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Tripterygium wilfordii Hook. f. versus azathioprine for prevention of postoperative recurrence in patients with Crohn's disease: A randomized clinical trial

Digestive and Liver Disease, Volume 47, Issue 1, January 2015, Pages 14–19

Abstract

Background

Tripterygium wilfordiiHook. 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.

Keywords: Azathioprine, Crohn's disease, Postoperative recurrence, Tripterygium wilfordii Hook. f..

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 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] and [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] and [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], [11], and [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 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 vineTripterygium wilfordiiHook. 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, Goldbach-Mansky 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 (<4000), or who had malignancies and/or ongoing infectious disease (such as active hepatitis) were also excluded. Patients were not eligible if they had a history of TwHF and/or AZA intolerance or had received treatment with anti-tumour necrosis factor α (TNF-α) agents, corticosteroids, oral antibiotics, or non-steroidal anti-inflammatory drugs (NSAIDs) within the preceding 4 weeks.

2.3. Randomization and drug therapy

Randomization and drug administration occurred within 2 weeks after surgical resection. The patients were randomized in a 1:1 ratio of AZA 2.0 mg/kg/day or TwHF 1.5 mg/kg/day using a randomization programme. The patients assigned to the TwHF group received oral administration of TwHF (Taizhou Pharmaceutical Co., Jiangsu Province, China) 3 times per day. The following medications were prohibited during the study: other immunosuppressants, corticosteroids, thiopurinol, allopurinol or oxipurinol, 5-ASA, anti-TNFα therapy, oral antibiotics for more than 2 weeks, NSAIDs for more than 1 week, and AZA-containing or TwHF-containing drugs other than the study drug.

2.4. Evaluation schedule and assessments

Patients underwent clinical evaluation with physical examination and biochemical analysis at baseline and at weeks 2, 6, 16, 26, 36, 46, and 52 after inclusion. The total Crohn's disease activity index (CDAI) score [21] was calculated, and the Inflammatory Bowel Disease Questionnaire (IBDQ) [22] was completed at baseline and at each visit. Vital signs and laboratory values (such as white blood cell count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)) were measured at each study visit. At weeks 26 and 52, an ileocolonoscopy was performed with the determination of Rutgeerts’ score for the ileal recurrence of CD by an endoscopist who was blind to the treatment assignment [3] .

At every scheduled or unscheduled visit, adverse events and concomitant medication were recorded. According to a previous study, the common side effects of TwHF are diarrhoea and nausea [18] . Information including stool frequency/type, abdominal pain and cramps, general well-being, consumption of study medication and other medication, and temperature were recorded by the patients every day. As leukopenia is a common dose-dependent side effect of AZA and TwHF, the white blood cell count was examined regularly and at any time if necessary. If the total white count was <3500, the dose of AZA was reduced to 1.0 mg/kg/day or TwHF was reduced to 0.75 mg/kg/day. If a patient with reduced AZA or TwHF still had a WBC count < 3000, the drug was discontinued, and the patient was withdrawn from the study.

2.5. Study end points

The primary end point of this trial was clinical recurrence. Clinical recurrence was defined as a patient presenting symptoms of CD having to undergo another medical or surgical treatment, with the recurrence being confirmed by endoscopic evidence. The secondary end point of this study was the proportion of patients with significant endoscopic recurrence in the neoterminal ileum at 26 and 52 weeks after surgery, defined as an endoscopic index ≥2 according to Rutgeerts’ endoscopic score. Patients who developed symptoms with the evidence of clinical recurrence were withdrawn from the trial and received further treatment according to the investigator's opinion. Other efficacy end points including the IBDQ score, ESR level, and CRP level were assessed between the two groups. Safety assessments including adverse events, laboratory parameters, vital signs, and physical examination were also evaluated in our study. Predetermined withdrawal criteria included clinical recurrence, an intolerable adverse drug reaction, and the presence of surgical indication (such as abscess and obstruction).

2.6. Statistical analysis

Clinical recurrence was evaluated in the intention-to-treat (ITT) population. Endoscopic examinations were analyzed in all ITT patients in whom endoscopy was performed at week 26 and at week 52 or at the time of study withdrawal. The analyses employed non-responder imputation (NRI) and last-observation-carried-forward (LOCF) in many assessments. To evaluate the effect of drug therapy on endoscopic recurrence and clinical recurrence between the treatment groups at 26 and 52 weeks, Fisher's exact test or the chi-square test was used. Quantitative variables were described using the mean ± standard deviation (SD) and were compared using a two sided Mann–WhitneyU-test.P < 0.05 was considered to be statistically significant.

