研究背景
發炎性腸道疾病 (Inflammatory bowel disease, IBD) 為自體免疫慢性疾病，分為克隆氏症 (Crohn's disease, CD) 以及潰瘍性大腸炎 (Ulcerative colitis, UC)。此疾病主要發生在西方國家以及已開發國家，然而亞洲和開發中國家在近幾年IBD的發生率與盛行率亦有增加的趨勢。治療藥品分為四大類，包含Aminosalicylates (5-ASA)、類固醇、免疫抑制劑以及近年來開始核准使用的生物製劑。
亞洲國家對於IBD的治療趨勢在近幾年有改變此外關於治療效果的研究相當的少，而台灣的研究也僅止於疾病的流行病學調查，因此本研究目的在討論台灣IBD的治療趨勢、藥品使用情況、共病症以及疾病復發相關因子。

研究方法
由1998年到2010年全民健康保險資料庫之重大傷病證明明細檔，擷取診斷代碼為「555」克隆氏症或「556」潰瘍性大腸炎，且重大傷病申請時間介於2000/1/1至2008/12/31之病患。將其重大傷病申請日定為「指標日期」，追蹤各病患的就醫紀錄以及IBD相關藥品的處方紀錄，分別進行下列分析。
1.藥品使用與疾病復發的累積機率百分比。
2.重大傷病申請前、後藥品使用與疾病復發的比例。
3.疾病復發風險因子的探討。

研究結果
本研究收入1,872位病患，332位為CD病患，其餘1540位罹患UC。CD與UC的平均年齡分別為37.12歲以及44.28歲，男女比為2.19：1及1.54：1。CD與UC病患中，口服5-ASA是疾病確診早期會使用的藥品而且使用比例最高，其第一年、五年及十年的累積機率百分比分別為71.4%、84.9%以及93.0%與68.4%、83.7%以及79.8%。口服類固醇也在疾病早期就開始使用，累積機率百分比分別是37.1%、66.7%以及74.4%與33.1%、51.1%以及61.4%，其中長時間類固醇使用的比例分別為23.5%、39.7%以及44.7%與14.0%、22.8%以及27.4%。Thiopurine類的藥品在台灣的使用比例比其他國家低，其累積機率百分比則為6.9%、16.9%以及21.1%與2.7%、8.0%以及9.7%。不同世代藥品使用的比較裡無論何種藥品，新世代 (2005-2008) 的使用比例都比舊世代 (2000-2004) 高而且使用時間提早，整體治療越趨積極。
大多數的病患主要在重大傷病前、後半年內藥品使用的比例最高，然而在後續的追蹤時間內藥品使用比例則緩慢下降。疾病復發事件的發生比例最高存在於重大傷病申請前半年。
無論是CD或是UC病患，重大傷病申請前有使用過高劑量類固醇或在重大傷病申請後曾經住院者，在未來兩年內都有2.3-2.7倍發生須以高劑量類固醇來控制的疾病嚴重復發。CD病患如果在重大傷病申請之後有使用高劑量類固醇，也能反應出未來疾病嚴重復發增加的風險。UC病患中門診就醫次數較高、重大傷病申請後合併多種藥品治療及重大傷病申請後使用過任何類固醇者，出未來疾病復發風險都會增加，而年齡越大的組別有降低疾病復發的產生。

研究結論
由本研究發現，5-ASA在台灣IBD病患的使用比例遠高於其他國家，類固醇使用情況並無差異，但Thiopurine的使用卻低於其他國家。台灣藥品的使用比其他國家保守，藥品使用趨勢與西方國家十年前的情形相似。因此建議未來台灣地區IBD病患，特別是類固醇依賴性病患，Thiopurine的使用可以更加積極以降低疾病再復發。重大傷病申請前曾使用高劑量類固醇、申請後曾住院、多次就醫以及合併多種藥品的病患，建議選擇比較積極的疾病治療。年齡的增加、手術及Thiopurine的使用則有降低IBD復發的趨勢。

SUMMARY
The incidence and prevalence of inflammatory bowel disease (IBD) in Taiwan was increased in recent year. However, the information of use of medication and disease flare up in Taiwan is still limited. Thus, we conducted a longitudinal study by National Health Insurance Research Database (NHIRD).
The study included the patients who applied catastrophic illness certificate between 2000 and 2008 and analyzed the cumulative probabilities of medication and disease flare up in follow-up period. We also analyzed the risk factors of disease flare up within the 2 year follow-up period.
