Postoperative Approach for Crohn's Disease: The

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Postoperative Approach for Crohn’s Disease: The Right Therapy to the Right Patient Paulo Gustavo Kotze1,*, Takayuki Yamamoto2 and Aderson O.M.C. Damião3 1

Colorectal Surgery Unit, Catholic University of Paraná (PUCPR), Curitiba, Brazil; 2IBD Centre, Yokkaichi Hazu Medical Centre, Yokkaichi, Japan; 3Gastroenterology Department, University of São Paulo Medical School (FMUSP), São Paulo, Brazil Please provide corresponding author(s) Abstract: Recurrence is a common event after surgical resections secondary to Crohn’s disease (CD). photograph Endoscopic signs of inflammation, defined as postoperative endoscopic recurrence (PER) occur in up to 90% of the patients after one year. PER precedes clinical recurrence and further need for reoperations due to consequent bowel damage. Therefore, controlling inflammation after surgery in a preventive way is essential for disease control. There is no fixed strategy to prevent recurrence after surgery in CD. There are several risk factors that must be taken into consideration to guide physicians to choose the best therapeutic agents and strategies in this scenario. In this review, the authors describe in details the stratification based on risk factors, the therapeutic agents mostly used to prevent recurrence and discuss the several options for the postoperative management in CD. No fixed strategy is recommended after surgical resections in CD. Thus, the need for a personalized approach for each patient is emphasized, in accordance with several conditions and variables.

Keywords: Crohn´s disease, recurrence, postoperative care. 1. INTRODUCTION Despite advances in medical therapy over the last years, up to 75 % of patients with Crohn's disease (CD) in the terminal ileum and colon will need surgery at some stage of the disease [1]. Ileocaecal resection usually is indicated in complicated CD, especially in retroperitoneal abscesses, abdominal fistulas, as well as symptomatic intestinal strictures, dysplasia and, more rarely, cancer [2]. It is also known that surgery does not cure the disease. Recurrence is a common event after surgery in CD. Postoperative endoscopic recurrence (PER) is usually the first to occur, achieving rates that can reach up to 90% in one year [3]. It precedes clinical and surgical recurrences, the latest occurring in 30-70% of patients 10 years after the first resection [2]. Therefore, it is important to properly detect endoscopic recurrence, in order to adequately treat patients before the development of symptoms and bowel damage, that can lead to a further need for repeated surgical procedures [4]. Ileocolonoscopy is the most performed test to detect recurrence, and the Rutgeerts' score is the most important tool to grade and classify PER [5]. It was validated to be used after ileocaecal resections in CD, and is currently not applied in other locations, such as proximal small bowel or in the colon. There is lack of evidence regarding which may be the best method to detect and classify recurrence in these different locations. This score classifies the inflammation in the neoterminal ileum, according to Table 1. PER is usually defined as the presence of a Rutgeerts' score ≥ i-2. This single *Address correspondence to this author at the Colorectal Surgery Unit, Catholic University of Paraná (PUCPR), Curitiba, Brazil; E-mail: [email protected] 1389-4501/16 $58.00+.00

finding of i-2 seems to be controversial nowadays, and a proposed difference between ulcerations located at the anastomotic site (i-2a) or at the neoterminal ileum (i-2b) is currenty under study and validation. Table 1.

Detailed description of the Rutgeerts’ score. Adapted from Rutgeerts et al. [5].

Rutgeerts’ Score

Endoscopic Description of Findings

i0

No lesions

i1

≤ 5 Aphthoid ulcers

i2

> 5 Aphthoid ulcers with normal mucosa inbetween or normal areas between larger ulcers or ulcers limited to ileocolic anastomosis

i3

Diffuse aphthoid Ileitis with diffusely inflamed mucosa

i4

Diffuse inflammation with large ulcers, nodulations or stenosis

Several agents have been studied in the prevention of recurrence after surgical resection in patients with CD, such as aminosalicylates, antibiotics, corticosteroids, probiotics, thiopurines and monoclonal antibodies, such as infliximab (IFX) and adalimumab (ADA) [6]. Conventional therapy (mesalazine, azathioprine or metronidazole, for example) is usually associated with limited efficacy, due to adherence problems and possible adverse events [7]. These agents (mainly thiopurines) are mostly used in patients with low risk for recurrence. The efficacy of biological agents in pre© 2016 Bentham Science Publishers