3. Results

3.1. Patients and study medication

Ninety Chinese patients (62 male, 68.9%) agreed to participate in the study, were randomized, and received study medication (45 AZA, 45 TwHF). The baseline characteristics were similar between the treatment groups ( Table 1 ).

Table 1 Baseline characteristics.

  TwHF (n = 45) AZA (n = 45) P value
Age (years), mean ± SD 33.2 ± 11.0 31.6 ± 12.0 0.55
Male gender, N (%) 30 (66.7%) 32 (71.1%) 0.82
Disease behaviour, N (%)     0.66
 B2 (stricturing) 18 (40%) 15 (33.3%)  
 B3 (fistulizing) 27 (60%) 30 (66.7%)  
Smoking history, N (%)
 None 30 (66.7%) 31 (68.9%) 0.98
 Former 14 (31.1%) 13 (28.9%) 0.97
 Current 1 (2.2%) 1 (2.2%) 1.00
Indication for surgery, N (%)
 Penetrating disease 25 (55.6%) 28 (62.2%) 0.67
Treatment prior to surgery, N (%)
 Mesalazine 33 (73.3%) 37 (82.2%) 0.45
 Corticosteroids 32 (71.1%) 30 (66.7%) 0.82
 Azathioprine 26 (57.8%) 22 (48.9%) 0.53
 Infliximab 5 (11.1%) 4 (8.9%) 0.99
 Other 7 (15.6%) 6 (13.3%) 0.97
Body mass index (kg/m2), mean ± SD 17.93 ± 1.5 17.44 ± 1.9 0.20
Baseline CDAI, mean ± SD 198.95 ± 25.4 193.15 ± 15.1 0.22
Baseline IBDQ, mean ± SD 160.8 ± 22.9 155 ± 24.5 0.28
CRP, mean ± SD 7.45 ± 4.0 7.60 ± 5.8 0.89
ESR, mean ± SD 26.8 ± 11.8 28.85 ± 15.0 0.50
Perianal disease, N (%) 14 (31.1%) 11 (24.4%) 0.64
Prior resections, mean ± SD 1.49 ± 0.8 1.38 ± 0.9 0.52

AZA: azathioprine; CDAI: Crohn's disease activity index; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; IBDQ: inflammatory bowel disease questionnaire; SD: standard deviation; TwHF:Tripterygium wilfordiiHook. f.

3.2. Patient flow and discontinuations

Eight patients in the TwHF group did not reach week 26; 2 patients were drop-outs, and 6 were withdrawn because of clinical recurrence, leaving 37 patients for analysis at week 26 (Supplementary Figure S1). Seven patients in the AZA group did not reach week 26; 3 patients were discontinued, and 4 patients experienced clinical recurrence, leaving 38 patients for analysis at week 26 (Supplementary Figure S1).

Thus, there were 37 and 38 patients in the TwHF and AZA groups, respectively, who continued the study. Between weeks 26 and 52, 6 patients in the TwHF group and 12 patients in the AZA group withdrew from the trial. A total of 6 patients in the TwHF group and 4 patients in the AZA group experienced clinical recurrence and received other medical therapy. Overall, 47 patients (25 in the TwHF group and 22 in the AZA group) completed the full trial and reached week 52 (Figure S1). The reasons for discontinuation are provided in Supplementary Table S1.

3.3. Clinical recurrence

The analysis was first conducted LOCF approach. Clinical recurrence during the first 26 weeks occurred in 4/45 of patients in the AZA arm (8.9%) and 6/45 of patients in the TwHF arm (13.3%); no significant difference (P = 0.74, Table 2 , Fig. 1 ) was found. At week 52, 20 clinical recurrences occurred, 12/45 in the TwHF group (26.7%) and 8/45 in the AZA group (17.8%, Table 3 ). The data indicated no difference between the AZA and TwHF groups with respect to clinical recurrence at week 52 (P = 0.45) ( Fig. 1 A).

Table 2 Outcomes at week 26.

