Ira Shafran

Mycobacterium avium subsp. paratuberculosis as one cause of Crohn’s disease

A number of theories regarding the aetiology of Crohn’s disease have been proposed. Diet, infections, other unidentified environmental factors and immune disregulation, all working under the influence of a genetic predisposition, have been viewed with suspicion. Many now believe that Crohn’s disease is a syndrome caused by several aetiologies. The two leading theories are the infectious and autoimmune theories. The leading infectious candidate is Mycobacterium avium subspecies paratuberculosis (Mycobacterium paratuberculosis), the causative agent of Johne’s disease, an inflammatory bowel disease in a variety of mammals including cattle, sheep, deer, bison, monkeys and chimpanzees. The evidence to support M. paratuberculosis infection as a cause of Crohn’s disease is mounting rapidly. Technical advances have allowed the identification and/or isolation of M. paratuberculosis from a significantly higher proportion of Crohn’s disease tissues than from controls. These methodologies include: (i) improved culture techniques; (ii) development of M. paratuberculosis‐specific polymerase chain reaction assays; (iii) development of a novel in situ hybridization method; (iv) efficacy of macrolide and anti‐mycobacterial drug therapies; and (v) discovery of Crohn’s disease‐specific seroreactivity against two specific M. paratuberculosis recombinant antigens. The causal role for M. paratuberculosis in Crohn’s disease and correlation of infection with specific stratification(s) of the disorder need to be investigated. The data implicating Crohn’s as an autoimmune disorder may be viewed in a manner that supports the mycobacterial theory. The mycobacterial theory and the autoimmune theory are complementary; the first deals with the aetiology of the disorder, the second deals with its pathogenesis. Combined therapies directed against a mycobacterial aetiology and inflammation may be the optimal treatment of the disease.

Specific seroreactivity of Crohn’s disease patients against p35 and p36 antigens of M. avium subsp. paratuberculosis

Crohns disease (CD) is a chronic inflammatory bowel disease that is similar to Johnes disease in ruminants. Recent data have strengthened the association of M. avium subsp. paratuberculosis (M. paratuberculosis) with CD. To provide more evidence of an etiological association, antibody reactivities from CD patients were tested by immunoblotting against recombinant antigens that were identified previously from our M. paratuberculosis genomic library. Two clones (designated pMptb#40 (3.2-kb insert) and #48 (1.4-kb insert) expressing a 35K (p35)- and 36K(p36)-antigens showed specific reactivities with serum samples from CD patients. Serum samples from 75% of 53 CD patients, 14% of 35 normal individuals and 10% of 10 ulcerative colitis patients reacted to p35 antigen. Reactivities were also observed with serum samples from 89% of 89 CD patients, 14% of 50 normal controls and 15% of 29 ulcerative colitis patients reacted with p36 antigen. When the reactivity results from p35 and p36 were combined, the background from the controls was eliminated, i.e. only the CD patients reacted to both p35 and p36. The positive predictive value was 98% with specificity of 98% and the negative predictive value was 76% with sensitivity of 74% (39 positive out of 53). A statistical significance (p<0.0001) was observed when the results from CD serum samples reacting with either or both antigens were compared to the controls. The reactivity of anti-M. paratuberculosis (specifically against p35 and p36 antigens) antibodies in a significant proportion of CD patients would suggest a causal role for the organism in CD.

Seroreactivities against Saccharomyces cerevisiae and Mycobacterium avium subsp. paratuberculosis p35 and p36 antigens in Crohn's disease patients

Crohns disease (CD) is an idiopathic chronic inflammatory bowel disease (IBD). Accurate diagnosis of the disease is of great clinical importance to assess its prognosis and success of therapy. Recent studies have validated and confirmed the potential utility of anti-Saccharomyces cerevisiae (bakers yeast; ASCA) IgG/IgA antibodies and anti-M. avium ss. paratuberculosis p35/p36 antibodies, separately, as serological markers to identify patients with CD. The efficacy of these markers was evaluated in the same patients with Crohns disease. The anti-ASCA IgA/IgG and the anti-M. avium ss. paratuberculosis p35/p36 antibodies were positive in 60% (36/60) and 86.7% (52/60) of CD patients, respectively. When all the serologic markers were considered, the sensitivity in detecting CD was increased to 95.0% (57/60); 21 of 24 ASCA-negative patients were p35/p36-positive and five of eight of p35/p36-negative patients were ASCA-positive. This investigation further establishes the utility of p35 and p36 recombinant clones for the diagnosis of CD, and reveals the complimentary role of ASCA and p35 and p36 for effective detection of CD. Larger studies are needed to investigate the combined use of these serologic markers for the diagnosis of CD.