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venting PER has been reported in some prospective studies and in different case series. Some small trials demonstrated superiority of this class of medications in preventing PER, as compared to conventional therapy [8-12]. Despite the fact that biological agents seem to be the most effective form of therapy to prevent PER, they cannot be used in every single patient. The limitations of costs, adverse events and reimbursement reflect the reality that justifies selection of proper patients to benefit from this specific therapy. There is always a risk of overtreatment with biologics, and some selected patients will benefit from conventional therapy as well. Therefore, a personalized management of postoperative recurrence in Crohn´s disease is needed, and a fixed single strategy for every patient is not recommended [13]. In this review, the authors will emphasize the need for risk stratification after surgery for CD, the best strategies to detect, prevent and treat PER, in order to achieve control of the disease and prevent future operations. Tailoring the right therapy for the right patient is a real need in the postoperative scenario. 2. DEFINITION OF RISK FACTORS FOR POSTOPERATIVE RECURRENCE AND STRATIFICATION As previously stated, there is a clear need to identify risk factors for postoperative recurrence in CD and to establish cost-effective and personalized preventive strategies to avoid future structural bowel damage. Recurrence is considered to be the result of a complex interface among several factors including genetic background, epigenetic and environmental features (active smoking), some special phenotypes (penetrating disease), intestinal dysbiosis and impaired mucosal immunity [14, 15]. That is the main reason why all patients should not be managed with the same strategy in the postoperative scenario. Establishing risk factors for postoperative recurrence in CD is not an easy task. In spite of significant limitations and several studies in the literature, at least five more established risk factors have been described: smoking, prior intestinal resection, penetrating phenotype, perianal disease and extensive small bowel resection (> 50 cm) [14, 16]. There is controversy regarding granulomas and myenteric plexitis in the specimens as established risk factors [14, 16]. A validated predictive index for risk factors for postoperative recurrence is desirable but it has not yet been developed. The ECCO guidelines consider the following predictors of recurrence after ileocolonic resection: smoking, prior intestinal surgery (grade of recommendation A), penetrating disease behaviour, perianal disease, extensive small bowel resection (grade of recommendation B) and absence of prophylactic treatment (grade of recommendation A) [17]. Typically, risk factors for recurrence have been classified into patient-related, disease-related, and operation-related factors, which are described in detail in Table 2 [3, 18, 19]. 2.1. Patient-Related Factors Smoking has consistently emerged as a strong, independent, and modifiable risk factor for postoperative recurrence in CD, and its cessation must be encouraged. Data have mainly come from referral centres and randomized con-

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trolled trials [14]. A meta-analysis conducted by Reese et al. (16 studies, 2962 patients) showed that smokers had a significantly higher clinical recurrence rate when compared with non-smokers (OR 2.15; 95% CI 1.42-3.27; P < 0.001) [20]. Despite these data, the use of biological therapy after surgery possibly may neutralize the effect of smoking, as discussed in previous trials [9, 12]. The influence of family history of inflammatory bowel disease, gender, and use of oral contraceptives on recurrence is controversial. Thus, a definite conclusion on their role as risk factors cannot be addressed. Table 2.

Risk factors for postoperative recurrence in CD. Established risk factors are underlined. TGF-beta 1: Transforming Growth Factor-beta1; IGF-1: Insulinlike Growth Factor-1; IL-10: Interleukin-10; ASCA: anti-Saccharomyces cerevisiae antibody.

Patient-Related Factors Smoking Family history of inflammatory bowel disease Gender Use of oral contraceptives Disease-Related Factors Penetrating disease Prior intestinal resection Perianal disease Age at diagnosis and age at time of operation Short duration of disease Anatomical site (ileocolonic > jejunal/ileal > colonic) Early versus late surgery (ileocaecal disease) Failure to immunomodulators/biologics Absence of prophylactic treatment Use of corticosteroids Histological parameters (granulomas, histological inflammation at the margins of resection, myenteric plexitis, lymphatic vessel density, abnormal Paneth cells) Genetic factors (NOD2/CARD15 mutations) Serologic markers (ASCA) Biologic and immunologic markers (TGF-beta 1, IGF-1, IL-10) Operation-Related Factors Length of resected segment (> 50 cm) Postoperative complications Type of anastomosis (handsewn end-to-end versus stapled side-to-side) Involvement of disease at resection margins Blood transfusion Laparoscopy versus open surgery Strictureplasty Permanent ileostomy (lower postoperative recurrence rates)

2.2. Disease-Related Factors The most consistent disease-related risk factors for recurrence are penetrating disease, perianal involvement and prior intestinal resections. The other factors described in Table 2 are less consistent and controversial (for example, granulomas and myenteric plexitis), due to conflicting results in the studies, and are not universally accepted [3, 14, 15].

