David Hudesman

The Real-World Effectiveness and Safety of Vedolizumab for Moderate-Severe Crohn's Disease: Results From the US VICTORY Consortium.

Objectives:We assessed the real-world effectiveness and safety of vedolizumab (VDZ) in moderate–severe Crohn’s disease (CD).Methods:Retrospective cohort study of seven medical centers, from May 2014 to December 2015. Adults with moderate-severe CD treated with VDZ, with follow-up after initiation of therapy, were included. Using the multivariable Cox proportional hazard analyses, we identified independent predictors of clinical remission or mucosal healing with VDZ. Rates of serious infection (requiring antibiotics, resulting in discontinuation of VDZ, hospitalization or death) and serious adverse events (discontinuation of VDZ, hospitalization or death) were described quantitatively.Results:We included 212 patients with moderate–severe CD (median age 34 years; 40% male; 90% tumor necrosis factor (TNF)-antagonist exposed) with a median follow-up (IQR) of 39 weeks (25–53). Twelve-month cumulative rates of clinical remission, mucosal healing, and deep remission (clinical remission+mucosal healing) were 35%, 63%, and 26%, respectively. Individuals with prior TNF-antagonist exposure (hazard ratio (HR) 0.40; 95% confidence interval (CI): 0.20–0.81), smoking history (HR 0.47; 95% CI: 0.25–0.89), active perianal disease (HR 0.49; 95% CI: 0.27–0.88), and severe disease activity (HR 0.54; 95% CI: 0.31–0.95) were less likely to achieve clinical remission. Those with prior TNF-antagonist exposure (HR 0.29; 95% CI: 0.12–0.73), and severe disease activity (HR 0.54; 95% CI: 0.31–0.95) were less likely to achieve mucosal healing. During 160 patient years of follow-up (PYF) and 1,433 VDZ infusions, 5 patients developed infusion reactions (3.5 per 1,000 infusions), 21 developed serious infections (13 per 100 PYF), and 17 developed serious adverse events (10 per 100 PYF). A minority of adverse events required discontinuation of therapy (6 per 100 PYF).Conclusions:VDZ is a safe and effective treatment option for moderate–severe CD in routine practice. Clinical remission and deep remission (clinical remission and mucosal healing) can be achieved in 1/3 of individuals, and a minority of individuals require discontinuation of therapy due to adverse events.

Disease monitoring in inflammatory bowel disease

The optimal method for monitoring quiescent disease in patients with Crohns disease (CD) and ulcerative colitis is yet to be determined. Endoscopic evaluation with ileocolonoscopy is the gold standard but is invasive, costly, and time-consuming. There are many commercially available biomarkers that may be used in clinical practice to evaluate disease status in patients with inflammatory bowel disease (IBD), but the most widely adopted biomarkers are C-reactive protein (CRP) and fecal calprotectin (FC). This review summarizes the evidence for utilizing CRP and FC for monitoring IBD during clinical remission and after surgical resection. Endoscopic correlation with CRP and FC is evaluated in each disease state. Advantages and drawbacks of each biomarker are discussed with special consideration of isolated ileal CD. Fecal immunochemical testing, traditionally used for colorectal cancer screening, is mentioned as a potential new alternative assay in the evaluation of IBD. Based on a mixture of information gleaned from biomarkers, clinical status, and endoscopic evaluation, the best treatment decisions can be made for the patient with IBD.

Risk of extraintestinal solid cancer with anti-TNF therapy in adults with inflammatory bowel disease: review of the literature.

AbsractWith the increased use of anti-TNF therapy for both ulcerative colitis and Crohn’s disease, there is serious concern about long term adverse events, especially malignancy. Recent data suggests that anti-TNF agents increase the risk of non-Hodgkin’s lymphoma; however, there is limited evidence on the risk of solid tumors. Many patients have been exposed to other immunosuppressive therapies in the past making it difficult to discern the true risk of malignancy with TNF-alpha inhibitors alone. The purpose of this review is to discuss the risk of extra-intestinal solid cancer, excluding skin cancer, in adult inflammatory bowel disease patients exposed to anti-TNF agents.

Capsule endoscopy in Crohn's disease: are we seeing any better?

