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Infliksimab (IFX) je spremenil način zdravljenja kronične vnetne črevesne bolezni (KVČB). Omogočil je doseganje globoke remisije in s tem zmanjšal potrebo po kirurških posegih, ki spremljajo napredovano bolezen. Ker pomemben delež bolnikov na zdravljenje ne odgovori ali kasneje odgovor izgubi, je smiselno iskanje novih pristopov za optimiziranje zdravljenja. Raziskave nakazujejo, da so pri nekaterih bolnikih za doseganje remisije potrebne višje serumske koncentracije IFX, zato bi lahko individualno prilagajanje odmerjanja na osnovi terapevtskega spremljanja koncentracij (TDM) vodilo k izboljšanju dolgoročnih kliničnih izidov zdravljenja. Namen naloge je bil ugotoviti, kako serumske koncentracije IFX korelirajo z učinkovitostjo in varnostjo zdravljenja KVČB ter kako korelirajo z biokemičnim označevalcem vnetja C-reaktivnim proteinom (CRP). Ugotavljali smo tudi, ali obstaja pražna serumska koncentracija IFX, s pomočjo katere bi lahko ločili med bolniki z aktivno boleznijo in bolniki v remisiji. Izvedli smo retrospektivno raziskavo, v katero smo vključili 164 bolnikov s KVČB, vodenih na Kliničnem oddelku za gastroenterologijo Univerzitetnega kliničnega centra Ljubljana, ki so med januarjem 2018 in oktobrom 2020 prejemali vzdrževalno farmakoterapijo z IFX. Njegovo odmerjanje je temeljilo na pristopu proaktivnega TDM, ki je omogočal individualno prilaganje odmerkov glede na sprotno določanje serumskih koncentracij IFX. Rezultati analize časa do prekinitve zdravljenja so bili spodbudni, saj je bila ukinitev IFX potrebna pri zgolj 18/164 (11,0 %) bolnikih, od katerih je 9 (5,5 %) bolnikov zdravljenje prekinilo zaradi izgube učinkovitosti, 9 bolnikov (5,5 %) pa zaradi varnostnih zapletov (okužbe, neželeni učinki na koži). Serumska koncentracija IFX ni imela statistično značilnega vpliva na ogroženost bolnika za ukinitev IFX zaradi izgube učinkovitosti (razmerje ogroženosti (HR): 0,973 95 % interval zaupanja (IZ): 0,806 – 1,174 p = 0,775), pojava okužbe (HR: 0,790 95 % IZ: 0,554 – 1,126 p = 0,192) ali neželenih učinkov na koži (HR: 0,961 95 % IZ: 0,766 – 1,206 p = 0,731). Negativno korelacijo med serumskimi koncentracijami IFX in CRP smo potrdili zgolj v zadnji časovni točki (ρ = – 0,354 p = 0,002). Ugotovili smo, da so imeli bolniki z nizkimi serumskimi koncentracijami IFX višjo mediano CRP vrednosti (7 mg/L interkvartilni razpon (IQR): 5 – 17 mg/L) kot bolniki s srednjimi (5 mg/L IQR: 5 – 34 mg/L) in visokimi (5 mg/L IQR: 5 – 26 mg/L) serumskimi koncentracijami IFX (p = 0,001). Ugotovili smo tudi, da so bolniki, ki so med vzdrževalnim zdravljenjem ohranjali visoke serumske koncentracije IFX, imeli po 24 mesecih raziskave večjo verjetnost za normalen CRP. Slednji so imeli bistveno višjo mediano serumske koncentracije IFX (8,7 µg/mL IQR: 4,4 – 24,0 µg/mL) kot bolniki s povišanim CRP (2,8 µg/mL IQR: 0,5 – 8,1 µg/mL) (p = 0,001). Optimalno pražno serumsko koncentracijo IFX ob začetku raziskave smo določili pri vrednosti 5,68 µg/mL, z 62,5 % občutljivostjo in 79,0 % specifičnostjo (ploščina pod ROC krivuljo: 0,720 95 % IZ: 0,492 – 0,947 p = 0,044). Bolniki, katerih serumske koncentracije IFX so bile ob začetku raziskave večje od 5,68 µg/mL, so imeli po 2 letih skoraj 3-krat večjo verjetnost za remisijo, kot bolniki, ki tega praga niso dosegli (pozitivno razmerje verjetja: 2,97). Infliximab (IFX) has changed the treatment of inflammatory bowel disease (IBD). It has made it possible to achieve deep remission and thereby reduced the need for surgical interventions associated with advanced disease. However, with a significant proportion of patients either not responding to treatment or experiencing a decline in its efficacy, exploring new approaches to optimize treatment is reasonable. Studies suggest that some patients require higher IFX serum concentrations to achieve remission, therefore individualized dosing adjustments based on therapeutic drug monitoring (TDM) could lead to improved long-term clinical outcomes. The aim of this study was to determine how IFX serum concentrations correlate with IBD treatment efficacy and safety and how they correlate with the biochemical inflammation marker C-reactive protein (CRP). We also investigated whether there is a threshold for IFX serum concentrations that could distinguish between patients with active disease and those in remission. We conducted a retrospective study that included 164 patients with IBD, managed at the Department of Gastroenterology University Medical Centre Ljubljana, who received maintenance pharmacotherapy with IFX between January 2018 and October 2020. Its dosing was based on proactive TDM approach with individualized dosage adjustments according to the continuous determination of IFX serum concentrations. The results of the time-to-treatment discontinuation analysis were encouraging, as only 18/164 (11,0 %) patients required IFX discontinuation, 9 (5,5 %) due to loss of efficacy and 9 (5,5 %) due to safety complications (infections, skin side effects). IFX serum concentration had no statistically significant effect on the risk of patients discontinuing treatment with IFX due to loss of efficacy (Hazard Ratio (HR): 0,973 95 % Confidence Interval (CI): 0,806 – 1,174 p = 0,775), infections (HR: 0,790 95 % CI: 0,554 – 1,126 p = 0,192) or skin side effects (HR: 0,961 95 % CI: 0,766 – 1,206 p = 0,731). We confirmed a negative correlation between IFX serum concentrations and CRP, but only at the final time point (ρ = – 0,354 p = 0,002). We found that patients with low IFX serum concentrations had higher median CRP levels (7 mg/L Interquartile Range (IQR): 5 – 17 mg/L) than patients with intermediate (5 mg/L IQR: 5 – 34 mg/L) and high (5 mg/L IQR: 5 – 26 mg/L) IFX serum concentrations (p = 0,001). We also found that patients who maintained high IFX serum concentrations during maintenance treatment, were more likely to have normal CRP after 24 months of the study. These patients had significantly higher median IFX serum concentrations (8,7 µg/mL IQR: 4,4 – 24,0 µg/mL) than patients with elevated CRP (2,8 µg/mL IQR: 0,5 – 8,1 µg/mL) (p = 0,001). The optimal threshold for IFX serum concentrations at the start of the study was determined at 5,68 µg/mL with a sensitivity of 62,5 % and a specificity of 79,0 % (Area Under the ROC Curve: 0,720 95 % CI: 0,492 – 0,947 p = 0,044). Patients whose IFX serum concentrations at the start of the study were greater than 5,68 µg/mL, were almost three times more likely to achieve remission after 2 years than patients who did not reach this threshold (positive likelihood ratio: 2,97). |
