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Treatment of inflammatory bowel disease in Asia: the results of a multinational web-based survey in the 2nd Asian Organization of Crohn's and Colitis (AOCC) meeting in Seoul

Treatment of inflammatory bowel disease in Asia: the results of a multinational web-based survey... ORIGINAL ARTICLE pISSN • eISSN 1598-9100 2288-1956 http://dx.doi.org/10.5217/ir.2016.14.3.231 Intest Res 2016;14(3):231-239 Treatment of inflammatory bowel disease in Asia: the nd results of a multinational web-based survey in the 2 Asian Organization of Crohn’s and Colitis (AOCC) meeting in Seoul 1 2 3 4 5 6 Hiroshi Nakase *, Bora Keum *, Byoung Duk Ye , Soo Jung Park , Hoon Sup Koo , Chang Soo Eun 1 2 Department of Gastroenterology and Hepatology, Sapporo Medical University, School of Medicine, Sapporo, Japan, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea, Department of Gastroenterology, Asan Medical Center, University of Ulsan 4 5 College of Medicine, Seoul, Korea, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea, Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea, Department of Internal Medicine, Hanyang University Guri Hosptial, Guri, Korea Background/Aims: Inflammatory bowel disease (IBD) management guidelines have been released from Western countries, but no adequate data on the application of these guidelines in Asian countries and no surveys on the treatment of IBD in real practice exist. Since there is a growing need for a customized consensus for IBD treatment in Asian countries, Asian Organi- zation of Crohn’s and Colitis performed a multinational survey of medical doctors who treat IBD patients in Asian countries. Methods: A questionnaire was developed between August 2013 and November 2013. It was composed of 4 domains: personal information, IBD diagnosis, IBD treatment, and quality of IBD care. Upon completion of the questionnaire, a web-based survey was conducted between 17 March 2014 and 12 May 2014. Results: In total, 353 medical doctors treating IBD from ten Asian countries responded to the survey. This survey data suggested a difference in available medical treatments (budesonide, tacro- limus) among Asian countries. Therapeutic strategies regarding refractory IBD (acute severe ulcerative colitis [UC] refractory to intravenous steroids and refractory Crohn’s disease [CD]) and active UC were coincident, however, induction therapies for mild to moderate inflammatory small bowel CD are different among Asian countries. Conclusions: This survey demonstrated that current therapeutic approaches and clinical management of IBD vary among Asian countries. Based on these results and discussions, we hope that optimal management guidelines for Asian IBD patients will be developed. (Intest Res 2016;14:231-239) Key Words: Asia; Inflammatory bowel diseases; Treatment; A web-survey INTRODUCTION Received April 4, 2016. Revised April 6, 2016. Accepted April 6, 2016. Inflammatory bowel disease (IBD) incidence and preva- Correspondence to Hiroshi Nakase, Department of Gastroenterology and lence have increased since the middle of the 20th Century. Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan. Tel: +81-11-611-2111, Fax: +81-11- Several studies indicated a dramatic rise of disease inci - 613-12411, E-mail: [email protected] dence not only in Western countries but also in Asian coun- *These authors contributed equally to this study. 1,2 tries. Until now, Asian physicians treating IBD patients Financial support: This work was supported by the Japanese Society for the have referred to consensus guidelines provided by Western Promotion of Science “KAKENHI” 24590941 and supported in part by Health and Labour Sciences Research Grants for research on intractable diseases committees. However, Asian physicians always consider from the Ministry of Health, Labour and Welfare of Japan (Investigation whether IBD treatment and diagnosis in Asia should be per- and Research for Intractable Inflammatory Bowel Disease). Conflict of formed the same way as in Western countries because the interest: None. © Copyright 2016. Korean Association for the Study of Intestinal Diseases. All rights reserved. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Hiroshi Nakase, et al. • Treatment of IBD in Asia differences in genetic background and environmental fac- RESULTS tors between Asian and Western countries are great. In ad- dition, the types of approved drugs differ even among Asian 1. Participant Characteristics countries. Under complicated circumstances, Asian physi- cians as well as Western physicians face common problems In total, 353 physicians from Korea, China, Japan, India, regarding what to do for patients with refractory IBD, such Hong Kong, Singapore, Taiwan, Malaysia, the Philippines, as second-line therapies for steroid-refractory UC and thera- and Indonesia participated in this survey. Most respondents peutic strategies for refractory CD with loss of response to were gastroenterologists who worked in academic teaching anti-tumor necrosis factor (TNF) therapies. hospitals. Thus, there is a growing need for a customized consensus for IBD treatment in Asian countries. For this purpose, the 2. UC Management Asian Organization of Crohn’s and Colitis (AOCC) per- formed a multinational survey of medical doctors who treat 1) Initial Treatment of Mild to Moderate UC IBD patients in Asian countries. For the treatment of mild to moderate UC, topical 5-ami- Our intent is to establish optimal treatment guidelines for nosalicylic acid (5-ASA) was most preferred, followed by Asian IBD patients based on of data from a multinational oral 5-ASA. In patients with left-sided UC, oral 5-ASA was survey of medical doctors treating IBD patients. most preferred, followed by topical 5-ASA. Many physicians used oral 5-ASA in combination with topical 5-ASA. Among participants, Chinese physicians preferred to use topical METHODS and systemic steroids compared with physicians from other Members of the IBD Study Group of Korean Association countries. for the Study of Intestinal Diseases (KASID) developed a The treatment employed for mild to moderate extensive questionnaire between August 2013 and November 2013. It UC is shown in Fig. 1. Oral 5-ASA was most preferred, fol- was composed of 4 domains: personal information (9 items), lowed by systemic steroids. In comparison with treatment IBD diagnosis (18 items), IBD treatment (30 items), and for left-sided UC and proctitis, systemic steroid use was pre- quality of IBD care (36 items). KASID officers and colleagues ferred, although physicians might consider cases refractory in China (M.H.C.) and Japan (H.N.) peer-reviewed the ques- to oral and topical 5-ASA. tionnaire. The questionnaires are shown in the Appendix. Upon completion of the questionnaire, a web-based survey 2) Treatment of Acute Severe UC was conducted between 17 March 2014 and 12 May 2014. It is very important that physicians cooperate with sur- geons when managing acute severe UC. Regarding surgical consultation at treatment initiation for acute severe UC, phy- sicians in China, Japan, and other countries always and usu- ally consult surgeons, while physicians in Korea sometimes and rarely consult them. Data regarding this question are quite different between Korea and other Asian countries. We usually use intravenous (IV) steroids for acute severe China Japan Korea Others UC; however, 69% and 28% of physicians judged the thera- Topical 5-ASA peutic response 3−5 days and 6−9 days after initiating IV ste- 17.8 8.8 16.4 4.5 47.5% (168) roids, respectively (Fig. 2). Thus, 93% of physicians assessed Topical steroids 12.2 3.9 3.72.8 22.6% steroid response as soon as possible because patients with (80) acute severe UC sometimes require second-line therapy and Oral 5-ASA 29.7 23.8 30.3 8.8 92.6% surgical treatment. (327) Regarding second-line therapy for patients with acute Systemic steroids 17.8 12.2 11.9 5.9 47.8% severe UC refractory to IV steroids, many physicians in Asia (169) except Japan selected anti-TNF therapies, followed by cy- (%) 020406080 100 closporine. On the other hand, Japanese physicians selected Fig. 1. The treatment employed for mild to moderate extensive UC. tacrolimus (TAC), followed by anti-TNF therapies. A few 5-ASA, 5-aminosalicylic acid. 232 www.irjournal.org http://dx.doi.org/10.5217/ir.2016.14.3.231 • Intest Res 2016;14(3):231-239 Cyclosporine Anti-TNF agent (infliximab or adalimumab) 2% Tacrolimus Leukocytapheresis Others Colectomy without changing medication 5% On 3-5 days On 6-9 days China (114) 45 60 On 10-14 days After 14 days 28% Japan (88) 61657 8 65% Korea (116) 12 102 11 19 2 22 Other (35) (%) 020406080 100 Fig. 2. The time assessing response to intravenous steroids in acute severe UC. Fig. 3. Second-line therapies in acute severe UC when intravenous ste- roids fail. TNF, tumor necrosis factor. Japanese physicians selected apheresis therapies (Fig. 3). 