研究背景：
克隆氏症（Crohn's disease, CD）是一種影響全球數百萬人的發炎性腸胃道疾病，該疾病可以影響口腔、食道、胃、小腸和大腸，主要表現為腹痛、腹瀉、體重減輕和貧血等症狀。近年來，以重大傷病證明為依據的台灣克隆氏症病例呈現逐漸上升的趨勢，但實際上克隆氏症的病人可能遠多於此。因此，全面瞭解克隆氏症在台灣的發生率對於制定適當的治療策略和降低疾病負擔至關重要。生物製劑自2011年起被核准用於中重度克隆氏症病人，但在使用上受到醫療保險政策的限制。透過文獻回顧，國內對於克隆氏症的研究仍未充分，了解對台灣克隆氏症的趨勢和治療效果的知識缺口，可以提供重要科學證據，幫助臨床醫師和公共衛生政策制定者做出更有根據的決策，以改善患者治療和健康管理。
研究目的：
本研究致力於分析克隆氏症在台灣的發生率及藥物處方型態，進一步探討生物製劑在治療克隆氏症中的療效、安全性與停用生物製劑後對疾病控制的影響。
研究方法：
本研究採用回溯性世代研究設計，分析台灣健保資料庫2004年至2018年18歲以上、符合研究定義納入與排除條件，且被診斷為克隆氏症的病人。以台灣核准生物製劑給付的時間點將病人分為生物製劑前與後兩個世代，了解不同時期的克隆氏症在台灣的發生率。每半年評估病人被處方的藥物，並探討克隆氏症相關藥物在時間軌跡上的變化情況。在生物製劑療效評估中，本研究以綜合性治療結果為指標，包括克隆氏症相關的住院、急診和手術等。生物製劑的安全性評估以感染症為研究目標；使用KM曲線描繪存活曲線，並評估事件發生率。為控制干擾因素，同時使用IPTW方法進行資料校正，並以Cox比例風險模型評估相對危險比。在停用生物製劑對疾病的影響研究，使用變數篩選方法進行危險因子的分析。整合敏感度分析增強研究結果的可靠性。所有資料處理和統計分析均使用SAS 9.4統計軟體進行。
結果：
本研究發現台灣克隆氏症每年的新發病例數保持穩定。處方型態分析研究中顯示，生物製劑時代之前，類固醇的處方比例相對較高；反之生物製劑時代後，類固醇的處方比例則有降低趨勢，而免疫調節劑的處方比例增高。類固醇的依賴率在後生物製劑時代也有下降趨勢，尤其是患有重大傷病的患者，其比例從每百人年的8.19人降低至6.29人。生物製劑的療效研究中顯示，使用生物製劑後，住院的結果有改善趨勢，然而未達統計學差異 (HR, 0.91; 95% CI, 0.61-1.37)。生物製劑使用並未增加感染發生的風險，不論是輕度（HR，0.83; 95% CI，0.66-1.03）或嚴重（HR，1.08; 95% CI，0.70-1.66）感染。研究分析同時也發現，在停用生物製劑後1年內觀察到有2/3的病人重新使用生物製劑，而其中1/2的病人的治療效果不理想。
結論：
本研究突顯了克隆氏症的穩定發病率以及在現行健保政策影響下免疫調節劑和生物製劑處方的增加。同時也了解，生物製劑治療有效降低了住院率，而不增加感染風險。然而健保限制而停藥後，需要面臨高比例重新使用生物製劑和治療不佳的挑戰。這些發現強調了修訂治療模式以增強病患照護和後續研究的必要性。

Background：
Crohn's disease (CD), a form of inflammatory bowel disease, affects millions globally, impairing quality of life with symptoms like abdominal pain and weight loss. In recent years, the number of Crohn's disease cases in Taiwan, based on catastrophic illness certificates, had shown a gradually increasing trend. However, the actual number of CD patients is likely much higher. Therefore, a comprehensive understanding of the incidence rate of Crohn's disease in Taiwan is important for formulating appropriate treatment strategies and reducing the disease burden. Since 2011, biologics for moderate to severe CD have been approved, albeit restricted by national healthcare insurance policies. Local research on CD remained inadequate, primarily constrained by restrictions imposed by healthcare insurance policies on its utilization. A knowledge gap in the epidemiological trends and treatment outcomes of CD in Taiwan was identified. This effort provided critical evidence to support clinician and public health decision-making.
