Shafran Gastroenterology Center

Background: Approval of vedolizumab (VDZ) for moderately to severely active ulcerative colitis (UC) was based on the phase 3 GEMINI 1 study. [1] The GEMINI open-label extension (OLE) trial is an ongoing study investigating the long-term safety of VDZ (NCT00790933). Here we report the 5-year exploratory analyses of effectiveness and safety in patients (pts) with UC who had completed GEMINI 1 and were enrolled in GEMINI OLE. Methods: Analyses included pts who responded to VDZ induction at Week (Wk) 6 and had received VDZ maintenance (every 8 or 4 wks; data were combined) to Wk 52 of GEMINI 1, followed by VDZ every 4 wks in GEMINI OLE. Pts with 248 wks of cumulative VDZ treatment (data were collected from 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) and health-related quality of life (HRQoL), including IBD Questionnaire (IBDQ) and Euro Quality of Life-5D visual analogue scale (EQ-5D VAS). Safety was also assessed. Results: Of 247 pts in GEMINI 1 who responded to VDZ induction at Wk 6 and received VDZ in maintenance, 154 (62%) completed VDZ maintenance and were enrolled in GEMINI OLE (anti-TNFα-naïve n=107; anti-TNFα failure n=42). At the time of this analysis, 63 pts had completed 248 wks of cumulative VDZ treatment; 54 had discontinued (n=19 [35%] due to lack of continued benefit) and 37 are ongoing (have not yet reached 248 wks of treatment). Of pts with data at Wk 248 (n=63), 98% had clinical response and 90% were in remission (Table). HRQoL improvements were observed at Wk 248, with mean change from BL IBDQ and EQ-5D-VAS scores of 58.7 and 24.0, respectively. In the safety population, 137 pts had adverse (AEs); 17 discontinued due to AEs. Serious AEs were reported in 44 pts (in 7 pts these were drug-related; 8 pts discontinued as a consequence of serious AEs). No deaths were reported. Table 1. Effectiveness outcomes in patients with UC and cumulative VDZ exposure for up to 248 wks Conclusions: In UC patients who were responders at Wk 6 of GEMINI 1 (who continued to respond during the study), long-term VDZ therapy (∼5 years) was associated with clinical benefits including clinical response, clinical remission and HRQoL improvements. The safety profile was consistent with that previously observed in a 3-year interim analysis of the OLE study.

Vedolizumab (VDZ) is a gut-selective monoclonal antibody to the α4β7 integrin for the treatment of moderately to severely active Crohn's disease (CD). The efficacy and safety of VDZ for CD were established in the placebo-controlled GEMINI 2 (NCT00783692)1 and GEMINI 3 (NCT01224171)2 trials and continue to be monitored in the ongoing open-label GEMINI Long-term Safety (LTS) trial (NCT00790933). Mucosal healing in CD—not pre-specified in any GEMINI trial—was previously demonstrated in 4 patients from GEMINI LTS.3 Here, we report follow-up of these 4 patients and evidence of initial and sustained mucosal healing in an additional 7 patients with CD receiving VDZ. Eligible patients (n = 9) from GEMINI 2 and GEMINI 3 were enrolled in GEMINI LTS and received VDZ 300 mg every 4 weeks. We treated an additional 2 patients with the approved VDZ induction and maintenance (dosed every 8 weeks) therapy outside of GEMINI LTS. Colonoscopic evaluations are a standard of care at our facility and were done before (up to 18 months before screening) and during the course of VDZ treatment. Retrospective chart reviews, including visual assessments of routine colonoscopies, for the 11 patients were described. Patients—6 men and 5 women—had a mean 13-year duration of CD with prior failure of tumor necrosis factor antagonist therapy. Seven patients had ileocolonic CD; 3 had disease involvement limited to the colon, and 1 to the small bowel. The majority of patients (n = 7) had a history of prior surgery for CD; 3 patients had a history of fistula. All 11 patients had significant mucosal ulcerations during baseline colonoscopic evaluation. Of patients previously demonstrating mucosal healing with VDZ,3 all 4 experienced sustained healing with continued treatment (≥4 years). Evidence of complete mucosal healing in 4 additional patients was observed with the second colonoscopy, performed within 1 to 4 years after initiating VDZ therapy. An additional 3 patients had partial mucosal healing upon their second colonoscopy, with complete healing observed at the third colonoscopy, 2.5 to 5 years after initiating VDZ therapy. Of all patients, mild recurrent CD was observed for 1 patient during a fifth colonoscopy, after >5 years of VDZ therapy. All patients experienced clinical benefit with VDZ therapy as evidenced by clinician and patient assessments. Endoscopic images show complete reversal of mucosal ulcerations in 11 patients with moderately to severely active CD within 1 to 5 years of VDZ therapy. Data provide evidence of sustained mucosal healing with long-term treatment in 10 patients; 1 patient experienced mild recurrent disease. Larger, prospective, controlled studies investigating the efficacy of VDZ in mucosal healing in CD are warranted.

