Chiara Praticò

Longitudinal analysis of inflammation and microbiota dynamics in a model of mild chronic dextran sulfate sodium-induced colitis in mice

AIM To characterize longitudinally the inflammation and the gut microbiota dynamics in a mouse model of dextran sulfate sodium (DSS)-induced colitis. METHODS In animal models, the most common method used to trigger colitis is based on the oral administration of the sulfated polysaccharides DSS. The murine DSS colitis model has been widely adopted to induce severe acute, chronic or semi-chronic colitis, and has been validated as an important model for the translation of mice data to human inflammatory bowel disease (IBD). However, it is now clear that models characterized by mild intestinal damage are more accurate for studying the effects of therapeutic agents. For this reason, we have developed a murine model of mild colitis to study longitudinally the inflammation and microbiota dynamics during the intestinal repair processes, and to obtain data suitable to support the recovery of gut microbiota-host homeostasis. RESULTS All plasma cytokines evaluated, except IL-17, began to increase (P < 0.05), after 7 d of DSS administration. IL-17 only began to increase 4 d after DSS withdrawal. IL-1β and IL-17 continue to increase during the recovery phase, even when clinical signs of colitis had disappeared. IL-6, IL-10 and IFN-γ reached their maxima 4 d after DSS withdrawal and decreased during the late recovery phase. TNFα reached a peak (a three- fold increase, P < 0.05), after which it slightly decreased, only to increase again close to the end of the recovery phase. DSS administration induced profound and rapid changes in the mice gut microbiota. After 3 d of DSS administration, we observed a major reduction in Bacteroidetes/Prevotella and a corresponding increase in Bacillaceae, with respect to control mice. In particular, Bacteroidetes/Prevotella decreased from a relative abundance of 59.42%-33.05%, while Bacillaceae showed a concomitant increase from 2.77% to 10.52%. Gut microbiota rapidly shifted toward a healthy profile during the recovery phase and returned normal 4 d after DSS withdrawal. Cyclooxygenase 2 expression started to increase 4 d after DSS withdrawal (P < 0.05), when dysbiosis had recovered, and continued to increase during the recovery phase. Taken together, these data indicated that a chronic phase of intestinal inflammation, characterized by the absence of dysbiosis, could be obtained in mice using a single DSS cycle. CONCLUSION Dysbiosis contributes to the local and systemic inflammation that occurs in the DSS model of colitis; however, chronic bowel inflammation is maintained even after recovery from dysbiosis.

Oral beclomethasone dipropionate in chronic refractory pouchitis

BACKGROUND Pouchitis is the major long-term complication after ileal-pouch anal-anastomosis for ulcerative colitis. Ten to 15% of patients develop chronic pouchitis, either treatment responsive or treatment refractory. AIM To evaluate the efficacy of oral beclomethasone dipropionate in inducing remission and improving quality of life in patients with chronic refractory pouchitis. METHODS Ten consecutive patients with active pouchitis, not responding to 1-month antibiotic treatment, were treated with beclomethasone dipropionate 10 mg⁄day for 8 weeks. Clinical, endoscopic and histological evaluations were undertaken before and after treatment, according to the Pouchitis Disease Activity Index (PDAI). Remission was defined as a combination of PDAI clinical score of ≤2, endoscopic score of ≤1 and a total PDAI score of ≤4. The quality of life was assessed with the Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS Eight of 10 patients (80%) achieved remission. The median total PDAI scores before and after therapy were, respectively, 12 (range 8-14) and 3 (range 2-9) (P<0.001). The median IBDQ score also significantly improved from 120 (range 77-175) to 175 (range 85-220) (p<0.001). CONCLUSION Eight-week treatment with oral beclomethasone dipropionate appears effective in inducing remission in patients with active pouchitis refractory to antibiotic treatment.