Objective：
This study aimed to analyze the incidence of CD and prescription patterns in Taiwan. Furthermore, this study investigated the effectiveness and safety of biologics in the treatment of CD, including the clinical effects on disease control after discontinuation of biologics.
Method：
This study used a retrospective cohort design, analyzing data from the Taiwan’s National Health Insurance database from 2004 to 2018 for patients over 18 years old who met the study's inclusion and exclusion criteria and were diagnosed with CD. Patients were divided into two cohorts based on the time point of biologic therapy approval in Taiwan to understand the incidence of CD in different periods. Drug prescriptions for each patient were evaluated every six months to investigate changes in the medication trajectory related to CD over time. In assessing the effectiveness of biologic therapy, the study utilized composite suboptimal outcomes, including CD-related hospitalizations, emergency visits, and surgeries. The safety evaluation of biologics focused on infections as the primary outcome. The survival curves used the Kaplan-Meier (KM) curve and assessed the event rates. To control for confounding factors, the study applied the Inverse Probability of Treatment Weighting (IPTW) method for data adjustment and evaluated the relative risk ratios using the Cox proportional hazards model. In the analysis of the impact of discontinuing biologics on disease, backward variable selection was used to analyze risk factors. Sensitivity analyses were integrated to ensure the reliability of the study results. All data processing and statistical analyses were conducted using SAS 9.4 software.
Result：
This study found that the annual number of new CD cases in Taiwan remained stable, without observing any noticeable increase or decrease. The analysis of prescription patterns revealed that, before the era of biologics, the proportion of steroid prescriptions was relatively high; conversely, after the introduction of biologics, there was a trend towards a decrease in steroid prescriptions and an increase in the proportion of immunomodulators. The steroid-dependent rate also showed a decreasing trend in the post-biologic era, particularly among patients with catastrophic illnesses certificate, decreasing from 8.19 per 100 person-years to 6.29 per 100 person-years. The effectiveness of biologics suggests an improving trend in CD-related hospitalization; however, statistical significance was not attained (HR, 0.91; 95% CI, 0.61-1.37). Additionally, the use of biologics did not increase the risk of infections, whether mild (HR, 0.83; 95% CI, 0.66-1.03) or severe (HR, 1.08; 95% CI, 0.70-1.66). The analysis also found that within one year after discontinuation of biologics, two-thirds of patients resumed biologic therapy, and among them, half experienced suboptimal outcomes.
Conclusion：
This study highlighted the stable incidence rates of Crohn's Disease and the increase in immunomodulators and biologic prescriptions, influenced by the current reimbursement policies. It has been demonstrated that biologic treatments effectively reduce hospitalization rates without increasing the risk of infections, despite encountering challenges such as high retreatment rates and suboptimal outcomes following discontinuation due to healthcare policy. These findings emphasize the need to revise treatment models to enhance patient care and guide further research.

[1] J. Torres, S. Mehandru, J.-F. Colombel, and L. Peyrin-Biroulet, "Crohn's disease," The Lancet, vol. 389, no. 10080, pp. 1741-1755, 2017, doi: 10.1016/S0140-6736(16)31711-1.
[2] L. Younge, "An overview of inflammatory bowel disease," (in eng), Nursing standard (Royal College of Nursing (Great Britain) : 1987), vol. 34, no. 1, pp. 75-82, Jan 4 2019, doi: 10.7748/ns.2018.e11265.
[3] S. Alatab et al., "The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017," The Lancet Gastroenterology & Hepatology, vol. 5, no. 1, pp. 17-30, 2020, doi: 10.1016/s2468-1253(19)30333-4.
[4] R. Wang, Z. Li, S. Liu, and D. Zhang, "Global, regional and national burden of inflammatory bowel disease in 204 countries and territories from 1990 to 2019: a systematic analysis based on the Global Burden of Disease Study 2019," BMJ Open, vol. 13, no. 3, p. e065186, 2023, doi: 10.1136/bmjopen-2022-065186.