3. CD Management 3) Treatment of Steroid-dependent or Steroid-refrac- 1) Treatment of CD according to disease Involvement tory UC This question was regarding the treatment of steroid- and Activity For induction therapy in mild to moderate inflammatory dependent UC. Many physicians in Asia favored the use of thiopurines. Overall, 78% of physicians selected thiopurines, small bowel CD, many Asian physicians considered the use of 5-ASA. Of note, survey data showed that more physicians and 11% of them selected anti-TNF therapies. Some Japa- nese physicians (3% of all participants) selected TAC and in Japan and China selected nutritional therapy than those in Korea and other Asian countries. In addition, Japanese apheresis. For steroid-refractory UC, many physicians in Asia except physicians did not prefer the corticosteroid use when treat- ing patients with mild to moderate active small intestinal CD Japan selected anti-TNF therapies in combination with thio- purines, while Japanese physicians selected TAC, followed (Fig. 5). In cases of mild to moderate inflammatory colonic CD, a similar tendency was observed. by anti-TNF. Overall, 44% of participants selected anti-TNF for steroid-refractory UC. Regarding the treatment of severe inflammatory small bowel CD, 25% of participants selected prednisolone in Cytomegalovirus (CMV) and Clostridium difficile infec- tion are possible factors exacerbating UC flares. Regarding combination with 5-ASA, followed by anti-TNF therapies (14%), nutritional therapy (14%), and thiopurines (13%). how concerned physicians are about these infections in cases of severe UC attacks, many physicians in China, Japan, Only 3% of physicians selected budesonides. Physicians in Japan and China preferred anti-TNF therapies, while those and Korea always tested for CMV infection; however, only 12% of other Asian physicians always tested for it. Overall, in Korea preferred prednisolone. In treating severe inflammatory colonic CD, a similar 59% of physicians always checked for CMV infection in se- vere UC. In C. difficile infection, a similar tendency was ob- tendency was observed. Physicians in Japan and China pre- ferred anti-TNF, while those in Korea and other Asian coun- served. Thus, most physicians in Asia are likely to consider the involvement of these infections in severe attacks of UC tries preferred prednisolone for remission induction. (Fig. 4). 2) Treatment of CD according to Disease Course These questions were regarding Asian physicians’ ap- 4) Maintenance of Remission When we use maintenance treatment with 5-ASA, ad- proach towards treating steroid-dependent or refractory CD. In cases of steroid-dependent CD, most physicians preferred herence to 5-ASA drugs is an important issue. This survey showed that many physicians seemed to prescribe 5-ASA to use thiopurine, followed by anti-TNF therapies. However, when treating steroid-refractory CD, physicians considered two times or once daily. Overall, 54% and 15% of participants selected twice daily and once daily regimens, respectively. using anti-TNF agents. In particular, Japanese physicians strongly favored anti-TNF agents. www.irjournal.org 233 Hiroshi Nakase, et al. • Treatment of IBD in Asia Always Usually Always Rarely Sometimes Usually Never Rarely Never Sometimes 1% China (114) 61 16 23 11 5% Japan (88) 66 15 6 14% Korea (116) 70 30 14 59% 20% 12 10 8 4 Other (35) 020406080 100 (%) Always Usually Always Rarely Usually Never Sometimes Rarely Never Sometimes China (114) 45 21 22 15 11 4% 7% Japan (88) 48 20 17 19% 48% Korea (116) 62 28 19 6 22% Fig. 4. Test for cytomegalovirus (CMV) Other (35) 13 98 32 and Clostridium difficile infection in a severe UC attack. 020406080 100 (%) 5-ASA Budesonide Antibiotics naïve CD patients, overall, 15% of participants always pre- Prednisolone Nutritional therapy Others ferred combination therapy and 41% usually preferred it. Interestingly, Japanese physicians preferred monotherapy China compared with physicians from other countries (Fig. 6). The duration of combination therapy is a clinically impor- Japan tant issue for physicians and patients because we are always concerned about its risks. Overall, 25% and 29% of Asian Korea physicians tended to continue combination therapy for 6 months and 1 year, respectively. In addition, Japanese physi- Others cians strongly preferred to continue combination therapy for a longer time (>2 years) (Fig. 7). 020406080 100 (%) When asked how to treat non-responders to anti-TNF Fig. 5. Induction therapy in mild to moderate inflammatory small therapies, all physicians agreed with dose escalation, fol- bowel CD. 5-ASA, 5-aminosalicylic acid. lowed by changing to another anti-TNF agents. Interestingly, >40% of physicians in China favored checking serum trough We sometimes encounter cases of thiopurine-intolerant levels of anti-TNF antibodies. or refractory CD. Most physicians favored anti-TNF antibod- ies. A few physicians in China and other countries selected 4) Maintenance of Remission methotrexate (MTX). Most physicians favored combination therapy in CD pa- tients whose remission was induced by anti-TNF therapies. 3) Treatment with Anti-TNF agents in CD In particular, Korean physicians favored combination thera- Regarding combination therapy with anti-TNF antibodies py compared with physicians from other countries. and thiopurines or anti-TNF monotherapy for thiopurine- 234 www.irjournal.org C. diffcicle CMV http://dx.doi.org/10.5217/ir.2016.14.3.231 • Intest Res 2016;14(3):231-239 Always Usually Always Rarely Sometimes Usually Never Rarely Never Sometimes China 16 36 5% 15% 11% Japan 237 Korea 27 59 28% 41% 913 Fig. 6. Combinationtherapy vs. monother- Other apy for remission induction in thiopurine- naïve inflammatory CD. 020406080 100(%) 2 years 6 months 1 year 6 month 1 year More than2 years Others 2 years More than2 years China 48 40 9 91 Others 5% Japan 31115 59 0 25% 23 38 13 35 7 Korea 30% Others 14 13 3 23 Fig. 7. Duration of combination therapy 29% 11% with an anti-tumor necrosis factor (TNF) (%) 020406080 100 agent and thiopurine for remission induction. 5) Monitoring When asked what treatments they would consider in post- To monitor CD patients during treatments, most physi- operative CD patients with moderate to severe endoscopic cians used clinical activity, blood tests, and colonoscopy recurrence who had been treated with a maximum thiopu- for disease monitoring. As for other imaging modalities, a rine dose, all Asian physicians agreed with additional use of few physicians favored CT enterography (11%), followed by anti-TNF agents. magnetic resonance (MR) enterography (6%). Regarding the treatment of postoperative CD patients When asked whether they monitored 6-thioguanine with moderate to severe endoscopic recurrence who had nucleotides and 6-methylmercaptopurine levels, serum inf- been treated with anti-TNF therapies, all Asian physicians liximab (IFX) levels, and antibodies to IFX (ATI), most physi- considered additional use of thiopurine, dose escalation, or cians answered “No.” These data indicated that facilities for shortened intervals of anti-TNF therapies. routine monitoring of these values in Asia are limited. DISCUSSION 6) Prerention of Post-operative Recurrence in CD As to when physicians performed colonoscopy for post- The present survey demonstrates that current therapeutic operative CD patients, most physicians performed it within approaches and clinical management of IBD vary among 1 year after the operation, even in patients who did not have Asian countries. First, this survey focused on UC treatment. abdominal symptoms related to CD flares. All participants agreed with 5-ASA use for mild to moder- When asked what treatments they would consider in ate UC as a first-line therapy with little difference among postoperative CD patients with moderate to severe endo- Asian countries. In the current survey, there was no ques- scopic recurrence who had been treated with 5-ASA, many tion regarding the optimal 5-ASA dose for induction and physicians selected thiopurine or anti-TNF agents. Japanese maintenance of remission or the 5-ASA types mainly used physicians preferred anti-TNF agents in comparison with in their countries. However, meta-analysis data have already thiopurines. demonstrated that there do not appear to be any differences www.irjournal.org 235 Hiroshi Nakase, et al. • Treatment of IBD in Asia in efficacy or safety among the various 5-ASA formulations. assessed the short-term outcomes of 29 severe UC patients In addition, a 2.4-g daily dosage appears to be a safe and ef- treated with TAC or IFX and concluded that the effects of fective induction therapy for patients with mild to moderate TAC are potentially similar to those of IFX on severe UC, active UC. Patients with moderate disease may benefit from despite the limited number of enrolled patients. Overall, the an initial dose of 4.8 g/day. Thus, although Asian physicians rescue effect of CIs (both cyclosporine and TAC) as second- need a consensus on the optimal 5-ASA dosage for induc- line therapies for severe UC refractory to IV corticosteroids tion of remission and maintenance for UC patients, this sur- is similar to that of IFX. However, how to optimally select vey showed that most physicians agreed with 5-ASA use as a CIs or IFX in such clinical settings remains unclear. first-line therapy. As for steroid-dependent UC, most physicians agree with The survey data from question 10 showed that many the use of thiopurines for tapering corticosteroids. The physicians prescribe 5-ASA two times or once daily because thiopurines, azathioprine and its metabolite 6-mercapto- they kept the patient’s adherence in mind. However, a meta- purine, are purine analogs that effectively maintain remis- analysis showed that adherence does not appear to be sion in patients with IBD, particularly in steroid-refractory enhanced by once daily dosing in the clinical trial setting. or steroid-dependent disease. All participants recognized Whether once daily dosing of 5-ASA improves adherence in that the effect of thiopurine on refractory IBD is apparent in a community-based setting is unknown, and whether time- clinical practice. Only a few prospective studies and meta- decreasing prescriptions contribute to