Pieter Dewint

Adalimumab combined with ciprofloxacin is superior to adalimumab monotherapy in perianal fistula closure in Crohn's disease: a randomised, double-blind, placebo controlled trial (ADAFI)

Objective To assess whether a combination of adalimumab and ciprofloxacin is superior to adalimumab alone in the treatment of perianal fistulising Crohns disease (CD). Design Randomised, double-blind, placebo controlled trial in eight Dutch hospitals. In total, 76 CD patients with active perianal fistulising disease were enrolled. After adalimumab induction therapy (160/80 mg week 0, 2), patients received 40 mg every other week together with ciprofloxacin 500 mg or placebo twice daily for 12 weeks. After 12 weeks, adalimumab was continued. Follow-up was 24 weeks. Primary endpoint (clinical response) was defined as 50% reduction of fistulas from baseline to week 12. Secondary endpoints included remission (closure of all fistulas), Perianal Crohns Disease Activity Index, Crohns Disease Activity Index (CDAI) and Inflammatory Bowel Disease Questionnaire (IBDQ). Results Clinical response was observed in 71% of patients treated with adalimumab plus ciprofloxacin and in 47% treated with adalimumab plus placebo (p=0.047). Likewise, remission rate at week 12 was significantly higher (p=0.009) in the combination group (65%) compared with adalimumab plus placebo (33%). Combination treatment was associated with a higher mean CDAI change and mean IBDQ change at week 12 (p=0.005 and p=0.009, respectively). At week 24, no difference in clinical response between the two treatment groups was observed (p=0.22). No difference in safety issues was observed. Conclusions Combination therapy of adalimumab and ciprofloxacin is more effective than adalimumab monotherapy to achieve fistula closure in CD. However, after discontinuation of antibiotic therapy, the beneficial effect of initial coadministration is not maintained. Trial registration ClinicalTrials.gov Identifier: NCT00736983.

Pirfenidone in idiopathic pulmonary fibrosis: expert panel discussion on the management of drug-related adverse events.

Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.

Use of visible light spectroscopy to diagnose chronic gastrointestinal ischemia and predict response to treatment

BACKGROUND & AIMS Chronic gastrointestinal ischemia (CGI) is more common than previously thought. Visible light spectroscopy (VLS) allows for noninvasive measurements of mucosal capillary hemoglobin oxygen saturation during endoscopy. We evaluated the response of patients with occlusive CGI to treatment after evaluation by radiologic imaging of the vasculature and VLS. We also identified factors associated with response to treatment in these patients. METHODS In a prospective study, we collected data from 212 patients referred for evaluation of suspected CGI from November 2008 through January 2011. Patients underwent an extensive evaluation that included visualization of gastrointestinal arteries and assessments of mucosal perfusion by means of VLS. Treatment response was evaluated in patients with occlusive CGI. Factors associated with response to therapy were assessed by using multivariate logistic regression analysis. RESULTS Occlusive CGI was diagnosed in 107 patients (50%); 96 were offered treatment (90%). After median follow-up period of 13 months, data on treatment response were available from 89 patients (93%); 62 patients had a sustained response (70%). Weight loss before treatment (odds ratio [OR], 1.93), presence of an abdominal bruit (OR, 2.36), and corpus mucosal saturation level <56% (OR, 4.84) were the strongest predictors of a positive response to treatment. CONCLUSIONS Treatment of CGI, diagnosed by a multimodal approach, provides a substantial long-term rate of response (70% in 13 months). Weight loss, abdominal bruit, and low corpus mucosal saturation identify patients most likely to respond to treatment. Multiple techniques should therefore be used to assess patients with CGI, including VLS measurements, to detect mucosal hypoxia.

Small bowel endoscopy and Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant inherited disease. It is clinically characterized by the development of gastrointestinal hamartomas, mainly located in the small bowel. These hamartomas are prone to complications such as intussusceptions, abdominal complaints and anaemia. Furthermore, patients are at increased risk for developing small bowel cancer. Therefore, regular surveillance of the small bowel is indicated. However, the optimal strategy for surveillance has not been determined yet. This review gives an overview of the different techniques that have been described to examine the small bowel of PJS patients. First, a number of radiologic and endoscopic imaging modalities with diagnostic value are discussed. Secondly, recently developed advanced endoscopy techniques are described that can serve both as a diagnostic and therapeutic tool in the surveillance of the small bowel. Finally, a recommendation is given how to apply these individual techniques for small bowel surveillance in a step-up approach.