  TwHF AZA P value
Endoscopic score
 Mean ± SD 2.0 ± 1.0 (n = 44) 1.9 ± 1.3 (n = 44) 0.55
 ≥i2, n/N 21/44 25/44 0.52
CDAI, mean ± SD 128.5 ± 50.6 (n = 44) 128.5 ± 58.8 (n = 44) 0.98
IBDQ, mean ± SD 158.4 ± 29.0 (n = 44) 144.7 ± 30.7 (n = 44) 0.04
CRP, mean ± SD 8.5 ± 5.0 (n = 45) 7.2 ± 4.5 (n = 45) 0.18
ESR, mean ± SD 16.8 ± 9.1 (n = 45) 15.3 ± 9.8 (n = 45) 0.47
Clinical recurrence 6/45 4/45 0.74

AZA: azathioprine; CDAI: Crohn's disease activity index; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; IBDQ: inflammatory bowel disease questionnaire; SD: standard deviation; TwHF:Tripterygium wilfordiiHook. f.

gr1

Fig. 1 Proportion of patients with endoscopic recurrence at week 26 and week 52 in both treatment groups. The analysis was performed by using last-observation-carried-forward (A) and non-responder imputation (B) approach respectively. AZA: azathioprine; LOCF: last-observation-carried-forward; NRI: non-responder imputation; TwHF:Tripterygium wilfordiiHook. f.

Table 3 Outcomes at week 52.

  TwHF AZA P value
Endoscopic score
 Mean ± SD 2.5 ± 1.8 (n = 43) 1.9 ± 1.1 (n = 42) 0.01
 ≥i2, n/N 32/43 21/42 0.03
CDAI, mean ± SD 148.6 ± 55.2 (n = 43) 128.3 ± 54.0 (n = 42) 0.09
IBDQ, mean ± SD 143.8 ± 28.5 (n = 43) 129.4 ± 28.7 (n = 42) 0.02
CRP, mean ± SD 11.6 ± 5.5 (n = 44) 11.3 ± 9.5 (n = 43) 0.90
ESR, mean ± SD 16.1 ± 7.3 (n = 44) 14.7 ± 9.6 (n = 43) 0.34
Clinical recurrence, n/N 12/45 8/45 0.45

AZA: azathioprine; CDAI: Crohn's disease activity index; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; IBDQ: inflammatory bowel disease questionnaire; SD: standard deviation; TwHF:Tripterygium wilfordiiHook. f.

The proportion of patients developing clinical recurrence in each group was also analyzed by applying NRI. The clinical recurrence during the first 26 weeks occurred in 4/42 of patients in the AZA arm (9.5%) and 6/43 of patients in the TwHF group (14.0%), with no difference (P = 0.74, Fig. 1 B) was found. At week 52, as data indicated, there was no difference between the AZA group (26.7%) compared with the TwHF group (32.4%) with respect to the clinical recurrence (P = 0.79, Fig. 1 B).

3.4. Endoscopy recurrence

The endoscopic findings were analyzed in all patients in whom endoscopy was performed at week 26 and at week 52. The analysis of endoscopic recurrence was first conducted LOCF approach. Two patients withdrawing due to intestinal obstruction did not receive the endoscopic examination in the first 26 weeks (1 in the TwHF group, 1 in the AZA group). Endoscopic recurrence in the first 26 weeks occurred in 21/44 of the patients in the AZA arm (47.7%) and 25/44 of the patients in the TwHF arm (56.8%), with no significant difference between the groups (P = 0.52, Table 2 , Fig. 2 ). Three patients did not undergo endoscopic evaluation at the time of withdrawal (1 in the TwHF group, 2 in the AZA group) between week 26 and week 52. At week 52, 21 of 42 (50%) patients in the AZA arm and 32 of the 43 (74.4%) patients in the TwHF arm had an endoscopic recurrence, with a significant difference observed (P = 0.03, Table 3 ). The comparison between both treatment groups is shown in Fig. 2 .

gr2

Fig. 2 Proportion of patients with clinical recurrence at first 26 weeks and 26–52 weeks in both treatment groups. The analysis was performed by using last-observation-carried-forward (A) and non-responder imputation (B) approach respectively. AZA: azathioprine; LOCF: last-observation-carried-forward; NRI: non-responder imputation; TwHF:Tripterygium wilfordiiHook. f.

The proportion of patients developing endoscopic recurrence in each group was also analyzed by applying NRI. The endoscopic recurrence at week 26 occurred in 21/42 of patients in the AZA arm (50%) and 25/43 of patients in the TwHF group (58.1%), with no significant difference between groups (P = 0.52) ( Fig. 2 B). At week 52, 21 of 30 (70%) patients in AZA and 32 of 37 (86.5%) patients in TwHF arm had an endoscopic recurrence with no significant deference was observed (P = 0.13). The comparison between both treatment groups is shown in Fig. 2 B.