This current study showed that 5-ASA was the most used medication in Taiwan and the proportion of 5-ASA was higher than the use in other countries. Systemic steroid use in Taiwan has the similar pattern with other studies. However, thiopurine use in Taiwan is less than in other countries. The risk factors of disease flare up were similar in Crohn’s disease (CD) and ulcerative colitis (UC) patients. High dose steroid use before the CIC being applied and hospitalization after CIC being applied would predict the disease flare up in both CD and UC. More clinic visits, combination medication therapy and younger age group would also increase the flare up in UC patient.
Thiopurine use is rare in Taiwan so it should be recommended only in severe patients who need to maintain disease remission. Besides, the patients who had the risk factors would had higher risk of disease severe flare up and need more aggressive strategies for maintaining disease remission.

1. Abraham C, Cho JH. Inflammatory bowel disease. The New England journal of medicine 2009;361:2066-78.
2. Dignass A, Eliakim R, Magro F, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. Journal of Crohn's & colitis 2012;6:965-90.
3. Van Assche G, Dignass A, Panes J, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis. Journal of Crohn's & colitis 2010;4:7-27.
4. Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571-607.
5. 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.
6. Thia KT, Loftus JEV, Sandborn WJ, Yang S-K. An Update on the Epidemiology of Inflammatory Bowel Disease in Asia. The American journal of gastroenterology 2008;103:3167-82.
7. Chuang CH, Lin SH, Chen CY, Sheu BS, Kao AW, Wang JD. Increasing incidence and lifetime risk of inflammatory bowel disease in Taiwan: a nationwide study in a low-endemic area 1998-2010. Inflammatory bowel diseases 2013;19:2815-9.
8. Peng YC, Lin CL, Hsu WY, et al. The risk of colorectal cancer is related to frequent hospitalization of IBD in an Asian population: results from a nationwide study. QJM 2014.
9. Ng SC. Epidemiology of inflammatory bowel disease: focus on Asia. Best practice & research Clinical gastroenterology 2014;28:363-72.
10. Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 2011;140:1785-94.
11. Ng SC, Tsoi KK, Kamm MA, et al. Genetics of inflammatory bowel disease in Asia: systematic review and meta-analysis. Inflammatory bowel diseases 2012;18:1164-76.
12. Prideaux L, Kamm MA, De Cruz PP, Chan FKL, Ng SC. Inflammatory bowel disease in Asia: A systematic review. Journal of gastroenterology and hepatology 2012;27:1266-80.
13. Wallace JL, Sharkey KA. Chapter 47. Pharmacotherapy of Inflammatory Bowel Disease. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. New York, NY: The McGraw-Hill Companies; 2011.
14. Prefontaine E, Sutherland LR, Macdonald JK, Cepoiu M. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease. The Cochrane database of systematic reviews 2009:Cd000067.
15. Chande N, Tsoulis DJ, MacDonald JK. Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. The Cochrane database of systematic reviews 2013;4:Cd000545.
16. Gordon M, Taylor K, Akobeng AK, Thomas AG. Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease. The Cochrane database of systematic reviews 2014;8:Cd010233.
17. Lichtenstein GR, Hanauer SB, Sandborn WJ. Management of Crohn's disease in adults. The American journal of gastroenterology 2009;104:465-83; quiz 4, 84.
18. Osterman MT, Kundu R, Lichtenstein GR, Lewis JD. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology 2006;130:1047-53.
19. Benchimol EI, Cook SF, Erichsen R, et al. International variation in medication prescription rates among elderly patients with inflammatory bowel disease. Journal of Crohn's & colitis 2013;7:878-89.
20. Kaplan GG, Seow CH, Ghosh S, et al. Decreasing colectomy rates for ulcerative colitis: a population-based time trend study. The American journal of gastroenterology 2012;107:1879-87.
21. Rungoe C, Langholz E, Andersson M, et al. Changes in medical treatment and surgery rates in inflammatory bowel disease: a nationwide cohort study 1979-2011. Gut 2014;63:1607-16.
22. Peyrin-Biroulet L, Loftus EV, Jr., Colombel JF, Sandborn WJ. The natural history of adult Crohn's disease in population-based cohorts. The American journal of gastroenterology 2010;105:289-97.
23. Nguyen GC, Nugent Z, Shaw S, Bernstein CN. Outcomes of patients with Crohn's disease improved from 1988 to 2008 and were associated with increased specialist care. Gastroenterology 2011;141:90-7.
24. Vester-Andersen MK, Prosberg MV, Jess T, et al. Disease course and surgery rates in inflammatory bowel disease: a population-based, 7-year follow-up study in the era of immunomodulating therapy. The American journal of gastroenterology 2014;109:705-14.
