Crohn’s disease (CD) is a disabling and progressive disorder involving the digestive tract that can lead to bowel damage as well as altered quality of life and high disability for patients [1,2]. Despite the larger use of biologics, bowel resection is required in almost one half of the patients [3]. After surgery, the reappearance of endoscopic lesions without symptoms, so-called endoscopic postoperative recurrence (POR), is very common, as 75% of the patients from referral centers have been reported to experience POR within the first year after surgery [4]. Endoscopic POR assessed by the Rutgeerts index (RI) is highly predictive of clinical POR, i.e. reoccurrence of CD-related symptoms [5,6]. The management of the postoperative period has evolved in recent years. It is currently recommended to perform a systematic colonoscopy at 6 months to assess the RI leading to therapeutic escalation in case of endoscopic POR defined as RI ≥ i2 [7]. In addition, most patients receive a prophylactic medication within the first month after surgery to prevent endoscopic POR. We recently reported that these modern strategies may have contributed to a decreased rate of POR [6]. However, the decision of starting a prophylactic medication should consider the risk of POR but also the risk of overtreatment for some patients (10% to 15% in the historical cohort described by Rutgeerts et al. [5]) who will not recur despite the absence of preventive treatment. Although several options are available, anti-tumor necrosis factor (TNF) agents are considered the most effective medications to prevent and to treat endoscopic POR in CD [8-14]. However, up to 30% of the patients experienced anti-TNF failure in this situation highlighting the need to identify predictors of therapeutic efficacy [8-14].

In this study, we assessed the effectiveness of anti-TNF agents compared to other medications and identified the factors associated with the effectiveness of anti-TNF agents to prevent endoscopic or clinical POR in patients with CD.

In this real-world cohort from a tertiary referral inflammatory bowel disease center, we confirmed that anti-TNF agents are the most effective option to prevent endoscopic and clinical POR in CD. In addition, we observed that combination therapy with anti-TNF and immunomodulatory agents was more effective than anti-TNF monotherapy in patients exposed to anti-TNF prior to surgery. Finally, we identified primary nonresponse to anti-TNF before surgery and prophylactic monotherapy as factors associated with anti-TNF failure to prevent endoscopic POR in patients with CD.

In our cohort, we analyzed anti-TNF effectiveness to prevent endoscopic POR in distinguishing the patients according to their exposition to anti-TNF prior to intestinal resection as this dichotomy has not been reported so far in the postoperative period. However, it seems to us relevant, as anti-TNF therapy is more effective in naïve patients to treat the traditional flare of CD [17]. In addition, the PREVENT trial suggested that patients who had not preoperatively been treated with antiTNF could be predictive of better efficacy to prevent clinical POR, even though the primary endpoint statistical significance was not reached (OR, 0.556; 95% CI, 0.301-1.026). It is further noteworthy that in the PREVENT trial, the secondary endpoint of endoscopic recurrence of RI ≥ i2 was less in the infliximab-treated patients (30.6% with infliximab vs. 60.0% with placebo; 95% CI, 18.6%-40.2%; P<0.001).

In anti-TNF-naïve patients, we report a very low rate of endoscopic POR (8.7%) without difference in patients with or without concomitant immunosuppressive therapy (1/12 vs. 1/11). In multivariable analysis adjusted for the usual risk factors, we showed that anti-TNF was much more effective than immunosuppressive agents (thiopurines or methotrexate) (OR, 8.8; 95% CI, 1.8-43.9; P=0.008) and no medication/5-ASA (OR, 5.2; 95% CI, 1.0-27.9; P=0.05). These data are in line with those compiled in a meta-analysis from very small-sample size cohorts reporting endoscopic POR rate from 0% to 26.6% which was lower than controls including placebo, 5-ASA and thiopurines [9]. It has been confirmed by 2 more recent network meta-analysis [18,19]. In a non-randomized sub-analysis of the POCER trial comparing 28 patients treated with adalimumab compared to 73 patients receiving thiopurines, the rate of endoscopic POR at 6 months was lower in patients treated with adalimumab (including 61% of anti-TNF-naïve patients and 100% of monotherapy) (21% vs. 45%, P=0.028). In the PREVENT trial, only 17% of the 147 patients received concomitant thiopurines with infliximab and 25.3% of the patients were already exposed to anti-TNF before surgery. The rate of endoscopic POR at 18 months was lower in the group treated with infliximab compared to placebo (22.4% vs. 51.3%, P<0.001). In our cohort from a referral center, 63% (199/316) of the patients were exposed to any anti-TNF prior to bowel resection. This higher rate of anti-TNF exposition is probably closer to the real-life practice as most of the patients currently receive at least 1 biologic before choosing the surgical option. Among these 199 patients, we showed, for the first time, that combination therapy with anti-TNF and immunosuppressive agents was more effective than anti-TNF monotherapy (OR, 2.32; 95% CI, 1.02-5.31; P=0.046) or other conventional medications (no medication, 5-ASA or immunosuppressive monotherapy) (OR, 3.65; 95% CI, 1.40-9.58; P=0.016) to prevent endoscopic POR.

