Differences between Treatment Guidelines in IBD Dig Dis 2013;31:363–367 DOI: 10.1159/000354696
Treatment Guidelines in Inflammatory Bowel Disease: The Japanese Perspectives Katsuyoshi Matsuoka a Toshifumi Hibi b a b
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, and Center for Advanced IBD Research and Treatment, Kitasato Institute Hospital, Kitasato University, Tokyo, Japan
Key Words Guidelines · Ulcerative colitis · Crohn’s disease
some distinctly different statements in the Japanese guidelines reflecting Japanese standard clinical practice, evidence, and the opinions of Japanese experts. © 2013 S. Karger AG, Basel
© 2013 S. Karger AG, Basel 0257–2753/13/0314–0363$38.00/0 E-Mail [email protected] www.karger.com/ddi
Introduction
The number of inflammatory bowel disease (IBD) patients has been constantly increasing for the last 40 years in Japan. There are currently more than 130,000 ulcerative colitis (UC) patients and 35,000 Crohn’s disease (CD) patients. Thus, the demand for practical guidelines for IBD emerged. The Japanese Society of Gastroenterology, in collaboration with the Research Group of Intractable Inflammatory Bowel Disease subsidized by the Ministry of Health, Labour, and Welfare of Japan published the set of practical guidelines for UC in 2006 and that for CD in 2011. The Japanese UC and CD guidelines were translated into English in 2010 and 2012, respectively [1, 2]. There are several sets of guidelines for IBD in different regional organizations including European Crohn’s and Colitis Organisation (ECCO), American College of Gastroenterology (ACG), and the British Society of Gastroenterology (BSG) [3–5]. The Japanese and ECCO guidelines were developed through the integration of literaToshifumi Hibi 5-9-1 Shirokane Minato, Tokyo 108-8642 (Japan) E-Mail thibi @ insti.kitasato-u.ac.jp
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 9:32:16 PM
Abstract The number of inflammatory bowel disease patients has been increasing in Japan and the demand for clinical practical guidelines emerged. A set of clinical practice guidelines for ulcerative colitis and Crohn’s disease were thus published in 2006 and 2011, respectively. Their English versions were then published in 2000 and 2012, respectively. These guidelines aim to provide appropriate clinical indicators to Japanese practitioners to improve the outcomes of inflammatory bowel disease patients. The guidelines are based on global literature-based evidence as well as evidence from Japan. The Japanese guidelines were developed based on the existing evidence with integration of the experts’ consensus. The criteria for recommendation grade were also determined by the level of evidence as well as by the experts’ consensus. It is a distinct feature of the Japanese guidelines to disclose this process explicitly. This recommendation rating is thus useful to fill the gap between evidence and daily clinical practice. Since the Japanese guidelines are primarily based on global literature-based evidence, most of the clinical indicators in them are consistent with those in other guidelines from the Western world. Meanwhile, there are
CS
CS 0
1
2
3
4
5
6
7
8
9
10
11
IC DAI
pDAI
Tacrolimus 65 patients
Litchtiger
Trough 5–10 ng/ml
5 mg/kg
65 patients Study completion
Drop-out
Ulcerative Colitis
Overview The Japanese UC guidelines have adopted the therapeutic algorithms that are quite similar to those of the Western guidelines. Treatment choices are determined according to the disease extent and severity. Oral 5-aminosalicylate (5-ASA) is the basic drug for patients with mild to moderate activity, combined with enemas in patients with distal colitis. Thiopurines are recommended for maintenance of remission, although the optimal doses (30 mg for 6-mercaptopurine and 50 mg for azathioprine) are less in Japanese than Caucasians. For severely active patients, intravenous corticosteroid is the primary therapy and, if it does not work, surgery or alternative therapy such as intravenous cyclosporine is considered. It should be noted that Dig Dis 2013;31:363–367 DOI: 10.1159/000354696
Litchtiger
Infliximab
ture-based evidence and experts’ consensus, while the BSG and ACG guidelines were developed mainly focusing on evidence. The Japanese guidelines are distinguished from the other three sets of guidelines in terms of the method to rate recommendation grades. In the Japanese guidelines, recommendation grades were rated based on the integration of evidence level and experts’ consensus, although recommendation grades in the other sets of guidelines were based on evidence level only. The Japanese rating is thus useful to fill the gap between evidence and daily clinical practice. We would like to overview the Japanese guidelines and discuss the Japanese perspectives for the treatment of IBD in this article.