Crohns disease (CD) is a complex, immune-mediated disorder that often requires a multi-modality approach for optimal diagnosis and management. While traditional methods include ileocolonoscopy and radiologic modalities, increasingly, capsule endoscopy (CE) has been incorporated into the algorithm for both the diagnosis and monitoring of CD. Multiple studies have examined the utility of this emerging technology in the management of CD, and have compared it to other available modalities. CE offers a noninvasive approach to evaluate areas of the small bowel that are difficult to reach with traditional endoscopy. Furthermore, CE maybe favored in specific sub segments of patients with inflammatory bowel disease (IBD), such as those with IBD unclassified (IBD-U), pediatric patients and patients with CD who have previously undergone surgery.

Integrated Analysis of Biopsies from Inflammatory Bowel Disease Patients Identifies SAA1 as a Link Between Mucosal Microbes with TH17 and TH22 Cells

Background: Inflammatory bowel diseases (IBD) are believed to be driven by dysregulated interactions between the host and the gut microbiota. Our goal is to characterize and infer relationships between mucosal T cells, the host tissue environment, and microbial communities in patients with IBD who will serve as basis for mechanistic studies on human IBD. Methods: We characterized mucosal CD4+ T cells using flow cytometry, along with matching mucosal global gene expression and microbial communities data from 35 pinch biopsy samples from patients with IBD. We analyzed these data sets using an integrated framework to identify predictors of inflammatory states and then reproduced some of the putative relationships formed among these predictors by analyzing data from the pediatric RISK cohort. Results: We identified 26 predictors from our combined data set that were effective in distinguishing between regions of the intestine undergoing active inflammation and regions that were normal. Network analysis on these 26 predictors revealed SAA1 as the most connected node linking the abundance of the genus Bacteroides with the production of IL17 and IL22 by CD4+ T cells. These SAA1-linked microbial and transcriptome interactions were further reproduced with data from the pediatric IBD RISK cohort. Conclusions: This study identifies expression of SAA1 as an important link between mucosal T cells, microbial communities, and their tissue environment in patients with IBD. A combination of T cell effector function data, gene expression and microbial profiling can distinguish between intestinal inflammatory states in IBD regardless of disease types.

Vedolizumab for Ulcerative Colitis: Treatment Outcomes from the VICTORY Consortium

OBJECTIVES: We aimed to quantify the safety and effectiveness of vedolizumab (VDZ) when used for UC, and to identify predictors of response to treatment. METHODS: Retrospective review (May 2014‐December 2016) of VICTORY Consortium data. Adults with follow‐up after starting VDZ for clinically active UC were included. Primary effectiveness outcomes were cumulative rates of clinical remission (resolution of all UC‐related symptoms) and endoscopic remission (Mayo endoscopic sub‐score 0). Key secondary effectiveness outcomes included cumulative rates of corticosteroid‐free remission and deep remission (clinical remission and endoscopic remission). Cox proportional hazard analyses were used to identify independent predictors of treatment effectiveness. Non‐response imputation (NRI) sensitivity analyses were performed for effectiveness outcomes. Key safety outcomes were rates of serious infection, serious adverse events, and colectomy. RESULTS: We included 321 UC patients (71% prior TNF&agr; antagonist exposure, median follow‐up 10 months). The 12‐month cumulative rates of clinical remission and endoscopic remission were 51% and 41%, respectively. Corresponding rates for corticosteroid‐free remission and deep remission were 37% and 30%, respectively. Using NRI, 12‐month rates were 20% (n = 64/321) for clinical remission, 17% (n=35/203) for endoscopic remission, 15% (n=30/195) for corticosteroid‐free remission, and 14% (n = 28/203) for deep remission. A majority of the patients without adequate follow‐up at 12 months who were deemed non‐responders using NRI had already achieved clinical remission (n = 70) or a significant clinical response (n=36) prior to 12 months. VDZ discontinuation prior to 12 months was observed in 91 patients, for lack of response (n =56), need for surgery (n=29), or adverse event (n=6). On multivariable analyses, prior exposure to a TNF&agr; antagonist was associated with a reduced probability of achieving clinical remission (HR 0.53, 95% CI 0.38–0.75) and endoscopic remission (HR 0.51, 95% CI 0.29–0.88). Serious adverse events and serious infections were reported in 6% and 4% of patients, respectively. Overall cumulative rates of colectomy over 12 months were 13%, with lower rates observed in patients naive to TNF&agr; antagonist therapy (2%) than those who had been exposed to TNF&agr; antagonists (19%). CONCLUSION: In this large real‐world cohort we observed that VDZ was well tolerated and effective in achieving key clinical outcomes.

