Factors Associated with the Immunogenicity of Anti-Tumor Necrosis Factor Agents in Pediatric Patients with Inflammatory Bowel Disease
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background/Aims: Anti-drug antibodies (ADAs) can develop during treatment with anti-tumor necrosis factor (TNF) agents. We aimed to investigate the factors associated with immunogenicity of anti-TNF agents in pediatric patients with inflammatory bowel disease (IBD) and observe the clinical course of ADA-positive patients. Methods: Pediatric IBD patients receiving maintenance treatment with anti-TNF agents who had been tested for ADAs against infliximab (IFX) or adalimumab (ADL) were included in this crosssectional study. Factors associated with ADA positivity were investigated by analyzing clinicodemographic, laboratory, and treatment-related factors. Results: A total of 76 patients (Crohn’s disease, 65; ulcerative colitis, 11) were included. Among these, 59 and 17 patients were receiving IFX and ADL, respectively. ADAs were found in 10 patients (13.2%), all of whom were receiving IFX. According to multivariable logistic regression analysis, the IFX trough level (TL) was associated with ADA positivity (odds ratio, 0.25; 95% confidence interval [CI], 0.08 to 0.51; p=0.002). According to the receiver operating characteristic analysis, the optimal cutoff of the IFX TLs for stratifying patients based on the presence of ADAs against IFX was 1.88 μg/mL (area under curve, 0.941; 95% CI, 0.873 to 1.000; sensitivity, 80.0%; specificity, 95.9%; p<0.001). Among the 10 patients with ADAs against IFX, five patients (50%) switched to ADL within 1 year, while five patients (50%) kept receiving IFX. Transient ADAs were observed in three patients (30%). Conclusions: IFX TL was the only factor associated with ADA formation in pediatric IBD patients receiving IFX. Future studies based on serial and proactive therapeutic drug monitoring are required in the future.
Abstract
Background/Aims: Anti-drug antibodies (ADAs) can develop during treatment with anti-tumor necrosis factor (TNF) agents. We aimed to investigate the factors associated with immunogenicity of anti-TNF agents in pediatric patients with inflammatory bowel disease (IBD) and observe the clinical course of ADA-positive patients. Methods: Pediatric IBD patients receiving maintenance treatment with anti-TNF agents who had been tested for ADAs against infliximab (IFX) or adalimumab (ADL) were included in this crosssectional study. Factors associated with ADA positivity were investigated by analyzing clinicodemographic, laboratory, and treatment-related factors. Results: A total of 76 patients (Crohn’s disease, 65; ulcerative colitis, 11) were included. Among these, 59 and 17 patients were receiving IFX and ADL, respectively. ADAs were found in 10 patients (13.2%), all of whom were receiving IFX. According to multivariable logistic regression analysis, the IFX trough level (TL) was associated with ADA positivity (odds ratio, 0.25; 95% confidence interval [CI], 0.08 to 0.51; p=0.002). According to the receiver operating characteristic analysis, the optimal cutoff of the IFX TLs for stratifying patients based on the presence of ADAs against IFX was 1.88 μg/mL (area under curve, 0.941; 95% CI, 0.873 to 1.000; sensitivity, 80.0%; specificity, 95.9%; p<0.001). Among the 10 patients with ADAs against IFX, five patients (50%) switched to ADL within 1 year, while five patients (50%) kept receiving IFX. Transient ADAs were observed in three patients (30%). Conclusions: IFX TL was the only factor associated with ADA formation in pediatric IBD patients receiving IFX. Future studies based on serial and proactive therapeutic drug monitoring are required in the future.
