Terapevticheskii arkhivTerapevticheskii arkhivТерапевтический архив0040-36602309-5342LLC Obyedinennaya Redaktsiya7936610.26442/00403660.2021.08.200982Editorial articleПередовая статьяResearch ArticlePharmacotherapy of inflammatory bowel diseases: efficacy performance and safety managementФармакотерапия воспалительных заболеваний кишечника: управление эффективностью и безопасностьюhttps://orcid.org/0000-0002-6151-2021BakulinIgor G.БакулинИгорь Геннадьевич
Russian Federation

доктор медицинских наук, профессор, заведующий кафедрой пропедевтики внутренних болезней, гастроэнтерологии и диетологии

mskalinskaya@yahoo.comhttps://orcid.org/0000-0003-0769-8176SkalinskayaMaria I.СкалинскаяМария Игоревна
Russian Federation

кандидат медицинских наук, доцент кафедры пропедевтики внутренних болезней и гастроэнтерологии

mskalinskaya@yahoo.comhttps://orcid.org/0000-0001-6114-564XMaevIgor V.МаевИгорь Вениаминович
Russian Federation

академик РАН, доктор медицинских наук, профессор, заведующий кафедрой пропедевтики внутренних болезней и гастроэнтерологии

mskalinskaya@yahoo.comhttps://orcid.org/0000-0002-8563-6870SkazyvaevaEkaterina V.СказываеваЕкатерина Васильевна
Russian Federation

кандидат медицинских наук, доцент кафедры пропедевтики внутренних болезней и гастроэнтерологии

mskalinskaya@yahoo.comhttps://orcid.org/0000-0003-4838-5707ZhuravlevaMariia S.ЖуравлеваМария Сергеевна
Russian Federation

кандидат медицинских наук, доцент кафедры пропедевтики внутренних болезней и гастроэнтерологии

mskalinskaya@yahoo.comhttps://orcid.org/0000-0003-1000-1114GaikovayaLarisa B.ГайковаяЛариса Борисовна
Russian Federation

доктор медицинских наук, доцент, заведующий кафедрой биологической и общей химии

mskalinskaya@yahoo.comhttps://orcid.org/0000-0003-4075-4096BakulinaNatalia V.БакулинаНаталья Валерьевна
Russian Federation

доктор медицинских наук, профессор, заведующий кафедрой внутренних болезней, клинической фармакологии и нефрологии

mskalinskaya@yahoo.comhttps://orcid.org/0000-0003-3435-5881ErmakovAleksei I.ЕрмаковАлексей Игоревич
Russian Federation

врач клинической лабораторной диагностики центральной клинико-диагностической лаборатории

mskalinskaya@yahoo.comhttps://orcid.org/0000-0001-8250-4197AlekseenkoEkaterina S.АлексеенкоЕкатерина Сергеевна
Russian Federation

врач-ординатор кафедры пропедевтики внутренних болезней, гастроэнтерологии и диетологии

mskalinskaya@yahoo.comIvanovaKristina N.ИвановаКристина Наполеоновна
Russian Federation

врач-ординатор каф. пропедевтики внутренних болезней, гастроэнтерологии и диетологии

mskalinskaya@yahoo.comhttps://orcid.org/0000-0001-6832-0498SolovevMikhail V.СоловьевМихаил Викторович
Russian Federation

кандидат медицинских наук, доцент, врач-гастроэнтеролог, старший преподаватель кафедры госпитальной терапии

mskalinskaya@yahoo.comMechnikov North-Western State Medical UniversityФГБОУ ВО «Северо-Западный государственный медицинский университет им. И.И. Мечникова» Минздрава РоссииYevdokimov Moscow State University of Medicine and DentistryФГБОУ ВО «Московский государственный медико-стоматологический университет им. А.И. Евдокимова» Минздрава РоссииKirov Military Medical AcademyФГБВОУ ВО «Военно-медицинская академия им. С.М. Кирова» Минобороны России150820219388418523008202130082021Copyright ©; 2021, Consilium MedicumCopyright ©; 2021, ООО "Консилиум Медикум"2021Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://ter-arkhiv.ru/0040-3660/article/view/79366