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Penetrating disease, characterized by abdominal fistulas, abscesses or free perforation, is considered an independent risk factor for both clinical and surgical recurrence [1]. A meta-analysis of 13 studies recognized that the probability of surgical recurrence was significantly higher in patients with penetrating disease as compared with those with a nonpenetrating phenotype (HR = 1.50; 95% CI 1.16-1.93) [20]. Apart from that, patients tend to recur with a similar disease phenotype and require repeated surgery for similar indications. Indeed, penetrating disease tends to recur again as penetrating, and non-perforating as non-perforating disease [21, 22].

rence rates when compared with wider resections. In the classic prospective study by Fazio et al., no difference in clinical and surgical recurrence was detected between patients randomly assigned to undergo 2 cm (limited) versus 12 cm (extended) resection margins [30]. Moreover, no significant difference in recurrence rates was noted among those with residual microscopic disease. These data have given rise to a minimalist philosophy in the surgical management of CD by removing grossly affected bowel and leaving behind margins that may harbour microscopic disease, in conflict to previous reports in the literature, that demonstrated opposite results [31].

Perianal disease (luminal or fistulizing) has also been associated with a higher rate of recurrence [22]. In fact, in some referral centre studies, perianal disease was the only independent risk factor for postoperative recurrence [15].

Data on other operation-related factors such as postoperative complications, perioperative blood transfusion, anastomotic configuration (handsewn end-to-end versus stapled side-to-side), surgical approach (laparoscopic versus open surgery) have yielded conflicting results [3, 14, 15].

Buisson et al., after reviewing population-based and referral centre studies concluded that prior intestinal resection is an established risk factor for recurrence [15]. Furthermore, patients with a previous resection required more intensive postoperative prophylaxis to prevent clinical recurrence [23-25]. Histological features possibly involved in PER have also been studied [26]. Data regarding granulomas are still conflicting. Controversial results have emerged, with studies showing increased clinical and surgical recurrence rates and others demonstrating a decreased number. A meta-analysis of 21 studies (n=2236 patients) reported that the number of patients with recurrence and further operations were higher in patients with granulomas as compared with those without (OR: 1.37; 95% CI: 1.02-1.84, and OR: 2.38; 95% CI: 1.433.95, respectively) [27]. Despite these findings, there is still controversy regarding this histological characteristic. Differences in sampling and serial sectioning methods probably account for these opposite results. Myenteric plexitis (inflammatory changes within the enteric nervous system of the proximal resection margin) is considered to be another reliable histological feature to predict postoperative recurrence [26]. Four well designed studies have independently found this characteristic to be a predictor of clinical and endoscopic recurrence, in spite of some variations in the definition of the plexitis. In one of them, the difference in clinical recurrence was not statistically different, but there was a trend to a higher rate in the myenteric plexitis group versus no plexitis (30% versus 16%, respectively, P= 0.17) [28]. The severity of the plexitis seems to correlate with the severity of endoscopic recurrence [29]. 2.3. Operation-Related Factors Most of the studies that dealt with the extent of the resected bowel have shown that resection of longer intestinal segments is associated with higher rates of PER [3, 15]. The definition of “extensive small bowel resection” is controversial, commonly referred as resections of intestinal segments longer than 50 cm [15]. Early studies suggested that limited instead of extensive resection was related to reduced rates of recurrence [3, 14, 15]. Subsequent studies, however, showed that limited resections were associated with similar clinical and surgical recur-

2.4. Risk Stratification to Improve Outcomes After Intestinal Surgery Due to significant rates of postoperative recurrence in CD, some preoperative stratification strategies have been proposed in order to help physicians to decide the best strategy for each patient, according to previously mentioned risk factors. These strategies would guide the best medical therapy for each type of patient, on an individualized basis. At present, three classifications of risk factors have been proposed (Table 3). Table 3

Different strategies for stratification of risk factors for recurrence in CD described in the literature.

