a
CC BY-NC-ND 2.0 AT - Creative Commons Attribution - Non-Commercial - No Derivative Works 2.0 Austria License.

CC BY-NC-ND 2.0 AT

http://creativecommons.org/licenses/by-nc-nd/2.0/at/

Subject

rheumatoid arthritis, methotrexate, polymorphism, adenosine receptors, haplotype

OSNO - Opšta sistematizacija nau?nih oblasti -- Medicina (29) -- Reumatologija (2935)

Identifiers