참고문헌 (50)
- Baumgart DC, "Inflammatory bowel disease : clinical aspects and established and evolving therapies", Lancet, 369, pp.1641~1657 (2007)
- Rosen MJ, "Inflammatory bowel disease in children and adolescents", JAMA Pediatr, 169, pp.1053~1060 (2015)
- Ben Kang, "Korean Children and Adolescents with Crohn's Disease Are More Likely to Present with Perianal Fistulizing Disease at Diagnosis Compared to Their European Counterparts", Pediatric Gastroenterology, Hepatology & Nutrition, 23(1), pp.49~62 (2020), 대한소아소화기영양학회[DOI]
- 김승, "Surgery in Pediatric Crohn’s Disease: Indications, Timing and Post-Operative Management", Pediatric Gastroenterology, Hepatology & Nutrition, 20(1), pp.14~21 (2017), 대한소아소화기영양학회
- Kang B, "Mucosal healing in paediatric patients with moderate-to-severe luminal Crohn’s disease under combined immunosuppression : escalation versus early treatment", J Crohns Colitis, 10, pp.1279~1286 (2016)
- Jaeyoung Choi, "Early Infliximab Yields Superior Long-Term Effects on Linear Growth in Pediatric Crohn’s Disease Patients", Gut and Liver, 12(3), pp.255~262 (2018), 거트앤리버 소화기연관학회협의회
- Ben Kang, "Early Biologic Treatment in Pediatric Crohn’s Disease: Catchingthe Therapeutic Window of Opportunity in Early Disease by Treat-to-Target", Pediatric Gastroenterology, Hepatology & Nutrition, 21(1), pp.1~11 (2018), 대한소아소화기영양학회
- Moss AC, "Review article : immunogenicity of anti-TNF biologics in IBD : the role of patient, product and prescriber factors", Aliment Pharmacol Ther, 38, pp.1188~1197 (2013)
- Vermeire S, "Immunogenicity of biologics in inflammatory bowel disease", Therap Adv Gastroenterol, 11, pp.1756283~ (2018)
- Roblin X, "Proactive therapeutic drug monitoring of TNF antagonists in inflammatory bowel disease", Inflamm Bowel Dis, 24, pp.1904~1909 (2018)
- Brandse JF, "Pharmacokinetic features and presence of antidrug antibodies associate with response to infliximab induction therapy in patients with moderate to severe ulcerative colitis", Clin Gastroenterol Hepatol, 14, pp.251~258 (2016)
- Nanda KS, "Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease(IBD) : a metaanalysis", Am J Gastroenterol, 108, pp.40~47 (2013)
- Colombel JF, "Infliximab, azathioprine, or combination therapy for Crohn’s disease", N Engl J Med, 362, pp.1383~1395 (2010)
- Lichtenstein GR, "Clinical trial : benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials", Aliment Pharmacol Ther, 30, pp.210~226 (2009)
- Yarur AJ, "Therapeutic drug monitoring of antitumor necrosis factor agents in patients with inflammatory bowel diseases", Inflamm Bowel Dis, 21, pp.1709~1718 (2015)
- Levine A, "ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents", J Pediatr Gastroenterol Nutr, 58, pp.795~806 (2014)
- Kang B, "Long-term outcomes after switching to CT-P13 in pediatric-onset inflam-matory bowel disease : a single-center prospective observational study", Inflamm Bowel Dis, 24, pp.607~616 (2018)
- So Yoon Choi, "Potential Utility of Therapeutic Drug Monitoring of Adalimumab in Predicting Short-Term Mucosal Healing and Histologic Remission in Pediatric Crohn's Disease Patients", Journal of Korean Medical Science, 35(16), pp.1~10 (2020), 대한의학회[DOI]
- Vande Casteele N, "American Gastroenterological Association Institute technical review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases", Gastroenterology, 153, pp.835~857 (2017)
- Carman N, "Therapeutic drug monitoring in pediatric inflammatory bowel disease", Curr Gastroenterol Rep, 20, pp.18~ (2018)
- Sharma S, "Pharmacokinetics and exposure-efficacy relationship of adalimumab in pediatric patients with moderate to severe Crohn’s disease : results from a randomized, multicenter, phase-3 study", Inflamm Bowel Dis, 21, pp.783~792 (2015)
- Matar M, "Combination therapy of adalimumab with an immunomodulator is not more effective than adalimumab monotherapy in children with Crohn’s disease : a post hoc analysis of the PAILOT randomized controlled trial", Inflamm Bowel Dis, 26, pp.1627~1635 (2020)
- Ungar B, "Prospective observational evaluation of time-dependency of adalimumab immunogenicity and drug concentrations : the POETIC study", Am J Gastroenterol, 113, pp.890~898 (2018)
- Ordás I, "Anti-TNF monoclonal antibodies in inflammatory bowel disease : pharmacokinetics-based dosing paradigms", Clin Pharmacol Ther, 91, pp.635~646 (2012)