Eviendep® reduces number and size of duodenal polyps in familial adenomatous polyposis patients with ileal pouch-anal anastomosis

AIM To evaluate if 3 mo oral supplementation with Eviendep® was able to reduce the number of duodenal polyps in familial adenomatous polyposis (FAP) patients with ileal pouch-anal anastomosis (IPAA). METHODS Eleven FAP patients with IPAA and duodenal polyps were enrolled. They underwent upper gastrointestinal (GI) endoscopy at the baseline and after 3 mo of treatment. Each patient received 5 mg Eviendep twice a day, at breakfast and dinner time, for 3 mo. Two endoscopists evaluated in a blinded manner the number and size of duodenal polyps. Upper GI endoscopies with biopsies were performed at the baseline (T0) with the assessment of the Spigelman score. Polyps > 10 mm were removed during endoscopy and at the end of the procedure a new Spigelman score was determined (T1). The procedure was repeated 3 mo after the baseline (T2). Four photograms were examined for each patient, at T1 and T2. The examined area was divided into 3 segments: duodenal bulb, second and third portion duodenum. Biopsy specimens were taken from all polyps > 10 mm and from all suspicious ones, defined by the presence of a central depression, irregular surface, or irregular vascular pattern. Histology was classified according to the updated Vienna criteria. RESULTS At baseline the mean number of duodenal detected polyps was 27.7 and mean sizes were 15.8 mm; the mean Spigelman score was 7.1. After polypectomy the mean number of duodenal detected polyps was 25.7 and mean sizes were 7.6 mm; the mean Spigelman score was 6.4. After 3 mo of Eviendep bid, all patients showed a reduction of number and size of duodenal polyps. The mean number of duodenal polyps was 8 (P = 0.021) and mean size was 4.4 mm; the mean Spigelman score was 6.6. Interrater agreement was measured. Lesions > 1 cm found a very good degree of concordance (kappa 0.851) and a good concordance was as well encountered for smaller lesions (kappa 0.641). CONCLUSION Our study demonstrated that short-term (90 d) supplementation with Eviendep® in FAP patients with IPAA and with recurrent adenomas in the duodenal mucosa, resulted effective in reducing polyps number of 32% and size of 51%.

The role of Budesonide-MMX in active ulcerative colitis

Traditional corticosteroids represent a well-established and effective treatment for active ulcerative colitis (UC). However, the severity of their systemic side effects, led in recent years to look for new steroid molecules that could reduce them, maximizing the anti-inflammatory activity. Budesonide has been one of the most studied steroid compounds and it has been approved for the treatment of mild to moderate active Crohns disease (CD). In order to extend the release until the distally located inflammation, budesonide has been coupled with a controlled delivery system, called Multi-Matrix system (MMX®), already successfully tested with oral mesalazine for the treatment of distal UC. After in vitro and in vivo models, the efficacy of Budesonide-MMX has been investigated in active UC with a first small phase II study, and partially encouraging results. This article will review the evidences on the use of budesonide in inflammatory bowel diseases and will discuss the role of Budesonide-MMX in active UC nowadays.

Four cases of carcinoid tumour in Crohn's disease: coincidence or correlation?

