Digestive and Liver Disease 47 (2015) 14–19
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
Tripterygium wilfordii Hook. f. versus azathioprine for prevention of postoperative recurrence in patients with Crohn’s disease: A randomized clinical trial Weiming Zhu ∗ , Yi Li, Jianfeng Gong, Lugen Zuo, Wei Zhang, Lei Cao, Lili Gu, Zhen Guo, Ning Li, Jieshou Li Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
a r t i c l e
i n f o
Article history: Received 25 April 2014 Accepted 14 September 2014 Available online 30 October 2014 Keywords: Azathioprine Crohn’s disease Postoperative recurrence Tripterygium wilfordii Hook. f.
a b s t r a c t Background: Tripterygium wilfordii Hook. f. (TwHF) has been used for many years to induce the remission of Crohn’s disease in China. Aims: To compare TwHF versus azathioprine for the prevention of postoperative recurrence in Crohn’s disease. Methods: 90 Crohn’s disease patients who had undergone resection were treated with TwHF 1.5 mg/kg/day or azathioprine 2.0 mg/kg/day. The primary endpoint was clinical recurrence, and the secondary endpoint was endoscopic recurrence. Results: 47 patients completed the trial. Clinical recurrence was observed in 6/45 patients in the TwHF group and 4/45 patients in the azathioprine group at week 26 (P = 0.74). At week 52, 8/45 azathioprine patients and 12/45 TwHF patients had clinical recurrence (P = 0.45). During the first 26 weeks, 56.8% of the patients in the TwHF group versus 47.7% in the azathioprine group experienced endoscopic recurrence (P = 0.52). However, at week 52, 74.4% of patients in the TwHF group and 50% in the azathioprine group had endoscopic recurrence (P = 0.03). Conclusions: TwHF was less effective in maintaining endoscopic remission at week 52, even though TwHF was comparable to azathioprine for preventing postoperative clinical recurrence. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Crohn’s disease (CD) is a chronic relapsing, progressive inflammatory disease of the gastrointestinal tract. When medical treatment is unsuccessful, surgery is indicated for CD, and more than 70% of patients with CD require surgery at least once during the course of their disease [1]. The majority of patients with ileocecal resection develop postoperative recurrence of CD in the neoterminal ileum [2]. It has been reported more than 70% of all patients undergoing surgery have endoscopic signs of recurrent disease at 1 year after surgery, with 85% having recurrence after 3 years [3]. Indeed, accumulated data show that postsurgical
∗ Corresponding author at: Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing 210002, PR China. Tel.: +86 25 84806839; fax: +86 25 84806839. E-mail address: [email protected] (W. Zhu).
clinical recurrence occurs in 30% of patients within 3 years [3] and in nearly 50% of all patients within 5 years [4]. Although there are many types of medical prophylaxis, effective therapeutic options for the prevention of postsurgical recurrence are limited [5,6], and none of the currently available medical prophylaxes have been shown to be effective in improving the incidence of postsurgical recurrence to an important extent [7,8]. Azathioprine (AZA) and mercaptopurine (MP) are currently widely recommended for reducing the risk of postoperative recurrence after surgery, particularly for high-risk CD [9]. Many studies have evaluated the benefit of AZA in preventing clinical recurrence in CD [10–12], and a randomized study reported a significantly lower rate of endoscopic recurrence in the first year postoperatively [13]. However, in another study, no difference between AZA and mesalamine was observed in the prevention of clinical recurrence [14]. In addition, biologics such as infliximab are increasingly used in patients for postoperative CD prophylaxis. In a well-designed clinical trial, Regueiro et al. demonstrated that infliximab is effective at preventing the endoscopic, clinical, and
http://dx.doi.org/10.1016/j.dld.2014.09.008 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
W. Zhu et al. / Digestive and Liver Disease 47 (2015) 14–19
histologic postoperative recurrence of CD [15]. Furthermore, a randomized study in patients who had undergone ileocolic resection confirmed that adalimumab was greatly effective in preventing the endoscopic and clinical recurrence of CD [16]. However, biologic agents are expensive and may not be appropriate for routine use in all patients with CD, especially in developing countries. In traditional Chinese medicine, extracts from the vine Tripterygium wilfordii Hook. f. (TwHF, known in China as “lei gong teng” or “thunder god vine”) have been widely used for many years in China to treat autoimmune diseases. In a clinical trial, GoldbachMansky et al. demonstrated that treatment with TwHF may be both effective and safe for patients with active rheumatoid arthritis [17]. Interestingly, TwHF has also been demonstrated to be effective in the treatment of mildly or moderately active CD [18]. We recently reported that triptolide, an active component of the extract isolated from TWHF, could effectively attenuate anastomosis inflammation in an inflammatory bowel disease animal model with ileocecal resection [19]. Furthermore, a recent work reported that TwHF appears to be effective and superior to mesalamine for preventing clinical and endoscopic recurrence in postsurgical CD [20]. To date, however, no randomized, controlled study has compared the use of TwHF and AZA for the prevention of postoperative clinical and endoscopic recurrence in patients with CD. Thus, to assess the efficacy and safety of postoperative prophylaxis in CD patients, a randomized, controlled, open-label study was designed comparing TwHF to AZA for the prevention of postoperative clinical and endoscopic recurrence in patients with CD.