Treatment of inflammatory bowel diseases – IBD (Crohn’s disease, ulcerative colitis) is aimed at achieving clinical, endoscopic and histological remission, minimizing surgical complications, and ensuring a normal quality of life. However, the use of medical treatment is potentially associated with various adverse events, among which infectious complications, malignant neoplasms, as well as myelotoxicity, hepatotoxicity, skin lesions and others. The risk of side effects depends on the type of drug therapy (5-aminosalicylates, thiopurines, biologicals, etc.), the duration of treatment, the presence of extra-intestinal manifestations, etc. The article provides an overview of data on both the effectiveness and frequency of various side effects of the main classes of drugs in IBD, presents methods of investigation which can predict the effectiveness and development of side effects, the implementation of which can be considered as a variant of personalized therapy in IBD.

Лечение воспалительных заболеваний кишечника – ВЗК (язвенного колита и болезни Крона) направлено на достижение клинической, эндоскопической и гистологической ремиссии, минимизацию хирургических осложнений, обеспечение нормального качества жизни. Однако применение медикаментозной терапии потенциально связано с разными нежелательными явлениями, среди которых особый риск представляют инфекционные осложнения, злокачественные новообразования, а также миелотоксичность, гепатотоксичность, поражения кожи и некоторые другие. Риск побочных эффектов зависит от вида лекарственной терапии (препараты 5-аминосалициловой кислоты, тиопурины, препараты биологической терапии и т.д.), длительности лечения, наличия внекишечных проявлений и т.д. В статье приводится обзор данных как по эффективности, так и по частоте разных побочных эффектов основных классов препаратов, применяемых при ВЗК, представлены методы исследования, на основе которых можно прогнозировать эффективность и развитие побочных эффектов и выполнение которых может рассматриваться как вариант персонифицированной терапии при ВЗК.