[5] S. Fourie, D. Jackson, and H. Aveyard, "Living with Inflammatory Bowel Disease: A review of qualitative research studies," (in eng), International journal of nursing studies, vol. 87, pp. 149-156, Nov 2018, doi: 10.1016/j.ijnurstu.2018.07.017.
[6] D. Turner et al., "STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD," Gastroenterology, vol. 160, no. 5, pp. 1570-1583, Apr 2021, doi: 10.1053/j.gastro.2020.12.031.
[7] H.-H. Yen et al., "Epidemiological trend in inflammatory bowel disease in Taiwan from 2001 to 2015: a nationwide populationbased study," Intest Res, vol. 17, no. 1, pp. 54-62, 1 2019, doi: 10.5217/ir.2018.00096.
[8] T. A. Malik, "Inflammatory Bowel Disease: Historical Perspective, Epidemiology, and Risk Factors," (in eng), The Surgical clinics of North America, vol. 95, no. 6, pp. 1105-22, v, Dec 2015, doi: 10.1016/j.suc.2015.07.006.
[9] C. Büning et al., "Mutations in the NOD2/CARD15 gene in Crohn's disease are associated with ileocecal resection and are a risk factor for reoperation," (in eng), Aliment Pharmacol Ther, vol. 19, no. 10, pp. 1073-8, May 15 2004, doi: 10.1111/j.1365-2036.2004.01967.x.
[10] C. I. de Bie et al., "Smoking behaviour and knowledge of the health effects of smoking in patients with inflammatory bowel disease," Alimentary Pharmacology & Therapeutics, vol. 42, 2015.
[11] N. To, D. J. Gracie, and A. C. Ford, "Letter: smoking as a modifiable risk factor for a complicated course in Crohn's disease," Alimentary Pharmacology & Therapeutics, vol. 43, 2016.
[12] Y. Chen, Y. Wang, and J. Shen, "Role of environmental factors in the pathogenesis of Crohn’s disease: a critical review," International Journal of Colorectal Disease, vol. 34, pp. 2023 - 2034, 2019.
[13] N. Li and R.-h. Shi, "Updated review on immune factors in pathogenesis of Crohn’s disease," World journal of gastroenterology, vol. 24, pp. 15 - 22, 2018.
[14] H. de Alencar Junior, A. P. R. Paiotti, H. B. de Araujo Filho, C. T. F. Oshima, S. J. Miszputen, and O. Ambrogini-Júnior, "The relationship between the commensal microbiota levels and Crohn's disease activity," JGH Open: An Open Access Journal of Gastroenterology and Hepatology, vol. 4, pp. 784 - 789, 2020.
[15] C. A. Lamb et al., "British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults," Gut, vol. 68, no. Suppl 3, pp. s1-s106, Dec 2019, doi: 10.1136/gutjnl-2019-318484.
[16] S. C. Wei et al., "Management of Crohn's disease in Taiwan: consensus guideline of the Taiwan Society of Inflammatory Bowel Disease," Intest Res, vol. 15, no. 3, pp. 285-310, Jul 2017, doi: 10.5217/ir.2017.15.3.285.
[17] J. Torres et al., "ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment," J Crohns Colitis, vol. 14, no. 1, pp. 4-22, Jan 1 2020, doi: 10.1093/ecco-jcc/jjz180.
[18] H. J. Su et al., "Inflammatory bowel disease and its treatment in 2018: Global and Taiwanese status updates," (in eng), J Formos Med Assoc, vol. 118, no. 7, pp. 1083-1092, Jul 2019, doi: 10.1016/j.jfma.2018.07.005.
[19] K. C. Cushing and P. D. R. Higgins, "Management of Crohn Disease: A Review," JAMA, vol. 325 1, pp. 69-80, 2021, doi: 10.1001/jama.2020.18936.
[20] K. Barrett, S. Saxena, and R. Pollok, "Using corticosteroids appropriately in inflammatory bowel disease: a guide for primary care," Br J Gen Pract, vol. 68, no. 675, pp. 497-498, Oct 2018, doi: 10.3399/bjgp18X699341.