364
㻌 Trough 10–15 ng/ml
DAI
the two important alternative options, infliximab (IFX) and oral tacrolimus, has emerged since the Japanese guidelines were published in 2006. Leukocyte apheresis is appreciated as a treatment option in steroid-refractory or -dependent patients. Below we will discuss those specific points that are different from the Western practice. Infliximab versus Tacrolimus IFX and tacrolimus were approved for use in UC in 2011 and 2010, respectively, in Japan. Both of the agents have become an important option for steroid-refractory or -dependent UC patients. Thus far, there have been no directly comparative data on efficacy between IFX and tacrolimus in UC patients. In the ACT I study [6], which examined the efficacy of IFX in moderate-to-severe active UC patients, the response rate at week 8 was 69.4%, while Ogata et al. [7] reported the response rate of 57.9% at week 10 in the patients treated with oral tacrolimus. Although the patient background and the definition of response are different between the two studies, the efficacy of the two agents looks quite comparable in moderate-tosevere UC patients. We have started a multicenter randomized study to compare the efficacy of tacrolimus and IFX in steroid-refractory or -dependent UC patients. A total of 130 UC patients with moderate to severe activity will be randomly assigned to either IFX or tacrolimus and be treated by the agent for 10 weeks (fig. 1). The primary endpoint is the response rate defined by an improved disease activity index (DAI) score. This study will answer the question which agent is superior to the other in moderate-to-severe UC patients. Matsuoka/Hibi
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 9:32:16 PM
the efficacy of tacrolimus and IFX. A total of 130 UC patients are randomly assigned to take either IFX or tacrolimus for 10 weeks. IC = Informed consent; CS = colonoscopy.
Randomization
Fig. 1. Study design of the study to compare
Eligibility check
Litchtiger Litchtiger
pDAI
Moderate
5-ASA preparation (salazosulfapyridine for colonic lesion) Antimicrobial drugs (colonic lesion) Enteral nutrition (small- intestial lesion)
Anal lesions (anal fistulas) Treatment of intestinal lesions Immunomodulators Antimicrobial drugs Anti-TNF-į agents Seton technique
Severe
Oral steroids Enteral nutrition
Remission maintenance 5-ASA preparations Enteral nutrition Immunomodulators Anti-TNF-į agents Prevention of postoperative relapse 5-ASA preparations Immunomodulators Anti-TNF-į agents Antimicrobial drugs
Fulminant
In principle, hospitalization and general care Total parental nutrition Intravenous steroids Consider surgical treatment
Color version available online
Mild
Refractory case Anti-TNF-į agents (Steroid-resistant) Immunomodulators (Steroid-dependent) Consider surgical treatment
Case with intestinal stenosis Steroids (case with inflammation) Endoscopic dilation Surgical operation
Fig. 2. Therapeutic algorithm of CD in
Japan.
Practical Guidelines for IBD in Japan
Crohn’s Disease
Overview Figure 2 shows the therapeutic algorithm of CD adapted in the Japanese guidelines. The statements in the Japanese guidelines for CD also mostly reached the same conclusions as the Western guidelines, basically based on the same evidence. However, some statements in the Japanese guidelines reflect Japanese perspectives and evidence, for example (1) elemental diet and leukocyte apheresis are more emphasized in the Japanese guidelines and (2) 5-ASA is not recommended in the Western guidelines because of its minimal effect on CD, but it has a role in the management of CD in the Japanese guidelines because of its safety profile. We summarized the therapeutic options for CD that are referred in the guidelines of the different regions (table 1). 5-Aminosalicylate The statement in the Japanese CD guidelines mentions that ‘5-ASA preparations have a limited effect on maintaining remission, but harm is minimal’. Japanese doctors understand the minimal efficacy of 5-ASA in induction and maintenance of remission in CD patients, but they Dig Dis 2013;31:363–367 DOI: 10.1159/000354696
365
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 9:32:16 PM
Leukocyte Apheresis The two types of leukocyte apheresis, granulocytemonocyte apheresis and leukocytapheresis (LCAP), are widely used in UC patients in Japan and leukocyte apheresis therapy has been adapted in the Japanese UC guidelines. In the guideline statement, leukocyte apheresis is recommended as a combination therapy with corticosteroids or as a primary therapy for moderate-to-severe UC patients. There are several small studies available to support the efficacy of leukocyte apheresis in UC patients. Sawada et al. [8] reported the results of a multicenter double-blind prospective case-control study between LCAP using active devices and sham devices as placebo, showing a significantly greater improvement (8 of 10, 80%) than the sham device group (3 of 9, 33%). Nishioka et al. [9] compared the clinical efficacy between LCAP and the corticosteroid group of patients with steroid-naive active UC. The efficacy of LCAP was equivalent to that of corticosteroid and the safety of LCAP, in terms of severe adverse effects, was superior to that of steroid therapy. Although high-quality evidence supporting leukocyte apheresis is still scarce, Japanese experts appreciate the safety of this treatment and rated a high consensus level in the guidelines.