Management of inflammatory bowel disease with oral serum-derived bovine immunoglobulin:

Introduction: The clinical effect of oral serum-derived bovine immunoglobulin/protein isolate (SBI) on symptom and disease management in patients with inflammatory bowel disease (IBD) is reported in this retrospective case series. Methods: A single-center, retrospective chart review of IBD patients [N = 45; Crohn’s disease (CD), n = 38 and ulcerative colitis (UC), n = 7] with limited to no response to traditional pharmaceutical therapies in controlling symptoms was performed after providing SBI (5 g/day) for nutritional support. Patients were contacted at least monthly to assess response to SBI for symptom management measured by a Likert scale (0 = none; 1 = minimal; 2 = moderate; 3 = significant; 4 = complete). Analysis of variance (ANOVA) was performed on response to therapy based on patient characteristics (age, gender, race) and IBD diagnosis. A multivariate ordered logistical regression model was performed to determine the odds ratio in overall disease management between week 1 and week 12. Finally, the overall group response and percent improvement to SBI was determined over 12 weeks. Results: The odds ratio from the regression model demonstrated that IBD patients were 2.8 times more likely to report clinical improvement in symptom scores with the addition of SBI to their therapeutic regimens [95% confidence interval (CI) 1.266–6.016, p = 0.011]. Disease management was not significantly associated with age, gender, race or disease state. The percentage of patients reporting a response to SBI therapy at week 1 was 49% which increased to 76% after 12 weeks with the fraction of responders gaining significant symptom improvement doubling during the same time period (9% versus 20%). Overall, this group of IBD patients showed increased, steady response to SBI therapy between week 1 and 12 with no reported side effects. Conclusion: These results suggest that SBI improves clinical management of IBD patients who are not fully managed on traditional therapies. SBI should be considered for the nutritional support of IBD regardless of disease activity, location, phenotype, duration, or complexity.

Long-Term Effectiveness and Safety of Vedolizumab in Patients with Crohn’s Disease: 5-Year Cumulative Exposure of Gemini 2 Completers Rolling Into the Gemini Open-Label Extension Study

Introduction Vedolizumab (VDZ), a gut-selective humanised monoclonal antibody that targets α4β7 integrin, is approved for moderately to severely active Crohn’s disease and ulcerative colitis (UC). The ongoing GEMINI open-label extension (OLE) trial is investigating the long-term safety of VDZ (NCT00790933). We report 5 year exploratory interim analyses of effectiveness and safety in patients (pts) with UC who completed GEMINI 1 and enrolled in GEMINI OLE. Method Pts who responded to VDZ induction at Week (Wk) 6 received VDZ maintenance (every 8 or 4wks) to Wk 52 of GEMINI 1 and VDZ every 4 wks in GEMINI OLE. In an interim analysis, pts with 248 wks of cumulative VDZ (22 May 2009 to 21 May 2015) were assessed for clinical response (decrease in partial Mayo Score [PMS] of 2 points and 25% change from baseline [BL], with an accompanying decrease in rectal bleeding subscore of 1 point from BL or absolute rectal bleeding subscore of 1 point), clinical remission (PMS of 2 with no individual subscore >1), health-related quality of life (HRQoL) and safety. Results Of 154 pts (anti-tumour necrosis factor-alpha: naive n=107, failure n=42), 63 had 248 wks’ cumulative VDZ treatment, 54 discontinued (n=19 [35%] due to lack of continued benefit) and a further 37 (24%) had not yet reached 248 wks at data cut-off. Of pts with Wk 248 data, 98% had clinical response and 90% were in remission. HRQoL was improved at Wk 248, with mean change from BL in the Inflammatory Bowel Disease Questionnaire and Euro Quality of Life-5D visual analogue scale scores of 58.7 and 24.0, respectively. At Wk 248, 142 pts had adverse events (AEs), of which 16 discontinued and 46 experienced a serious AE (drug-related n=7; 8 pts discontinued; no deaths). Abstract AODWE-002 Table 1 Effectiveness of long-term VDZ in pts with UC Conclusion Continued clinical response, remission and HRQoL improvements were observed throughout 248 wks (~5 years) of cumulative VDZ therapy in pts with UC who responded at Wk 6, completed GEMINI 1 and enrolled in the OLE. The long-term safety profile of VDZ was consistent with that reported in previous studies. Disclosure of Interest A Kaser Conflict with: Boehringer Ingelheim, Eisai, Ferring, Genentech, GlaxoSmithKline, Hospira, Janssen J and J, Kymab, Second Genome, Shire, VHsquared, Conflict with: Lecture fee(s): Falk, Ferring, Takeda; serves as course director of the Cambridge – MedImmune PhD programme