[21] A. K. Waljee et al., "Corticosteroid Use and Complications in a US Inflammatory Bowel Disease Cohort," PLoS One, vol. 11, no. 6, p. e0158017, 2016, doi: 10.1371/journal.pone.0158017.
[22] S. F. Jeuring et al., "Improvements in the Long-Term Outcome of Crohn's Disease Over the Past Two Decades and the Relation to Changes in Medical Management: Results from the Population-Based IBDSL Cohort," (in eng), Am J Gastroenterol, vol. 112, no. 2, pp. 325-336, Feb 2017, doi: 10.1038/ajg.2016.524.
[23] S. Chang and D. Hudesman, "First-Line Biologics or Small Molecules in Inflammatory Bowel Disease: a Practical Guide for the Clinician," (in eng), Current gastroenterology reports, vol. 22, no. 2, p. 7, Jan 30 2020, doi: 10.1007/s11894-020-0745-y.
[24] G. R. D'Haens and S. van Deventer, "25 years of anti-TNF treatment for inflammatory bowel disease: lessons from the past and a look to the future," Gut, vol. 70, no. 7, pp. 1396-1405, Jul 2021, doi: 10.1136/gutjnl-2019-320022.
[25] 台灣發炎性腸道疾病學會, "克隆氏症台灣診療現況," 2021.
[26] G. R. Lichtenstein, E. V. Loftus, K. L. Isaacs, M. D. Regueiro, L. B. Gerson, and B. E. Sands, "ACG Clinical Guideline: Management of Crohn's Disease in Adults," Am J Gastroenterol, vol. 113, no. 4, pp. 481-517, Apr 2018, doi: 10.1038/ajg.2018.27.
[27] M. T. Weng et al., "Trends of Medication Usage and Associated Outcomes for Taiwanese Patients with Inflammatory Bowel Disease from 2001 to 2015," (in eng), J Clin Med, vol. 7, no. 11, Oct 27 2018, doi: 10.3390/jcm7110394.
[28] S. Alulis et al., "Treatment patterns for biologics in ulcerative colitis and Crohn's disease: a Danish Nationwide Register Study from 2003 to 2015," Scand J Gastroenterol, vol. 55, no. 3, pp. 265-271, Mar 2020, doi: 10.1080/00365521.2020.1726445.
[29] J. E. Brady, M. Stott-Miller, G. Mu, and S. Perera, "Treatment Patterns and Sequencing in Patients With Inflammatory Bowel Disease," Clin Ther, vol. 40, no. 9, pp. 1509-1521 e5, Sep 2018, doi: 10.1016/j.clinthera.2018.07.013.
[30] S. Danese, L. Vuitton, and L. Peyrin-Biroulet, "Biologic agents for IBD: practical insights," Nat Rev Gastroenterol Hepatol, vol. 12, no. 9, pp. 537-45, Sep 2015, doi: 10.1038/nrgastro.2015.135.
[31] S. Paramsothy, A. K. Rosenstein, S. Mehandru, and J. F. Colombel, "The current state of the art for biological therapies and new small molecules in inflammatory bowel disease," (in eng), Mucosal Immunol, vol. 11, no. 6, pp. 1558-1570, Nov 2018, doi: 10.1038/s41385-018-0050-3.
[32] W. J. Sandborn et al., "Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial," (in eng), Gut, vol. 56, no. 9, pp. 1232-9, Sep 2007, doi: 10.1136/gut.2006.106781.
[33] J. F. Colombel et al., "Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial," (in eng), Gastroenterology, vol. 132, no. 1, pp. 52-65, Jan 2007, doi: 10.1053/j.gastro.2006.11.041.
[34] S. B. Hanauer et al., "Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial," The Lancet, vol. 359, no. 9317, pp. 1541-1549, 2002, doi: 10.1016/S0140-6736(02)08512-4.
[35] W. J. Sandborn et al., "Vedolizumab as induction and maintenance therapy for Crohn's disease," (in eng), N Engl J Med, vol. 369, no. 8, pp. 711-21, Aug 22 2013, doi: 10.1056/NEJMoa1215739.