3.5. Other efficacy endpoints

The mean CDAI score (LOCF) was similar in the two groups at week 26 ( Table 2 ) and at week 52 ( Table 3 ). However, the mean IBDQ (LOCF) scores both at week 26 (P = 0.04, Table 2 ) and week 52 (P = 0.02, Table 3 ) were significantly better in the TwHF arm than in the AZA arm. In contrast, the mean CRP level (LOCF) was similar in the groups at week 26 ( Table 2 ) and week 52 ( Table 3 ). In addition, no difference was observed with respect to ESR (LOCF) between the two groups at week 26 ( Table 2 ) or at week 52 ( Table 3 ).

3.6. Safety and tolerability

An overview of the adverse events is given in Table 4 . In the first 26 weeks, adverse events were more frequent in the AZA-treated patients (71.1%) than in the TwHF-treated patients (43.2%,P = 0.02). However, the incidence of adverse events was similar between the treatment groups at week 52. During the first 26 weeks, 1/45 of the TwHF-treated patients (2.22%) and 2/45 of the AZA-treated patients (4.4%) withdrew prematurely from the study because of adverse events (P = 0.98). At week 26 and week 52, 4/45 patients (8.9%) in the TwHF group and 7/45 patients (15.6%) in the AZA group discontinued the study due to the adverse events of the drugs, and there was no significant difference between the two groups (P = 0.52).

Table 4 Adverse events.

Any adverse event
  At week 26   At week 52
  TwHF (n = 45) AZA (n = 45) P value   TwHF (n = 45) AZA (n = 45) P value
Total events 16 27 0.03 Total events 22 35 0.23
Gastrointestinal 12 21 0.06 Gastrointestinal 16 26 0.06
Infectious 4 8 0.35 Infectious 6 11 0.28
WBC < 4000/mm3 2 5 0.43 WBC < 4000/mm3 2 6 0.27
Other 3 9 0.11 Other 5 12 0.10
Adverse events leading to withdrawal
At week 26 At week 52
TwHF (n = 45) AZA (n = 45) P value TwHF (n = 45) AZA (n = 45) P value
1 2 0.98 4 7 0.52

AZA: azathioprine; TwHF:Tripterygium wilfordiiHook. f.; WBC: white blood cell.

4. Discussion

The prevention of the postoperative recurrence of CD remains a challenge to both patients and physicians. AZA is currently recommended and is effective for the prevention postoperative CD recurrence [9] . It has been demonstrated that AZA is more effective than placebo in preventing postoperative clinical recurrence. Furthermore, it was also reported that the efficacy of AZA is superior to that of placebo for the prevention of postoperative endoscopic recurrence [23] , indicating that AZA is effective for the prevention of post-surgical recurrence in CD. However, the data also showed that the rate of adverse events leading to drug withdrawal was higher in thiopurine-treated patients than in the control arms [24] .

The central question we addressed in this clinical trial is whether TwHF, established for the treatment of active CD, would lead to a stronger reduction of recurrence than a thiopurine immunosuppressive agent. Compared with those receiving AZA, this study is the first to demonstrate that patients with CD have a similar rate of endoscopic recurrence when they receive TwHF treatment for 26 weeks, though this was not observed at week 52. Endoscopic recurrence is suggested to be predictive of subsequent clinical recurrence after ileocolic resection for CD[3] and [25], though it is also reported that the CDAI shows poor agreement with endoscopic recurrence at 1 year after intestinal resection [26] . In our study, AZA was demonstrated to be more effective than TwHF for preventing endoscopic recurrence at week 52; however, similar results were observed for TwHF and AZA in preventing postoperative clinical recurrence.

In a well-designed clinical trial, the authors demonstrated that 6-mercaptopurine (6-MP) reduced the rate of endoscopic recurrence compared with mesalazine [27] ; at 24 months, the clinical recurrence rates were 50% and the endoscopic recurrence rates 43% in patients receiving 6-MP. Another clinical trial regarding azathioprine consisted of an open-label, randomized study including 142 patients with CD receiving either AZA 2 mg/kg/day or mesalazine 3 g/day [14] . In this study, Ardizzone et al. found no difference in the efficacy of azathioprine and mesalamine in preventing clinical and surgical relapses, with an observed rate of clinical recurrence at 2 years for azathioprine of 17%. In addition, more patients receiving azathioprine withdrew from treatment due to adverse events than those receiving mesalamine (22% versus 8%) [14] . In our study, at week 52, 26.67% of the patients in the TwHF group and 17.78% in the AZA group had clinical recurrence, which was comparable with previous reports[14] and [27]. In a controlled randomized trial including “high-risk” patients, significant endoscopic recurrence was observed in 43.7% patients in an AZA-treated group [13] , which was similar to our results.

