Are immunomodulatory therapies safe in patients with inflammatory bowel disease? 23 years of single center experience

Yıl 2023, Cilt: 22 Sayı: 3, 142 - 149, 22.12.2023

Ali Atay , Yasemin Özderin Özin Dilara Turan Gökçe Müge Büyükaksoy , Gamze Demirel Meral Akdoğan Kayhan Zeki Mesut Yalın Kılıç Emin Altıparmak

https://doi.org/10.17941/agd.1405423

Cited By: 1

Öz

Background and Aims: Immunomodulatory therapies are important cornerstones in the treatment of inflammatory bowel disease, and azathioprine and methotrexate are the agents that are mainly use, which inhibit purine synthesis. It may not always be possible to use these agents in effective doses due to their unresponsiveness or side-effect profiles. In our study, it was aimed to present a 23-year experience compiling side effects requiring treatment discontinuation in order to evaluate the safety profile of immunomodulatory agents. Materials and Method: Adverse effects that necessitate discontinuation of treatment in patients who were followed up with the diagnosis of inflammatory bowel disease between 1999-2022, were currently receiving anti-tumor necrosis factor therapy, and had a history of using azathioprine or methotrexate at the treatment dose were retrospectively evaluated. Patients who did not receive immunomodulatory agents at the therapeutic dose and patients who had conditions that did not require discontinuation of treatment were excluded. Results: The study group consisted of 410 patients, 310 patients with Crohn's disease and 100 patients with ulcerative colitis. Azathioprine was used in 325 patients and methotrexate was used in 85 patients. The mean age of the patients was 42.6 ± 13.4 years, and 257 of them were male (62.6%). Azathioprine treatment duration was 4.2 ± 3.5 years in patients with Crohn's disease and 3.0 ± 2.6 years in patients with ulcerative colitis. Side effects that required discontinuation were determined that 18 (5.5%) patients who used azathioprine and 6 (7%) patients who used methotrexate, and all of side effects consisted of grade 2 side effects. There was no significant difference between the two groups in the frequency of side effects (p: 0.59). Treatment-related hematologic or solid organ malignancy were not detected in either treatment group during the follow-up period. Conclusion: Considering the side-effect profile of azathioprine and methotrexate in patients followed up with the diagnosis of inflammatory bowel disease, there is no significant difference between the two groups, and these agents can be used safely with closely follow-up during the treatment.

Anahtar Kelimeler

Immunomodulatory therapy, Crohn, ulcerative colitis

Etik Beyan

Bu çalışma 16.08.2023 tarihinde Ankara Şehir Hastanesi Yerel Etik Kurulu’nun E1-21-3893 sayılı kararı ile onaylanmıştır. Araştırma protokolünde Helsinki Deklarasyon protokolüne uyulmuştur. Çalışmamızda Helsinki Deklerasyonu Prensiplerine uyulmuştur.

İnflamatuvar bağırsak hastalığı olan hastalarda immünmodülatör tedaviler güvenli mi? 23 yıllık tek merkez deneyimi

Öz

Giriş ve Amaç: İmmünmodülatör ajanlar inflamatuvar bağırsak hastalığı tedavisinde önemli köşe taşlarından olup pürin sentezini inhibe eden azatioprin ve metotreksat başlıca kullanılmakta olan ajanlardandır. Bu ajanların yanıtsızlık veya yan etki profilleri nedeni ile her zaman efektif dozda kullanılmaları mümkün olmayabilir. Çalışmamızda immünmodülatör ajanların güvenlik profilinin değerlendirilmesi amacı ile tedavi kesilmesini gerektirecek yan etkilerin derlendiği 23 yıllık deneyimin sunulması amaçlandı. Gereç ve Yöntem: 1999-2022 yılları arasında inflamatuvar bağırsak hastalığı tanısı ile takipli olan, halihazırda anti-tümör nekrozis faktör tedavisi almakta olup tedavi dozunda azatioprin veya metotreksat kullanım geçmişi olan hastalarda tedavi kesilmesini gerektirecek yan etkiler geriye dönük olarak incelendi. İmmünmodülatör ajanları tedavi dozunda almamış olan hastalar ile tedavi kesilmesini gerektirmeyecek durumların gözlendiği hastalar dışlandı. Bulgular: Çalışma grubu 310 Crohn hastalığı ve 100 ülseratif koliti olan hasta olmak üzere 410 hastadan oluşuyordu. 325 hastada azatioprin, 85 hastada metotreksat kullanım öyküsü mevcuttu. Hastaların ortalama yaşı 42.6 ± 13.4 yıl olup 257’si erkek (%62.6) idi. Azatioprin kullanım süresi Crohn hastalarında 4.2 ± 3.5 yıl, ülseratif kolit olan hastalarda 3.0 ± 2.6 yıl idi. Azatioprin kullanmış olan hastaların 18’inde (%5.5), metotreksat kullanmış olan hastaların 6’sında (%7) kesilmesini gerektirecek yan etkiler geliştiği tespit edildi ve yan etkilerin tamamı 2. derece yan etkilerden oluşmaktaydı. İmmünmodülatör ajanların tedavi bırakmayı gerektiren yan etki sıklığında iki grup arasında anlamlı fark saptanmadı (p: 0.59). Her iki tedavi grubunda da takip süresince tedavi ilişkili hematolojik veya solid organ malignitesi saptanmadı. Sonuç: İnflamatuvar bağırsak hastalığı tanısı ile takipli hastalarda azatioprin ve metotreksat yan etki profili göz önüne alındığında iki grup arasında anlamlı fark olmayıp tedavi süresince yakın takip ile güvenli kullanılabilecek ajanlardır.