862 A Randomized Controlled Trial of Mesalamine Dose Escalation for Ulcerative Colitis in Remission

marker levels included sex and inflammation. Phase 2: Among 10 BE cases and 10 controls, median age was 64 (59-70) and 66 (49, 71) and men comprised 80 and 30% respectively. Median BE length was 2 cm (range 1-4). Discrimination of BE by markers was extraordinary with AUC of 1.0 for NDRG4 and 0.99 for BMP3; levels were >100 times higher in cases than controls (Figure). Conclusions: Selected methylated DNA markers highly discriminate BE from normal GC and SE, both in biopsy and brushed specimens, and hold promise for non-endoscopic screening applications. Further research and development are warranted. Table 1

Evaluation of mucosal healing in Small Bowel Crohn’s disease treated with Certolizumab Pegol assessed by wireless capsule endoscopy

Crohn’s disease (CD) is a chronic inflammatory bowel disorder that can affect any part of the gastrointestinal tract. In approximately 30%-40% of patients it involves the small bowel, most commonly the terminal ileum, but lesions proximal to the terminal ileum are often present [1-3]. The goal of medical treatment for CD includes improving patients’ quality of life while reducing complications of disease including hospitalizations and surgery [4]. Current medical treatments and past studies have defined response to treatment by measuring clinical symptoms of response and remission without consistently including mucosal healing endpoints. With the current use of diseasemodifying medications such as certolizumab pegol, mucosal healing has emerged as an increasingly important goal of therapy [3]. Mucosal healing, or endoscopic remission, is associated with increased rates of clinical remission, fewer hospitalizations and abdominal surgeries, and increased work productivity with improved quality of life for patients [2,3]. There is a growing realization that these goals of treatment translate into an overall reduction of the cost-burden of CD [5-11].

P-083 Evaluation of Mucosal Healing in Small Bowel Crohn’s Disease Treated with Certolizumab Pegol Assessed by Wireless Capsule Endoscopy

BACKGROUND: Certolizumab pegol (CZP), a pegylated anti-TNF agent is currently approved to reduce the signs and symptoms of Crohn’s disease (CD) and maintain clinical response in adult patients with moderately to severely active CD who have had inadequate response to conventional therapy. Biologic agents have demonstrated efficacy in the healing of gut mucosa leading to better long-term outcomes by sustaining steroid free remission, decreasing the need for major surgery and hospitalizations, and by improving patients overall quality of life. The MUSIC trial revealed CZP-induced endoscopic response and remission at 10 and 54 weeks. Our primary objective was to evaluate mucosal healing assessed by wireless capsule endoscopy (WCE) using the Lewis scoring system (LS) in patients with moderate-to-severe Crohn’s disease treated with CZP. METHODS: We performed a prospective, open-label trial in 14 patients with documented moderate-to-severe Crohn’s disease for a period of six months. All patients were given standard induction dose therapy with CZP at 0, 2, and 4 weeks, then standard maintenance dose therapy with CZP every 4 weeks through the end of the study period. WCE was performed at baseline, 16 weeks, and 26 weeks. Blood work including CMP, HEMGPD, and CRP were obtained, as well as Crohn’s Disease Activity Index (CDAI) and Short Inflammatory Bowel Disease Questionnaire (SIBDQ) at baseline and every 4 weeks throughout the study. RESULTS: Twelve patients have completed the trial. Of the 12 patients, 6 were male and 6 were female, with an average age of 31.4 and a mean disease duration of 11.2 years. Nine patients had no prior Crohn’s surgery and 3 had previous small bowel resection. Eight of the 12 patients were secondary non-responders (SNR) to biologics, 3 lost response to both infliximab (IFX) and adalimumab (ADA), 5 lost response to either IFX or ADA, 2 were biologically naïve, and 2 had an allergic reaction to IFX. Ten of the 12 patients who completed this trial demonstrated an overall clinical improvement in mucosal healing, CDAI, and SIBDQ. Of those who responded to CZP, the mean LS at baseline fell from 1663 to 226 at 26 weeks and the mean CDAI decreased from 266 at baseline to 140 at 26 weeks. The mean SIBDQ increased in responders from 40 at baseline to 49 by the end of study. CONCLUSIONS: This study demonstrates clear evidence of mucosal healing using CZP in patients with moderate-to-severe Crohn’s disease. This study establishes a proof of concept that WCE used in conjunction with the LS is a valuable diagnostic test to assess mucosal healing in patients with small bowel Crohn’s disease treated with CZP. CZP was well-tolerated in this population with no safety issues. Larger, placebo controlled trials are warranted to assess small bowel mucosal healing in patients treated with CZP.