The high rate of adverse events in the azathioprine arm in our study was similar to previous reports in patients with postoperative CD[23] and [28]. In contrast, one study involving azathioprine in combination with metronidazole observed a lower incidence of adverse events [13] . Previous studies[14] and [28]have indicated the high frequency of discontinuation resulting from side effects in patients receiving AZA at a dose of 2 mg/kg/day, which was shown to be effective in other trials[29] and [30]. In addition, a high dropout rate (56%) was also reported in patients receiving metronidazole with 100–150 mg AZA [13] . Compared with other trials, a high rate of adverse events resulting from AZA and TwHF was observed in the present study. Although supporting evidence is lacking, according to our actual routine clinical practice, a relatively high rate of adverse events resulting from AZA is observed in patients in China compared to other ethnic populations. It should be noted that our findings of adverse events leading to withdrawal were similar to other observations [23] . A comparative randomized, double-dummy study in patients with postoperative moderate or severe endoscopic recurrence confirmed that AZA reduced the rate of postoperative recurrence compared with mesalazine [28] . In that study, a high rate of discontinuation (22.0%) resulting from the side effect profile of AZA was found, which was confirmed by our results.

Accumulated data indicate that factors such as a young age, current smoker, the number of surgical resections, penetrating disease, and abscess or fistula as an indication for surgery are associated with the early recurrence of CD[31] and [32]. In our clinical practice, smoking cessation is strongly recommended because smoke is considered to be the most important environmental risk factor in CD pathogenesis [33] . Although having a low rate of active smoking, the patients included in our study presented elevated risk for recurrence. According to the data, more than 60% of the patients presented fistulizing CD; furthermore, more than half of all the patients received surgery with abscess or fistula as the indication for surgery. The reason for this is that our medical centre serves as a tertiary referral centre for patients with IBD, and the disease in the patients with CD admitted to our centre for surgery may be more complex, with high rates of postoperative recurrence, which may affect the actual rate [34] .

In this clinical trial, we found that more patients in the AZA group experienced adverse events at week 26, suggesting that AZA treatment is less tolerated than TwHF therapy. Our results confirm the results of another study, which showed that TwHF is both effective and safe in treating patients with active rheumatoid arthritis [17] . IBDQ is a disease-specific instrument that measures quality of life in patients with IBD, and IBDQ scores range from 32 to 224, with a higher score indicating a better quality of life [22] . It should be noted that patients receiving the TwHF treatment showed significantly better IBDQ scores both at week 26 and at week 52 than those undergoing the AZA treatment, which may be related to the results that less adverse events occurred in the TwHF group.

The present study has limitations. First, this was a single-centre study with a small sample size. Second, our institute is a tertiary referral centre for patients with IBD, and many of the patients who underwent resection at our hospital are those with more complicated disease, which may result in bias in the complexity of the cases managed. Third, a lack of a placebo arm in the study may lessen the power of the study. Forth, the high rate of withdrawal may result in potential bias. Finally, the results for the endoscopic recurrence at week 52 changed with the use of NRI and LOCF approach. Hence, the results are potentially to be biased. This may be resulted from the high dropout rate in AZA arm.

This is the first published study comparing TwHF versus AZA for preventing endoscopic and clinical recurrence after intestinal resection for CD. Although the data indicated that AZA may be more effective for maintaining endoscopic recurrence at week 52, our results also suggest that TwHF is safe and effective in preventing postoperative clinical recurrence. Further randomized controlled trials with a better design and a larger number of patients conducted by multi-centres are needed to confirm our conclusions and to determine the duration of postoperative TwHF maintenance treatment.

Conflict of interest

None declared.

Acknowledgements

This work was partly supported by National Ministry of Health for the Digestive Disease (Grant 201002020) and National Natural Science Foundation of China (Grants 81200263 and 81170365).

Appendix A. Supplementary data

The following are the supplementary data to this article:

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Supplementary Figure S1 Study flow diagram. AZA: azathioprine;TwHF: Tripterygium wilfordiiHook. f.

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Footnotes

Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China

lowast 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.