Povezanost polimorfizama gena za TNF-α s učinkovitošću terapije antagonistima TNF-α infliksimabom i adalimumabom i brzinom razvoja protutijela na te lijekove

doctoral thesis

• 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
• Author: Marijana Miler
• Mentor: Nora Nikolac Gabaj (mentor)
• Mentor: Nada Vrkić (komentor)
• Committee member: Jerka Dumić (predsjednik povjerenstva)
• Committee member: Lidija Bach-Rojecky (član povjerenstva)
• Committee member: Mario Štefanović (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medical biochemistry and haematology); Zagreb
• Defense date and country: 2022-06-02, 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: adalimumab; infliksimab; polimorfizmi gena TNF-α; protutijela; autoimune reumatoidne bolesti; upalne bolesti crijeva; C reaktivni protein; fekalni kalprotektin
• Keywords (english): adalimumab; infliximab; polymorphisms in TNF-α gene; antibodies; autoimmune rheumatoid diseases; inflammatory bowel disease; C reactive protein; fecal calprotectin
• Language: croatian
• URN:NBN: urn:nbn:hr:163:600855
• Promotion: 2022
• Study programme: Title: Pharmacy and biochemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor znanosti (doktor znanosti)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2022-06-21 15:09:52