25. Williet N, Pillot C, Oussalah A, et al. Incidence of and impact of medications on colectomy in newly diagnosed ulcerative colitis in the era of biologics. Inflammatory bowel diseases 2012;18:1641-6.
26. Lee HS, Park SH, Yang SK, et al. Long-term prognosis of ulcerative colitis and its temporal change between 1977 and 2013: a hospital-based cohort study from Korea. Journal of Crohn's & colitis 2015;9:147-55.
27. Sung JJ, Kamm MA, Marteau P. Asian perspectives in the management of inflammatory bowel disease: findings from a recent survey. Journal of gastroenterology and hepatology 2010;25:183-93.
28. Park SH, Yang SK, Park SK, et al. Long-term prognosis of crohn's disease and its temporal change between 1981 and 2012: a hospital-based cohort study from Korea. Inflammatory bowel diseases 2014;20:488-94.
29. Chen C-Y, Lee K-T, Charles Tzu-Chi L, Lai W-T, Huang Y-B. Epidemiology and Disease Burden of Ulcerative Colitis in Taiwan: A Nationwide Population-Based Study. Value in Health Regional Issues 2013;2:127-34.
30. Frolkis AD, Dykeman J, Negron ME, et al. Risk of surgery for inflammatory bowel diseases has decreased over time: a systematic review and meta-analysis of population-based studies. Gastroenterology 2013;145:996-1006.
31. Jung YS, Park DI, Ye BD, et al. Long-term clinical outcomes of urban versus rural environment in Korean patients with Crohn's disease: results from the CONNECT study. Journal of Crohn's & colitis 2015;9:246-51.
32. Chen M, Yi F, Zhou F, et al. Risk factors for initial surgery in patients with Crohn's disease in Central China. Surg Today 2014.
33. Song XM, Gao X, Li MZ, et al. Clinical features and risk factors for primary surgery in 205 patients with Crohn's disease: analysis of a South China cohort. Dis Colon Rectum 2011;54:1147-54.
34. Ye BD, Yang SK, Cho YK, et al. Clinical features and long-term prognosis of Crohn's disease in Korea. Scandinavian journal of gastroenterology 2010;45:1178-85.
35. Sato Y, Matsui T, Yano Y, et al. Long-term course of Crohn's disease in Japan: Incidence of complications, cumulative rate of initial surgery, and risk factors at diagnosis for initial surgery. Journal of gastroenterology and hepatology 2015.
36. Chow DK, Leong RW, Tsoi KK, et al. Long-term follow-up of ulcerative colitis in the Chinese population. The American journal of gastroenterology 2009;104:647-54.
37. Hilmi I, Singh R, Ganesananthan S, et al. Demography and clinical course of ulcerative colitis in a multiracial Asian population: a nationwide study from Malaysia. J Dig Dis 2009;10:15-20.
38. The International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM). March 2015, at http://http://icd9cm.chrisendres.com/.)
39. 高雅慧, 鄭靜蘭. 健保給付藥品品項的藥品藥理治療分類代碼之建立. 100年度委託科技研究計畫期末報告2011.
40. Tsai MS, Lin CL, Chen HP, Lee PH, Sung FC, Kao CH. Long-term risk of acute coronary syndrome in patients with inflammatory bowel disease: a 13-year nationwide cohort study in an Asian population. Inflammatory bowel diseases 2014;20:502-7.
41. Wei SC, Lin MH, Tung CC, et al. A nationwide population-based study of the inflammatory bowel diseases between 1998 and 2008 in Taiwan. BMC gastroenterology 2013;13:166.
42. Kuo CJ, Yu KH, See LC, et al. The Trend of Inflammatory Bowel Diseases in Taiwan: A Population-Based Study. Digestive diseases and sciences 2015.
43. Prideaux L, Kamm MA, De Cruz PP, Chan FK, Ng SC. Inflammatory bowel disease in Asia: a systematic review. Journal of gastroenterology and hepatology 2012;27:1266-80.
44. Peyrin-Biroulet L, Oussalah A, Williet N, Pillot C, Bresler L, Bigard MA. ParkImpact of azathioprine and tumour necrosis factor antagonists on the need for surgery in newly diagnosed Crohn's disease. Gut 2011;60:930-6.
45. Dignass 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. Journal of Crohn's & colitis 2010;4:28-62.
46. Ford AC, Kane SV, Khan KJ, et al. Efficacy of 5-aminosalicylates in Crohn's disease: systematic review and meta-analysis. The American journal of gastroenterology 2011;106:617-29.