Postoperative Outcomes in Vedolizumab-Treated Patients Undergoing Major Abdominal Operations for Inflammatory Bowel Disease: Retrospective Multicenter Cohort Study

Background Vedolizumab is now widely available for the treatment of moderate to severe ulcerative colitis (UC) and Crohns disease (CD). We sought to quantify the rates of postoperative complications with preoperative vedolizumab compared with anti-tumor necrosis factor (anti-TNF) therapy. Methods A multicenter retrospective review of adult inflammatory bowel disease (IBD) patients who underwent an abdominal operation between May 20, 2014, and December 31, 2015, was performed. The study cohort was comprised of patients who had received vedolizumab within 12 weeks of their abdominal operation, and the control cohort was IBD patients who had received anti-TNF therapy. Results A total of 146 patients received vedolizumab within 12 weeks before an abdominal operation (64% female; n = 93; median age, 33 years; range, 15-74 years), and 289 patients received anti-TNF therapy (49% female; n = 142; median age, 36 years; range, 17-73 years). Vedolizumab-treated patients were younger (P = 0.015) and were more likely to have taken corticosteroids (P < 0.01) within the 12 weeks before surgery. Vedolizumab-treated patients had a significantly increased risk of any postoperative surgical site infection (SSI; P < 0.01), superficial SSI (P < 0.01), deep space SSI (P = 0.39), and mucocutaneous separation of the diverting stoma (P < 0.00) as compared with patients taking anti-TNF therapy. On multivariate analysis, after adjusting for body mass index, steroids at the time of operation, and institution, exposure to vedolizumab remained a significant predictor of postoperative SSI (P < 0.01). Conclusions We observed that vedolizumab-treated patients were at significantly increased risk of postoperative SSIs after a major abdominal operation, as compared with anti-TNF-treated patients.

The nocebo effect and patient perceptions of biosimilars in inflammatory bowel disease

We read with great interest a recent paper by Boone et al. [1]. In this 1-year observational study, the authors sought to quantify the nocebo rate in individuals with an immune-mediated inflammatory disease who were switched from the originator infliximab to a biosimilar for a non-medical reason. Patients were provided informed consent and voluntarily agreed to transition to the infliximab biosimilar. The patients in this study were stable on infliximab, with the average duration of infliximab treatment being more than 3 years prior to switching. The results demonstrated an overall nocebo response of 12.8%, (12.5% for rheumatologic disorders and 12.9% for inflammatory bowel disease (IBD)). Patients with a nocebo response endorsed Bless exerted effect,^ chills during infusions, numbness, and tingling, and headache. All nocebo-response patients were able to be re-initiated on the infliximab originator. The authors concluded that non-medical switching may have a negative impact on patient’s perceived disease burden and sense of well-being. The investigators hypothesized that shared decision-making and patient education may decrease the nocebo-response rate. However, there is currently limited data regarding patient perception and knowledge of biosimilars to help physicians address potential concerns with their patients [2, 3]. The infliximab biosimilar was approved in the USA in 2016, but penetration into our marketplace has only recently accelerated. As such, we recently performed a small, prospective study aimed at gauging IBD patients’ initial perceptions of biosimilars. In 2017, we surveyed 132 adult patients with IBD at two university-affiliated gastroenterology clinics regarding their current impression of biosimilars. A standardized cover sheet was included with the 14-question survey which described the purpose of the study and a brief explanation of biosimilars. We found that a large proportion of surveyed participants (75%), despite themajority beingwell-educated with a university education or more, had never heard of biosimilar medications. In regard to participant concerns with biosimilars, 81% were concerned with the efficacy, 74% were concerned with the side effects, and 70% were concerned with the safety of these medications. Significantly more biologic-experienced participants were concerned about the effectiveness and the safety of biosimilars when compared to biologic-naive participants (86 vs 62%, p = 0.003 and 75 vs 55%, p = 0.041, respectively). Regarding switching, 58% of all participants were uncomfortable exchanging their current medication for a biosimilar. Not surprisingly, significantly more patients currently or previously on a biologic were uncomfortable switching to a biosimilar compared to patients not currently on a biologic (61 vs 45%, p = 0.032). Our study highlights a lack of awareness of biosimilars as well as main concerns regarding these medications. These findings can be used to help physicians to construct a patient-centered approach to introducing biosimilars. For the most part, the decision to switch to a biosimilar will be driven by economics rather than patient preference. Patients who switch to the biosimilar are at risk of nocebo effects given concerns regarding efficacy, side effects, and safety. In the study by Boone et al., patients voluntarily switched to the biosimilar. In real-world practice, the nocebo response may be higher in patients who do not voluntarily switch. We agree with Boone et al. that patient education is paramount to limiting patient noncompliance and the nocebo effect. * Shannon Chang shannon.chang@nyumc.org