1) High and Low Risk [13, 19, 32]: High risk patients defined as active smokers, with perforating disease and previous resection(s). Other risk factors suggested: perianal lesions, extensive small bowel disease and intestinal resection > 50 cm. Low risk patients defined as those with absence of high risk factors. Commentaries: Validated in the POCER trial, risk factors are well defined, no incorporation of recent described factors such as histological markers. 2) Stratification According to Number of Risk Factors (0, 1, ≥2) [6, 15, 16]: Risk factors included: active smoking, prior intestinal resection, penetrating behaviour, perianal disease, intestinal resection > 50 cm, histological findings (e.g., myenteric plexitis). Commentaries: Wider inclusion of established risk factors, better characterization of possible “moderate/intermediate“ risk patients, no validation. 3) Very Low, Low/Moderate (Intermediate), High Risk [1, 33, 34]: Definitions: Very low risk: long-standing CD, first surgery, short stricture; intermediate: less than 10 years of duration of CD, long strictures or inflammatory CD; high risk: penetrating disease, more than two previous operations, smoking, complicated peri and postoperative course. Commentaries: Intermediate cases poorly defined, not validated.

The traditional stratification strategy considers only patients with high and low risk for postoperative recurrence


[13, 19, 32]. High risk is usually defined as having one or more of the following: active smoking, perforating disease or previous resection(s). Patients without those risk factors are deemed to be at low risk. This stratification was recently validated in the POCER study with considerable benefits [13]. Some authors add perianal lesions, extensive small bowel disease and intestinal resection > 50 cm to the high risk list [16]. New markers of recurrence, including histological, serological and genetic features, will probably be incorporated to this high/low risk stratification in a near future, increasing its accuracy and effectiveness. The second stratification strategy takes into consideration the number of risk factors presented (0, 1 or ≥ 2 risk factors) [6, 15, 16]. Patients with no risk factors have a very low likelihood of recurrence. Those patients with 1 risk factor have an intermediate chance of recurrence and patients with 2 or more risk factors are at higher risk of PER. The risk factors considered were: active smoking, prior intestinal resection(s), penetrating phenotype, perianal disease, intestinal resection > 50 cm and histological findings (mainly myenteric plexitis). This strategy still needs to be validated in clinical trials. Finally, a third strategy classifies the patients into three categories: very low risk, low/moderate risk and high risk [1, 33, 34]. Patients at very low risk for recurrence are those with long-standing CD, submitted to first resection and with short strictures. Low/moderate risk patients (intermediate risk patients) are defined as those with less than 10 years of disease duration, long strictures or inflammatory CD. Patients at high risk for recurrence are those with penetrating disease, more than two previous resections, smokers and those with complicated peri and postoperative course. This strategy has not been validated in controlled trials and the limits of the intermediate group of patients are controversial. The first strategy of risk stratification of patients (high and low risk) is the most used in case series and in clinical trials. It was also used in the study that showed a perfect example of personalized management of postoperative CD, the POCER trial. Therefore, for its simplicity and previous validation in a prospective trial, it is the most recommended. The definition of the type of patient according to the risk factor profile will define the specific strategy of prevention of PER. Some patients, mostly the patients with lower risk for recurrence, will benefit from conventional therapy. Patients with higher risk for PER will definitely benefit from more effective strategies, such as the use of biological therapy with or without combination with immunomodulators. In the next sessions, the indication for each type of treatment is discussed, and some algorithms are suggested. 3. IS THERE ROOM FOR CONVENTIONAL THERAPY AFTER SURGERY IN CD? 3.1. Aminosalicylates Sulphasalazine was not proved to be effective in preventing PER in CD [35]. Regarding oral mesalazine, at least five randomized controlled trials (versus placebo) were performed (time of follow-up 3 to 24 months) [16]. Only in two of them a statistically significant benefit was seen. The largest trial enrolled 318 patients and found no difference in