favorable effects for analyses have been reported, although little is known about UC patients might depend on not only adherence but also the long-term clinical outcomes of UC patients who initially mucosal concentration of 5-ASA. responded to thiopurine treatment. Most importantly, when Despite the development of several medical therapies, patients who are maintained in remission on azathioprine acute severe UC treatment is still challenging. All partici- or 6-mercaptopurine discontinue their medications, a very 8-10 pants considered consulting surgeons when treating acute high relapse rate of 70%−87% occurs. In this regard, our severe UC. Additionally, 93% of physicians assessed steroid next step is to survey how to optimize the dose of thiopurine response within 9 days. Taken together, these data suggested drugs and how long we should continue thiopurines for that many physicians felt the importance of cooperation maintenance. To establish this, we might require votes re- with surgeons for starting severe acute UC treatment and the garding the adjustment of thiopurine dose as the European necessity of rapid decision-making in patients with UC who Crohn’s and Colitis Organization members did. fail to respond to IV steroids. The next question concerned Numerous case series have reported the involvement of optimal second-line therapy for patients with acute severe CMV and C. difficile infection in patients with severe UC UC refractory to IV steroids. In general, for patients with refractory to standard immunosuppressive therapy because refractory acute severe UC, after initially using IV steroids the prognosis of patients with UC complicated by these in- for 5−7 days, possible treatment choices included either IV fections is poor. Survey data demonstrated that more than cyclosporine or IV IFX. Most physicians in Asia except Japan half of physicians in China, Japan, and Korea always tested selected anti-TNF therapies, followed by cyclosporine. On for CMV and C. difficile infection in refractory UC cases. the contrary, Japanese physicians favored TAC, followed CMV is often overlooked in refractory UC cases, and it is of by anti-TNF therapies. A few Japanese physicians selected particular importance to have an expert pathologist carefully apheresis therapies. These survey data strongly suggested examine mucosal biopsies for evidence of this pathogen. a difference in available medical treatments among Asian However, previous survey data showed that many physi- countries. cians diagnosed CMV infection with antigenemia assay, Which is better as a second-line therapy for steroid-refrac- although many experts recognized that CMV antigenemia tory severe UC, anti-TNF therapy or calcineurin inhibitors assay was not necessarily useful for the decision to start anti- (CIs)? Use of both cyclosoprine and IFX has appeared to viral therapy. As reported previously, the sensitivity of CMV be effective and safe as a rescue therapy compared to pla- diagnosis with histopathology in biopsy specimens was cebo in acute severe UC; however, data regarding head-to- relatively low. Therefore, we always encounter a dilemma head comparisons of CIs and anti-TNF agents are limited regarding diagnosis of CMV infection in refractory UC pa- and based on retrospective observational studies. Also, no tients. Unfortunately, the questions of this survey did not prospective studies have compared the efficacy of TAC with include diagnostic criteria regarding CMV infection. In the IFX as a second-line therapy. Minami et al. retrospectively future, we will need a consensus on the diagnosis of CMV 236 www.irjournal.org http://dx.doi.org/10.5217/ir.2016.14.3.231 • Intest Res 2016;14(3):231-239 infection in Asia. This is a big issue for clinical practice. efficacy data with these agents are limited to those collected Survey data regarding induction therapy for mild to mod- during relatively short-term (up to 1 year) clinical trials. erate inflammatory small bowel CD showed that many Because of the chronic relapsing and progressive nature of Asian physicians first selected 5-ASA. Of note, this survey re- CD, clinical trial data over longer durations of treatment are vealed that more physicians in Japan and China selected nu- desirable to demonstrate both long-term efficacy and safety tritional therapy than those in Korea and other Asian coun- of these agents. tries. Safety and therapeutic efficacy of nutritional therapy Considering several risks of combination therapy, mono- for CD patients is well known, despite no placebo-controlled therapy might be favorable after remission induction with trial data. Whether physicians select nutritional therapy combination therapy. However, the outcome of anti-TNF depends on patients’ acceptability, convenience, and adher- therapy cessation for CD in clinical and/or endoscopic re- ence. Treatment for severe inflammatory small bowel CD mission in routine clinical practice is uncertain. Louis et al. varied among the countries. Overall, 25% of participants reported that approximately 50% of 115 patients with CD selected prednisolone in combination with 5-ASA, followed who were treated for at least 1 year with IFX and an antime- by anti-TNF therapies, nutritional therapy, and thiopurines. tabolite agent experienced a relapse within 1 year after IFX Only 3% of physicians selected budesonides, which might discontinuation. In addition, they commented that patients differ from the tendency in Western countries. Also, the use with a low risk of relapse can be identified using a combina- of budesonide might be limited to the countries whose gov- tion of clinical and biologic markers. ernments permit its use. Of note, physicians in Japan and Brooks et al. also reported that relapse rates at 1 year fol- China selected anti-TNF therapies, while those in Korea se- lowing elective withdrawal of anti-TNF were 36%, with high lected prednisolone. In treating severe inflammatory colonic retreatment response rates. Predictors of relapse include CD, a similar tendency was observed. Overall, physicians in ileocolonic involvement, previous anti-TNF therapy, and Japan and China preferred to use anti-TNF therapies, while raised fecal calprotectin. As mentioned previously, we will those in Korea and other Asian countries preferred prednis- need to identify several factors (clinical and biologic mark- olone for remission induction. The reason why preferences ers) that contribute to the cessation of anti-TNF therapies in differed in remission induction among Asian countries re- CD patients in the future. mains unclear. A recent critical issue is the therapeutic strategy for treat- Treatments for steroid-dependent and refractory CD were ing CD patients who lose response to anti-TNF therapy. thiopurine drugs and anti-TNF agents, which Asian physi- Also, no consensus exists regarding therapies for patients cians selected first. These results were similar to those for UC with CD refractory to anti-TNF therapy and thiopurines. All treatment. Recently, data from Western countries suggested physicians considered dose escalation, followed by chang- 22,23 the following factors as potential predictors of an aggressive ing to another anti-TNF agent. In cases refractory to a disease course in CD: age <40 years at diagnosis, presence of standard regimen of anti-TNF therapies, a pharmacokinetic perianal lesions, early need for steroids, severe endoscopic study measuring serum trough levels of anti-TNF antibodies, 16-19 lesions, and the existence of NOD2/CARD15 mutation. ATI, and anti-adalimumab antibodies will be required in the In these cases, Western physicians would recommend top- future, as >40% of the participants in China checked serum down therapy with anti-TNF antibodies. Therefore, in AOCC, trough levels of anti-TNF antibodies. The survey results for Asian physicians cooperate to identify the risk factors in question 5-3 and 5-4 showed that most physicians could which poor prognoses of Asian CD patients are involved to not check serum trough levels of IFX, ATI, and 6TG levels determine who requires early anti-TNF therapies. in RBC. However, this monitoring is essential for optimizing Most physicians favored combination therapy in CD treatment for individual IBD patients. patients whose remission was induced by anti-TNF thera- To monitor CD patients, many physicians used clinical ac- pies. In particular, Korean physicians favored combination tivity, blood tests, and colonoscopy for disease monitoring. therapy compared with physicians in other countries. Also, On imaging modalities for evaluating small intestinal lesions, Japanese physicians strongly preferred to continue combi- physicians favored CT enterography, followed by 6-thiogua- nation therapy for more time. However, the optimal duration nine nucleotides enterography. These data suggested that of combination anti-TNF therapies and thiopurine for CD many Asian physicians were not familiar with using MR remains unclear. The use of anti-TNF antibodies has sig- enterography to follow CD patients. However, the sensitiv- nificantly impacted the management of CD patients. Most ity and specificity of MRI for the detection of active disease www.irjournal.org 237 Hiroshi Nakase, et al. • Treatment of IBD in Asia and correlation with segmental endoscopic disease severity REFERENCES and detection of complications are high, with >80% sensi- 1. Ng SC, Tang W, Ching JY, et al. Incidence and phenotype of tivity and >90% specificity. MRI also has been a valuable inflammatory bowel disease based on results from the Asia- tool in the assessment of response to therapy; pathological pacific Crohn’s and colitis epidemiology study. 