Table 1. Therapeutic options in different regions
Japan
ECCO
BSG
ACG
5-ASA
Harm is minimal (CL 8, RG A)
Benefit is limited (EL1a, RG B)
No clinical benefit
Not recommended (EL low, RG weak)
Steroids
EL V, CL 8, RG A Budesonide is not available
Budesonide for mild disease (EL2a, RG B) Systemic steroid for severe disease (EL1a, RG A)
Budesonide or PSL for moderate disease (EL1a)
Budesonide for mild-moderate disease (EL low, RG strong) Standard CS for active disease (EL low, RG strong)
Anti-TNF
EL Ia, RG A
CL 9, RG A
EL1a, RG B
EL moderate, RG strong
Thiopurine
CL 8, RG A
EL1b, RG A
EL1b, RG A
EL low, RG weak
EN
EN = Steroids (EL III, CL 8, RG B)
Steroids > EN
Steroids > EN (EL2b)
No description (EL2b, RG C)
Cytapheresis
CL 7, RG C1
Evidence is limited
No description
No description
CL = Consensus level; RG = recommendation grade; EL = evidence level; PSL = prednisolone; CS = corticosteroid; EN = enteral nutrition.
Elementary Diet Elementary diet had been a primary therapy for CD in Japan before the emergence of anti-TNF-α agents. It has become much less frequent that elementary diet is used as a primary therapy for CD, but it still has a role in the management of CD in Japan and is adapted in the statement of the Japanese CD guidelines. Although the guidelines mention that ‘The efficacy of enteral nutrition to induce remission in active CD is equivalent or slightly inferior to that of corticosteroids and elemental diet is effective in maintaining remission in CD’, elementary diet is recently used as supplementary therapy in postoperative patients or for secondary failures to anti-TNF-α agents in daily clinical practice. Several studies to prove the efficacy of elementary diet in those clinical situations are currently under way in Japan. Top-Down or Step-Up? Anti-TNF-α agents are preserved for patients refractory to conventional therapies in the guidelines, but an increasing number of CD patients have been treated with top-down therapy in Japan. Thus far, there are no precise data on how many of the newly diagnosed CD patients take top-down therapy in Japan, but the rate of top-down therapy has been increasing and in our estimation more than half of Japanese patients are treated with anti-TNF-α 366
Dig Dis 2013;31:363–367 DOI: 10.1159/000354696
agents as the primary therapy, which may be higher than any other areas. One of the reasons is that the financial support from the government is intense for CD patients in Japan. Since 1973, the government has designated 56 diseases that are hard to treat and supports the patients with these diseases financially. The maximum monthly payment is fixed according to the annual tax for household income, which is approximately USD 110 for outpatient clinic and approximately USD 230 for inpatients. Doctors do not need any approval for use of anti-TNF-α agents in advance. In this situation, paying little attention to cost, either doctors or patients do not hesitate to use anti-TNF-α agents. This situation reflects the daily clinical practice in Japan without any medical or economical evidence.