inflammatory bowel diseasesCrohn’s diseaseulcerative colitissafety of inflammatory bowel diseases therapyefficacy of inflammatory bowel diseases therapy5-aminosalicylatesthiopurinesbiologic therapyвоспалительные заболевания кишечникаболезнь Кронаязвенный колитнежелательные явления5-аминосалициловая кислотатиопуриныбиологическая терапияМаев И.В., Шелыгин Ю.А., Скалинская М.И., и др. Патоморфоз воспалительных заболеваний кишечника. Вестник РАМН. 2020;75(1):27-35 [Maev IV, Shelygin IuA, Skalinskaia MI, et al. Patomorfoz vospalitel’nykh zabolevanii kishechnika. Vestnik RAMN. 2020;75(1):27-35 (in Russian)]. DOI:10.15690/vramn1219Веселов А.В., Белоусова Е.А., Бакулин И.Г., и др. Оценка экономического бремени и текущего состояния организации лекарственного обеспечения пациентов с иммуновоспалительными заболеваниями (на примере язвенного колита и болезни Крона) в Российской Федерации. Проблемы социальной гигиены, здравоохранения и истории медицины. 2020;28(S2):1137-45 [Veselov AV, Belousova EA, Bakulin IG, et al. Otsenka ekonomicheskogo bremeni i tekushchego sostoianiia organizatsii lekarstvennogo obespecheniia patsientov s immunovospalitel’nymi zabolevaniiami (na primere iazvennogo kolita i bolezni Krona) v Rossiiskoi Federatsii. Problemy sotsial’noi gigieny, zdravookhraneniia i istorii meditsiny. 2020;28(S2):1137-45 (in Russian)]. DOI:10.32687/0869-866X-2020-28-s2-1137-1145Бакулин И.Г., Авалуева Е.Б., Сказываева Е.В., и др. Воспалительные заболевания кишечника. Карманные рекомендации для врачей по ведению пациентов с воспалительными заболеваниями кишечника. М.; СПб: Группа Ремедиум, 2018 [Bakulin IG, Avalueva EB, Skazyvaeva EV, et al. Inflammatory bowel diseases: Pocket recommendations for doctors on the management of patients with inflammatory bowel diseases. Moscow; Saint Petersburg: Gruppa Remedium, 2018 (in Russian)].Бакулин И.Г., Жигалова Т.Н., Латария Э.Л., и др. Опыт внедрения федерального регистра пациентов с воспалительными заболеваниями кишечника в Санкт-Петербурге. Фарматека. 2017;S5:56-9 [Bakulin IG, Zhigalova TN, Latariia EL, et al. Experience of implementing a federal register of patients with inflammatory bowel diseases in St. Petersburg. Farmateka. 2017;S5:56-9 (in Russian)].Giraud EL, Thomas PWA, van Lint JA, et al. Adverse Drug Reactions from Real-World Data in Inflammatory Bowel Disease Patients in the IBDREAM Registry. Drug Saf. 2021. DOI:10.1007/s40264-021-01045-3Mouyis M, Flint JD, Giles IP. Safety of anti-rheumatic drugs in men trying to conceive: A systematic review and analysis of published evidence. Semin Arthritis Rheum. 2019;48(5):911-20. DOI:10.1016/j.semarthrit.2018.07.011Ransford RA, Langman MJ. Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the Committee on Safety of Medicines. Gut. 2002;51(4):536-9. DOI:10.1136/gut.51.4.536Nguyen NH, Fumery M, Dulai PS, et al. Comparative efficacy and tolerability of pharmacological agents for management of mild to moderate ulcerative colitis: a systematic review and network meta-analyses. Lancet Gastroenterol Hepatol. 2018;3(11):742-53. DOI:10.1016/S2468-1253(18)30231-0Adiga A, Goldfarb DS. The Association of Mesalamine With Kidney Disease. Adv Chronic Kidney Dis. 2020;27(1):72-6. DOI:10.1053/j.ackd.2019.09.002Ambruzs JM, Walker PD, Larsen CP. The histopathologic spectrum of kidney biopsies in patients with inflammatory bowel disease. Clin J Am Soc Nephrol. 2014;9(2):265-70. DOI:10.2215/cjn.04660513Corica D, Romano C. Renal involvement in inflammatory bowel diseases. J Crohns Colitis. 2016;10(2):226-35. DOI:10.1093/ecco-jcc/jjv138Van Staa TP, Travis S, Leufkens HG, Logan RF. 5-aminosalicylic acids and the risk of renal disease: a large British epidemiologic study. Gastro-enterology. 2004;126(7):1733-9. DOI:10.1053/j.gastro.2004.03.016Le Berre C, Roda G, Protic NM, et al. Modern use of 5-aminosalicylic acid compounds for ulcerative colitis. Expert Opin Biol Ther. 2020;20(4):363-78. DOI:10.1080/14712598.2019.1666101Heap GA, So K, Weedon M, et al. Clinical features and HLA association of 5-aminosalicylate (5-ASA)-induced nephrotoxicity in inflammatory bowel disease. J Crohns Colitis. 