Úvod: Přestože je infliximab (IFX) dosud „zlatým standardem“ biologické léčby Crohnovy nemoci (CN), jeho účinnost se může lišit v závislosti na mnoha faktorech. Jedním z nich je individuální reakce pacienta na lék. Významným klinickým problémem je imunogenicita IFX, kdy může až u 60 % léčených pacientů dojít k vývoji protilátek proti léčivu, což vede ke ztrátě odpovědi na léčbu a/nebo k nežádoucím reakcím na terapii. Od roku 2020 je k léčbě nemocných s CN k dispozici infliximab k subkutánnímu podání (IFX-SC), jehož farmakokinetika se vyznačuje stabilní a vysokou údolní koncentrací léčiva (TL – trough level) v krevním oběhu. Je možné, že jedním z důsledků této vlastnosti IFX-SC je jeho nižší míra imunogenicity. Předkládáme prospektivní studii sledování pacientů s diagnózou CN s velmi těžkým až refrakterním průběhem, kteří byli léčeni IFX-SC. Cílem studie bylo sledování imunogenicity IFX-SC včetně sledování dynamiky TL a protilátek proti léčivu (anti-IFX). Je popsána dynamika klinických, zobrazovacích a laboratorních markerů CN v průběhu jednoho roku sledování a léčby. Materiál a metodika: Do studie bylo zařazeno 23 pacientů s diagnózou CN s anamnézou selhání 2–6 předchozích linií biologické léčby, přičemž jednou z proběhlých terapií byl nitrožilní infliximab (IFX-IV). Pacienti byli rozděleni do dvou ramen indukční léčby na základě přítomnosti anti-IFX. Udržovací terapie představovala 120 mg s.c. ? 14 dní, v případě potřeby intenzifikace se jednalo o 240 mg s.c. ? 14 dní. Nemocní byli sledováni v týdnech (W – week) W0, W4, W14, W30 a W52, přičemž byly zaznamenány Harvey-Bradshawův index (HBI), sérová hladina C-reaktivního proteinu (CRP), fekální koncentrace kalprotektinu (FC), hladina léku (TL IFX) a anti-IFX. Dále bylo stanoveno endoskopické a ultrasonografické skóre nemoci (SES-CD a IUS) a u všech pacientů byl vyšetřen haplotyp HLA DQA1*05. Data byla analyzována pomocí softwaru MedCalc® s použitím neparametrických statistických metod a binární logistické regrese. Výsledky: U 13 z 23 pacientů (56,5 %) bylo zaznamenáno 52týdenní setrvání na léčbě IFX-SC se signifikantním poklesem všech sledovaných klinických, zobrazovacích i laboratorních markerů aktivity CN. V průběhu terapie došlo u 8 ze 16 vstupně anti-IFX pozitivních osob k sérokonverzi k negativním anti-IFX (50 %). Žádný z pacientů léčených IFX-SC ve W52 již nepotřeboval konkomitantní léčbu imunomodulátory. Během 52 týdnů terapie nebyla ve sledované kohortě zaznamenána ani jedna nová senzibilizace infliximabem. Závěr: Subkutánní cesta podání infliximabu může být vhodným a úspěšným řešením v situaci, kdy je žádoucí reindukce terapie infliximabem, a to včetně pacientů s přítomností neutralizujících protilátek proti léčivu.
Introduction: Despite infliximab (IFX) still being the “gold standard” of biological therapy for Crohn’s disease (CD), its effectiveness may vary depending on many factors. One of these factors is the individual patient’s reaction to the drug. A significant clinical problem is the immunogenicity of IFX, where up to 60% of treated patients may develop antibodies against the drug, leading to a loss of response to treatment and/or adverse reactions to therapy. Since 2020, subcutaneous infliximab (IFX-SC) has been available for treating CD patients, characterized by its stable and high trough level (TL) concentration in blood. It is possible that one consequence of this property of IFX-SC is its lower rate of immunogenicity. We present a prospective study of patients diagnosed with CD with severe to refractory courses, treated with IFX-SC. The aim of the study was to monitor the immunogenicity of IFX-SC, including the dynamics of TL and anti-drug antibodies (anti-IFX). The dynamics of clinical, imaging, and laboratory markers of CD over one year of monitoring and treatment are described. Materials and methods: The study included 23 patients diagnosed with CD who had failed 2 to 6 previous lines of biological therapy, one of which was intravenous infliximab (IFX-IV). Patients were divided into two arms of induction therapy based on the presence of anti-IFX. Maintenance therapy consisted of 120 mg s.c. every 14 days, and intensification was 240 mg s.c. every 14 days if necessary. Patients were monitored at weeks W0, W4, W14, W30, and W52, recording Harvey-Bradshaw Index (HBI), serum C-reactive protein (CRP), fecal calprotectin (FC) concentrations, drug trough levels (TL IFX) and serum anti-drug antibodies (anti-IFX). Endoscopic and ultrasonographic disease scores (SES-CD and IUS) were determined, and HLA DQA1*05 haplotype was examined in all patients. Data were analyzed using MedCalc® Statistical Software with non-parametric statistical methods and binary logistic regression. Results: 52-week persistence on IFX-SC treatment was recorded in 13 out of 23 patients (56.5%), with a significant decrease in all monitored clinical, imaging, and laboratory markers of CD activity. During the therapy, 8 out of 16 initially anti-IFX positive individuals seroconverted to negative anti-IFX (50%). None of the patients treated with IFX-SC in W52 needed concomitant immunomodulator treatment. No new sensitization to infliximab was recorded in the cohort during the 52-week therapy. Conclusion: The subcutaneous route of infliximab administration may be a suitable and successful solution in situations where reinduction of infliximab therapy is desired, including patients with the presence of neutralizing antibodies against the drug.