The use of anti-TNF mono or combined therapy was matter of debate during the last decade in the management of CD. The short-term benefit of combination therapy with infliximab and azathioprine was clearly demonstrated in the SONIC trial, which has included only patients without use of both thiopurines and anti-TNF before participating to the study [20]. This benefit is more controversial in patients treated with adalimumab [21-23]. In contrast, the long-term positive impact has been demonstrated for the 2 anti-TNF agents in reducing the risk of immunogenicity and preventing the risk of secondary loss of response [23]. The impact of combination therapy was not previously investigated in the postoperative situation. The use of combination therapy could be supported by the higher risk of immunogenicity in patients previously exposed to at least 1 anti-TNF [24]. We cannot evaluate whether pharmacokinetics and immunogenicity were related to the superiority of combination therapy, as we did not perform systematically drug monitoring in our center. However, the relevance of using drug monitoring in the postoperative management remains questionable and poorly investigated [25,26]. We also focused on the factors associated with anti-TNF effectiveness in patients previously exposed to anti-TNF. Whether the history of anti-TNF use and response before surgery could have an impact on anti-TNF efficacy to prevent endoscopic POR is a highly relevant question, which has not been addressed so far. We showed that primary failure to at least 1 anti-TNF was associated with therapeutic failure. It is consistent with the data reported by a meta-analysis showing that primary nonresponse was associated with decreased likelihood of efficacy with a second anti-TNF [27]. In this situation, the use of other biologics could be discussed even though the preliminary data on vedolizumab are disappointing [28] while there is no data on ustekinumab so far.

As the risk of clinical POR is very high in case of endoscopic POR at 6 months [5,6], the efficacy of therapeutic escalation in this situation is a key point. In patients who did not receive any anti-TNF as prophylactic medication, we reported that anti-TNF is the most effective option to prevent clinical POR (OR, 3.10; 95% CI, 1.09-8.83; P=0.034). These data are consistent with the data from Yamamoto et al. [29] comparing 10 patients treated with continuous mesalamine (3 g/day), 8 patients treated with azathioprine therapy (50 mg/day), and 8 patients treated with infliximab (5 mg/kg, every 8 weeks). The authors reported that no patient in the infliximab group, 3 patients (38%) in the azathioprine group, and 7 patients (70%) in the mesalamine group developed clinical recurrence (Crohn’s Disease Activity Index ≥ 150), respectively (P=0.01). In patients who received anti-TNF as prophylactic medications, we found that optimizing the anti-TNF (shortening the interval or increasing the dose) and adding an immunosuppressive agent in the same time is the best option to prevent clinical POR (OR, 7.38; 95% CI, 1.54-35.30; P=0.012). Owing to the high risk of symptomatic recurrence in this situation, our data suggest maximizing the chance of success with the most potent option. In our cohort, we cannot draw any conclusion on the swap to another class of biological therapy to treat endoscopic POR and prevent clinical POR as only a few patients received these medications as rescue.

Our study has several limitations including that it is a single referral center with potentially more medically resistant CD, absence of a central review process for endoscopic scoring and relatively small-sample size for some subgroups. In addition, this is a retrospective analysis randomization to compare therapeutic options. However, all our comparisons were adjusted on usual risk factors and potential confounders. Strengths of this analysis is the large real-world cohort with standardized management and evaluation of endoscopic POR by experienced inflammatory bowel disease physicians. We also were able to identify specific some factors associated with anti-TNF effectiveness to prevent endoscopic and clinical POR.

In conclusion, in this retrospective study we identified that anti-TNF was the most effective medication to prevent endoscopic and clinical POR. We also identified that primary nonresponse to anti-TNF therapy before surgery was associated with anti-TNF failure to prevent endoscopic POR. In case of endoscopic POR despite anti-TNF therapy, optimizing the anti-TNF combined with addition of immunosuppressive drug seems to be the best option to prevent clinical POR. We recommend consideration of combination of anti-TNF and immunosuppressive therapy in patients with pre-operative exposure to anti-TNFs in order to prevent recurrence.