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doctoral thesis
Povezanost polimorfizama gena za TNF-α s učinkovitošću terapije antagonistima TNF-α infliksimabom i adalimumabom i brzinom razvoja protutijela na te lijekove
Zagreb: University of Zagreb, Faculty of Pharmacy and Biochemistry, 2022. urn:nbn:hr:163:600855
Miler, Marijana
University of Zagreb
Faculty of Pharmacy and Biochemistry
Department of medical biochemistry and haematology

Institutional repository: Repository of Faculty of Pharmacy and Biochemistry University of Zagreb

Cite this document

Miler, M. (2022). Povezanost polimorfizama gena za TNF-α s učinkovitošću terapije antagonistima TNF-α infliksimabom i adalimumabom i brzinom razvoja protutijela na te lijekove (Doctoral thesis). Zagreb: University of Zagreb, Faculty of Pharmacy and Biochemistry. Retrieved from https://urn.nsk.hr/urn:nbn:hr:163:600855

Miler, Marijana. "Povezanost polimorfizama gena za TNF-α s učinkovitošću terapije antagonistima TNF-α infliksimabom i adalimumabom i brzinom razvoja protutijela na te lijekove." Doctoral thesis, University of Zagreb, Faculty of Pharmacy and Biochemistry, 2022. https://urn.nsk.hr/urn:nbn:hr:163:600855

Miler, Marijana. "Povezanost polimorfizama gena za TNF-α s učinkovitošću terapije antagonistima TNF-α infliksimabom i adalimumabom i brzinom razvoja protutijela na te lijekove." Doctoral thesis, University of Zagreb, Faculty of Pharmacy and Biochemistry, 2022. https://urn.nsk.hr/urn:nbn:hr:163:600855

Miler, M. (2022). 'Povezanost polimorfizama gena za TNF-α s učinkovitošću terapije antagonistima TNF-α infliksimabom i adalimumabom i brzinom razvoja protutijela na te lijekove', Doctoral thesis, University of Zagreb, Faculty of Pharmacy and Biochemistry, accessed 22 November 2024, https://urn.nsk.hr/urn:nbn:hr:163:600855

Miler M. Povezanost polimorfizama gena za TNF-α s učinkovitošću terapije antagonistima TNF-α infliksimabom i adalimumabom i brzinom razvoja protutijela na te lijekove [Doctoral thesis]. Zagreb: University of Zagreb, Faculty of Pharmacy and Biochemistry; 2022 [cited 2024 November 22] Available at: https://urn.nsk.hr/urn:nbn:hr:163:600855

M. Miler, "Povezanost polimorfizama gena za TNF-α s učinkovitošću terapije antagonistima TNF-α infliksimabom i adalimumabom i brzinom razvoja protutijela na te lijekove", Doctoral thesis, University of Zagreb, Faculty of Pharmacy and Biochemistry, Zagreb, 2022. Available at: https://urn.nsk.hr/urn:nbn:hr:163:600855