Conclusions
Since the Japanese guidelines for IBD are primarily based on global literature-based evidence, most of the clinical indicators in them are consistent with those in other guidelines from the Western world. Meanwhile, there are some distinctly different statements in the Japanese guidelines reflecting Japanese standard clinical practice, evidence, and the opinions of Japanese experts.
Disclosure Statement The authors have no conflicts of interest to disclose.
Matsuoka/Hibi
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 9:32:16 PM
also appreciate the safety profile of the agents and gave a high consensus grade to it, resulting in a high recommendation grade in the guidelines.
References
Practical Guidelines for IBD in Japan
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 Talley NJ, Abreu MT, Achkar JP, et al: An evidence-based systematic review on medical therapies for inflammatory bowel disease. Am J Gastroenterol 2011;106(suppl 1):S2–S25, quiz S26. 6 Rutgeerts P, Sandborn WJ, Feagan BG, et al: Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–2476. 7 Ogata H, Kato J, Hirai F, et al: Double-blind, placebo-controlled trial of oral tacrolimus (FK506) in the management of hospitalized patients with steroid-refractory ulcerative colitis. Inflamm Bowel Dis 2012;18:803–808.
Dig Dis 2013;31:363–367 DOI: 10.1159/000354696
8 Sawada K, Kusugami K, Suzuki Y, et al: Leukocytapheresis in ulcerative colitis: results of a multicenter double-blind prospective casecontrol study with sham apheresis as placebo treatment. Am J Gastroenterol 2005;100: 1362–1369. 9 Nishioka C, Aoyama N, Maekawa S, et al: Leukocytapheresis therapy for steroid-naive patients with active ulcerative colitis: its clinical efficacy and adverse effects compared with those of conventional steroid therapy. J Gastroenterol Hepatol 2005;20:1567–1571.
367
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 9:32:16 PM
1 Guidelines for the management of ulcerative colitis in Japan. http://minds4.jcqhc.or.jp/ minds/kaiyouseida/ucgl+201102.pdf. 2 Ueno F, Matsui T, Matsumoto T, et al: Evidence-based clinical practice guidelines for Crohn’s disease, integrated with formal consensus of experts in Japan. J Gastroenterol 2013;48:31–72. 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. J Crohns Colitis 2010;4:7–27.
Treatment Guidelines in Inflammatory Bowel Disease: The Japanese Perspectives Katsuyoshi Matsuoka a Toshifumi Hibi b a b
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, and Center for Advanced IBD Research and Treatment, Kitasato Institute Hospital, Kitasato University, Tokyo, Japan
Key Words Guidelines · Ulcerative colitis · Crohn’s disease
some distinctly different statements in the Japanese guidelines reflecting Japanese standard clinical practice, evidence, and the opinions of Japanese experts. © 2013 S. Karger AG, Basel
© 2013 S. Karger AG, Basel 0257–2753/13/0314–0363$38.00/0 E-Mail [email protected] www.karger.com/ddi
Introduction
The number of inflammatory bowel disease (IBD) patients has been constantly increasing for the last 40 years in Japan. There are currently more than 130,000 ulcerative colitis (UC) patients and 35,000 Crohn’s disease (CD) patients. Thus, the demand for practical guidelines for IBD emerged. The Japanese Society of Gastroenterology, in collaboration with the Research Group of Intractable Inflammatory Bowel Disease subsidized by the Ministry of Health, Labour, and Welfare of Japan published the set of practical guidelines for UC in 2006 and that for CD in 2011. The Japanese UC and CD guidelines were translated into English in 2010 and 2012, respectively [1, 2]. There are several sets of guidelines for IBD in different regional organizations including European Crohn’s and Colitis Organisation (ECCO), American College of Gastroenterology (ACG), and the British Society of Gastroenterology (BSG) [3–5]. The Japanese and ECCO guidelines were developed through the integration of literaToshifumi Hibi 5-9-1 Shirokane Minato, Tokyo 108-8642 (Japan) E-Mail thibi @ insti.kitasato-u.ac.jp
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 9:32:16 PM