2016;10(2):149-58. DOI:10.1093/ecco-jcc/jjv219Kornbluth A, Sachar DB. Practice Parameters Committee of the American College of Gastroenterology Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105(3):501-23;quiz 524. DOI:10.1038/ajg.2010.52Dignass A, Van Assche G, Lindsay JO, et al. The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: current management. J Crohns Colitis. 2010;4(1):28-62. DOI:10.1016/j.crohns.2009.12.002Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2011;60(5):571-607. DOI:10.1136/gut.2010.224154Hibiya S, Matsuyama Y, Fujii T, et al. 5-aminosalicylate-intolerant patients are at increased risk of colectomy for ulcerative colitis. Aliment Pharmacol Ther. 2021;53(1):103-13. DOI:10.1111/apt.16120Annex I. Summary of product characteristics. Committee for Proprietary Medicinal Products. The European Public Assessment Report (EPAR). Stocrin. The European Agency for the Evaluation of Medicinal Products. London, 1999.Biemans VBC, Savelkoul E, Gabriëls RY, et al. A comparative analysis of tioguanine versus low-dose thiopurines combined with allopurinol in inflammatory bowel disease patients. Aliment Pharmacol Ther. 2020;51(11):1076-86. DOI:10.1111/apt.15730Coenen MJ, de Jong DJ, van Marrewijk CJ, et al.; TOPIC Recruitment Team. Identification of patients with variants in TPMT and dose reduction reduces hematologic events during thiopurine treatment of inflammatory bowel disease. Gastroenterology. 2015;149(4):907-17.e7. DOI:10.1053/j.gastro.2015.06.002Calafat M, Mañosa M, Cañete F, et al.; ENEIDA registry of GETECCU. Increased risk of thiopurine-related adverse events in elderly patients with IBD. Aliment Pharmacol Ther. 2019;50(7):780-8. DOI:10.1111/apt.15458Macaluso FS, Renna S, Maida M, et al. Tolerability profile of thiopurines in inflammatory bowel disease: a prospective experience. Scand J Gastroenterol. 2017;52(9):981-7. DOI:10.1080/00365521.2017.1333626López-Martín C, Chaparro M, Espinosa L, et al. Adverse events of thiopurine immunomodulators in patients with inflammatory bowel disease. Gastroenterol Hepatol. 2011;34(6):385-92. DOI:10.1016/j.gastrohep.2011.03.023de Jong DJ, Derijks LJ, Naber AH, et al. Scand Safety of thiopurines in the treatment of inflammatory bowel disease. J Gastroenterol Suppl. 2003;239:69-72. DOI:10.1080/00855920310002726Saibeni S, Virgilio T, D’Incà R, et al. The use of thiopurines for the treatment of inflammatory bowel diseases in clinical practice. Dig Liver Dis. 2008;40(10):814-20. DOI:10.1016/j.dld.2008.03.016Jharap B, Seinen ML, de Boer NK, et al. Thiopurine therapy in inflammatory bowel disease patients: analyses of two 8-year intercept cohorts. Inflamm Bowel Dis. 2010;16(9):1541-9. DOI:10.1002/ibd.21221Costantino G, Furfaro F, Belvedere A, et al. Thiopurine treatment in inflammatory bowel disease: response predictors, safety, and withdrawal in follow-up. J Crohns Colitis. 2012;6(5):588-96. DOI:10.1016/j.crohns.2011.11.007Moran GW, Dubeau MF, Kaplan GG, et al. Clinical predictors of thiopurine-related adverse events in Crohn’s disease. World J Gastroenterol. 2015;21(25):7795-804. DOI:10.3748/wjg.v21.i25.7795Van Asseldonk DP, de Boer NK, Peters GJ, et al. On therapeutic drug monitoring of thiopurines in inflammatory bowel disease; pharmacology, pharmacogenomics, drug intolerance and clinical relevance. Curr Drug Metab. 2009;10(9):981-97. DOI:10.2174/138920009790711887de Boer NKH, Peyrin-Biroulet L, Jharap B, et al. Thiopurines in Inflammatory Bowel Disease: New Findings and Perspectives. J Crohns Colitis. 2018;12(5):610-20. DOI:10.1093/ecco-jcc/jjx181Roberts RL, Barclay ML. Update on thiopurine pharmacogenetics in inflammatory bowel disease. Pharmacogenomics. 