OP18 Treatment of perianal fistulas in Crohn’s Disease: Surgical closure after anti-TNF induction treatment versus anti-TNF without surgery (PISA II) - A patient preference RCT

Background Current guidelines on Crohn’s perianal fistulas recommend anti-TNF treatment and suggest to consider surgical closure in amendable patients. However, long-term outcome of both treatments have not been directly compared. The aim of this study was to assess MRI healing in a patient preference RCT comparing both treatment modalities. Methods This multicentre, international trial compared surgical closure following anti-TNF induction (4 months) to anti-TNF therapy without surgery. Patients were counselled for both treatment arms and randomised if there was no preference. Due to the combination of a preference and randomised cohort, the appropriate sample size to detect a clinically relevant increase of 25% closure (from 15% to 40%) was flexible and adjusted for a possible skewed distribution (86 patients in case of 1:1 treatment allocation). All Crohn’s patients ≥ 18 years with a (re)active high perianal fistula and a single internal opening were eligible. Exclusion criteria were previous failure of anti-TNF, recto-vaginal fistula, proctitis, or stoma. Patients received seton placement prior to treatment. Primary outcome was MRI healing after 18 months (defined as a complete fibrotic fistula or MAGNIFI-CD score of 0–5). Secondary outcomes included clinical healing, re-interventions and fistula recurrence. Results Between September 2013 and December 2019, 7 hospitals in the Netherlands and Italy included 93 patients (59% females, median age 34 years) of which 32 were randomised. Thirty-seven patients were treated in the surgical closure group and 56 in the anti-TNF group, with comparable baseline characteristics. After 18 months, MRI healing was significantly higher after surgical closure (41% vs 11%; P=0.002). Although a trend was seen in favour of surgical closure, clinical healing rates and surgical re-interventions were not significantly different between groups (65% vs 45%, P=0.07 and 19% vs 34%, P=0.1). After median 38 months follow-up, 12 patients in the anti-TNF group crossed over to surgical closure. Both long-term MRI healing and clinical closure in the per protocol analysis remained significantly higher for the surgical closure group (46% vs 11%, P=0.002 and 65% vs 29%, P=0.006). One patient (4%) with a MAGNIFI-CD score ≤5 developed a recurrent fistula after 46 months, whereas recurrences occurred in 37% of patients with MAGNIFI-CD score >5 (P=0.004). Conclusion These results demonstrate that surgical closure following anti-TNF induction treatment induces MRI healing more frequently than anti-TNF alone. This is associated with increased long-term clinical closure and reduced recurrences. These data suggest that Crohn’s perianal fistula patients amendable for surgical closure should be counselled for this therapeutic approach.

Apoptotic and cell cycle response to homoharringtonine and harringtonine in wild and mutant p53 hepatocarcinoma cells

This study aimed to evaluate the modes of action of harringtonine (HT) and homoharringtonine (HHT) alkaloids in cell with wild (HepG2/C3A) and mutant p53 (HuH-7.5). We performed assays for cytotoxicity, genotoxicity, induction of apoptosis, cell cycle phase, and membrane integrity. Obtained data were compared with the relative expression of mRNA of genes related to proliferation, apoptosis, cell cycle control, metabolism of xenobiotics, and reticulum endoplasmic stress. The relative expression of the genes showed an increase in apoptosis-inducing mRNAs, such as TNF and BBC3, as well as a reduction in BCL2 and BAK. The mRNAs of CYP2E1 and CYP2C19 xenobiotic metabolism genes increased in both lineages, while CYP3A4 increased only in the HuH-7.5 lineage. The mRNA expression of endoplasmic reticulum (ER) stress genes ( ERN1 and EIF2AK3) was shown to increase in HHT and HT treatments. A similar increase was recorded in the mRNA expression of the TRAF2 gene. The changes observed in this study support the hypothesis that ER stress was more strongly associated with TNF induction, causing cell death by apoptosis in p53 mutant cells. This result with wild and mutant p53 cells may have clinical implications in the use of these compounds.