[36] B. E. Sands et al., "Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy," (in eng), Inflamm Bowel Dis, vol. 23, no. 1, pp. 97-106, Jan 2017, doi: 10.1097/mib.0000000000000979.
[37] B. G. Feagan et al., "Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease," (in eng), N Engl J Med, vol. 375, no. 20, pp. 1946-1960, Nov 17 2016, doi: 10.1056/NEJMoa1602773.
[38] H. Seo et al., "Long-Term Outcomes of Adalimumab Treatment in 254 Patients with Crohn's Disease: A Hospital-Based Cohort Study from Korea," (in eng), Dig Dis Sci, vol. 62, no. 10, pp. 2882-2893, Oct 2017, doi: 10.1007/s10620-017-4715-7.
[39] T. Hisamatsu et al., "Long-term safety and effectiveness of adalimumab in Japanese patients with Crohn's disease: 3-year results from a real-world study," (in eng), Intest Res, vol. 19, no. 4, pp. 408-418, Oct 2021, doi: 10.5217/ir.2020.00025.
[40] P. Hoffmann, J. Krisam, W. Stremmel, and A. Gauss, "Real-World Outcomes of Vedolizumab Therapy in Ulcerative Colitis and Crohn's Disease at a Tertiary Referral Center," (in eng), Digestive diseases (Basel, Switzerland), vol. 37, no. 1, pp. 33-44, 2019, doi: 10.1159/000492322.
[41] H. Patel, T. Lissoos, and D. T. Rubin, "Indicators of suboptimal biologic therapy over time in patients with ulcerative colitis and Crohn's disease in the United States," (in eng), PLoS One, vol. 12, no. 4, p. e0175099, 2017, doi: 10.1371/journal.pone.0175099.
[42] J. K. Yamamoto-Furusho et al., "Incidence of suboptimal response to tumor necrosis factor antagonist therapy in inflammatory bowel disease in newly industrialised countries: The EXPLORE study," Dig Liver Dis, vol. 52, no. 8, pp. 869-877, Aug 2020, doi: 10.1016/j.dld.2020.05.031.
[43] N. N. Andersen and T. Jess, "Risk of infections associated with biological treatment in inflammatory bowel disease," World journal of gastroenterology, vol. 20, no. 43, pp. 16014-9, Nov 21 2014, doi: 10.3748/wjg.v20.i43.16014.
[44] C. L. Wheat, C. W. Ko, K. Clark-Snustad, D. Grembowski, T. A. Thornton, and B. Devine, "Inflammatory Bowel Disease (IBD) pharmacotherapy and the risk of serious infection: a systematic review and network meta-analysis," BMC Gastroenterol, vol. 17, no. 1, p. 52, Apr 14 2017, doi: 10.1186/s12876-017-0602-0.
[45] G. R. Lichtenstein et al., "Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT™ registry," (in eng), Am J Gastroenterol, vol. 107, no. 9, pp. 1409-22, Sep 2012, doi: 10.1038/ajg.2012.218.
[46] C. G. Grijalva et al., "Initiation of tumor necrosis factor-α antagonists and the risk of hospitalization for infection in patients with autoimmune diseases," (in eng), Jama, vol. 306, no. 21, pp. 2331-9, Dec 7 2011, doi: 10.1001/jama.2011.1692.
[47] P. Deepak, D. J. Stobaugh, and E. D. Ehrenpreis, "Infectious complications of TNF-α inhibitor monotherapy versus combination therapy with immunomodulators in inflammatory bowel disease: analysis of the Food and Drug Administration Adverse Event Reporting System," (in eng), J Gastrointestin Liver Dis, vol. 22, no. 3, pp. 269-76, Sep 2013.
[48] E. Louis, "Stopping Biologics in IBD-What Is the Evidence?," Inflamm Bowel Dis, vol. 24, no. 4, pp. 725-731, Mar 19 2018, doi: 10.1093/ibd/izx098.
[49] D. T. Rubin, "Restarting Biologic Agents After a Drug Holiday," astroenterology & Hepatology, vol. 15, no. 11, 2019.