2015;16:891-903. DOI:10.2217/pgs.15.29Wong DR, Coenen MJ, Vermeulen SH, et al.; TOPIC recruitment team. Early assessment of thiopurine metabolites identifies patients at risk of thiopurine-induced leukopenia in inflammatory bowel disease. J Crohns Colitis. 2017;11:175-84. DOI:10.1093/ecco-jcc/jjw130Wong DR, Coenen MJ, Derijks LJ, et al.; TOPIC Recruitment Team. Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45:391-402. DOI:10.1111/apt.13879Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther. 2019;105(5):1095-105. DOI:10.1002/cpt.1304Suiter CC, Moriyama T, Matreyek KA, et al. Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity. Proc Natl Acad Sci USA. 2020;117(10):5394-401. DOI:10.1073/pnas.1915680117Kang B, Kim TJ, Choi J, et al. Adjustment of azathioprine dose should be based on a lower 6-TGN target level to avoid leucopenia in NUDT15 intermediate metabolisers. Aliment Pharmacol Ther. 2020;52(3):459-70. DOI:10.1111/apt.15810Teich N, Mohl W, Bokemeyer B, et al.; German IBD Study Group. Azathioprine-induced Acute Pancreatitis in Patients with Inflammatory Bowel Diseases – A Prospective Study on Incidence and Severity. J Crohns Colitis. 2016;10(1):61-8. DOI:10.1093/ecco-jcc/jjv188Timmer A, Patton PH, Chande N, et al. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2016;2016(5):CD000478. DOI:10.1002/14651858Lakatos PL, Kiss LS. Current status of thiopurine analogues in the treatment in Crohn’s disease. World J Gastroenterol. 2011;17(39):4372-81. DOI:10.3748/wjg.v17.i39.4372Siegel CA. Review article: explaining risks of inflammatory bowel disease therapy to patients. Aliment Pharmacol Ther. 2011;33(1):23-32. DOI:10.1111/j.1365-2036.2010.04489.xJess T, Horváth-Puhó E, Fallingborg J, et al. Cancer Risk in Inflammatory Bowel Disease According to Patient Phenotype and Treatment: A Danish Population-Based Cohort Study. Am J Gastroenterol. 2013. DOI:10.1038/ajg.2013.249Ariyaratnam J, Subramanian V. Association between thiopurine use and nonmelanoma skin cancers in patients with inflammatory bowel disease: a meta-analysis. Am J Gastroenterol. 2014;109:163-9. DOI:10.1038/ajg.2013.451Peyrin-Biroulet L, Chevaux JB, Bouvier AM, et al. Risk of melanoma in patients who receive thiopurines for inflammatory bowel disease is not increased. Am J Gastroenterol. 2012;107:1443-4. DOI:10.1038/ajg.2012.181Jess T, Lopez A, Andersson M, et al. Thiopurines and risk of colorectal neoplasia in patients with inflammatory bowel disease: a meta-analysis. Clin Gastroenterol Hepatol. 2014;12:1793-800.e1. DOI:10.1016/j.cgh.2014.05.019Kotlyar DS, Lewis JD, Beaugerie L, et al. Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine: a meta-analysis. Clin Gastroenterol Hepatol. 2015;13:847-58.e4;quiz e48-50. DOI:10.1016/j.cgh.2015.03.008Bourrier A, Carrat F, Colombel JF, et al.; CESAME study group. Excess risk of urinary tract cancers in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Aliment Pharmacol Ther. 2016;43:252-61. DOI:10.1111/apt.13466Sokol H, Beaugerie L, Maynadié M, et al.; CESAME Study Group. Excess primary intestinal lymphoproliferative disorders in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:2063-71. DOI:10.1002/ibd.22889Mitrev N, Leong RW. Therapeutic drug monitoring of anti-tumour necrosis factor-α agents in inflammatory bowel disease. Expert Opin Drug Saf. 2016;16:303-17. DOI:10.1080/14740338.2017.1269169Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious Infection and Mortality in Patients With Crohn’s Disease: More Than 5 Years of Follow-Up in the TREAT™ Registry. Am J Gastroenterol. 2012;107:1409-22. DOI:10.1038/ajg.2012.218Bonovas S, Fiorino G, Allocca M, et al. Biologic therapies and risk of infection and malignancy in patients with inflammatory bowel disease: a systematic review and network meta-analysis. Clin Gastroenterol Hepatol. 