Risk Factors and Clinical Outcomes in Patients with IBD with Melanoma

Background: Patients with inflammatory bowel disease (IBD) are at increased risk to develop malignant melanoma and this risk may increase with use of anti-tumor necrosis factor (TNF) therapy. Impaired survival of immunosuppressed melanoma patients is reported in transplant and rheumatology patients. This study aims to (1) identify risk factors for melanoma development in patients with IBD, (2) compare clinical characteristics of melanoma in patients with IBD to the general population, and (3) assess the influence of immunosuppressive medication on survival. Methods: We retrospectively searched the Dutch Pathology Database to identify all Dutch patients with IBD with cutaneous melanoma between January 1991 and December 2011. We then performed 2 case–control studies. To identify risk factors for melanoma development in IBD, we compared patients with IBD with melanoma to the general IBD population. To compare outcome and survival after melanoma diagnosis, we compared cases with non-IBD melanoma patients. Results: We included 304 patients with IBD with melanoma, 1800 IBD controls, and 8177 melanoma controls. IBD cases had more extensive IBD (ulcerative colitis: pancolitis: cases 44.5% versus IBD controls without melanoma 28.1%; P < 0.01; Crohns disease: ileal and colonic disease: cases 57.9% versus controls 48.9%; P = 0.02). Despite a lower Nodes (N)-stage in patients with IBD (N1+ 8.3% versus 18.2%; P < 0.01) with comparable Tumor (T) and Metastasis (M) stages, survival was similar between groups, regardless of immunosuppressive or anti-TNF therapy. Conclusions: This study showed that IBD extent is a risk factor for melanoma development. Despite the lower N-stage in patients with IBD, we could not confirm impaired survival after melanoma in patients with IBD, regardless of anti-TNF and/or thiopurine use.

1160 Adding Ciprofloxacin to Adalimumab Results in a Higher Fistula Closure Rate in Perianal Fistulizing Crohn's Disease

Background: There is clear benefit of combination therapy for infliximab (IFX) with immunosuppressive drugs (IS), whether commenced together, or later, but no data are available for ADA. The aim was to assess whether IS combotherapy (CoT) was more effective than monotherapy for Crohn’s disease (CD) patients treated with ADA, using the semester approach. Methods: Retrospective study of patients with CD (n = 181) treated for at least one year with ADA in Oxford, UK or Liege, Belgium. Treatment periods were divided into 6 month semesters and the treatment failure compared between semesters with or without CoT (thiopurines or methotrexate). ADA failure was defined as dose modification during therapy, drug modification, perineal complications, or surgery for active CD. Results: 569 semesters were studied in 181 patients (Oxford n = 98, Liege 83), including 147 semesters in 45 patients having received CoT during the first semester. More patients in Oxford received CoT than Liege (OR: 4.82, p < 0.0001) and fewer females (OR 0.50, p = 0.01). When considering only patients on CoT during the first semester, treatment failures were less frequent in semesters with IS (20%) compared to semesters without IS (80%; OR 0.30, p = 0.02). This protective effect of the CoT was maintained over time (p = 0.01). When considering all the patients, CoT in the first semester was associated with a lower frequency of treatment failures (34% vs 66%, OR 0.69, p = 0.046) in univariate analysis but not in multivariate analysis. CoT later after induction of ADA was not associated with treatment failures. Female gender (OR 1.68, p = 0.01), previous surgery (OR 1.89, p = 0.001) and active perianal disease (OR 1.57, p = 0.02) were risk factors of failure on multivariate analysis. Although failures were less common in Oxford (OR 0.52, p = 0.001), more failures in Oxford had surgery (OR 8.85, p = 0.001) or perianal complications (OR 3.33, p = 0.01) and fewer had ADA weekly (OR 0.24, p = 0.0003) on multivariate analysis. The overall number of operations and perianal complications did not differ between CoT and ADA monotherapy. Thiopurines appeared more effective than methotrexate for preventing failure (OR 0.35, p = 0.03). The probablility of failure did not increase over the semesters (p = 0.86). Conclusions: When it was given during the first semester, CoT with ADA in CD was associated with fewer semesters with treatment failures (essentially the need for dose escalation or treatment modification, but not the rate of surgery or perianal complications). OP16 Adding ciprofloxacin to adalimumab results in a higher fistula closure rate in perianal fistulizing Crohn’s disease P. Dewint1 *, B. Hansen1, E. Verhey1, B. Oldenburg2, D.W. Hommes3, M. Pierik4, C. Ponsioen5, H. van Dullemen6, M.G. Russel7, A. van Bodegraven8, C.J. van der Woude1, on behalf of ICC (Initative on Crohn’s and Colitis). 1Erasmus Medical Center, Department of Gastroenterology & Hepatology, Rotterdam, Netherlands, 2University Medical Centre Utrecht, Department of Gastroenterology, Utrecht, Netherlands, 3UCLA, Division of Digestive Diseases, Los Angeles, United States, 4Maastricht University Medical Center, Dept of Gastroenterology, Maastricht, Netherlands, 5Academic Medical Center, Gastroenterology and Hepatology, Amsterdam, Netherlands, 6UMC Groningen, Gastroenterology, Groningen, Netherlands, 7Medisch Spectrum Twente, Gastroenterology, Enschede, Netherlands, 8VU University Medical Center, Gastroenterology, Amsterdam, Netherlands