The Use of Wireless Capsule Endoscopy in Community Practice: An 11 Year Experience: P-132

approved for the induction and maintenance of response and remission in adult patients with moderate to severe Crohn’s disease. Biologic agents have demonstrated efficacy in the healing of gut mucosa leading to better long-term outcomes by sustaining steroid free remission, decreasing the need for major surgery and hospitalizations, and by improving patients overall quality of life. The MUSIC trial revealed CZP-induced endoscopic response and remission at 10 and 54 weeks. Our primary objective is to evaluate mucosal healing assessed by wireless capsule endoscopy (WCE) using the Lewis scoring system (LS) in patients with moderate-to-severe Crohn’s disease treated with CZP. METHODS: We performed a prospective, open-label trial in 10 patients with documented moderate-to-severe Crohn’s disease for a period of six months. All patients were given standard induction dose therapy with CZP at 0, 2, and 4 weeks, then standard maintenance dose therapy with CZP every 4 weeks through the end of the study period. WCE was performed at baseline, 16 weeks, and 26 weeks. Blood work including CMP, HEMGPD, and CRP were obtained, as well as Crohn’s disease activity index (CDAI) and Short Inflammatory Bowel Disease Questionnaire (SIBDQ) at baseline and every 4 weeks throughout the study. RESULTS: Ten patients were enrolled in this trial. Of the 10 patients, 6 were male and 4 were female, with an average age of 33.4 and a mean disease duration of 13.1 years. Seven patients had no prior Crohn’s surgery, 3 had previous small bowel resection. Eight of the ten patients were secondary non-responders (SNR) to biologics; 3 lost response to both infliximab (IFX) and adalimumab, 5 lost response to either IFX or adalimumab, 1 was biologically naı̈ve and the last had an early allergic reaction to IFX. Eight of the ten patients who completed this trial demonstrated an overall clinical improvement in mucosal healing, CDAI and SIBDQ. Of those who responded to CZP, the mean LS at baseline fell from 1861 to 226 at 26 weeks and the mean CDAI decreased from 265 at baseline to 117 at 26 weeks. The mean SIBDQ increased in responders from 39 at baseline to 50 by the end of study. CONCLUSION(S): This study demonstrates clear evidence of mucosal healing using CZP in patients with moderate-to-severe Crohn’s disease. All patients who responded to CZP had prior exposure to anti-TNF therapy. This study establishes a proof of concept that WCE used in conjunction with the LS is a valuable diagnostic test to assess mucosal healing in patients with small bowel Crohn’s disease treated with CZP. CZP was well-tolerated in this population with no safety issues. Larger, placebo controlled trials are warranted to assess small bowel mucosal healing in patients treated with CZP.

Fistula healing in MAP positive Crohn's disease patients following rifabutin and macrolide antibiotic therapy

Clarithromycin Treatment In Patients With Chronic Treatment-Resiatant Ponchitis Fernando Ri77ello, Paolo Gionchetti, Cristina Amadini, Alessandro Ventud, Oept of Int Med and Gastroenterol, Univ of Bologna, Bologna Italy; Federica Ugolini, Surg Unit, Univ of Bologna, Bologna Italy; Karen M. Lammers, Rossella Romagnoli, Dept of Int Med and Gastroenterol, Univ of Bologna, Bologna Italy; Gill)erto Poggioli, Surg Unit, Univ of Bologna, Bologna Italy; Massimo Campieri, Dept of Int Med and Gastroenterol, Univ of Bologna, Bologna Italy