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clinical PER rates between mesalazine (4g/day) and placebo after 18 months (24.5% vs 31.4%, respectively, p=0.10). Pooled data of these five trials were evaluated in a metaanalysis [7]. Compared with placebo, mesalazine was associated with a significantly reduced risk of clinical recurrence (RR 0.76; 95% CI 0.62-0.94; number needed to treat [NNT]=12), and severe (Rutgeerts' score i3 and i4) endoscopic recurrence (RR 0.50; 95% CI 0.29-0.84; NNT=8). However, any endoscopic recurrence was not significantly reduced by mesalazine. Moreover, mesalazine was inferior to azathioprine/6-mercaptopurine in preventing any endoscopic recurrence, but had a lower risk of serious adverse effects. A second meta-analysis confirmed these data and showed that mesalazine was more effective than placebo or no therapy with an NNT of 10 [35]. Thus, the current evidence indicates that mesalazine provides, at best, a very small reduction in PER, and seems to be not cost-effective. 3.2. Thiopurines (Azathioprine [AZA]/6-Mercaptopurine [6-MP]) In general, thiopurines have been shown to be more effective than placebo and mesalazine for prevention of postoperative recurrence in CD [16]. One meta-analysis showed that thiopurines were associated with a significantly reduced risk of clinical recurrence (RR 0.59; 95% CI 0.38-0.92, NNT=7), and severe endoscopic recurrence (RR 0.64; 95% CI 0.44-0.92, NNT=4), when compared with placebo[7]. A second meta-analysis confirmed the superiority of AZA/6MP over placebo or mesalazine at preventing one-year clinical and endoscopic recurrence, with an NNT of 13 and 7, respectively [36]. These “NNTs” turned out to be 7 and 4, respectively, if only studies comparing placebo were taken into account. Long-term maintenance therapy (≥ 36 months) seems to be beneficial in those who can tolerate the drug [37]. Overall, AZA/6-MP have modest efficacy in preventing PER in CD. There is also controversy if immediate use of azathioprine after surgery may be superior to an endoscopicdriven approach, as studied in a prospective trial from the IOIBD (International Organization of Inflammatory Bowel diseases). In this study, no difference was found between the two strategies, but the sample was limited and the study was interrupted due to slow patient recruitment [38]. 3.3. Antibiotics A placebo-controlled trial of metronidazole (20 mg/kg) for 3 months showed reduced prevalence of severe PER at 3 months [39]. Adverse events were 3 times more common in the metronidazole group. Moreover, metronidazole for 3 months at a lower dose (750 mg/day) in combination with AZA for 12 months was superior to metronidazole (3 months) associated with placebo (12 months) in reducing PER, pointing out a possible synergic effect [40]. Metronidazole, at this lower dose, was well tolerated. The same positive effect was seen with another imidazole antibiotic, ornidazole (1 g/day), in a trial that showed a significant reduction in both clinical and severe endoscopic recurrence rates at 1 year [41]. Again, adverse events were more common in the ornidazole group. Thus, metronidazole and ornidazole were more effective than placebo in preventing PER, but their effect is not long-standing (beyond 1 year) and poor tolerability may preclude their use in some patients beyond 3

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months. In a recent randomized, double-blind, placebocontrolled pilot study with oral ciprofloxacin (500 mg twice daily), the drug was not more effective than placebo in preventing PER in patients with CD at 6 months after surgery (65% in the ciprofloxacin group vs 69% in the placebo group, p < 0.805) [42]. Drug-associated adverse events occurred significantly more often in the ciprofloxacin group. 3.4. Enteral Nutritional Therapy Enteral nutrition (EN) is an attractive treatment due to its favourable safety profile. Yamamoto et al. [43] conducted a prospective, non-randomized, parallel-controlled study in which 20 historically high compliance patients, after ileal or ileocaecal resection for CD, received 1200-1800 mL of a monomeric (elemental) diet at night-time through a nasogastric self-intubated tube plus a low-fat diet during the day for 1 year. The historically low compliance patients (n=20) were assigned to non-EN group. All patients in both groups received mesalazine, 3 g/day. After 1 year, clinical recurrence (CDAI ≥ 150) was 5% in the EN and 35% in the control group (p=0.048). The values for endoscopic recurrence (Rutgeerts score ≥ 2) were 30% and 70%, respectively, after 12 months (p=0.027). At 5-year follow-up, the cumulative recurrence incidence rate of patients requiring infliximab was significantly lower in the EN group vs the non-EN group (p=0.02). One patient (5%) in the EN group and 5 (25%) in the control group required reoperation for recurrence, the difference not being significant (p=0.18) [44]. Another Japanese study also obtained positive results with a polymeric diet given orally, provided the patient received more than 1200 Kcal/day and especially in patients with the penetrating phenotype [45]. Studies with a larger number of high- compliant patients are necessary to broadly assess EN efficacy in the postoperative setting. This could be a valid opportunity in Asian countries, where compliance to EN is higher than in western countries. 3.5. Corticosteroids Traditional steroids (prednisone, methylprednisolone) are not recommended either for maintenance therapy in CD or for postoperative prophylaxis owing to both adverse events and ineffectiveness [46]. In addition, a meta-analysis with budesonide showed no benefit for reduction of either endoscopic or clinical postoperative recurrence [47]. 3.6. Probiotics Since dysbiosis plays a crucial role in CD recurrence, it is reasonable to think that modification of the microbiota with a probiotic may be effective in preventing PER [14]. Unfortunately, the results have been disappointing with several strains and cocktails (Lactobacillus rhamnosus strain GG, L. johnsonii [LA1], Synbiotic 2000, and VSL#3) [6]. Accordingly, a meta-analysis showed that probiotics were of no benefit in preventing PER in CD [48]. A recent prospective study also demonstrated that there was no difference in using VSL#3 or placebo in endoscopic recurrence rates, evaluated at 3 and 12 months [49]. 3.7. Other Therapies