Abstract The number of inflammatory bowel disease patients has been increasing in Japan and the demand for clinical practical guidelines emerged. A set of clinical practice guidelines for ulcerative colitis and Crohn’s disease were thus published in 2006 and 2011, respectively. Their English versions were then published in 2000 and 2012, respectively. These guidelines aim to provide appropriate clinical indicators to Japanese practitioners to improve the outcomes of inflammatory bowel disease patients. The guidelines are based on global literature-based evidence as well as evidence from Japan. The Japanese guidelines were developed based on the existing evidence with integration of the experts’ consensus. The criteria for recommendation grade were also determined by the level of evidence as well as by the experts’ consensus. It is a distinct feature of the Japanese guidelines to disclose this process explicitly. This recommendation rating is thus useful to fill the gap between evidence and daily clinical practice. Since the Japanese guidelines are primarily based on global literature-based evidence, most of the clinical indicators in them are consistent with those in other guidelines from the Western world. Meanwhile, there are
CS
CS 0
1
2
3
4
5
6
7
8
9
10
11
IC DAI
pDAI
Tacrolimus 65 patients
Litchtiger
Trough 5–10 ng/ml
5 mg/kg
65 patients Study completion
Drop-out
Ulcerative Colitis
Overview The Japanese UC guidelines have adopted the therapeutic algorithms that are quite similar to those of the Western guidelines. Treatment choices are determined according to the disease extent and severity. Oral 5-aminosalicylate (5-ASA) is the basic drug for patients with mild to moderate activity, combined with enemas in patients with distal colitis. Thiopurines are recommended for maintenance of remission, although the optimal doses (30 mg for 6-mercaptopurine and 50 mg for azathioprine) are less in Japanese than Caucasians. For severely active patients, intravenous corticosteroid is the primary therapy and, if it does not work, surgery or alternative therapy such as intravenous cyclosporine is considered. It should be noted that Dig Dis 2013;31:363–367 DOI: 10.1159/000354696
Litchtiger
Infliximab
ture-based evidence and experts’ consensus, while the BSG and ACG guidelines were developed mainly focusing on evidence. The Japanese guidelines are distinguished from the other three sets of guidelines in terms of the method to rate recommendation grades. In the Japanese guidelines, recommendation grades were rated based on the integration of evidence level and experts’ consensus, although recommendation grades in the other sets of guidelines were based on evidence level only. The Japanese rating is thus useful to fill the gap between evidence and daily clinical practice. We would like to overview the Japanese guidelines and discuss the Japanese perspectives for the treatment of IBD in this article.
364
㻌 Trough 10–15 ng/ml
DAI
the two important alternative options, infliximab (IFX) and oral tacrolimus, has emerged since the Japanese guidelines were published in 2006. Leukocyte apheresis is appreciated as a treatment option in steroid-refractory or -dependent patients. Below we will discuss those specific points that are different from the Western practice. Infliximab versus Tacrolimus IFX and tacrolimus were approved for use in UC in 2011 and 2010, respectively, in Japan. Both of the agents have become an important option for steroid-refractory or -dependent UC patients. Thus far, there have been no directly comparative data on efficacy between IFX and tacrolimus in UC patients. In the ACT I study [6], which examined the efficacy of IFX in moderate-to-severe active UC patients, the response rate at week 8 was 69.4%, while Ogata et al. [7] reported the response rate of 57.9% at week 10 in the patients treated with oral tacrolimus. Although the patient background and the definition of response are different between the two studies, the efficacy of the two agents looks quite comparable in moderate-tosevere UC patients. We have started a multicenter randomized study to compare the efficacy of tacrolimus and IFX in steroid-refractory or -dependent UC patients. A total of 130 UC patients with moderate to severe activity will be randomly assigned to either IFX or tacrolimus and be treated by the agent for 10 weeks (fig. 1). The primary endpoint is the response rate defined by an improved disease activity index (DAI) score. This study will answer the question which agent is superior to the other in moderate-to-severe UC patients. Matsuoka/Hibi
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 9:32:16 PM
the efficacy of tacrolimus and IFX. A total of 130 UC patients are randomly assigned to take either IFX or tacrolimus for 10 weeks. IC = Informed consent; CS = colonoscopy.