Anahtar Kelimeler

İmmünmodülatör tedavi, Crohn hastalığı, ülseratif kolit

Kaynakça

• 1. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142:46-54.e42; quiz e30.
• 2. Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target. Am J Gastroenterol 2015;110:1324-38.
• 3. Bryant R V, Brain O, Travis SPL. Conventional drug therapy for inflammatory bowel disease. Scand J Gastroenterol 2015;50:90-112.
• 4. Nielsen OH, Coskun M, Steenholdt C, Rogler G. The role and advances of immunomodulator therapy for inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2015;9:177-89.
• 5. Sharara AI. When to Start Immunomodulators in Inflammatory Bowel Disease? Dig Dis 2016;34:125-31.
• 6. Bär F, Sina C, Fellermann K. Thiopurines in inflammatory bowel disease revisited. World J Gastroenterol 2013;19:1699-706.
• 7. González-Lama Y, Taxonera C, López-Sanromán A, et al; Madrid Group for Study of Inflammatory Bowel Diseases (ENICMAD). Methotrexate in inflammatory bowel disease: a multicenter retrospective study focused on long-term efficacy and safety. The Madrid experience. Eur J Gastroenterol Hepatol 2012;24:1086-91.
• 8. AlAmeel T, Al Sulais E, Raine T. Methotrexate in inflammatory bowel disease: A primer for gastroenterologists. Saudi J Gastroenterol 2022;28:250-60.
• 9. Shamberg L, Vaziri H. Hepatotoxicity of Inflammatory Bowel Disease Medications. J Clin Gastroenterol 2018;52:674-84.
• 10. Banks PA, Bollen TL, Dervenis C, et al; Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013;62:102-11.
• 11. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 2012;120:c179-84.
• 12. Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr 2021;112:90-2.
• 13. Bradford K, Shih DQ. Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease. World J Gastroenterol 2011;17:4166-73.
• 14. Freitas M, Lima Capela T, Macedo Silva V, et al. Finding Predictors of Azathioprine-Induced Pancreatitis in Patients With Inflammatory Bowel Disease. Pancreas 2022;51:288-94.
• 15. Eskazan T, Bozcan S, Atay K, et al. Frequency, Predisposing Factors, and Clinical Outcome of Azathioprine-Induced Pancreatitis Among Patients With Inflammatory Bowel Disease: Results From a Tertiary Referral Center. Pancreas 2021;50:1274-80.
• 16. Koller T, Galambosova M, Filakovska S, et al. Drug-induced liver injury in inflammatory bowel disease: 1-year prospective observational study. World J Gastroenterol 2017;23:4102-11.
• 17. Pasternak B, Svanström H, Schmiegelow K, Jess T, Hviid A. Use of azathioprine and the risk of cancer in inflammatory bowel disease. Am J Epidemiol 2013;177:1296-305.
• 18. Armstrong RG, West J, Card TR. Risk of cancer in inflammatory bowel disease treated with azathioprine: a UK population-based case-control study. Am J Gastroenterol 2010;105:1604-9.
• 19. Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet (London, England) 2009;374:1617-25.
• 20. Smeltzer JP, Viswanatha DS, Habermann TM, Patnaik MM. Secondary Epstein-Barr virus associated lymphoproliferative disorder developing in a patient with angioimmunoblastic T cell lymphoma on vorinostat. Am J Hematol 2012;87:927-8.
• 21. Thomas JA, Aithal GP. Monitoring liver function during methotrexate therapy for psoriasis: are routine biopsies really necessary? Am J Clin Dermatol 2005;6:357-63.
• 22. Khan N, Abbas AM, Whang N, Balart LA, Bazzano LA, Kelly TN. Incidence of liver toxicity in inflammatory bowel disease patients treated with methotrexate: a meta-analysis of clinical trials. Inflamm Bowel Dis 2012;18:359-67.
• 23. Chande N, Wang Y, MacDonald JK, McDonald JW. Methotrexate for induction of remission in ulcerative colitis. Cochrane database Syst Rev 2014;2014:CD006618.
• 24. Wang Y, MacDonald JK, Vandermeer B, Griffiths AM, El-Matary W. Methotrexate for maintenance of remission in ulcerative colitis. Cochrane database Syst Rev 2015;2015:CD007560.
• 25. Carbonnel F, Colombel JF, Filippi J, et al; European Crohn's and Colitis Organisation; Groupe d'Étude Thérapeutique des Affections Inflammatoires Digestives. Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis. Gastroenterology 2016;150:380-8.e4.