Citokini kot biološki označevalci imunske remisije pri bolnikih z juvenilnim idiopatskim artritisom

Morozova, Nataliia (author), Avčin, Tadej (mentor)

Namen dela: Namen raziskave je bil ugotoviti pomen in vlogo serumskih citokinov faktorja tumorske nekroze alfa (TNF-?) in interlevkina-6 (IL-6) kot bioloških označevalcev za spremljanje aktivnosti bolezni in kot napovednih dejavnikov za dolgoročni potek bolezni pri bolnikih z juvenilnim idiopatskim artritisom (JIA), zdravljenih z biološkimi zdravili. Preiskovanci in metode dela: Raziskava je bila zastavljena kot bidirekcionalna študija in je potekala od julija 2018 do vključno januarja 2021 na Pediatrični kliniki Univerzitetnega kliničnega centra Ljubljana. V raziskavo smo vključili 101 bolnikov z JIA (32 fantov in 69 deklic, povprečna starost 13,8 let), zdravljenih z biološkimi zdravili. Podatke smo zbrali retrospektivno za bolnike, ki so z biološko terapijo začeli pred julijem 2018 in prospektivno za bolnike, ki so z biološko terapijo pričeli od julija 2018 naprej. Aktivnost bolezni smo določali s kliničnimi in laboratorijskimi merili ter z mednarodno uveljavljenim merilom aktivnosti bolezni JADAS10 (angl. Juvenile Arthritis Disease Activity Score). Koncentracijo TNF-? in IL-6 v serumu smo določali pred uvedbo terapije z biološkimi zdravili in ob 6-mesečnih intervalih do največ 2,5 let po uvedbi terapije. Za bolnike iz retrospektivne skupine smo dodatne meritve izvajali ob daljših časovnih intervalih do 10 let po uvedbi terapije z biološkimi zdravili. Rezultati: V raziskavo smo vključili 101 bolnikov, od tega 43 bolnikov (42,6 %) z oligoartritisom, 55 (54,4 %) s poliartritisom in 3 bolnike (3,0 %) s sistemskim artritisom. Med potekom raziskave je bilo 60 bolnikov zdravljenih z etanerceptom, 53 z adalimumabom in 7 s tocilizumabom. Sedemdeset bolnikov je bilo na terapiji z biološkim zdravilom že pred pričetkom raziskave, pri 31 bolnikih pa smo zdravljenje z biološkimi zdravili uvedli na novo v času raziskave. Povprečna začetna serumska koncentracija TNF-? pred uvedbo terapije z etanerceptom je znašala 35,6 ± 32,8 pg/ml in je bila statistično značilno nižja kot vse nadaljnje določitve serumske koncentracije TNF-? med terapijo z etanerceptom. Povprečna začetna serumska koncentracija TNF-? pred terapijo z adalimumabom je znašala 36,3 ± 36,7 pg/ml in je bila statistično značilno nižja kot koncentracija TNF-? pri prvi (p=0,005) in drugi določitvi med spremljanjem (p=0,003). Povprečna začetna serumska koncentracija IL-6 pred uvedbo terapije s tocilizumabom je znašala 29,6 ± 14,3 pg/ml in je bila statistično značilno nižja od koncentracije IL-6 pri drugi določitvi med spremljanjem (p=0,033). Med začetno serumsko koncentracijo IL-6 in drugimi določitvami med spremljanjem ni bilo statistično značilnih razlik. Naša raziskava je z analizo serumske koncentracije TNF-? v povezavi z aktivnostjo bolezni pokazala, da so bile najvišje povprečne serumske koncentracije TNF-? prisotne pri bolnikih, zdravljenih z etanerceptom (123,2 pg/ml) in z nizko aktivnostjo bolezni, ter pri bolnikih, zdravljenih z adalimumabom (55,4 pg/ml) in z neaktivno boleznijo. Nasprotno smo najvišje serumske koncentracije IL-6 ugotovili pri bolnikih, zdravljenih s tocilizumabom in z aktivno boleznijo. Analiza povezanosti med serumsko koncentracijo TNF-? in aktivnostjo bolezni (JADAS10) pri bolnikih na terapiji z adalimumabom ali etanerceptom v celotni kohorti bolnikov z JIA je pokazala negativno in šibko korelacijo med serumsko koncentracijo TNF-? in JADAS10 (p=0,007), (r=0,177). Pri bolnikih, zdravljenih s tocilizumabom, smo med JADAS10 in serumsko koncentracijo IL-6 ugotovili srednjo močno povezanost (p=0,006), (r=0,448). Zaključek: Opravili smo eno izmed najbolj obsežnih pediatričnih raziskav z longitudinalnim sledenjem bolnikov, v kateri smo analizirali pomen in vlogo serumskih citokinov TNF-? in IL-6 kot bioloških označevalcev imunske remisije pri bolnikih z JIA, zdravljenih z biološkimi zdravili. V raziskavi smo ugotovili najvišje serumske koncentracije TNF-? pri bolnikih na terapiji z zaviralci TNF-? z nizko aktivnostjo bolezni. Omenjena najdba je presenetljiva in kaže, da serumski nivo TNF-? ne odraža vnetnega stanja bolezni, temveč nanj lahko vpliva spremenjena presnova v času zdravljenja in posledično podaljšan razpolovni čas TNF-? v serumu. Na podlagi rezultatov naše raziskave sklepamo, da določanje koncentracije TNF-? med zdravljenjem z zaviralci TNF-? ni zanesljiv označevalec za napoved uspešnosti zdravljenja z biološkimi zdravili ali tveganja za ponoven zagon bolezni. Nasprotno je bila serumska koncentracija IL-6 pri bolnikih z JIA, zdravljenih s tocilizumabom, povezana z visoko aktivnostjo bolezni in bi lahko predstavljala potencialni biološki označevalec imunske remisije pri bolnikih z JIA.