Randomization
Fig. 1. Study design of the study to compare
Eligibility check
Litchtiger Litchtiger
pDAI
Moderate
5-ASA preparation (salazosulfapyridine for colonic lesion) Antimicrobial drugs (colonic lesion) Enteral nutrition (small- intestial lesion)
Anal lesions (anal fistulas) Treatment of intestinal lesions Immunomodulators Antimicrobial drugs Anti-TNF-į agents Seton technique
Severe
Oral steroids Enteral nutrition
Remission maintenance 5-ASA preparations Enteral nutrition Immunomodulators Anti-TNF-į agents Prevention of postoperative relapse 5-ASA preparations Immunomodulators Anti-TNF-į agents Antimicrobial drugs
Fulminant
In principle, hospitalization and general care Total parental nutrition Intravenous steroids Consider surgical treatment
Color version available online
Mild
Refractory case Anti-TNF-į agents (Steroid-resistant) Immunomodulators (Steroid-dependent) Consider surgical treatment
Case with intestinal stenosis Steroids (case with inflammation) Endoscopic dilation Surgical operation
Fig. 2. Therapeutic algorithm of CD in
Japan.
Practical Guidelines for IBD in Japan
Crohn’s Disease
Overview Figure 2 shows the therapeutic algorithm of CD adapted in the Japanese guidelines. The statements in the Japanese guidelines for CD also mostly reached the same conclusions as the Western guidelines, basically based on the same evidence. However, some statements in the Japanese guidelines reflect Japanese perspectives and evidence, for example (1) elemental diet and leukocyte apheresis are more emphasized in the Japanese guidelines and (2) 5-ASA is not recommended in the Western guidelines because of its minimal effect on CD, but it has a role in the management of CD in the Japanese guidelines because of its safety profile. We summarized the therapeutic options for CD that are referred in the guidelines of the different regions (table 1). 5-Aminosalicylate The statement in the Japanese CD guidelines mentions that ‘5-ASA preparations have a limited effect on maintaining remission, but harm is minimal’. Japanese doctors understand the minimal efficacy of 5-ASA in induction and maintenance of remission in CD patients, but they Dig Dis 2013;31:363–367 DOI: 10.1159/000354696
365
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 9:32:16 PM
Leukocyte Apheresis The two types of leukocyte apheresis, granulocytemonocyte apheresis and leukocytapheresis (LCAP), are widely used in UC patients in Japan and leukocyte apheresis therapy has been adapted in the Japanese UC guidelines. In the guideline statement, leukocyte apheresis is recommended as a combination therapy with corticosteroids or as a primary therapy for moderate-to-severe UC patients. There are several small studies available to support the efficacy of leukocyte apheresis in UC patients. Sawada et al. [8] reported the results of a multicenter double-blind prospective case-control study between LCAP using active devices and sham devices as placebo, showing a significantly greater improvement (8 of 10, 80%) than the sham device group (3 of 9, 33%). Nishioka et al. [9] compared the clinical efficacy between LCAP and the corticosteroid group of patients with steroid-naive active UC. The efficacy of LCAP was equivalent to that of corticosteroid and the safety of LCAP, in terms of severe adverse effects, was superior to that of steroid therapy. Although high-quality evidence supporting leukocyte apheresis is still scarce, Japanese experts appreciate the safety of this treatment and rated a high consensus level in the guidelines.
Table 1. Therapeutic options in different regions
Japan
ECCO
BSG
ACG
5-ASA
Harm is minimal (CL 8, RG A)
Benefit is limited (EL1a, RG B)
No clinical benefit
Not recommended (EL low, RG weak)
Steroids
EL V, CL 8, RG A Budesonide is not available
Budesonide for mild disease (EL2a, RG B) Systemic steroid for severe disease (EL1a, RG A)
Budesonide or PSL for moderate disease (EL1a)
Budesonide for mild-moderate disease (EL low, RG strong) Standard CS for active disease (EL low, RG strong)
Anti-TNF
EL Ia, RG A
CL 9, RG A
EL1a, RG B
EL moderate, RG strong
Thiopurine
CL 8, RG A
EL1b, RG A
EL1b, RG A
EL low, RG weak
EN
EN = Steroids (EL III, CL 8, RG B)
Steroids > EN
Steroids > EN (EL2b)
No description (EL2b, RG C)
Cytapheresis
CL 7, RG C1
Evidence is limited
No description
No description
CL = Consensus level; RG = recommendation grade; EL = evidence level; PSL = prednisolone; CS = corticosteroid; EN = enteral nutrition.