- Vande Casteele N, "The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn’s disease", Gut, 64, pp.1539~1545 (2015)
- Ben-Horin S, "Review article : loss of response to anti-TNF treatments in Crohn’s disease", Aliment Pharmacol Ther, 33, pp.987~995 (2011)
- 최소윤, "Clinical Use of Measuring Trough Levels and Antibodies against Infliximab in Patients with Pediatric Inflammatory Bowel Disease", Gut and Liver, 11(1), pp.55~61 (2017), 거트앤리버 소화기연관학회협의회
- Merras-Salmio L, "Clinical use of infliximab trough levels and antibodies to infliximab in pediatric patients with inflammatory bowel disease", J Pediatr Gastroenterol Nutr, 64, pp.272~278 (2017)
- O’Meara S, "Antibodies to infliximab and risk of infusion reactions in patients with inflammatory bowel disease : a systematic review and meta-analysis", Inflamm Bowel Dis, 20, pp.1~6 (2014)
- Vermeire S, "Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease", Gut, 56, pp.1226~1231 (2007)
- Kansen HM, "Less antiinfliximab antibody formation in paediatric Crohn patients on concomitant immunomodulators", J Pediatr Gastroenterol Nutr, 65, pp.425~429 (2017)
- Chi LY, "The impact of combination therapy on infliximab levels and antibodies in children and young adults with inflammatory bowel disease", Inflamm Bowel Dis, 24, pp.1344~1351 (2018)
- Qiu Y, "Effects of combination therapy with immunomodulators on trough levels and antibodies against tumor necrosis factor antagonists in patients with inflammatory bowel disease : a meta-analysis", Clin Gastroenterol Hepatol, 15, pp.1359~1372 (2017)
- Ma C, "Advances in therapeutic drug monitoring for small-molecule and biologic therapies in inflammatory bowel disease", Curr Treat Options Gastroenterol, 17, pp.127~145 (2019)
- Feuerstein JD, "American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease", Gastroenterology, 153, pp.827~834 (2017)
- Vande Casteele N, "Antibody response to infliximab and its impact on pharmacokinetics can be transient", Am J Gastroenterol, 108, pp.962~971 (2013)
- Yanai H, "Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab", Clin Gastroenterol Hepatol, 13, pp.522~530 (2015)
- Brandse JF, "A real-life population pharmacokinetic study reveals factors associated with clearance and immunogenicity of infliximab in inflammatory bowel disease", Inflamm Bowel Dis, 23, pp.650~660 (2017)
- Lega S, "Therapeutic drug monitoring in pediatric IBD : current application and future perspectives", Curr Med Chem, 25, pp.2840~2854 (2018)
- Ben-Horin S, "Drug level-based anti-tumor necrosis factor therapy: ready for prime time?", Gastroenterology, 148, pp.1268~1271 (2015)
- Vande Casteele N, "Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease", Gastroenterology, 148, pp.1320~1329 (2015)
- Assa A, "Proactive monitoring of adalimumab trough concentration associated with increased clinical remission in children with Crohn’s disease compared with reactive monitoring", Gastroenterology, 157, pp.985~996 (2019)
- Ungar B, "Optimizing anti-TNF-αtherapy : serum levels of infliximab and adalimumab are associated with mucosal healing in patients with inflammatory bowel diseases", Clin Gastroenterol Hepatol, 14, pp.550~557 (2016)
- Kang B, "Infliximab trough levels are associated with mucosal healing during maintenance treatment with infliximab in paediatric Crohn’s disease", J Crohns Colitis, 13, pp.189~197 (2019)
- Louis E, "Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped", Gastroenterology, 142, pp.63~70 (2012)
- Papamichael K, "Long-term outcome of patients with Crohn’s disease who discontinued infliximab therapy upon clinical remission", Clin Gastroenterol Hepatol, 13, pp.1103~1110 (2015)
- Ben-Horin S, "Undetectable antiTNF drug levels in patients with long-term remission predict successful drug withdrawal", Aliment Pharmacol Ther, 42, pp.356~364 (2015)
- Torres J, "Systematic review of effects of withdrawal of immunomodulators or biologic agents from patients with inflammatory bowel disease", Gastroenterology, 149, pp.1716~1730 (2015)
- Kang B, "Subtherapeutic infliximab trough levels and complete mucosal healing are associated with sustained clinical remission after infliximab cessation in paediatric-onset Crohn’s disease patients treated with combined immunosuppressive therapy", J Crohns Colitis, 12, pp.644~652 (2018)
- Ungar B, "The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab", Gut, 63, pp.1258~1264 (2014)