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Accuracy of magnetic reso- prine/biological therapy are predictors of disease behavior nance enterography in assessing response to therapy and mu- change in patients with Crohn’s disease. World J Gastroenterol cosal healing in patients with Crohn’s disease. Gastroenterology 2009;15:3504-3510. 2014;146:374-382. 19. Dubinsky MC. Serologic and laboratory markers in prediction 26. Jones GR, Kennedy NA, Lees CW, Arnott ID, Satsangi J. System- of the disease course in inflammatory bowel disease. World J atic review: The use of thiopurines or anti-TNF in post-oper- Gastroenterol 2010;16:2604-2608. ative Crohn’s disease maintenance – progress and prospects. 20. Louis E, Mary JY, Vernier-Massouille G, et al. Maintenance of re- Aliment Pharmacol Ther 2014;39:1253-1265. mission among patients with Crohn’s disease on antimetabolite 27. Baudry C, Pariente B, Lourenço N, et al. Tailored treatment therapy after infliximab therapy is stopped. Gastroenterology according to early post-surgery colonoscopy reduces clinical 2012;142:63-70. recurrence in Crohn’s disease: a retrospective study. Dig Liver Dis 2014;46:887-892. www.irjournal.org 239 nd See “Treatment of inflammatory bowel disease in Asia: the results of a multinational web-based survey in the 2 Asian Orga- nization of Crohn’s and Colitis (AOCC) meeting in Seoul” on page 231. Appendix. Questionnaires regarding the treatment of IBD Practice pattern for the treatment of ulcerative colitis [1] Initial treatment of mild to moderate UC 1-1. Which of the followings would you use to treat mild to moderate ulcerative proctitis? (Please choose all of the followings that you use) 1) Topical 5-ASA(suppository or enema) 2) Topical steroids 3) Oral 5-ASA 4) Systemic steroids 1-2. Which of the followings would you use to treat mild to moderate left-sided active UC? (Please choose all of the followings that you use) 1) Topical 5-ASA (suppository or enema) 2) Topical steroids 3) Oral 5-ASA 4) Systemic steroids 1-3. Which of the followings would you use to treat mild to moderately extensive UC? (Please choose all of the followings that you use) 1) Topical 5-ASA (suppository or enema) 2) Topical steroids 3) Oral 5-ASA 4) Systemic steroids [2] Treatment of acute severe UC 2-1. How often do you seek consultation from a surgeon at the initiation of treatment for patients with acute severe UC? 1) Always 2) Usually 3) Sometimes 4) Rarely 5) Never 2-2. When would you first assess response to intravenous corticosteroids therapy in patients with acute severe UC? 1) On 3−5 days 2) On 6−9 days 3) On 10−14 days 4) After 14 days nd 2-3. Which of the followings would you consider 2 -line therapy for acute severe UC patients who fail to improve on in- travenous corticosteroids? 1) Cyclosporine 2) Anti-TNF agent (infliximab or adalimumab) 3) Tacrolimus 4) Leukocytapheresis 5) Colectomy without changing medication 6) Others (please specify, ) [3] Treatment of steroid-dependent or steroid-refractory UC 3-1. Which of the followings would be your first choice for steroid-dependent UC? 1) Repeated steroid regimens 2) Thiopurines (azathioprine or 6-mercaptopurine) 3) Anti-TNF agent (infliximab or adalimumab) 4) Tacrolimus 5) Leukocytapheresis 6) Colectomy 7) Others (please specify, ) 3-2. Which of the followings would be your first choice for steroid-refractory UC? 1) Repeated steroid regimens 2) Thiopurines (azathioprine or 6-mercaptopurine) 3) Anti-TNF agent (infliximab or adalimumab) 4) Tacrolimus 5) Leukocytapheresis 6) Colectomy 7) Others (please specify, ) 3-3. How often would you test for Cytomegalovirus (CMV) infection in a severe attack of UC? 1) Always 2) Usually 3) Sometimes 4) Rarely 5) Never 3-4. How often would you test for Clostridium difficile infection in a severe attack of UC? 1) Always 2) Usually 3) Sometimes 4) Rarely 5) Never [4] Maintenance of remission 4-1. How would you prescribe a regimen of oral 5-ASA for maintenance of remission in UC? 1) Once daily 2) Two times daily 3) Three times daily 4) Four times daily Practice pattern for the treatment of Crohn’s disease [1] Treatment of CD according to disease involvement and disease activity 1-1. Which of the followings would you use for the first induction of remission in mild to moderate inflammatory small bowel CD (with or without colonic involvement)? (If you use combination therapy, please choose all of the follow- ings that you use) 1) 5-ASA 2) Budesonide 3) Antibiotics 4) Prednisolone 5) Nutritional therapy 6) Others (please specify, ) 1-2. Which of the followings would you use for the first induction of remission in mild to moderate inflammatory co- lonic CD (without small bowel involvement)? (If you use combination therapy, please choose all of the followings that you use) 1) 5-ASA 2) Budesonide 3) Antibiotics 4) Prednisolone 5) Nutritional therapy 6) Others (please specify, ) 1-3. Which of the followings would you use for the first induction of remission in moderate to severe inflammatory small bowel CD (with or without colonic involvement)? (If you use combination therapy, please choose all of the followings that you use) 1) 5-ASA 2) Budesonide 3) Antibiotics 4) Prednisolone 5) Thiopurine 6) Methotrexate 7) Anti-TNF agent 8) Nutritional therapy 9) Others (please specify, ) 1-4. Which of the followings would you use for the first induction of remission in moderate to severe inflammatory co- lonic CD (without small bowel involvement)? (If you use combination therapy, please choose all of the followings that you use) 1) 5-ASA 2) Budesonide 3) Antibiotics 4) Prednisolone 5) Thiopurine 6) Methotrexate 7) Anti-TNF agent 8) Nutritional therapy 9) Others (please specify, ) [2] Treatment of CD according to disease course 2-1.Which of the followings would be your first choice for treatment of steroid-dependent CD? 1) Thiopurine 2) Methotrexate 3) Tacrolimus 4) Anti-TNF agent 5) Others (please specify, ) 2-2. Which of the followings would be your first choice for treatment of steroid-refractory CD? 1) Thiopurine 2) Methotrexate 3) Tacrolimus 4) Anti-TNF agent 5) Others (please specify, ) 2-3. Which of the followings would you use for treatment of thiopurine-refractory or intolerant CD? 1) Methotrexate 2) Tacrolimus 3) Anti-TNF agent 4) Others (please specify, ) [3] Treatment with anti-TNF agents in CD 3-1. How often do you use thiopurine in combination with anti-TNF agents rather than anti-TNF monotherapy for induc- tion of remission in thiopurine-naïve inflammatory CD? 1) Always 2) Usually 3) Sometimes 4) Rarely 5) Never 3-2. How long would you use combination therapy with anti-TNF agents and thiopurine for induction of remission? 1) 6 months 2) 1 year 3) 2years 4) More than 2 years 5) Others (please specify, ) 3-3. How would you treat non-responders to anti-TNF therapy? 1) I would make a decision according to the serum levels of anti-TNF agents and antibodies to anti-TNF agents. 2) I would use empiric dose escalation (double dosing or shortening of drug interval). 3) I would change to another anti-TNF agents. 4) Others (please specify, ) [4] Maintenance of remission 4-1. Which of the followings would you use for maintenance of remission in CD patients whose remission has been in- duced with prednisolone? (If you use combination therapy, please choose all of the followings that you use) 1) 5-ASA 2) Budesonide 3) Antibiotics 4) Prednisolone 5) Thiopurine 6) Methotrexate 7) Anti-TNF agent 8) Nutritional therapy 9) Others (please specify, ) 4-2. Which of the followings would you use for maintenance of remission in CD patients whose remission has been in- duced with anti-TNF agents? 1) Anti-TNF agent only 2) Thiopurine only 3) Combination therapy with anti-TNF agent and thiopurine 4) Others (please specify, ) [5] Monitoring 5-1. What would you use for monitoring disease activity during treatment of CD? (Please choose all of the followings that you use) 1) Clinical activity index 2) Colonoscopy 3) Video capsule endoscopy 4) Wired enteroscopy (balloon-assisted enteroscopy, sonde enteroscopy, or push enteroscopy) 5) Blood tests (CRP/ESR) 6) Fecal calprotectin 7) Magnetic resonance enterography/enteroclysis 8) Computed tomographic enterography/enteroclysis 9) Bowel ultrasonography 10) Others (please specify, ) 5-3. Is it available to monitor the level of 6-TGN, 6-MMP in your practice? 1) Yes 2) No 5-4. Is it available to monitor the level of serum infliximab and antibodies to infliximab in your practice? 1) Yes 2) No [6] Prevention of post-operative recurrence in CD 6-1. When would you perform colonoscopy after surgery in CD patients? 1) I seldom perform colonoscopy after surgery. 2) When clinical symptoms worsen 3) 6 months after surgery 4) 12 months after surgery 5) Others (please specify, ) 6-2. Which of the followings would you use to treat postoperative CD patients with moderate to severe endoscopic re- currence, who have been treated with 5-ASA? (If you use combination therapy, please choose all of the followings that you use) 1) 5-ASA 2) Thiopurine 3) Metronidazole 4) Anti-TNF agent 5) Others (please specify, ) 6-3. Which of the followings would you use to treat postoperative CD patients with moderate to severe endoscopic re- currence, who have been treated with the maximal tolerable dose of thiopurine? (If you use combination therapy, please choose all of the followings that you use) 1) Thiopurine 2) Metronidazole 3) Anti-TNF agent 4) Others (please specify, ) 6-4. Which of the followings would you use to treat postoperative CD patients with moderate to severe endoscopic re- currence, who have been treated with an anti-TNF agent? (If you use combination therapy, please choose all of the following that you use) 1) Add thiopurine 2) Add metronidazole 3) Maintain anti-TNF agent 4) Dose escalation or reduction of infusion intervals of anti-TNF agents 5) Others (please specify, ) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Intestinal Research Pubmed Central