Chemoprevention in Patients with Peutz‐Jeghers Syndrome: Lessons Learned

Abstract Lessons Learned. Motivating patients to enroll in chemopreventive studies is challenging. Chemoprevention with toxic drugs is not feasible. Background. LKB1 mutations are the underlying genetic abnormality causing Peutz‐Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. Methods. Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high‐risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. Results. Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49‐year‐old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52‐year‐old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse events included dental inflammations, mucositis, and rash. In 2016, the trial was aborted for lack of accrual, despite extensive accrual efforts in an area where PJS is highly prevalent and care is highly centralized. Conclusion. Due to accrual problems, no conclusions can be drawn about the value of everolimus in PJS treatment, questioning the feasibility of this agent for chemoprevention.

Incidence and Predictors of Success of Adalimumab Dose Escalation and De-escalation in Ulcerative Colitis: a Real-World Belgian Cohort Study

Background Adalimumab (ADM) has been shown efficacious in ulcerative colitis (UC). In randomized controlled trials, dose escalation from 40 mg ADM every other week to 40 mg every week was required in 20%-25% of patients within 1 year. Real-life data suggest higher escalation rates. Attempts for dose de-escalation have not been studied yet. We assessed the need for, outcome of, and predictors of dose escalation and de-escalation in a large retrospective cohort of UC patients treated with ADM. Methods We included 231 consecutive patients from 10 Belgian centers initiating ADM treatment for active UC before September 1, 2015 (follow-up ≥1 year in each patient). We performed detailed chart review to identify variables associated with short-term clinical benefit (based on physician global assessment and absence of rectal bleeding at week 10), success of dose escalation, and dose de-escalation. Backward Cox regression and Wald Logistic regression were used to identify predictive variables. Results Short-term clinical benefit was achieved in 101 patients (44%) and was less frequent in infliximab failures [37% vs 50%, Odds ratio 0.57 (95% CI 0.34-0.97), P = 0.038]. After a median of 2.8 (1.7-5.1) months, 164 patients (71%) needed ADM discontinuation (n = 35, 15%) or dose escalation (n = 129, 56%). Dose escalation was successful in 77/129 (60%). Dose de-escalation was attempted in 71% (55/77) after a median of 4.3 (2.9-7.2) months and was successful in 80% (43/54). Conclusions In this cohort, 56% of patients with UC required ADM dose escalation with a 60% success rate. Of note, most patients could be successfully de-escalated later on.

Risk factors and clinical outcome in IBD patients with melanoma

Background: Patients with inflammatory bowel disease (IBD) are at increased risk to develop malignant melanoma andthis risk may increase with the use of anti-TNF therapy. Impaired survival of immunosuppressed melanoma patients is reported in transplant and rheumatology patientsThis study aims to 1)