Dear Editor:Inflammatoryboweldiseasesareassociatedwithanincreasedrisk of large and small bowel cancers.The association between Crohn’s disease and adenocarci-noma of the small intestine has been established, but therelation between Crohn’s and carcinoid tumours remains un-certain, although the diagnosis of carcinoid tumours has sig-nificantly increased in the last years.We describe four cases of carcinoid tumour diagnosed inpatients with Crohn’s disease followed at our IBD outpa-tients’ clinic.First case A 46-year-old male non-smoker presented with26 years history of ileocolonic Crohn ’s disease and psoriasis.The patient underwent several surgeries over these years, endingup with colectomy with ileal–rectal anastomosis. After that, thedisease has been poorly controlled by the therapy (mesalazine),andseveralsteroidscourseswereneeded.In2011,anabdominalCT scan showed a pre-anastomotic Crohn ’s disease relapse andan unexpected expansive mass in the left kidney. The patientunderwent resection of the anastomosis and left nephrectomy.Post-operative histology showed active ileal and rectal Crohn ’sdisease and papillary renal can cer type 1, with Fuhrman nucleargradeof2andnopyeluminfiltration.Noadjuvantchemotherapytreatment was set. Few months after, he presented a Crohn’srelapse,withtwentybowelmovementsperdaywithurgencyandsevere weight loss. He also repor ted unusual skin rushes aftersomekindoffoodconsumption, whichwereself-solving.Bloodtests were normal, except for a mild creatinine rise. The endos-copy revealed normal ileal mucosa with a small polyp, whichwas removed, regular anastomo sis and rectal erosions. Polyp ’shistology pointed out muscularis propria infiltrating cells withdiffuse positivity for neuroe ndocrine markers, includingchromograninAandCD56andlownuclearproliferationmarkerKi-67(<2%).Immunohistochemist rystainingforsomatostatin2receptor (SSTR2A) was positive. These findings resulted in thediagnosis of well-differentiated neuroendocrine tumour (NET)-G1 (G1 category according to the WHO 2010).An abdominal CT scan showed no signs of renal tumourlocal recurrence but thickened anastomotic wall andoedematous mesenteric fat. The SPECTscan with a somato-statin receptor marker as contrast agent pointed out a roundarea on the anterior abdominal wall, lymph node like.A second endoscopy detected severe endoscopic Crohn’srelapse associated with another polyp, which was positivefor a new carcinoid recurrence (NET-G1). The patientunderwent proctectomy with ileal stoma.Second case A 45-year-old male smoker presented with12 years history of ileocolonic Crohn’s disease and vitiligo.Crohn’s diagnosis was made after an emergency rightemicolectomy due to peritonitis. In 2011, he started to expe-rience obstructive symptoms with low response to steroids.The enteric MRI detected two stenotic segments of the pre-anastomotic ileum and a voluminous solid lesion (O70×40×70 mm) in the retroperitoneum, adjacent to thepancreatic head, duodenum and inferior caval vein. Histologyof CT-guided biopsy revealed a well-differentiated NET-G1.The patient was referred to the surgeon and underwent apancreatic duodenectomy (Whipple procedure) and resectionof the previous ileal colonic anastomosis. Post-operative his-tology pointed out an infiltrating neoplasia of the duodenumwall, next to the duodenal papilla. The pancreas was cancerfree as well as the surgical resection borders; two peri-duodenal lymph nodes were infiltrated. Neoplastic cells werediffusely positive for the neuroendocrine marker synap-tophysin and for the nuclear proliferation marker Ki-67(1 %). Immunohistochemistry staining for SSTR2A was

Rescue therapy: ciclosporin or infliximab?

Evaluation of: Laharie D, Bourreille A, Branche J et al.; Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives. Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet 380(9857), 1909–1915 (2012). Severe active refractory ulcerative colitis is a potentially life-threatening disease. The introduction of intensive steroid treatment and early surgery has reduced mortality in recent years. Ciclosporin and infliximab are effective rescue therapies in steroid refractory colitis. A head-to-head study proposed by Laharie et al. failed to demonstrate the superiority of ciclosporin but confirmed the efficacy and safety of infliximab to control active disease and to maintain remission.

P110 The use of the Pediatric Ulcerative Colitis Activity Index (PUCAI) in adults with acute severe ulcerative colitis (ASC)

P110 The use of the Pediatric Ulcerative Colitis Activity Index (PUCAI) in adults with acute severe ulcerative colitis (ASC) B. Koslowsky1 *, A. Gupta2, D.M. Livovsky1, T. Adar1, D. Turner3, F. Hartnell4, C. Pratico5, S. Travis6. 1Shaare Zedek Medical Center, Gastroenterology, Jerusalem, Israel, 2The Canberra Hospital, Gastroenterology, Woden, Australian Capital Territory, Australia, 3Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Pediatric Gastroenterology, Jerusalem, Israel, 4Royal Brisbane and Women’s Hospital, Gastroenterology, Brisbane, Queensland, Australia, 5University of Bologna, Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Bologna, Italy, 6Oxford University Hospital, Translational Gastroenterology Unit, Oxford, United Kingdom

P395 Re-induction regimen in Crohn's disease adalimumab failure or disease relapse after a first adalimumab course. A single centre experience