Treatment of inflammatory bowel disease in Asia: the results of a multinational web-based survey in the 2nd Asian Organization of Crohn's and Colitis (AOCC) meeting in Seoul

Nakase, Hiroshi; Keum, Bora; Ye, Byoung Duk; Park, Soo Jung; Koo, Hoon Sup; Eun, Chang Soo
Intestinal Research , Volume 14 (3) – Jun 27, 2016
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10.5217/ir.2016.14.3.231
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ORIGINAL ARTICLE pISSN • eISSN 1598-9100 2288-1956 http://dx.doi.org/10.5217/ir.2016.14.3.231 Intest Res 2016;14(3):231-239 Treatment of inflammatory bowel disease in Asia: the nd results of a multinational web-based survey in the 2 Asian Organization of Crohn’s and Colitis (AOCC) meeting in Seoul 1 2 3 4 5 6 Hiroshi Nakase *, Bora Keum *, Byoung Duk Ye , Soo Jung Park , Hoon Sup Koo , Chang Soo Eun 1 2 Department of Gastroenterology and Hepatology, Sapporo Medical University, School of Medicine, Sapporo, Japan, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea, Department of Gastroenterology, Asan Medical Center, University of Ulsan 4 5 College of Medicine, Seoul, Korea, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea, Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea, Department of Internal Medicine, Hanyang University Guri Hosptial, Guri, Korea Background/Aims: Inflammatory bowel disease (IBD) management guidelines have been released from Western countries, but no adequate data on the application of these guidelines in Asian countries and no surveys on the treatment of IBD in real practice exist. Since there is a growing need for a customized consensus for IBD treatment in Asian countries, Asian Organi- zation of Crohn’s and Colitis performed a multinational survey of medical doctors who treat IBD patients in Asian countries. Methods: A questionnaire was developed between August 2013 and November 2013. It was composed of 4 domains: personal information, IBD diagnosis, IBD treatment, and quality of IBD care. Upon completion of the questionnaire, a web-based survey was conducted between 17 March 2014 and 12 May 2014. Results: In total, 353 medical doctors treating IBD from ten Asian countries responded to the survey. This survey data suggested a difference in available medical treatments (budesonide, tacro- limus) among Asian countries. Therapeutic strategies regarding refractory IBD (acute severe ulcerative colitis [UC] refractory to intravenous steroids and refractory Crohn’s disease [CD]) and active UC were coincident, however, induction therapies for mild to moderate inflammatory small bowel CD are different among Asian countries. Conclusions: This survey demonstrated that current therapeutic approaches and clinical management of IBD vary among Asian countries. Based on these results and discussions, we hope that optimal management guidelines for Asian IBD patients will be developed. (Intest Res 2016;14:231-239) Key Words: Asia; Inflammatory bowel diseases; Treatment; A web-survey INTRODUCTION Received April 4, 2016. Revised April 6, 2016. Accepted April 6, 2016. Inflammatory bowel disease (IBD) incidence and preva- Correspondence to Hiroshi Nakase, Department of Gastroenterology and lence have increased since the middle of the 20th Century. Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan. Tel: +81-11-611-2111, Fax: +81-11- Several studies indicated a dramatic rise of disease inci - 613-12411, E-mail: [email protected] dence not only in Western countries but also in Asian coun- *These authors contributed equally to this study. 1,2 tries. Until now, Asian physicians treating IBD patients Financial support: This work was supported by the Japanese Society for the have referred to consensus guidelines provided by Western Promotion of Science “KAKENHI” 24590941 and supported in part by Health and Labour Sciences Research Grants for research on intractable diseases committees. However, Asian physicians always consider from the Ministry of Health, Labour and Welfare of Japan (Investigation whether IBD treatment and diagnosis in Asia should be per- and Research for Intractable Inflammatory Bowel Disease). Conflict of formed the same way as in Western countries because the interest: None. © Copyright 2016. Korean Association for the Study of Intestinal Diseases. All rights reserved. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Hiroshi Nakase, et al. • Treatment of IBD in Asia differences in genetic background and environmental fac- RESULTS tors between Asian and Western countries are great. In ad- dition, the types of approved drugs differ even among Asian 1. Participant Characteristics countries. Under complicated circumstances, Asian physi- cians as well as Western physicians face common problems In total, 353 physicians from Korea, China, Japan, India, regarding what to do for patients with refractory IBD, such Hong Kong, Singapore, Taiwan, Malaysia, the Philippines, as second-line therapies for steroid-refractory UC and thera- and Indonesia participated in this survey. Most respondents peutic strategies for refractory CD with loss of response to were gastroenterologists who worked in academic teaching anti-tumor necrosis factor (TNF) therapies. hospitals. Thus, there is a growing need for a customized consensus for IBD treatment in Asian countries. For this purpose, the 2. UC Management Asian Organization of Crohn’s and Colitis (AOCC) per- formed a multinational survey of medical doctors who treat 1) Initial Treatment of Mild to Moderate UC IBD patients in Asian countries. For the treatment of mild to moderate UC, topical 5-ami- Our intent is to establish optimal treatment guidelines for nosalicylic acid (5-ASA) was most preferred, followed by Asian IBD patients based on of data from a multinational oral 5-ASA. In patients with left-sided UC, oral 5-ASA was survey of medical doctors treating IBD patients. most preferred, followed by topical 5-ASA. Many physicians used oral 5-ASA in combination with topical 5-ASA. Among participants, Chinese physicians preferred to use topical METHODS and systemic steroids compared with physicians from other Members of the IBD Study Group of Korean Association countries. for the Study of Intestinal Diseases (KASID) developed a The treatment employed for mild to moderate extensive questionnaire between August 2013 and November 2013. It UC is shown in Fig. 1. Oral 5-ASA was most preferred, fol- was composed of 4 domains: personal information (9 items), lowed by systemic steroids. In comparison with treatment IBD diagnosis (18 items), IBD treatment (30 items), and for left-sided UC and proctitis, systemic steroid use was pre- quality of IBD care (36 items). KASID officers and colleagues ferred, although physicians might consider cases refractory in China (M.H.C.) and Japan (H.N.) peer-reviewed the ques- to oral and topical 5-ASA. tionnaire. The questionnaires are shown in the Appendix. Upon completion of the questionnaire, a web-based survey 2) Treatment of Acute Severe UC was conducted between 17 March 2014 and 12 May 2014. It is very important that physicians cooperate with sur- geons when managing acute severe UC. Regarding surgical consultation at treatment initiation for acute severe UC, phy- sicians in China, Japan, and other countries always and usu- ally consult surgeons, while physicians in Korea sometimes and rarely consult them. Data regarding this question are quite different between Korea and other Asian countries. We usually use intravenous (IV) steroids for acute severe China Japan Korea Others UC; however, 69% and 28% of physicians judged the thera- Topical 5-ASA peutic response 3−5 days and 6−9 days after initiating IV ste- 17.8 8.8 16.4 4.5 47.5% (168) roids, respectively (Fig. 2). Thus, 93% of physicians assessed Topical steroids 12.2 3.9 3.72.8 22.6% steroid response as soon as possible because patients with (80) acute severe UC sometimes require second-line therapy and Oral 5-ASA 29.7 23.8 30.3 8.8 92.6% surgical treatment. (327) Regarding second-line therapy for patients with acute Systemic steroids 17.8 12.2 11.9 5.9 47.8% severe UC refractory to IV steroids, many physicians in Asia (169) except Japan selected anti-TNF therapies, followed by cy- (%) 020406080 100 closporine. On the other hand, Japanese physicians selected Fig. 1. The treatment employed for mild to moderate extensive UC. tacrolimus (TAC), followed by anti-TNF therapies. A few 5-ASA, 5-aminosalicylic acid. 232 www.irjournal.org http://dx.doi.org/10.5217/ir.2016.14.3.231 • Intest Res 2016;14(3):231-239 Cyclosporine Anti-TNF agent (infliximab or adalimumab) 2% Tacrolimus Leukocytapheresis Others Colectomy without changing medication 5% On 3-5 days On 6-9 days China (114) 45 60 On 10-14 days After 14 days 28% Japan (88) 61657 8 65% Korea (116) 12 102 11 19 2 22 Other (35) (%) 020406080 100 Fig. 2. The time assessing response to intravenous steroids in acute severe UC. Fig. 3. Second-line therapies in acute severe UC when intravenous ste- roids fail. TNF, tumor necrosis factor. Japanese physicians selected apheresis therapies (Fig. 3). 