The pathophysiology of lymphocytic colitis (LC) is not completely understood. Current hypotheses implicate abnormal mucosal immune response to luminal antigens in combination with genetic predisposition. Five cases detail the outcomes of adding serum-derived bovine immunoglobulin/protein isolate (SBI) for the nutritional management of these unresponsive LC patients. SBI's unique mechanism includes binding microbial components and maintaining normal GI immune balance which makes it a candidate therapy in LC patients. Five patients were administered SBI for LC. All patients were female with an average age of 71±7.1 yrs. Patient 1 was admitted to the hospital with 20-24 bowel movements (BM) per day with cramps and urgency. Biopsies from a colonoscopy were consistent with LC. She was placed on mesalamine and methylprednisolone without any change. Patient 2 had tried and failed multiple tapering doses of budesonide for 2 yrs with continual multiple, loose stools per day. Patient 3 had been diagnosed with IBS-D for 15 yrs and failed all over-the-counter options. Recent biopsies, however, indicated LC. Patient 4 had a poor response to steroids and psyllium fiber for 2.5 yrs with a history of fecal incontinence (FI). Patient 5 had a diagnosis of LC for 1.5 yrs; she had a history of anal fistula repairs with multiple loose BM in the a.m. accompanied by intermittent episodes of FI. She had no response to mesalamine, loperamide or antibiotics. Incorporating SBI dramatically improved symptoms for all patients. Patient 1 was discharged from the hospital on SBI 5g QD and continued on 1.2g mesalamine having 4 formed BM without cramping, urgency or bleeding. However, if the patient missed more than two days of SBI, she quickly experienced 10-14 watery BM daily. Patient 2 first began SBI 5g BID with budesonide, but was able to discontinue the steroid while maintaining normal BM on SBi monotherapy. Patient 3 was placed on budesonide and SBI 5g QD normal BM within a week. Patient 4 began SBI 5g QD in addition to psyllium fiber and at follow-up reported formed stools with no episodes of FI. After initiating SBI 5g QD, Patient 5 reported 1-2 formed BM without FI. All patients are currently maintained on SBI in combination with the therapies indicated above for more than 6 months. No side effects have been experienced on SBI during that time. The exact manner in which SBI manages LC is not known. The outcomes of these cases, however, suggest that LC patients may benefit from the distinct nutritional proteins in SBI for management of their conditions. Larger, well-controlled studies in patients with LC and/or FI should be performed to corroborate these findings.

Purpose: Our community based IBD practice acknowledges the importance of developing consistent health maintenance strategies specific to the needs of the IBD population. Immunization status, B12 and vitamin D testing, osteoporosis screening and cancer surveillance are essential components of a comprehensive plan. We have strived to understand the real risk and prevalence of non-immunity among our IBD population (both biologic exposed and naive patients), in order to implement an appropriate and cost effective program for screening and immunizing both before and during treatment decisions. Methods: Forty two IBD patients (38 Crohn's, 4 UC) were evaluated between 1/1/2010 and 4/30/2010. Fifty seven percent (24 of 42 patients) were on biologic or immunosuppressive therapies at the time of evaluation. Serum titers were drawn to identify active immunity to measles, mumps, rubella, varicella, hepatitis A & B. Both vitamin B12 and vitamin D levels were also obtained. All 48 patients were advised to obtain DEXA scan and all female patients (16) were advised to obtain yearly PAP testing and HPV screening. Results: Ninety three percent of patients demonstrated active immunity to measles, 86% to mumps, 90% to rubella, 100% to varicella with only 8% immune to hepatitis A and 21% to hepatitis B. B12 levels were low in 19% of patients with 36% found to be vitamin D deficient. Of the 42 patients advised to obtain DEXA scanning, 9 patients (21%) completed the exam; 4 having normal bone density, 4 with osteopenia, and 1 with osteoporosis. One of 16 female patients scheduled PAP testing. All 18 patients not on immunosuppressants were advised to update all immunizations, with those immunocompromised advised to avoid all live virus vaccines. All patients who were vitamin B12 and D deficient were started on appropriate replacement. Conclusion: The role of the gastroenterologist as primary decision maker in the health care of IBD patients is essential to assure that patients are educated, and that a general preventative health maintenance plan is implemented. We are continuing to provide guidance to our patients on a broad range of issues such as vaccinations, osteoporosis screening and cancer/dysplasia surveillance. Our analysis clearly uncovered issues with non-adherence to recommendations in regards to DEXA scanning and PAP testing specifically, warranting dynamic follow up strategies to encourage improved adherence to health maintenance recommendations.