Elementary Diet Elementary diet had been a primary therapy for CD in Japan before the emergence of anti-TNF-α agents. It has become much less frequent that elementary diet is used as a primary therapy for CD, but it still has a role in the management of CD in Japan and is adapted in the statement of the Japanese CD guidelines. Although the guidelines mention that ‘The efficacy of enteral nutrition to induce remission in active CD is equivalent or slightly inferior to that of corticosteroids and elemental diet is effective in maintaining remission in CD’, elementary diet is recently used as supplementary therapy in postoperative patients or for secondary failures to anti-TNF-α agents in daily clinical practice. Several studies to prove the efficacy of elementary diet in those clinical situations are currently under way in Japan. Top-Down or Step-Up? Anti-TNF-α agents are preserved for patients refractory to conventional therapies in the guidelines, but an increasing number of CD patients have been treated with top-down therapy in Japan. Thus far, there are no precise data on how many of the newly diagnosed CD patients take top-down therapy in Japan, but the rate of top-down therapy has been increasing and in our estimation more than half of Japanese patients are treated with anti-TNF-α 366
Dig Dis 2013;31:363–367 DOI: 10.1159/000354696
agents as the primary therapy, which may be higher than any other areas. One of the reasons is that the financial support from the government is intense for CD patients in Japan. Since 1973, the government has designated 56 diseases that are hard to treat and supports the patients with these diseases financially. The maximum monthly payment is fixed according to the annual tax for household income, which is approximately USD 110 for outpatient clinic and approximately USD 230 for inpatients. Doctors do not need any approval for use of anti-TNF-α agents in advance. In this situation, paying little attention to cost, either doctors or patients do not hesitate to use anti-TNF-α agents. This situation reflects the daily clinical practice in Japan without any medical or economical evidence.
Conclusions
Since the Japanese guidelines for IBD are primarily based on global literature-based evidence, most of the clinical indicators in them are consistent with those in other guidelines from the Western world. Meanwhile, there are some distinctly different statements in the Japanese guidelines reflecting Japanese standard clinical practice, evidence, and the opinions of Japanese experts.
Disclosure Statement The authors have no conflicts of interest to disclose.
Matsuoka/Hibi
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 9:32:16 PM
also appreciate the safety profile of the agents and gave a high consensus grade to it, resulting in a high recommendation grade in the guidelines.
References
Practical Guidelines for IBD in Japan
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 Talley NJ, Abreu MT, Achkar JP, et al: An evidence-based systematic review on medical therapies for inflammatory bowel disease. Am J Gastroenterol 2011;106(suppl 1):S2–S25, quiz S26. 6 Rutgeerts P, Sandborn WJ, Feagan BG, et al: Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–2476. 7 Ogata H, Kato J, Hirai F, et al: Double-blind, placebo-controlled trial of oral tacrolimus (FK506) in the management of hospitalized patients with steroid-refractory ulcerative colitis. Inflamm Bowel Dis 2012;18:803–808.
Dig Dis 2013;31:363–367 DOI: 10.1159/000354696
8 Sawada K, Kusugami K, Suzuki Y, et al: Leukocytapheresis in ulcerative colitis: results of a multicenter double-blind prospective casecontrol study with sham apheresis as placebo treatment. Am J Gastroenterol 2005;100: 1362–1369. 9 Nishioka C, Aoyama N, Maekawa S, et al: Leukocytapheresis therapy for steroid-naive patients with active ulcerative colitis: its clinical efficacy and adverse effects compared with those of conventional steroid therapy. J Gastroenterol Hepatol 2005;20:1567–1571.
367
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/10/2015 9:32:16 PM
1 Guidelines for the management of ulcerative colitis in Japan. http://minds4.jcqhc.or.jp/ minds/kaiyouseida/ucgl+201102.pdf. 2 Ueno F, Matsui T, Matsumoto T, et al: Evidence-based clinical practice guidelines for Crohn’s disease, integrated with formal consensus of experts in Japan. J Gastroenterol 2013;48:31–72. 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. J Crohns Colitis 2010;4:7–27.