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Although preliminary evidence suggests fish oils may be effective in prevention of severe endoscopic postoperative recurrence at 1 year, these findings need to be reproduced in larger controlled, randomized, prospective studies [3]. Interleukin-10 (IL-10) was tested but there is no evidence for its use in the prevention of PER in CD [3, 6]. A retrospective study in 258 patients showed daikenchuto, a traditional Japanese herbal medicine with anti-inflammatory properties, to be of benefit in reducing the 3-year surgical recurrence, as compared to the non-daikenchuto group (11.3% vs 24.5%, p=0.01) [50]. In this context, a small, prospective, singlecentre study with Tripterygium wilfordii polyglycoside (GTW, 1 mg/Kg/day), a traditional vine used in Chinese medicine for the treatment of autoimmune and inflammationrelated diseases, versus mesalazine (4 g/day) showed that both 1-year clinical and endoscopic recurrence rates were lower in the GTW group versus the mesalazine group (clinical recurrence – 5.3% vs. 23.5%, p < 0.001; endoscopic recurrence – 21.1% vs. 52.9%, p < 0.001) [51]. GTW positive effects were attributed to its anti-inflammatory and immunosuppressive activities. No serious adverse events were reported. The authors mentioned that a multicentre, randomized, controlled trial is planned, following ethical approval. 4. WHEN BIOLOGICAL AGENTS CAN BE USED IN THE POSTOPERATIVE SETTING? Biological agents, mainly ADA and IFX, are mostly indicated after surgical resection in CD in selected patients with high risk for recurrence, as previously defined. Some patients have a quite clear indication for postoperative biological therapy, like patients submitted to previous intestinal resections in the past, that are submitted to repeated operations, who may be at risk to develop short bowel syndrome. Patients with penetrating CD, as well, are good candidates for this kind of therapy after resection [3]. It is also clear that anti-TNF agents cannot be used in all patients with high risk for recurrence, due to limitations in costs and access to these medications. Decisions should be individualized when to indicate biological agents, mainly if not used preoperatively. In patients under these conditions, that had conventional treatment before surgery, biological therapy can be started usually 2-4 weeks after the procedure, once surgical and infectious complications are ruled out. On the other hand, most patients in high risk for recurrence are already using biological agents before the procedures. In these cases, restarting the medication without reinduction doses is usually the best strategy, again, once complications are not seen in 2-4 weeks after surgery. This is a common situation, mostly because several patients would still have residual disease (active CD in another location, for example, perianal or proximal small bowel) that still needs to be treated properly. In this case, proper treatment is continued after surgery, not meaning a strategy of prevention of recurrence. In patients with "curative resection" (no residual disease and no macroscopic CD in other locations), the strategy to interrupt biological therapy (that was used before the operation) has not been studied to date. In these specific cases, a specific prospective trial, comparing patients with continuous use after surgery versus patients with treatment interruption, could elucidate several questions regarding these issues.


Data that demonstrate the efficacy of biologics are mostly based on the experience with IFX and ADA. There are no specific studies published to date, defining the role of certolizumab pegol or vedolizumab in the postoperative scenario. Regueiro et al. demonstrated 9.1% of PER with IFX as compared to 84.6% in patients with placebo infusions, after a follow-up period of one year after ileocaecal resections [9]. In a longer follow-up of these same patients (at least 5 years), the authors demonstrated that patients on long term use of IFX had lower rates of endoscopic and surgical recurrences, as well as longer time until reoperation when needed [52]. In a prospective trial, Armuzzi et al. showed no significant difference between the use of IFX or azathioprine in a small sample of 21 patients, but a tendency towards better results with IFX could be demonstrated [53]. In a multicenter prospective randomized study, presented at the DDW in 2015, entitled the PREVENT trial, the role of IFX in preventing clinical recurrence was studied. The primary endpoint was not met, and no significant difference between IFX and placebo was found regarding clinical recurrence after 76 and 104 weeks. The secondary endpoint of this study was endoscopic recurrence. Regarding this, a significant difference was observed between patients in the IFX group (22.4%) as compared to placebo (51.3%), with p