• Language: Slovenian
• Keywords: citokini, faktor tumorske nekroze alfa, interlevkin-6, etanercept, adalimumab, tocilizumab
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2025
• PID: 20.500.12556/RUL-167083
• Publication date in RUL: 07.02.2025

Secondary language

• Language: English
• Title: Cytokines as biomarkers of immunological remission in patients with juvenile idiopathic arthritis

Abstract

Objective: The aim of this study was to investigate the significance and the role of serum cytokines (TNF-α in IL-6) as biological markers for monitoring the disease activity of juvenile idiopathic arthritis (JIA) and as predictive factors of the long-term course of disease in patients treated with biological drugs. Patients and methods: We conducted a bidirectional cohort study between July 2018 and January 2021 at the University Children՚s Hospital Ljubljana. Our study included 101 patients with JIA (32 boys and 69 girls, mean age 13.8 years) treated with biological drugs. The data were collected retrospectively for patients who started with biological therapy before July 2018 and prospectively for patients who initiated biological therapy after July 2018. Disease activity was measured by clinical and laboratory measures, and by internationally established measure of disease activity JADAS10 (Juvenile Arthritis Disease Activity Score). The serum levels of TNF-α and IL-6 were determined at baseline before starting therapy with biological drugs and afterwards at 6-month intervals up to 2.5 years. Patients from the retrospective group had additional measurements at various longer time intervals up to 10 years after treatment initiation with biological drugs. Results: Out of 101 patients included in our study, 43 (42.6%) had oligoarticular, 55 (54.4%) polyarticular and 3 (3.0%) systemic disease. During the study, 60 patients were receiving etanercept, 53 adalimumab and 7 tocilizumab. Seventy patients were already taking biological drugs before the patient enrolment had started and 31 patients started taking biological therapy during the course of our study. The initial mean level of TNF-α before therapy with etanercept was 35.6 ± 32.8 pg/ml and was significantly lower compared to all subsequent determinations of TNF-α during the therapy with etanercept. The initial mean level of TNF-α before therapy with adalimumab was 36.3 ± 36.7 pg/ml and was significantly lower compared to TNF-α level at the 1st (p=0.005) and 2nd follow-up measurement (p=0.003). The initial mean level of IL-6 before therapy with tocilizumab was 29.6 ± 14.3 pg/ml and was significantly lower compared to IL-6 level at the 2nd follow-up measurement (p=0.033). There were no statistically significant differences between the baseline level of IL-6 and any of the follow-up measurements. The analysis of serum levels of TNF-α in relation to disease activity showed the highest mean serum levels of TNF-α in patients treated with etanercept (123.2 pg/ml) who had low disease activity, and in patients treated with adalimumab (55.4 pg/ml) who had inactive disease. On the contrary, the highest serum levels of IL-6 were observed in patients treated with tocilizumab who had active disease states. The correlation analysis between serum levels of TNF-α and disease activity (JADAS10) in patients treated with adalimumab or etanercept from the total cohort of JIA patients showed a weak negative correlation between serum levels of TNF-α and JADAS10 (p=0.007), (r=0.177). The correlation analysis between serum levels of IL-6 and JADAS10 revealed a moderate positive correlation (p=0.006), (r=0.448). Conclusion: We conducted one of the most comprehensive pediatric studies with longitudinal follow-ups of patients, in which we analysed the role of serum cytokines TNF-α and IL-6 as biomarkers of immunological remission in patients with JIA treated with biological drugs. The highest mean serum levels of TNF-α were observed in JIA patients treated with biological drugs who had low disease activity. This finding was unexpected and suggested that the serum level of TNF-α does not reflect the inflammatory state of disease, but may be influenced by altered metabolism during the treatment and, consequently, by extended half-life of TNF-α in the serum. Based on the results of our study we suggest that determining serum levels of TNF-α during the treatment with TNF-α inhibitors is not a reliable biomarker of predicting treatment success with biological drugs or the risk of relapsed disease. On the contrary, the serum levels of IL-6 in patients with JIA treated with tocilizumab were associated with high disease activity and may represent a potential biomarker of immunological remission in patients with JIA.

• Keywords: cytokines, tumor necrosis factor alpha, interleukin-6, etanercept, adalimumab, tocilizumab