3. CD Management 3) Treatment of Steroid-dependent or Steroid-refrac- 1) Treatment of CD according to disease Involvement tory UC This question was regarding the treatment of steroid- and Activity For induction therapy in mild to moderate inflammatory dependent UC. Many physicians in Asia favored the use of thiopurines. Overall, 78% of physicians selected thiopurines, small bowel CD, many Asian physicians considered the use of 5-ASA. Of note, survey data showed that more physicians and 11% of them selected anti-TNF therapies. Some Japa- nese physicians (3% of all participants) selected TAC and in Japan and China selected nutritional therapy than those in Korea and other Asian countries. In addition, Japanese apheresis. For steroid-refractory UC, many physicians in Asia except physicians did not prefer the corticosteroid use when treat- ing patients with mild to moderate active small intestinal CD Japan selected anti-TNF therapies in combination with thio- purines, while Japanese physicians selected TAC, followed (Fig. 5). In cases of mild to moderate inflammatory colonic CD, a similar tendency was observed. by anti-TNF. Overall, 44% of participants selected anti-TNF for steroid-refractory UC. Regarding the treatment of severe inflammatory small bowel CD, 25% of participants selected prednisolone in Cytomegalovirus (CMV) and Clostridium difficile infec- tion are possible factors exacerbating UC flares. Regarding combination with 5-ASA, followed by anti-TNF therapies (14%), nutritional therapy (14%), and thiopurines (13%). how concerned physicians are about these infections in cases of severe UC attacks, many physicians in China, Japan, Only 3% of physicians selected budesonides. Physicians in Japan and China preferred anti-TNF therapies, while those and Korea always tested for CMV infection; however, only 12% of other Asian physicians always tested for it. Overall, in Korea preferred prednisolone. In treating severe inflammatory colonic CD, a similar 59% of physicians always checked for CMV infection in se- vere UC. In C. difficile infection, a similar tendency was ob- tendency was observed. Physicians in Japan and China pre- ferred anti-TNF, while those in Korea and other Asian coun- served. Thus, most physicians in Asia are likely to consider the involvement of these infections in severe attacks of UC tries preferred prednisolone for remission induction. (Fig. 4). 2) Treatment of CD according to Disease Course These questions were regarding Asian physicians’ ap- 4) Maintenance of Remission When we use maintenance treatment with 5-ASA, ad- proach towards treating steroid-dependent or refractory CD. In cases of steroid-dependent CD, most physicians preferred herence to 5-ASA drugs is an important issue. This survey showed that many physicians seemed to prescribe 5-ASA to use thiopurine, followed by anti-TNF therapies. However, when treating steroid-refractory CD, physicians considered two times or once daily. Overall, 54% and 15% of participants selected twice daily and once daily regimens, respectively. using anti-TNF agents. In particular, Japanese physicians strongly favored anti-TNF agents. www.irjournal.org 233 Hiroshi Nakase, et al. • Treatment of IBD in Asia Always Usually Always Rarely Sometimes Usually Never Rarely Never Sometimes 1% China (114) 61 16 23 11 5% Japan (88) 66 15 6 14% Korea (116) 70 30 14 59% 20% 12 10 8 4 Other (35) 020406080 100 (%) Always Usually Always Rarely Usually Never Sometimes Rarely Never Sometimes China (114) 45 21 22 15 11 4% 7% Japan (88) 48 20 17 19% 48% Korea (116) 62 28 19 6 22% Fig. 4. Test for cytomegalovirus (CMV) Other (35) 13 98 32 and Clostridium difficile infection in a severe UC attack. 020406080 100 (%) 5-ASA Budesonide Antibiotics naïve CD patients, overall, 15% of participants always pre- Prednisolone Nutritional therapy Others ferred combination therapy and 41% usually preferred it. Interestingly, Japanese physicians preferred monotherapy China compared with physicians from other countries (Fig. 6). The duration of combination therapy is a clinically impor- Japan tant issue for physicians and patients because we are always concerned about its risks. Overall, 25% and 29% of Asian Korea physicians tended to continue combination therapy for 6 months and 1 year, respectively. In addition, Japanese physi- Others cians strongly preferred to continue combination therapy for a longer time (>2 years) (Fig. 7). 020406080 100 (%) When asked how to treat non-responders to anti-TNF Fig. 5. Induction therapy in mild to moderate inflammatory small therapies, all physicians agreed with dose escalation, fol- bowel CD. 5-ASA, 5-aminosalicylic acid. lowed by changing to another anti-TNF agents. Interestingly, >40% of physicians in China favored checking serum trough We sometimes encounter cases of thiopurine-intolerant levels of anti-TNF antibodies. or refractory CD. Most physicians favored anti-TNF antibod- ies. A few physicians in China and other countries selected 4) Maintenance of Remission methotrexate (MTX). Most physicians favored combination therapy in CD pa- tients whose remission was induced by anti-TNF therapies. 3) Treatment with Anti-TNF agents in CD In particular, Korean physicians favored combination thera- Regarding combination therapy with anti-TNF antibodies py compared with physicians from other countries. and thiopurines or anti-TNF monotherapy for thiopurine- 234 www.irjournal.org C. diffcicle CMV http://dx.doi.org/10.5217/ir.2016.14.3.231 • Intest Res 2016;14(3):231-239 Always Usually Always Rarely Sometimes Usually Never Rarely Never Sometimes China 16 36 5% 15% 11% Japan 237 Korea 27 59 28% 41% 913 Fig. 6. Combinationtherapy vs. monother- Other apy for remission induction in thiopurine- naïve inflammatory CD. 020406080 100(%) 2 years 6 months 1 year 6 month 1 year More than2 years Others 2 years More than2 years China 48 40 9 91 Others 5% Japan 31115 59 0 25% 23 38 13 35 7 Korea 30% Others 14 13 3 23 Fig. 7. Duration of combination therapy 29% 11% with an anti-tumor necrosis factor (TNF) (%) 020406080 100 agent and thiopurine for remission induction. 5) Monitoring When asked what treatments they would consider in post- To monitor CD patients during treatments, most physi- operative CD patients with moderate to severe endoscopic cians used clinical activity, blood tests, and colonoscopy recurrence who had been treated with a maximum thiopu- for disease monitoring. As for other imaging modalities, a rine dose, all Asian physicians agreed with additional use of few physicians favored CT enterography (11%), followed by anti-TNF agents. magnetic resonance (MR) enterography (6%). Regarding the treatment of postoperative CD patients When asked whether they monitored 6-thioguanine with moderate to severe endoscopic recurrence who had nucleotides and 6-methylmercaptopurine levels, serum inf- been treated with anti-TNF therapies, all Asian physicians liximab (IFX) levels, and antibodies to IFX (ATI), most physi- considered additional use of thiopurine, dose escalation, or cians answered “No.” These data indicated that facilities for shortened intervals of anti-TNF therapies. routine monitoring of these values in Asia are limited. DISCUSSION 6) Prerention of Post-operative Recurrence in CD As to when physicians performed colonoscopy for post- The present survey demonstrates that current therapeutic operative CD patients, most physicians performed it within approaches and clinical management of IBD vary among 1 year after the operation, even in patients who did not have Asian countries. First, this survey focused on UC treatment. abdominal symptoms related to CD flares. All participants agreed with 5-ASA use for mild to moder- When asked what treatments they would consider in ate UC as a first-line therapy with little difference among postoperative CD patients with moderate to severe endo- Asian countries. In the current survey, there was no ques- scopic recurrence who had been treated with 5-ASA, many tion regarding the optimal 5-ASA dose for induction and physicians selected thiopurine or anti-TNF agents. Japanese maintenance of remission or the 5-ASA types mainly used physicians preferred anti-TNF agents in comparison with in their countries. However, meta-analysis data have already thiopurines. demonstrated that there do not appear to be any differences www.irjournal.org 235 Hiroshi Nakase, et al. • Treatment of IBD in Asia in efficacy or safety among the various 5-ASA formulations. assessed the short-term outcomes of 29 severe UC patients In addition, a 2.4-g daily dosage appears to be a safe and ef- treated with TAC or IFX and concluded that the effects of fective induction therapy for patients with mild to moderate TAC are potentially similar to those of IFX on severe UC, active UC. Patients with moderate disease may benefit from despite the limited number of enrolled patients. Overall, the an initial dose of 4.8 g/day. Thus, although Asian physicians rescue effect of CIs (both cyclosporine and TAC) as second- need a consensus on the optimal 5-ASA dosage for induc- line therapies for severe UC refractory to IV corticosteroids tion of remission and maintenance for UC patients, this sur- is similar to that of IFX. However, how to optimally select vey showed that most physicians agreed with 5-ASA use as a CIs or IFX in such clinical settings remains unclear. first-line therapy. As for steroid-dependent UC, most physicians agree with The survey data from question 10 showed that many the use of thiopurines for tapering corticosteroids. The physicians prescribe 5-ASA two times or once daily because thiopurines, azathioprine and its metabolite 6-mercapto- they kept the patient’s adherence in mind. However, a meta- purine, are purine analogs that effectively maintain remis- analysis