Shafran Gastroenterology CenterWinter Park, Florida The data was originally presented at the American College of Gastroenterology Annual Scientific Meeting, October 12–17, 2007, Philadelphia, PA.

Bacteria may play an important role in the inflammatory cascade of Crohn's disease (CD), and antibiotics may be useful in CD management. Rifaximin is a nonabsorbed, oral antibiotic with broad-spectrum activity and a safety profile comparable to placebo. Given these favorable characteristics, the potential benefits of rifaximin in CD management were examined. A chart review of CD patients (pts) treated with rifaximin from 2001 to 2005 was conducted at a single center. Concomitant medications were permitted. Crohn's Disease Activity Index (CDAI) scores were determined retrospectively with remission defined as CDAI score < 150 and secondary efficacy endpoints determined as 70-point or 100-point reductions from baseline. Data from 68 pts (mean CD duration, 17 y) were analyzed. Most pts (94%) were treated with rifaximin 200 mg t.i.d., with treatment lasting a median of 16.6 wk. Additionally, 31 pts (46%) were also treated with steroids at least once during rifaximin therapy. The median baseline CDAI score was 221, and 34 pts (50%) were identified with fistulizing disease. Overall, induction of CD remission was reported in 44 pts (65%), with a similar response rate (65%) achieved in 17 pts with CD in the small intestine only. A slightly lower response rate (55%) was observed in 11 pts with CD in the large intestine only. A slightly higher rate of remission (70%) was achieved in 37 pts who did not receive steroids compared with the rate (58%) for 31 pts treated with steroids. In addition, a 70-point reduction from baseline CDAI score was observed in 34 pts (50%), and a 100-point reduction was observed in 29 pts (43%). Consistently greater monthly improvements from baseline in CDAI scores occurred through at least 4 months post-rifaximin initiation. Interestingly, remission was detected in 67% of 18 patients who received rifaximin monotherapy. Rifaximin therapy was associated with clinical improvement in pts with CD. Although the direct contribution of rifaximin could not be fully evaluated in this observational study, data suggest that rifaximin, with or without steroids, may be beneficial in the treatment of CD, warranting further studies.

Treatments for Crohn's disease (CD) are currently designed to control intestinal inflammation, including precipitators of the inflammatory cascade. Bacteria may play an important role in CD inflammation, and antibiotics may be useful in CD management. However, many clinicians avoid the long-term use of antibiotics, particularly in light of concerns with systemic toxicity and development of antibiotic resistance. Rifaximin is a nonabsorbed antibiotic with broad-spectrum antibacterial activity and a safety profile similar to placebo. Given these favorable characteristics, a retrospective chart review was conducted to examine the potential benefits of nonsystemic antibiotic monotherapy in CD management. A single-center chart review was conducted to identify patients with CD treated with rifaximin monotherapy from 2001 to 2005. Patients treated concomitantly with CD medications (eg, steroids) during antibiotic therapy were excluded from the analysis. Crohn's Disease Activity Index (CDAI) scores were determined retrospectively, with remission defined as CDAI score <150 and secondary efficacy endpoints determined as 70-point or 100-point reductions from baseline CDAI score. Data from 18 patients were analyzed, and the median baseline CDAI score was 237. Patients were treated with rifaximin 200 mg t.i.d. for a median of 13 weeks. Remission was achieved in 67% of 18 patients, and 70-point and 100-point reductions in CDAI score were observed in 50% and 39% of these patients, respectively. Seven patients (39%) exhibited disease of the small intestine only, and 5 of these (71%) achieved remission. This small observational study suggests that nonsystemic antibiotic therapy may provide clinically meaningful improvements in patients with CD. Nonsystemic antibiotics may play an important role in the management of patients with inflammatory bowel disease, and further investigations of monotherapy and adjunctive antibiotic therapy are warranted.