47. Lim WC, Hanauer S. Aminosalicylates for induction of remission or response in Crohn's disease. The Cochrane database of systematic reviews 2010:CD008870.
48. Gordon M, Naidoo K, Thomas AG, Akobeng AK. Oral 5-aminosalicylic acid for maintenance of surgically-induced remission in Crohn's disease. The Cochrane database of systematic reviews 2011:CD008414.
49. Duricova D, Pedersen N, Elkjaer M, Jensen JK, Munkholm P. 5-aminosalicylic acid dependency in Crohn's disease: a Danish Crohn Colitis Database study. Journal of Crohn's & colitis 2010;4:575-81.
50. Moja L, Danese S, Fiorino G, Del Giovane C, Bonovas S. Systematic review with network meta-analysis: comparative efficacy and safety of budesonide and mesalazine (mesalamine) for Crohn's disease. Alimentary pharmacology & therapeutics 2015;41:1055-65.
51. Schoepfer AM, Bortolotti M, Pittet V, et al. The gap between scientific evidence and clinical practice: 5-aminosalicylates are frequently used for the treatment of Crohn's disease. Alimentary pharmacology & therapeutics 2014;40:930-7.
52. Sebastian S, Hernandez V, Myrelid P, et al. Colorectal cancer in inflammatory bowel disease: results of the 3rd ECCO pathogenesis scientific workshop (I). Journal of Crohn's & colitis 2014;8:5-18.
53. Zhao LN, Li JY, Yu T, Chen GC, Yuan YH, Chen QK. 5-Aminosalicylates reduce the risk of colorectal neoplasia in patients with ulcerative colitis: an updated meta-analysis. PloS one 2014;9:e94208.
54. Chow DK, Sung JJ, Tsoi KK, et al. Predictors of corticosteroid-dependent and corticosteroid-refractory inflammatory bowel disease: analysis of a Chinese cohort study. Alimentary pharmacology & therapeutics 2009;29:843-54.
55. Samuel S, Ingle SB, Dhillon S, et al. Cumulative incidence and risk factors for hospitalization and surgery in a population-based cohort of ulcerative colitis. Inflammatory bowel diseases 2013;19:1858-66.
56. Vester-Andersen MK, Vind I, Prosberg MV, et al. Hospitalisation, surgical and medical recurrence rates in inflammatory bowel disease 2003-2011-a Danish population-based cohort study. Journal of Crohn's & colitis 2014;8:1675-83.
57. Khan N, Abbas AM, Bazzano LA, Koleva YN, Krousel-Wood M. Long-term oral mesalazine adherence and the risk of disease flare in ulcerative colitis: nationwide 10-year retrospective cohort from the veterans affairs healthcare system. Alimentary pharmacology & therapeutics 2012;36:755-64.
58. Bernstein CN, Loftus EV, Jr., Ng SC, Lakatos PL, Moum B. Hospitalisations and surgery in Crohn's disease. Gut 2012;61:622-9.
59. Vavricka SR, Spigaglia SM, Rogler G, et al. Systematic evaluation of risk factors for diagnostic delay in inflammatory bowel disease. Inflammatory bowel diseases 2012;18:496-505.
60. Kane S, Huo D, Aikens J, Hanauer S. Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis. Am J Med 2003;114:39-43.
61. Robinson A, Hankins M, Wiseman G, Jones M. Maintaining stable symptom control in inflammatory bowel disease: a retrospective analysis of adherence, medication switches and the risk of relapse. Alimentary pharmacology & therapeutics 2013;38:531-8.
62. Kawakami A, Tanaka M, Nishigaki M, et al. Relationship between non-adherence to aminosalicylate medication and the risk of clinical relapse among Japanese patients with ulcerative colitis in clinical remission: a prospective cohort study. Journal of gastroenterology 2013;48:1006-15.
63. Mitra D, Hodgkins P, Yen L, Davis KL, Cohen RD. Association between oral 5-ASA adherence and health care utilization and costs among patients with active ulcerative colitis. BMC gastroenterology 2012;12:132.
64. Kane S, Shaya F. Medication non-adherence is associated with increased medical health care costs. Digestive diseases and sciences 2008;53:1020-4.
65. Ramadas AV, Gunesh S, Thomas GA, Williams GT, Hawthorne AB. Natural history of Crohn's disease in a population-based cohort from Cardiff (1986-2003): a study of changes in medical treatment and surgical resection rates. Gut 2010;59:1200-6.