2. Materials and methods 2.1. Study design We conducted a 52-week, randomized, controlled, open-label study at the Inflammatory Bowel Disease Center of Jinling Hospital during the period of November 2009 to October 2012 (Clinical trial registration number NCT01015391). The study was approved by the Ethics Committee of the Jinling Hospital, Medical School of Nanjing University. Written informed consent was obtained from all patients following the regulatory authority and ethics committee approvals.
2.2. Patient selection criteria Between November 2009 and October 2012, eligible patients with ileal or ileocolic CD undergoing macroscopic disease resection with anastomoses, which were side-to-side and stapled, were recruited for this study. Prior to formation of the anastomoses, it was confirmed that there was no evidence of apparent mucosal lesion. Women of childbearing age were required to have a negative pregnancy test and to use adequate birth control measures during the entire study. Patients who received proximal intestinal resections or had an ileocolonic stoma or strictureplasty at the time of ileocolic anastomosis were excluded. Patients with short bowel syndrome, who wished to become pregnant during the study, who had a low white blood cell (WBC) count at inclusion (
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
Tripterygium wilfordii Hook. f. versus azathioprine for prevention of postoperative recurrence in patients with Crohn’s disease: A randomized clinical trial Weiming Zhu ∗ , Yi Li, Jianfeng Gong, Lugen Zuo, Wei Zhang, Lei Cao, Lili Gu, Zhen Guo, Ning Li, Jieshou Li Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
a r t i c l e
i n f o
Article history: Received 25 April 2014 Accepted 14 September 2014 Available online 30 October 2014 Keywords: Azathioprine Crohn’s disease Postoperative recurrence Tripterygium wilfordii Hook. f.
a b s t r a c t Background: Tripterygium wilfordii Hook. f. (TwHF) has been used for many years to induce the remission of Crohn’s disease in China. Aims: To compare TwHF versus azathioprine for the prevention of postoperative recurrence in Crohn’s disease. Methods: 90 Crohn’s disease patients who had undergone resection were treated with TwHF 1.5 mg/kg/day or azathioprine 2.0 mg/kg/day. The primary endpoint was clinical recurrence, and the secondary endpoint was endoscopic recurrence. Results: 47 patients completed the trial. Clinical recurrence was observed in 6/45 patients in the TwHF group and 4/45 patients in the azathioprine group at week 26 (P = 0.74). At week 52, 8/45 azathioprine patients and 12/45 TwHF patients had clinical recurrence (P = 0.45). During the first 26 weeks, 56.8% of the patients in the TwHF group versus 47.7% in the azathioprine group experienced endoscopic recurrence (P = 0.52). However, at week 52, 74.4% of patients in the TwHF group and 50% in the azathioprine group had endoscopic recurrence (P = 0.03). Conclusions: TwHF was less effective in maintaining endoscopic remission at week 52, even though TwHF was comparable to azathioprine for preventing postoperative clinical recurrence. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Crohn’s disease (CD) is a chronic relapsing, progressive inflammatory disease of the gastrointestinal tract. When medical treatment is unsuccessful, surgery is indicated for CD, and more than 70% of patients with CD require surgery at least once during the course of their disease [1]. The majority of patients with ileocecal resection develop postoperative recurrence of CD in the neoterminal ileum [2]. It has been reported more than 70% of all patients undergoing surgery have endoscopic signs of recurrent disease at 1 year after surgery, with 85% having recurrence after 3 years [3]. Indeed, accumulated data show that postsurgical
∗ Corresponding author at: Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing 210002, PR China. Tel.: +86 25 84806839; fax: +86 25 84806839. E-mail address: [email protected] (W. Zhu).