showed that adherence does not appear to be sion in patients with IBD, particularly in steroid-refractory enhanced by once daily dosing in the clinical trial setting. or steroid-dependent disease. All participants recognized Whether once daily dosing of 5-ASA improves adherence in that the effect of thiopurine on refractory IBD is apparent in a community-based setting is unknown, and whether time- clinical practice. Only a few prospective studies and meta- decreasing prescriptions contribute to favorable effects for analyses have been reported, although little is known about UC patients might depend on not only adherence but also the long-term clinical outcomes of UC patients who initially mucosal concentration of 5-ASA. responded to thiopurine treatment. Most importantly, when Despite the development of several medical therapies, patients who are maintained in remission on azathioprine acute severe UC treatment is still challenging. All partici- or 6-mercaptopurine discontinue their medications, a very 8-10 pants considered consulting surgeons when treating acute high relapse rate of 70%−87% occurs. In this regard, our severe UC. Additionally, 93% of physicians assessed steroid next step is to survey how to optimize the dose of thiopurine response within 9 days. Taken together, these data suggested drugs and how long we should continue thiopurines for that many physicians felt the importance of cooperation maintenance. To establish this, we might require votes re- with surgeons for starting severe acute UC treatment and the garding the adjustment of thiopurine dose as the European necessity of rapid decision-making in patients with UC who Crohn’s and Colitis Organization members did. fail to respond to IV steroids. The next question concerned Numerous case series have reported the involvement of optimal second-line therapy for patients with acute severe CMV and C. difficile infection in patients with severe UC UC refractory to IV steroids. In general, for patients with refractory to standard immunosuppressive therapy because refractory acute severe UC, after initially using IV steroids the prognosis of patients with UC complicated by these in- for 5−7 days, possible treatment choices included either IV fections is poor. Survey data demonstrated that more than cyclosporine or IV IFX. Most physicians in Asia except Japan half of physicians in China, Japan, and Korea always tested selected anti-TNF therapies, followed by cyclosporine. On for CMV and C. difficile infection in refractory UC cases. the contrary, Japanese physicians favored TAC, followed CMV is often overlooked in refractory UC cases, and it is of by anti-TNF therapies. A few Japanese physicians selected particular importance to have an expert pathologist carefully apheresis therapies. These survey data strongly suggested examine mucosal biopsies for evidence of this pathogen. a difference in available medical treatments among Asian However, previous survey data showed that many physi- countries. cians diagnosed CMV infection with antigenemia assay, Which is better as a second-line therapy for steroid-refrac- although many experts recognized that CMV antigenemia tory severe UC, anti-TNF therapy or calcineurin inhibitors assay was not necessarily useful for the decision to start anti- (CIs)? Use of both cyclosoprine and IFX has appeared to viral therapy. As reported previously, the sensitivity of CMV be effective and safe as a rescue therapy compared to pla- diagnosis with histopathology in biopsy specimens was cebo in acute severe UC; however, data regarding head-to- relatively low. Therefore, we always encounter a dilemma head comparisons of CIs and anti-TNF agents are limited regarding diagnosis of CMV infection in refractory UC pa- and based on retrospective observational studies. Also, no tients. Unfortunately, the questions of this survey did not prospective studies have compared the efficacy of TAC with include diagnostic criteria regarding CMV infection. In the IFX as a second-line therapy. Minami et al. retrospectively future, we will need a consensus on the diagnosis of CMV 236 www.irjournal.org http://dx.doi.org/10.5217/ir.2016.14.3.231 • Intest Res 2016;14(3):231-239 infection in Asia. This is a big issue for clinical practice. efficacy data with these agents are limited to those collected Survey data regarding induction therapy for mild to mod- during relatively short-term (up to 1 year) clinical trials. erate inflammatory small bowel CD showed that many Because of the chronic relapsing and progressive nature of Asian physicians first selected 5-ASA. Of note, this survey re- CD, clinical trial data over longer durations of treatment are vealed that more physicians in Japan and China selected nu- desirable to demonstrate both long-term efficacy and safety tritional therapy than those in Korea and other Asian coun- of these agents. tries. Safety and therapeutic efficacy of nutritional therapy Considering several risks of combination therapy, mono- for CD patients is well known, despite no placebo-controlled therapy might be favorable after remission induction with trial data. Whether physicians select nutritional therapy combination therapy. However, the outcome of anti-TNF depends on patients’ acceptability, convenience, and adher- therapy cessation for CD in clinical and/or endoscopic re- ence. Treatment for severe inflammatory small bowel CD mission in routine clinical practice is uncertain. Louis et al. varied among the countries. Overall, 25% of participants reported that approximately 50% of 115 patients with CD selected prednisolone in combination with 5-ASA, followed who were treated for at least 1 year with IFX and an antime- by anti-TNF therapies, nutritional therapy, and thiopurines. tabolite agent experienced a relapse within 1 year after IFX Only 3% of physicians selected budesonides, which might discontinuation. In addition, they commented that patients differ from the tendency in Western countries. Also, the use with a low risk of relapse can be identified using a combina- of budesonide might be limited to the countries whose gov- tion of clinical and biologic markers. ernments permit its use. Of note, physicians in Japan and Brooks et al. also reported that relapse rates at 1 year fol- China selected anti-TNF therapies, while those in Korea se- lowing elective withdrawal of anti-TNF were 36%, with high lected prednisolone. In treating severe inflammatory colonic retreatment response rates. Predictors of relapse include CD, a similar tendency was observed. Overall, physicians in ileocolonic involvement, previous anti-TNF therapy, and Japan and China preferred to use anti-TNF therapies, while raised fecal calprotectin. As mentioned previously, we will those in Korea and other Asian countries preferred prednis- need to identify several factors (clinical and biologic mark- olone for remission induction. The reason why preferences ers) that contribute to the cessation of anti-TNF therapies in differed in remission induction among Asian countries re- CD patients in the future. mains unclear. A recent critical issue is the therapeutic strategy for treat- Treatments for steroid-dependent and refractory CD were ing CD patients who lose response to anti-TNF therapy. thiopurine drugs and anti-TNF agents, which Asian physi- Also, no consensus exists regarding therapies for patients cians selected first. These results were similar to those for UC with CD refractory to anti-TNF therapy and thiopurines. All treatment. Recently, data from Western countries suggested physicians considered dose escalation, followed by chang- 22,23 the following factors as potential predictors of an aggressive ing to another anti-TNF agent. In cases refractory to a disease course in CD: age <40 years at diagnosis, presence of standard regimen of anti-TNF therapies, a pharmacokinetic perianal lesions, early need for steroids, severe endoscopic study measuring serum trough levels of anti-TNF antibodies, 16-19 lesions, and the existence of NOD2/CARD15 mutation. ATI, and anti-adalimumab antibodies will be required in the In these cases, Western physicians would recommend top- future, as >40% of the participants in China checked serum down therapy with anti-TNF antibodies. Therefore, in AOCC, trough levels of anti-TNF antibodies. The survey results for Asian physicians cooperate to identify the risk factors in question 5-3 and 5-4 showed that most physicians could which poor prognoses of Asian CD patients are involved to not check serum trough levels of IFX, ATI, and 6TG levels determine who requires early anti-TNF therapies. in RBC. However, this monitoring is essential for optimizing Most physicians favored combination therapy in CD treatment for individual IBD patients. patients whose remission was induced by anti-TNF thera- To monitor CD patients, many physicians used clinical ac- pies. In particular, Korean physicians favored combination tivity, blood tests, and colonoscopy for disease monitoring. therapy compared with physicians in other countries. Also, On imaging modalities for evaluating small intestinal lesions, Japanese physicians strongly preferred to continue combi- physicians favored CT enterography, followed by 6-thiogua- nation therapy for more time. However, the optimal duration nine nucleotides enterography. These data suggested that of combination anti-TNF therapies and thiopurine for CD many Asian physicians were not familiar with using MR remains unclear. The use of anti-TNF antibodies has sig- enterography to follow CD patients. However, the sensitiv- nificantly impacted the management of CD patients. Most ity and specificity of MRI for the detection of active disease www.irjournal.org 237 Hiroshi Nakase, et al. • Treatment of IBD in Asia and correlation with segmental endoscopic disease severity REFERENCES and detection of complications are high, with >80% sensi- 1. Ng SC, Tang W, Ching JY, et al. Incidence and phenotype of tivity and >90% specificity. MRI also has been a valuable inflammatory bowel disease based on results from the Asia- tool in the assessment of response to therapy; pathological pacific Crohn’s and colitis epidemiology study. 