2016;14:1385-97. DOI:10.1016/j.cgh.2016.04.039Meserve J, Aniwan S, Koliani-Pace JL, et al. Retrospective analysis of safety of vedolizumab in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2019;17:1533-40. DOI:10.1016/j.cgh.2018.09.035D’Haens G, Reinisch W, Colombel JF, et al.; ENCORE investigators. Five-year Safety Data From ENCORE, a European Observational Safety Registry for Adults With Crohn’s Disease Treated With Infliximab [Remicade®] or Conventional Therapy. J Crohns Colitis. 2017;11(6):680-9. DOI:10.1093/ecco-jcc/jjw221Kirchgesner J, Lemaitre M, Carrat F, et al. Risk of Serious and Opportunistic Infections Associated With Treatment of Inflammatory Bowel Diseases. Gastroenterology. 2018;155(2):337-46.e10. DOI:10.1053/j.gastro.2018.04.012Andersen N, Pasternak B, Friis-Møller N, et al. Association between tumour necrosis factor-α inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study. NMJ. 2015;350:h2809. DOI:10.1136/bmj.h2809Yiu ZZN, Smith CH, Ashcroft DM, et al.; BADBIR Study Group. Risk of Serious Infection in Patients with Psoriasis Receiving Biologic Therapies: A Prospective Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR). J Invest Dermatol. 2018;138(3):534-41. DOI:10.1016/j.jid.2017.10.005Papp K, Gottlieb AB, Naldi L, et al. Safety Surveillance for Ustekinumab and Other Psoriasis Treatments From the Psoriasis Longitudinal Assessment and Registry (PSOLAR). Drugs Dermatol. 2015;14(7):706-14.Sandborn WJ, Su C, Sands BE, et al. OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2017;376(18):1723-36. DOI:10.1056/nejmoa1606910Colombel JF, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut. 2017;66(5):839-51. DOI:10.1136/gutjnl-2015-311079Dulai PS, Singh S, Jiang X, et al. The Real-World Effectiveness and Safety of Vedolizumab for Moderate-Severe Crohn’s Disease: Results From the US VICTORY Consortium. Am J Gastroenterol. 2016;111(8):1147-55. DOI:10.1038/ajg.2016.236Ko JM, Gottlieb AB, Kerbleski JF. Induction and exacerbation of psoriasis with TNF-blockade therapy: A review and analysis of 127 cases. J Dermatolog Treat. 2009;20:100-8. DOI:10.1080/09546630802441234Cleynen I, Moerkercke WV, Billiet T, et al. Characteristics of Skin Lesions Associated With Anti-Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease. Ann Intern Med. 2015;164:10. DOI:10.7326/m15-0729Osterman MT, Sandborn WJ, Colombel JF, et al. Increased Risk of Malignancy With Adalimumab Combination Therapy, Compared With Monotherapy, for Crohns Disease. Gastroenterology. 2014;146(4). DOI:10.1053/j.gastro.2013.12.025Deepak P, Sifuentes H, Sherid M, et al. T-Cell Non-Hodgkin’s Lymphomas Reported to the FDA AERS With Tumor Necrosis Factor-Alpha (TNF-α) Inhibitors: Results of the REFURBISH Study. Am J Gastroenterol. 2013;108:99-105. DOI:10.1038/ajg.2012.334Lemaitre M, Kirchgesner J, Rudnichi A, et al. Association Between Use of Thiopurines or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma in Patients With Inflammatory Bowel Disease. JAMA. 2017;318:1679. DOI:10.1001/jama.2017.16071Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review. BioDrugs. 2017;31(4):299-316. DOI:10.1007/s40259-017-0231-8Vermeire S, Gils A, Accossato P, et al. Immunogenicity of biologics in inflammatory bowel disease. Therap Adv Gastroenterol. 2018;11:1-13. DOI:10.1177/1756283x17750355Reinhold I, Blümel S, Schreiner J, et al. Clinical Relevance of Anti-TNF Antibody Trough Levels and Anti-Drug Antibodies in Treating Inflammatory Bowel Disease Patients. Inflamm Intest Dis. 2021;6(1):38-47. DOI:10.1159/000511296Grinman AB, de Souza MDGC, Bouskela E, et al. Clinical and laboratory markers associated with anti-TNF-alpha trough levels and anti-drug antibodies in patients with inflammatory bowel diseases. Medicine (Baltimore). 2020;99(10):e19359. DOI:10.1097/MD.0000000000019359Wilson A, Peel C, Wang Q, et al. HLADQA1*05 genotype predicts anti-drug antibody formation and loss of response during infliximab therapy for inflammatory bowel disease. Aliment Pharmacol Ther. 2020;51(3):356-63. DOI:10.1111/apt.15563.