BACKGROUND: A subcutaneous formulation of infliximab (IFX-SC) approved to treat patients with inflammatory bowel disease may offer improved efficacy versus intravenous infliximab. METHODS: Patients with refractory Crohn's disease (CD, n = 32) previously treated unsuccessfully with at least 2 biologics were treated with IFX-SC and followed from baseline at Week 0 (W0) to Week 30 (W30). The study's primary endpoint was the treatment's persistence at W30, while secondary goals included the analysis of serum infliximab trough levels (TL IFX), dynamics of anti-IFX antibodies (ATIs), and clinical, serum and fecal markers of CD activity during IFX-SC treatment. RESULTS: Midterm treatment persistence with the continuation of treatment after W30 was 53%. TL IFX median values showed rapid, significant upward dynamics and exceeded 15.5 μg/mL at W30, whereas median ATI levels significantly declined. Among ATI-negative patients at W0 (n = 15), only one showed IFX immunogenicity with newly developed ATIs at W30. Among ATI-positive patients at W0, ATI seroconversion from ATI-positive to ATI-negative status was observed in 10 of 17 patients (58.8%). Patients who had continued IFX-SC treatment at W30 showed significant decreases in C-reactive protein (P = .0341), fecal calprotectin (P = .0002), and Harvey-Bradshaw index (P = .0029) since W0. CONCLUSIONS: Patients with refractory CD previously treated with at least 2 biologics exhibited clinically relevant improvement with IFX-SC, which showed less immunogenic potential than IFX-IV and highly stable TL IFX.
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BACKGROUND: Tumor necrosis factor-alpha (TNF-α) agonists revolutionized therapeutic algorithms in inflammatory bowel disease (IBD) management. However, approximately every third IBD patient does not respond to this therapy in the long term, which delays efficient control of the intestinal inflammation. METHODS: We analyzed the power of serum biomarkers to predict the failure of anti-TNF-α. We collected serum of 38 IBD patients at therapy prescription and 38 weeks later and analyzed them with relation to therapy response (no-, partial-, and full response). We used enzyme-linked immunosorbent assay to quantify 16 biomarkers related to gut barrier (intestinal fatty acid-binding protein, liver fatty acid-binding protein, trefoil factor 3, and interleukin (IL)-33), microbial translocation, immune system regulation (TNF-α, CD14, lipopolysaccharide-binding protein, mannan-binding lectin, IL-18, transforming growth factor-β1 (TGF-β1), osteoprotegerin (OPG), insulin-like growth factor 2 (IGF-2), endocrine-gland-derived vascular endothelial growth factor), and matrix metalloproteinase system (MMP-9, MMP-14, and tissue inhibitors of metalloproteinase-1). RESULTS: We found that future full-responders have different biomarker profiles than non-responders, while partial-responders cannot be distinguished from either group. When future non-responders were compared to responders, their baseline contained significantly more TGF-β1, less CD14, and increased level of MMP-9, and concentration of these factors could predict non-responders with high accuracy (AUC = 0.938). Interestingly, during the 38 weeks, levels of MMP-9 decreased in all patients, irrespective of the outcome, while OPG, IGF-2, and TGF-β1 were higher in non-responders compared to full-responders both at the beginning and the end of the treatment. CONCLUSIONS: The TGF-β1 and CD14 can distinguish non-responders from responders. The changes in biomarker dynamics during the therapy suggest that growth factors (such as OPG, IGF-2, and TGF-β) are not markedly influenced by the treatment and that anti-TNF-α therapy decreases MMP-9 without influencing the treatment outcome.