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Gastroenterology according to early post-surgery colonoscopy reduces clinical 2012;142:63-70. recurrence in Crohn’s disease: a retrospective study. Dig Liver Dis 2014;46:887-892. www.irjournal.org 239 nd See “Treatment of inflammatory bowel disease in Asia: the results of a multinational web-based survey in the 2 Asian Orga- nization of Crohn’s and Colitis (AOCC) meeting in Seoul” on page 231. Appendix. Questionnaires regarding the treatment of IBD Practice pattern for the treatment of ulcerative colitis [1] Initial treatment of mild to moderate UC 1-1. Which of the followings would you use to treat mild to moderate ulcerative proctitis? (Please choose all of the followings that you use) 1) Topical 5-ASA(suppository or enema) 2) Topical steroids 3) Oral 5-ASA 4) Systemic steroids 1-2. Which of the followings would you use to treat mild to moderate left-sided active UC? (Please choose all of the followings that you use) 1) Topical 5-ASA (suppository or enema) 2) Topical steroids 3) Oral 5-ASA 4) Systemic steroids 1-3. Which of the followings would you use to treat mild to moderately extensive UC? (Please choose all of the followings that you use) 1) Topical 5-ASA (suppository or enema) 2) Topical steroids 3) Oral 5-ASA 4) Systemic steroids [2] Treatment of acute severe UC 2-1. How often do you seek consultation from a surgeon at the initiation of treatment for patients with acute severe UC? 1) Always 2) Usually 3) Sometimes 4) Rarely 5) Never 2-2. When would you first assess response to intravenous corticosteroids therapy in patients with acute severe UC? 1) On 3−5 days 2) On 6−9 days 3) On 10−14 days 4) After 14 days nd 2-3. Which of the followings would you consider 2 -line therapy for acute severe UC patients who fail to improve on in- travenous corticosteroids? 1) Cyclosporine 2) Anti-TNF agent (infliximab or adalimumab) 3) Tacrolimus 4) Leukocytapheresis 5) Colectomy without changing medication 6) Others (please specify, ) [3] Treatment of steroid-dependent or steroid-refractory UC 3-1. Which of the followings would be your first choice for steroid-dependent UC? 1) Repeated steroid regimens 2) Thiopurines (azathioprine or 6-mercaptopurine) 3) Anti-TNF agent (infliximab or adalimumab) 4) Tacrolimus 5) Leukocytapheresis 6) Colectomy 7) Others (please specify, ) 3-2. Which of the followings would be your first choice for steroid-refractory UC? 1) Repeated steroid regimens 2) Thiopurines (azathioprine or 6-mercaptopurine) 3) Anti-TNF agent (infliximab or adalimumab) 4) Tacrolimus 5) Leukocytapheresis 6) Colectomy 7) Others (please specify, ) 3-3. How often would you test for Cytomegalovirus (CMV) infection in a severe attack of UC? 1) Always 2) Usually 3) Sometimes 4) Rarely 5) Never 3-4. How often would you test for Clostridium difficile infection in a severe attack of UC? 1) Always 2) Usually 3) Sometimes 4) Rarely 5) Never [4] Maintenance of remission 4-1. How would you prescribe a regimen of oral 5-ASA for maintenance of remission in UC? 1) Once daily 2) Two times daily 3) Three times daily 4) Four times daily Practice pattern for the treatment of Crohn’s disease [1] Treatment of CD according to disease involvement and disease activity 1-1. Which of the followings would you use for the first induction of remission in mild to moderate inflammatory small bowel CD (with or without colonic involvement)? (If you use combination therapy, please choose all of the follow- ings that you use) 1) 5-ASA 2) Budesonide 3) Antibiotics 4) Prednisolone 5) Nutritional therapy 6) Others (please specify, ) 1-2. Which of the followings would you use for the first induction of remission in mild to moderate inflammatory co- lonic CD (without small bowel involvement)? (If you use combination therapy, please choose all of the followings that you use) 1) 5-ASA 2) Budesonide 3) Antibiotics 4) Prednisolone 5) Nutritional therapy 6) Others (please specify, ) 1-3. Which of the followings would you use for the first induction of remission in moderate to severe inflammatory small bowel CD (with or without colonic involvement)? (If you use combination therapy, please choose all of the followings that you use) 1) 5-ASA 2) Budesonide 3) Antibiotics 4) Prednisolone 5) Thiopurine 6) Methotrexate 7) Anti-TNF agent 8) Nutritional therapy 9) Others (please specify, ) 1-4. Which of the followings would you use for the first induction of remission in moderate to severe inflammatory co- lonic CD (without small bowel involvement)? (If you use combination therapy, please choose all of the followings that you use) 1) 5-ASA 2) Budesonide 3) Antibiotics 4) Prednisolone 5) Thiopurine 6) Methotrexate 7) Anti-TNF agent 8) Nutritional therapy 9) Others (please specify, ) [2] Treatment of CD according to disease course 2-1.Which of the followings would be your first choice for treatment of steroid-dependent CD? 1) Thiopurine 2) Methotrexate 3) Tacrolimus 4) Anti-TNF agent 5) Others (please specify, ) 2-2. Which of the followings would be your first choice for treatment of steroid-refractory CD? 1) Thiopurine 2) Methotrexate 3) Tacrolimus 4) Anti-TNF agent 5) Others (please specify, ) 2-3. Which of the followings would you use for treatment of thiopurine-refractory or intolerant CD? 1) Methotrexate 2) Tacrolimus 3) Anti-TNF agent 4) Others (please specify, ) [3] Treatment with anti-TNF agents in CD 3-1. How often do you use thiopurine in combination with anti-TNF agents rather than anti-TNF monotherapy for induc- tion of remission in thiopurine-naïve inflammatory CD? 1) Always 2) Usually 3) Sometimes 4) Rarely 5) Never 3-2. How long would you use combination therapy with anti-TNF agents and thiopurine for induction of remission? 1) 6 months 2) 1 year 3) 2years 4) More than 2 years 5) Others (please specify, ) 3-3. How would you treat non-responders to anti-TNF therapy? 1) I would make a decision according to the serum levels of anti-TNF agents and antibodies to anti-TNF agents. 2) I would use empiric dose escalation (double dosing or shortening of drug interval). 3) I would change to another anti-TNF agents. 4) Others (please specify, ) [4] Maintenance of remission 4-1. Which of the followings would you use for maintenance of remission in CD patients whose remission has been in- duced with prednisolone? (If you use combination therapy, please choose all of the followings that you use) 1) 5-ASA 2) Budesonide 3) Antibiotics 4) Prednisolone 5) Thiopurine 6) Methotrexate 7) Anti-TNF agent 8) Nutritional therapy 9) Others (please specify, ) 4-2. Which of the followings would you use for maintenance of remission in CD patients whose remission has been in- duced with anti-TNF agents? 1) Anti-TNF agent only 2) Thiopurine only 3) Combination therapy with anti-TNF agent and thiopurine 4) Others (please specify, ) [5] Monitoring 5-1. What would you use for monitoring disease activity during treatment of CD? (Please choose all of the followings that you use) 1) Clinical activity index 2) Colonoscopy 3) Video capsule endoscopy 4) Wired enteroscopy (balloon-assisted enteroscopy, sonde enteroscopy, or push enteroscopy) 5) Blood tests (CRP/ESR) 6) Fecal calprotectin 7) Magnetic resonance enterography/enteroclysis 8) Computed tomographic enterography/enteroclysis 9) Bowel ultrasonography 10) Others (please specify, ) 5-3. Is it available to monitor the level of 6-TGN, 6-MMP in your practice? 1) Yes 2) No 5-4. Is it available to monitor the level of serum infliximab and antibodies to infliximab in your practice? 1) Yes 2) No [6] Prevention of post-operative recurrence in CD 6-1. When would you perform colonoscopy after surgery in CD patients? 1) I seldom perform colonoscopy after surgery. 2) When clinical symptoms worsen 3) 6 months after surgery 4) 12 months after surgery 5) Others (please specify, ) 6-2. Which of the followings would you use to treat postoperative CD patients with moderate to severe endoscopic re- currence, who have been treated with 5-ASA? (If you use combination therapy, please choose all of the followings that you use) 1) 5-ASA 2) Thiopurine 3) Metronidazole 4) Anti-TNF agent 5) Others (please specify, ) 6-3. Which of the followings would you use to treat postoperative CD patients with moderate to severe endoscopic re- currence, who have been treated with the maximal tolerable dose of thiopurine? (If you use combination therapy, please choose all of the followings that you use) 1) Thiopurine 2) Metronidazole 3) Anti-TNF agent 4) Others (please specify, ) 6-4. Which of the followings would you use to treat postoperative CD patients with moderate to severe endoscopic re- currence, who have been treated with an anti-TNF agent? (If you use combination therapy, please choose all of the following that you use) 1) Add thiopurine 2) Add metronidazole 3) Maintain anti-TNF agent 4) Dose escalation or reduction of infusion intervals of anti-TNF agents 5) Others (please specify, )

Journal

Intestinal Research – Pubmed Central

Published: Jun 27, 2016

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