[50] E. Louis et al., "Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped," (in eng), Gastroenterology, vol. 142, no. 1, pp. 63-70.e5; quiz e31, Jan 2012, doi: 10.1053/j.gastro.2011.09.034.
[51] J. P. Gisbert, A. C. Marin, and M. Chaparro, "The Risk of Relapse after Anti-TNF Discontinuation in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis," Am J Gastroenterol, vol. 111, no. 5, pp. 632-47, May 2016, doi: 10.1038/ajg.2016.54.
[52] L. Y. Lin, C. Warren-Gash, L. Smeeth, and P. C. Chen, "Data resource profile: the National Health Insurance Research Database (NHIRD)," Epidemiol Health, vol. 40, p. e2018062, 2018, doi: 10.4178/epih.e2018062.
[53] C. Y. Hsieh et al., "Taiwan's National Health Insurance Research Database: past and future," Clin Epidemiol, vol. 11, pp. 349-358, 2019, doi: 10.2147/CLEP.S196293.
[54] G. Chen, T. Lissoos, C. Dieyi, and K. D. Null, "Development and Validation of an Inflammatory Bowel Disease Severity Index Using US Administrative Claims Data: A Retrospective Cohort Study," (in eng), Inflamm Bowel Dis, vol. 27, no. 8, pp. 1177-1183, Jul 27 2021, doi: 10.1093/ibd/izaa263.
[55] Y. Ye, S. Manne, and D. Bennett, "Identifying Patients With Inflammatory Bowel Diseases in an Administrative Health Claims Database: Do Algorithms Generate Similar Findings?," (in eng), Inquiry : a journal of medical care organization, provision and financing, vol. 56, p. 46958019887816, Jan-Dec 2019, doi: 10.1177/0046958019887816.
[56] S. Thirumurthi, R. Chowdhury, P. Richardson, and N. S. Abraham, "Validation of ICD-9-CM diagnostic codes for inflammatory bowel disease among veterans," Dig Dis Sci, vol. 55, no. 9, pp. 2592-8, Sep 2010, doi: 10.1007/s10620-009-1074-z.
[57] M. S. Kwak et al., "Emerging trends of inflammatory bowel disease in South Korea: A nationwide population-based study," J Gastroenterol Hepatol, vol. 34, no. 6, pp. 1018-1026, Jun 2019, doi: 10.1111/jgh.14542.
[58] G. G. Kaplan and J. W. Windsor, "The four epidemiological stages in the global evolution of inflammatory bowel disease," Nat Rev Gastroenterol Hepatol, vol. 18, no. 1, pp. 56-66, Jan 2021, doi: 10.1038/s41575-020-00360-x.
[59] S. C. Ng et al., "Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies," (in eng), Lancet, vol. 390, no. 10114, pp. 2769-2778, Dec 23 2018, doi: 10.1016/s0140-6736(17)32448-0.
[60] S. H. Park, "Update on the epidemiology of inflammatory bowel disease in Asia: where are we now?," Intest Res, vol. 20, no. 2, pp. 159-164, 4 2022, doi: 10.5217/ir.2021.00115.
[61] C. J. Kuo et al., "The Trend of Inflammatory Bowel Diseases in Taiwan: A Population-Based Study," (in eng), Dig Dis Sci, vol. 60, no. 8, pp. 2454-62, Aug 2015, doi: 10.1007/s10620-015-3630-z.
[62] L. Y. Yao et al., "Trends in medication use and treatment patterns in Chinese patients with inflammatory bowel disease," (in eng), World journal of gastroenterology, vol. 28, no. 30, pp. 4102-4119, Aug 14 2022, doi: 10.3748/wjg.v28.i30.4102.
[63] M. Noureldin et al., "Trends of 5-Aminosalicylate Medication Use in Patients With Crohn Disease," (in eng), Inflamm Bowel Dis, vol. 27, no. 4, pp. 516-521, Mar 15 2021, doi: 10.1093/ibd/izaa127.