Background: Adalimumab (ADA) is a fully human monoclonal antibody targeting TNF-alfa with proven efficacy in the treatment of Crohn’s disease (CD). We evaluate the efficacy of a second new ADA induction regimen. Methods: Forty-six CD patients were treated with a second ADA induction regimen (40 patients with 160/80mg, 6 with 80/40mg) and maintenance with 40mg every other week (22 patients) or weekly (24 patients). Patients were divided into 3 groups: moderate CD relapses [Harvey Bradshaw score (HBI) >8] during ADA maintenance treatment after an initial response were defined as ‘secondary non responders’ (SNR), failures at week 12 of the first induction regimen as ‘primary non responders’ (PNR) and CD recurrences [HBI score >5] within 6 months after the first successful ADA course as ‘early relapses’ (ER). Three of them received azathioprine (AZA) plus ADA. Clinical response or remission were evaluated at week 12 [remission: HBI <4; response: 3-point reduction in the HBI vs baseline]. Results: Of 149 CD patients treated with ADA and followed prospectively, 46 patients [M/F: 24/22; mean age 31.7 years (18 63 years); median disease duration 7 years (0.3 18 years); disease location: 7 ileal, 23 ileo-colonic, 16 colonic; mean HBI at the baseline 11.9 (6 38)] were enrolled. Eighteen patients were SNR (mean first ADA treatment duration: 50 weeks), 14 were PNR (mean first ADA treatment duration:14 weeks) and 14 had an ER (mean first ADA treatment duration:77 weeks). Considering the overall group of patients, at week 12 remission was observed in 24 patients (52.2%), 10 patients (21.7%) had partial response, while 12 patients (26.1%) had no improvement. In the subgroup of SNR, 5 patients (27.8%) regained remission, 5 regained (27.8%) response, while 8 (44.4%) had no response. Seven patients (50.0%) out of the 14 PNR gained remission, 3 patients (21.4%) had a partial response and 4 patients (28.6%) had no response to the second ADA course. The 3 patients treated with ADA plus AZA achieved complete remission around week 24. All of the 14 ER patients responded to the second ADA course: 12 (85.7%) showed new complete remission, 2 patients (14.3%) had partial response. Conclusions: ADA re-induction regimen seems to be effective in patients who lost response during ADA maintenance treatment (SNR). Dose intensification with a new early induction regimen showed efficacy to gain response in PNR. A new induction regimen with ADA seems to be extremely effective to regain remission in patients with ER and previous ADA-response.

P.01.2 ADALIMUMAB FOR THE TREATMENT OF POST-OPERATIVE RECURRENCE OF CROHN'S DISEASE. A SINGLE CENTRE EXPERIENCE

Background: Tumour necrosis factor alpha (TNF-a) plays an important role in malnutrition and growth retardation in paediatric inflammatory bowel disease (IBD) due to perpetuation of chronic inflammation. One of the objectives in the management of these patients should be to optimize their growth, which may be compromised due to uncontrolled disease and the effect of steroids. We aimed to study anti-TNF treatment effect on nutritional recovery in paediatric IBD, in relation to their efficacy in clinical response, both in shortand medium-term. Methods: Retrospective analysis of our paediatric IBD patients treated with anti-TNF between January 2002 and December 2010. We evaluated clinical response as defined by changes in activity scores (Paediatric Crohn’s Disease Activity Index [PCDAI] and Paediatric Ulcerative Colitis Activity Index [PUCAI]) at 2 and 8 weeks, 6 months and 1 year after its initiation. Changes in anthropometric measures (height and weight for age and body mass index [BMI]) and biochemical modifications (ESR, CRP, haemoglobin, platelets and albumin) were evaluated at 6 and 12 months. Results: 54 patients (34 boys) received anti-TNF (44 CD, 8 UC, 2 IBDU). Age at diagnosis: 11 years 5 months. Mean time from diagnosis to anti-TNF treatment: 17 months (range 0 121). Mean age at first infusion 13 years (1.1 17.3). Mean followup 35 months and mean number of infusions per patient 17. Forty-one patients received infliximab (IFX), 21 adalimumab (ADA) and 1 certolizumab pegol. Thirty-one patients (63%) had not previously received steroids. Mean basal PCDAI and PUCAI: 28.6 (2.5 62) and 39 (27 55) respectively. Clinical response was achieved in 47 cases (87%). Remission rate was 74.2% at 2 weeks, 87.7% at 8 weeks, 90% at 6 months, and 90.6% at 12 months. Seven patients experienced a relapse at some point of the follow-up. Median steroid-free time from the beginning of anti-TNF was 25.9 months (1 76). Mean BMI prior to treatment was 17, z-score 1.04 ( 4.2, +1.64). We observed improvement of anthropometry, with a mean BMI of 19.2 [z-score 0.27 ( 2.3, +1.78)] after 12 months. Biochemical parameters improvement was also observed at 6 and 12 months, with significant reduction of inflammatory markers and increase in haemoglobin and albumin levels. Conclusions: Anti-TNF treatment shows high efficacy in obtaining and maintaining clinical remission in paediatric IBD. Furthermore it has a positive impact on the nutritional status. This effect is parallel to the decrease in disease activity.