66. Beaugerie L, Seksik P, Nion-Larmurier I, Gendre JP, Cosnes J. Predictors of Crohn's disease. Gastroenterology 2006;130:650-6.
67. Targownik LE, Nugent Z, Singh H, Bernstein CN. Prevalence of and outcomes associated with corticosteroid prescription in inflammatory bowel disease. Inflammatory bowel diseases 2014;20:622-30.
68. Yarur AJ, Strobel SG, Deshpande AR, Abreu MT. Predictors of Aggressive Inflammatory Bowel Disease. Gastroenterology & Hepatology 2011;7:652-9.
69. Romberg-Camps MJ, Dagnelie PC, Kester AD, et al. Influence of phenotype at diagnosis and of other potential prognostic factors on the course of inflammatory bowel disease. The American journal of gastroenterology 2009;104:371-83.
70. Solberg IC, Vatn MH, Hoie O, et al. Clinical course in Crohn's disease: results of a Norwegian population-based ten-year follow-up study. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2007;5:1430-8.
71. Moon CM, Park DI, Kim ER, et al. Clinical features and predictors of clinical outcomes in Korean patients with Crohn's disease: a Korean association for the study of intestinal diseases multicenter study. Journal of gastroenterology and hepatology 2014;29:74-82.
72. Roth LS, Chande N, Ponich T, Roth ML, Gregor J. Predictors of disease severity in ulcerative colitis patients from Southwestern Ontario. World journal of gastroenterology : WJG 2010;16:232-6.
73. Timmer A, McDonald JW, Tsoulis DJ, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. The Cochrane database of systematic reviews 2012;9:CD000478.
74. Lakatos PL, Golovics PA, David G, et al. Has there been a change in the natural history of Crohn's disease? Surgical rates and medical management in a population-based inception cohort from Western Hungary between 1977-2009. The American journal of gastroenterology 2012;107:579-88.
75. Chatu S, Subramanian V, Saxena S, Pollok RC. The role of thiopurines in reducing the need for surgical resection in Crohn's disease: a systematic review and meta-analysis. The American journal of gastroenterology 2014;109:23-34; quiz 5.
76. Panes J, Lopez-Sanroman A, Bermejo F, et al. Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn's disease. Gastroenterology 2013;145:766-74 e1.
77. Cosnes J, Bourrier A, Laharie D, et al. Early administration of azathioprine vs conventional management of Crohn's Disease: a randomized controlled trial. Gastroenterology 2013;145:758-65 e2; quiz e14-5.
78. Kyllo RL, Anadkat MJ. Dermatologic adverse events to chemotherapeutic agents, part 1: cytotoxics, epidermal growth factor receptors, multikinase inhibitors, and proteasome inhibitors. Seminars in cutaneous medicine and surgery 2014;33:28-39.
79. Lacouture ME, Wu S, Robert C, et al. Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. The oncologist 2008;13:1001-11.
80. 抗癌藥物治療自我照護手冊. 台灣癌症臨床研究發展基金會; 2006.
81. Managing Chemotherapy Side Effects. National Cancer Institute, 2015. at http://www.cancer.gov/about-cancer/treatment/side-effects.)
82. Loprinzi CL, Bensinger WI, Peterson DE, Messner C. Understanding and Managing Chemotherapy Side Effects. Cancercare; 2014.
83. Anderson R, Jatoi A, Robert C, Wood LS, Keating KN, Lacouture ME. Search for evidence-based approaches for the prevention and palliation of hand-foot skin reaction (HFSR) caused by the multikinase inhibitors (MKIs). The oncologist 2009;14:291-302.
84. Wood LS, Lemont H, Jatoi A, et al. Practical considerations in the management of hand-foot skin reaction caused by multikinase inhibitors 2010.
85. Manchen E, Robert C, Porta C. Management of tyrosine kinase inhibitor-induced hand-foot skin reaction: viewpoints from the medical oncologist, dermatologist, and oncology nurse. The journal of supportive oncology 2011;9:13-23.
86. Wood LS. Managing the side effects of sorafenib and sunitinib. community oncology 2006.
87. Lilly E, Burke M, Kluger H, Choi J. PRegabalin for the treatment of painful hand-foot skin reaction associated with dabrafenib. JAMA Dermatology 2015;151:102-3.
88. Ren Z, Zhu K, Kang H, et al. Randomized controlled trial of the prophylactic effect of urea-based cream on sorafenib-associated hand-foot skin reactions in patients with advanced hepatocellular carcinoma. J Clin Oncol 2015;33:894-900.