[64] B. Bokemeyer et al., "Indicators of active disease and steroid dependency in patients with inflammatory bowel diseases not treated with biologics in a German real-world-setting," (in eng), Int J Colorectal Dis, vol. 35, no. 8, pp. 1587-1598, Aug 2020, doi: 10.1007/s00384-020-03588-w.
[65] V. Chhaya et al., "Steroid dependency and trends in prescribing for inflammatory bowel disease - a 20-year national population-based study," Aliment Pharmacol Ther, vol. 44, no. 5, pp. 482-94, Sep 2016, doi: 10.1111/apt.13700.
[66] C. Chen et al., "Real-world Pattern of Biologic Use in Patients With Inflammatory Bowel Disease: Treatment Persistence, Switching, and Importance of Concurrent Immunosuppressive Therapy," (in eng), Inflamm Bowel Dis, vol. 25, no. 8, pp. 1417-1427, Jul 17 2019, doi: 10.1093/ibd/izz001.
[67] E. J. Jang, J. E. Ha, S. G. Im, M. G. Kim, and H. S. Sohn, "A Real-World Analysis of Prescribing Patterns and Non-persistence of Anti-TNFalpha Therapy for Inflammatory Bowel Disease," (in eng), Clin Drug Investig, vol. 39, no. 7, pp. 625-630, Jul 2019, doi: 10.1007/s40261-019-00784-7.
[68] S. H. Park et al., "Long-Term Outcomes of Infliximab Treatment in 582 Korean Patients with Crohn's Disease: A Hospital-Based Cohort Study," Dig Dis Sci, vol. 61, no. 7, pp. 2060-7, Jul 2016, doi: 10.1007/s10620-016-4105-6.
[69] J. Kirchgesner, M. Lemaitre, F. Carrat, M. Zureik, F. Carbonnel, and R. Dray-Spira, "Risk of Serious and Opportunistic Infections Associated With Treatment of Inflammatory Bowel Diseases," Gastroenterology, vol. 155, no. 2, pp. 337-346 e10, Aug 2018, doi: 10.1053/j.gastro.2018.04.012.
[70] S. Singh, A. Facciorusso, P. S. Dulai, V. Jairath, and W. J. Sandborn, "Comparative Risk of Serious Infections With Biologic and/or Immunosuppressive Therapy in Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis," Clin Gastroenterol Hepatol, vol. 18, no. 1, pp. 69-81 e3, Jan 2020, doi: 10.1016/j.cgh.2019.02.044.
[71] N. A. Kennedy et al., "Relapse after withdrawal from anti-TNF therapy for inflammatory bowel disease: an observational study, plus systematic review and meta-analysis," Aliment Pharmacol Ther, vol. 43, no. 8, pp. 910-923, Apr 2016, doi: 10.1111/apt.13547.
[72] M. J. Casanova et al., "Evolution After Anti-TNF Discontinuation in Patients With Inflammatory Bowel Disease: A Multicenter Long-Term Follow-Up Study," Am J Gastroenterol, vol. 112, no. 1, pp. 120-131, Jan 2017, doi: 10.1038/ajg.2016.569.
[73] W. C. Lin et al., "Outcomes of limited period of adalimumab treatment in moderate to severe Crohn's disease patients: Taiwan Society of Inflammatory Bowel Disease Study," (in eng), Intest Res, vol. 15, no. 4, pp. 487-494, Oct 2017, doi: 10.5217/ir.2017.15.4.487.
[74] J. H. Song et al., "Long-term Outcomes after the Discontinuation of Anti-Tumor Necrosis Factor-alpha Therapy in Patients with Inflammatory Bowel Disease under Clinical Remission: A Korean Association for the Study of Intestinal Disease Multicenter Study," Gut Liver, vol. 15, no. 5, pp. 752-762, Sep 15 2021, doi: 10.5009/gnl20233.
[75] G. Doherty et al., "European Crohn's and Colitis Organisation Topical Review on Treatment Withdrawal ['Exit Strategies'] in Inflammatory Bowel Disease," (in eng), J Crohns Colitis, vol. 12, no. 1, pp. 17-31, Jan 5 2018, doi: 10.1093/ecco-jcc/jjx101.