clinical recurrence occurs in 30% of patients within 3 years [3] and in nearly 50% of all patients within 5 years [4]. Although there are many types of medical prophylaxis, effective therapeutic options for the prevention of postsurgical recurrence are limited [5,6], and none of the currently available medical prophylaxes have been shown to be effective in improving the incidence of postsurgical recurrence to an important extent [7,8]. Azathioprine (AZA) and mercaptopurine (MP) are currently widely recommended for reducing the risk of postoperative recurrence after surgery, particularly for high-risk CD [9]. Many studies have evaluated the benefit of AZA in preventing clinical recurrence in CD [10–12], and a randomized study reported a significantly lower rate of endoscopic recurrence in the first year postoperatively [13]. However, in another study, no difference between AZA and mesalamine was observed in the prevention of clinical recurrence [14]. In addition, biologics such as infliximab are increasingly used in patients for postoperative CD prophylaxis. In a well-designed clinical trial, Regueiro et al. demonstrated that infliximab is effective at preventing the endoscopic, clinical, and
http://dx.doi.org/10.1016/j.dld.2014.09.008 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
W. Zhu et al. / Digestive and Liver Disease 47 (2015) 14–19
histologic postoperative recurrence of CD [15]. Furthermore, a randomized study in patients who had undergone ileocolic resection confirmed that adalimumab was greatly effective in preventing the endoscopic and clinical recurrence of CD [16]. However, biologic agents are expensive and may not be appropriate for routine use in all patients with CD, especially in developing countries. In traditional Chinese medicine, extracts from the vine Tripterygium wilfordii Hook. f. (TwHF, known in China as “lei gong teng” or “thunder god vine”) have been widely used for many years in China to treat autoimmune diseases. In a clinical trial, GoldbachMansky et al. demonstrated that treatment with TwHF may be both effective and safe for patients with active rheumatoid arthritis [17]. Interestingly, TwHF has also been demonstrated to be effective in the treatment of mildly or moderately active CD [18]. We recently reported that triptolide, an active component of the extract isolated from TWHF, could effectively attenuate anastomosis inflammation in an inflammatory bowel disease animal model with ileocecal resection [19]. Furthermore, a recent work reported that TwHF appears to be effective and superior to mesalamine for preventing clinical and endoscopic recurrence in postsurgical CD [20]. To date, however, no randomized, controlled study has compared the use of TwHF and AZA for the prevention of postoperative clinical and endoscopic recurrence in patients with CD. Thus, to assess the efficacy and safety of postoperative prophylaxis in CD patients, a randomized, controlled, open-label study was designed comparing TwHF to AZA for the prevention of postoperative clinical and endoscopic recurrence in patients with CD.
2. Materials and methods 2.1. Study design We conducted a 52-week, randomized, controlled, open-label study at the Inflammatory Bowel Disease Center of Jinling Hospital during the period of November 2009 to October 2012 (Clinical trial registration number NCT01015391). The study was approved by the Ethics Committee of the Jinling Hospital, Medical School of Nanjing University. Written informed consent was obtained from all patients following the regulatory authority and ethics committee approvals.
2.2. Patient selection criteria Between November 2009 and October 2012, eligible patients with ileal or ileocolic CD undergoing macroscopic disease resection with anastomoses, which were side-to-side and stapled, were recruited for this study. Prior to formation of the anastomoses, it was confirmed that there was no evidence of apparent mucosal lesion. Women of childbearing age were required to have a negative pregnancy test and to use adequate birth control measures during the entire study. Patients who received proximal intestinal resections or had an ileocolonic stoma or strictureplasty at the time of ileocolic anastomosis were excluded. Patients with short bowel syndrome, who wished to become pregnant during the study, who had a low white blood cell (WBC) count at inclusion (