P136 Faecal calprotectin as therapeutic target in patients with Crohn’s disease treated with anti-TNF: a meta-analysis of individual data

Background Faecal calprotectin (Fcal) could be a non-invasive alternative to endoscopy to assess therapeutic efficacy in patients with Crohn’s disease (CD). We performed a systematic review and meta-analysis of individual data to assess the performances of FCal after anti-TNF induction therapy to predict mid-term steroids-free clinical remission (CFREM) in CD. Methods We included all the studies reporting patients with CD receiving anti-TNF agents with Fcal measurement before and after induction therapy (from 8 to 14 weeks) with follow-up > 6 months, no therapeutic intervention based on FCal during the follow-up and mid-term clinical evaluation between week 32 and week 54. CFREM was defined as CDAI < 150 and continuation of the same anti-TNF agent without steroids. Results We identified five articles including 165 patients with CD (mean age = 34.5 ± 12.8 years, median CD duration 5 years [2–12], female gender = 52.7%, active smokers = 33.3%, prior bowel resection = 25.6%, CD location (L1 = 32.1%, L2 = 15.8%, L3 = 52.1%), perianal lesions = 22.4%). The patients were treated with infliximab (50.9%), adalimumab (47.3%) or certolizumab (1.8%), and received concomitant immunosuppressants in 48.5% of the patients. Mid-term CFREM was achieved in 57.3% of the patients. Fcal level after anti-TNF induction therapy was lower in patients who achieved mid-term CFREM (100 µg/g [48–267] compared with those who did not (491 µg/g [165–856]; p < 0.001). The relative decrease of Fcal between before and after induction therapy was also associated with mid-term CFREM (p = 0.022). In multivariable analysis adjusted on CDAI, CRP and disease duration, FCal level (p = 0.014) and relative decrease of anti-TNF (p = 0.025) after induction were associated with mid-term CFREM. Cut-off values between 200 and 400 µg/g showed close performances to predict mid-term CFREM. FCal <250µg/g predicted mid-term CFREM with: Se = 73.3%[63.0%-82.1%], Spe = 67.7%[54.9%-78.8%], PPV = 75.9%[65.5%-84.4%] and NPV= 64.7%[52.2%-75.9%]. A relative decrease ≥ 50% between baseline and the end of induction was the best threshold to predict mid-term CFREM (Se = 59.6%[48.6–69.8%], Spe = 78.5%[66.5–87.7%], PPV = 79.1%[67.4–88.1%] and NPV = 58.6% [47.6–69.1%]). We found a significant study effect (ICC =0.36 ± 0.18) due to the variability according to FCal assay. The likelihood of being in CFREM at mid-term (PPV) according to the combination of CDAI, CRP and Fcal was presented in Figure 1. Conclusion The improvement of Fcal after anti-TNF induction therapy is predictive of mid-term CFREM in patients with IBD. The combination of clinical remission, CRP normalisation and FCal improvement should be a therapeutic target in patients with CD. Our work highlighted the need of international standardisation of Fcal measurement.

Similar Clinical and Surgical Outcomes Achieved with Early Compared to Late Anti-TNF Induction in Mild-to-Moderate Ulcerative Colitis: A Retrospective Cohort Study

Background.Biologic agents targeting tumor necrosis factor alpha are effective in the management of ulcerative colitis (UC), but their use is often postponed until after failure of other treatment modalities.Objectives.We aim to determine if earlier treatment with infliximab or adalimumab alters clinical and surgical outcomes in UC patients.Methods.A retrospective cohort study was conducted evaluating UC outpatients treated with infliximab or adalimumab from 2003 to 2014. Patients were stratified by time to first anti-TNF exposure; early initiation was defined as starting treatment within three years of diagnosis. Primary outcomes were colectomy, UC-related hospitalization, and clinical secondary loss of response. Kaplan-Meier analysis was used to assess time to the primary outcomes.Results.115 patients were included (78 infliximab, 37 adalimumab). Median follow-up was 175.6 weeks (IQR 72.4–228.4 weeks). Fifty-seven (49.6%) patients received early anti-TNF therapy; median time to treatment in this group was 38.1 (23.3–91.0) weeks compared to 414.0 (254.0–561.3) weeks in the late initiator cohort (p<0.0001). Patients treated with early anti-TNF therapy had more severe endoscopic disease at induction (mean Mayo endoscopy subscore 2.46 (SD ± 0.66) versus 1.86 (±0.67),p<0.001) and trended towards increased risk of colectomy (17.5% versus 8.6%,p=0.16) and UC-related hospitalization (43.9% versus 27.6%,p=0.07). In multivariate regression analysis, early anti-TNF induction was not associated with colectomy (HR 2.02 [95% CI: 0.57–7.20]), hospitalization (HR 1.66 [0.84–3.30]), or secondary loss of response (HR 0.86 [0.52–1.42]).Conclusions.Anti-TNF therapy is initiated earlier in patients with severe UC but earlier treatment does not prevent hospitalization, colectomy, or secondary loss of response.