Predictors and Management of Loss of Response to Vedolizumab in Inflammatory Bowel Disease

Background We quantified loss of response (LOR) to vedolizumab (VDZ) in clinical practice and assessed the effectiveness of VDZ dose intensification for managing LOR. Methods Retrospective review (May 2014-December 2016) of a prospectively maintained inflammatory bowel disease (IBD) registry. Kaplan-Meier estimates were used to determine rates of LOR to VDZ . Independent predictors of LOR were identified using univariate and multivariable Cox proportional hazard regression. Success of recapturing response (>50% reduction in symptoms from baseline) and remission (complete resolution of symptoms) after dose intensification was quantified. Results Cumulative rates for VDZ LOR were 20% at 6 months and 35% at 12 months, with slightly lower rates in Crohns disease than in ulcerative colitis (6 months 15% vs 18% and 12 months 30% vs 39%, P = 0.03). On multivariable analysis, LOR to a tumor necrosis factor (TNF) antagonist before VDZ use was associated with an increased risk for LOR to VDZ [hazard ratio (HR) 1.93; 95% confidence interval (CI) 1.25-2.97] in all patients. For Crohns disease patients specifically, higher baseline C-reactive protein concentration was associated with increased risk for LOR to VDZ (HR 1.01 per mg/dL increase, 95% CI 1.01-1.02). Shortening of VDZ infusion interval from 8 to every 4 or 6 weeks recaptured response in 49% and remission in 18% of patients. Conclusions LOR to a TNF antagonist before VDZ use and higher baseline C-reactive protein are important predictors of VDZ LOR. Treatment response can be recaptured in almost half of these patients with VDZ infusion interval shortening.

Escalation of Immunosuppressive Therapy for Inflammatory Bowel Disease Is Not Associated With Adverse Outcomes After Infection With Clostridium difficile

BACKGROUND Clostridium difficile infection (CDI) is common in patients with inflammatory bowel disease (IBD), often leading to diagnostic confusion and delays in IBD therapy escalation. This study sought to assess outcomes after CDI in IBD patients exposed to new or escalated immunosuppressive therapy. METHODS This multicenter retrospective cohort study included IBD patients with documented CDI at 4 academic medical centers. Data were abstracted from clinical databases at each institution. Outcomes at 30 and 90 days were compared between patients undergoing new or intensified immunosuppressive therapy and those without therapy escalation. Continuous variables were compared using t tests, and proportions using chi-square tests. Multivariable logistic regression was used to determine the association of individual variables with severe outcomes (including death, sepsis, and/or colectomy) within 90 days. Secondary outcomes included CDI recurrence, rehospitalization, worsening of IBD, and severe outcomes within 30 days. RESULTS A total of 207 adult patients with IBD and CDI were included, of whom 62 underwent escalation to biologic or corticosteroid therapy (median time to escalation, 13 days). Severe outcomes within 90 days occurred in 21 (15.6%) nonescalated and 1 (1.8%) therapy-escalated patients. Serum albumin <2.5 mg/dL, lactate >2.2 mg/dL, intensive care unit admission, hypotension, and comorbid disease were associated with severe outcomes. Likelihood of severe outcomes was decreased in patients undergoing escalation of IBD therapy after CDI (adjusted odds ratio [aOR], 0.12) and increased among patients aged >65 years (aOR, 4.55). CONCLUSIONS Therapy escalation for IBD within 90 days of CDI was not associated with worse clinical outcomes. Initiation of immunosuppression for active IBD may therefore be appropriate in carefully selected patients after treatment of CDI.