Metadata
TitlePovezanost polimorfizama gena za TNF-α s učinkovitošću terapije antagonistima TNF-α infliksimabom i adalimumabom i brzinom razvoja protutijela na te lijekove
Title (english)Association between TNF-α gene polymorphism and efficiency of therapy with the TNF-α antagonists infliximab and adalimumab and development of antibodies to those drugs
AuthorMarijana Miler
MentorNora Nikolac Gabaj (mentor)
MentorNada Vrkić (komentor)
Committee memberJerka Dumić (predsjednik povjerenstva)
Committee memberLidija Bach-Rojecky (član povjerenstva)
Committee memberMario Štefanović (član povjerenstva)
GranterUniversity of Zagreb
Faculty of Pharmacy and Biochemistry
(Department of medical biochemistry and haematology)
Zagreb
Defense date and country2022-06-02, Croatia
Scientific / art field,
discipline and subdiscipline		BIOMEDICINE AND HEALTHCARE
Pharmacy
Medical Biochemistry
Universal decimal classification
(UDC)		615 - Pharmacology. Therapeutics. Toxicology
Abstract
Antagonisti faktora nekroze tumora α (engl. Tumor Necrosis Factor, TNF-α) učinkoviti su u liječenju autoimunih reumatoidnih i upalnih bolesti crijeva, ali se čak u 30 % bolesnika ne postiže remisija bolesti. Cilj istraživanja bio je ispitati postoji li razlika u kliničkom i biokemijskom odgovoru na terapiju anti-TNF-α protutijelima ovisno o polimorfizmima gena TNF-α na položajima -238 G/A (rs361525) i - 308 G/A (rs1800629). U istraživanje je bilo uključeno 112 bolesnika od čega 66 s upalnim bolestima crijeva te 46 bolesnika s autoimunim reumatoidnim bolestima. Na terapiji infliksimabom (IFX) bilo je ukupno je 73 bolesnika, a 39 na terapiji adalimumabom (ADM). Bolesnici su praćeni 6 do 12 mjeseci od početka biološke terapije. Svim je bolesnicima određena koncentracija C reaktivnog proteina (CRP), lijekova IFX i ADM i protutijela na te lijekove kao i genotip polimorfizama rs361525 i rs1800629 gena TNF-α. Bolesnicima s upalnim bolestima crijeva određena je i koncentracija fekalnog kalprotektina (fKal), dok je onima s autoimunim reumatoidnim bolestima klinički odgovor praćen ocjenama aktivnosti reumatoidnih bolesti. Ni koncentracije IFX i ADM kao ni pojavnost i koncentracije protutijela na studirane lijekove nisu se razlikovale ovisno o genotipovima polimorfizama rs361525 i rs1800629 gena TNF-α. Koncentracija CRP nakon 12 mjeseci terapije bila je viša u bolesnika s genotipom GG nego u onih s genotipom GA na položaju -238 gena TNF-α, dok nije bilo razlike u koncentraciji CRP kod različitih genotipova na položaju -308 gena TNF-α. Koncentracija fKal nije se razlikovala ovisno o genotipu polimorfizama rs361525 i rs1800629 gena TNF-α. Remisija je postignuta kod 63 % bolesnika, neovisno o genotipu studiranih polimorfizama. Bolesnici s autoimunim reumatoidnim bolestima genotipa GG u oba ispitivana polimorfizma imali su statistički značajno bolji odgovor na terapiju u odnosu na bolesnike s genotipom GA ili AA. Univarijatnom regresijskom analizom pokazano je da je postizanje terapijske koncentracije IFX i ADM izglednije kod muškaraca, a pojava protutijela na lijekove manje izgledna. U bolesnika s RA izglednija je pojava protutijela na lijekove, a manje izgledno je postizanje terapijske koncentracije lijekova, dok kod ostalih bolesti univarijatnom regresijskom analizom nisu dobiveni statistički značajni omjeri izgleda. Remisiju bolesti može predvidjeti koncentracija CRP 6 i 12 mjeseci nakon terapije, dok se klinički odgovor na terapiju ne može predvidjeti ne temelju genotipa studiranih polimorfizama.
Abstract (english)
Tumor necrosis factor α (TNF-α) inhibitors are effective in the treatment of autoimmune rheumatoid disease (ARD) and inflammatory bowel diseases (IBD), but almost 30 % of patients do not achieve remission of the disease. Objectives of the study were to examine the association of genotypes of -238 G/A (rs361525) and -308 G/A (rs1800629) polymorphisms in TNF-α gene with the clinical and biochemical response to the therapy. The study included 112 patients, of which 66 with IBD and 46 patients with ARD. There was a total of 73 patients on infliximab (IFX) therapy and 39 on adalimumab (ADM) therapy. Patients were followed for 6 to 12 months from the start of biologic therapy. All patients were tested for reactive protein C (CRP), IFX and ADM, and antibodies to these drugs, as well as the genotype polymorphisms rs361525 and rs1800629 of the TNF-α gene. Patients with IBD were also tested for fecal calprotectin (fCal) levels, while those with ARD had a clinical response followed by assessments of rheumatoid disease activity. Concentrations of IFX and ADM after at least 6 months of therapy did not differ depending on genotypes TNF-α gene polymorphisms -238 G/A and -308 G/A. The incidence of antibody development, as well as the concentration of anti-drug antibodies, did not differ depending on tested polymorphisms. After 12 months of therapy, CRP concentration was higher in patients with GG than in patients with GA genotype in the -238 position of the TNF-α gene. fCal concentration did not differ depending on the studied polymorphisms. Remission was achieved in 63 % of patients, with no difference depending on the genotypes. Patients with ARD carrying the GG genotypes in both positions, -238 and -308, had a significantly better response to the therapy compared to patients with GA or AA genotypes. The univariate logistic regression analysis has shown that males are more likely to achieve therapeutic levels of IFX and ADM and less likely to develop antibodies to drugs. The studied polymorphisms were not factors that can predict the clinical response to the therapy. Genotyping of polymorphisms -238 G/A and -308 G/A in the TNF-α gene before the introduction of IFX and ADM therapy does not contribute to the prediction of clinical outcomes monitored by blood concentration of drugs and antibodies to the drugs, or clinical remission of IBD or ARD.
Keywords
Keywords (english)
Languagecroatian
URN:NBNurn:nbn:hr:163:600855
Promotion2022
Study programmeTitle: Pharmacy and biochemistry
Study programme type: university
Study level: postgraduate
Academic / professional title: doktor znanosti (doktor znanosti)
Type of resourceText
File originBorn digital
Access conditionsOpen access
Terms of useLicence In copyright icon
Created on2022-06-21 15:09:52