Comparative Safety and Effectiveness of Vedolizumab to Tumor Necrosis Factor Antagonist Therapy for Ulcerative Colitis.

BACKGROUND & AIMS: We aimed to compare safety and effectiveness of vedolizumab to tumor necrosis factor (TNF)-antagonist therapy in ulcerative colitis in routine practice. METHODS: A multicenter, retrospective, observational cohort study (May 2014 to December 2017) of ulcerative colitis patients treated with vedolizumab or TNF-antagonist therapy. Propensity score weighted comparisons for development of serious adverse events and achievement of clinical remission, steroid-free clinical remission, and steroid-free deep remission. A priori determined subgroup comparisons in TNF-antagonist-naïve and -exposed patients, and for vedolizumab against infliximab and subcutaneous TNF-antagonists separately. RESULTS: A total of 722 (454 vedolizumab, 268 TNF antagonist) patients were included. Vedolizumab-treated patients were more likely to achieve clinical remission (hazard ratio [HR], 1.651; 95% confidence interval [CI], 1.229-2.217), steroid-free clinical remission (HR, 1.828; 95% CI, 1.135-2.944), and steroid-free deep remission (HR, 2.819; 95% CI, 1.496-5.310) than those treated with TNF antagonists. Results were consistent across subgroup analyses in TNF-antagonist-naïve and -exposed patients, and for vedolizumab vs infliximab and vs subcutaneous TNF-antagonist agents separately. Overall, there were no statistically significant differences in the risk of serious adverse events (HR, 0.899; 95% CI, 0.502-1.612) or serious infections (HR, 1.235; 95% CI, 0.608-2.511) between vedolizumab-treated and TNF-antagonist-treated patients. However, in TNF-antagonist-naïve patients, vedolizumab was less likely to be associated with serious adverse events than TNF antagonists (HR, 0.192; 95% CI, 0.049-0.754). CONCLUSIONS: Treatment of ulcerative colitis with vedolizumab is associated with higher rates of remission than treatment with TNF-antagonist therapy in routine practice, and lower rates of serious adverse events in TNF-antagonist-naïve patients.

Development and Validation of Clinical Scoring Tool to Predict Outcomes of Treatment With Vedolizumab in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: We created and validated a clinical decision support tool (CDST) to predict outcomes of vedolizumab therapy for ulcerative colitis (UC). METHODS: We performed logistic regression analyses of data from the GEMINI 1 trial, from 620 patients with UC who received vedolizumab induction and maintenance therapy (derivation cohort), to identify factors associated with corticosteroid-free remission (full Mayo score of 2 or less, no subscore above 1). We used these factors to develop a model to predict outcomes of treatment, which we called the vedolizumab CDST. We evaluated the correlation between exposure and efficacy. We validated the CDST in using data from 199 patients treated with vedolizumab in routine practice in the United States from May 2014 through December 2017. RESULTS: Absence of exposure to a tumor necrosis factor (TNF) antagonist (+3 points), disease duration of 2 y or more (+3 points), baseline endoscopic activity (moderate vs severe) (+2 points), and baseline albumin concentration (+0.65 points per 1 g/L) were independently associated with corticosteroid-free remission during vedolizumab therapy. Patients in the derivation and validation cohorts were assigned to groups of low (CDST score, 26 points or less), intermediate (CDST score, 27-32 points), or high (CDST score, 33 points or more) probability of vedolizumab response. We observed a statistically significant linear relationship between probability group and efficacy (area under the receiver operating characteristic curve, 0.65), as well as drug exposure (P < .001) in the derivation cohort. In the validation cohort, a cutoff value of 26 points identified patients who did not respond to vedolizumab with high sensitivity (93%); only the low and intermediate probability groups benefited from reducing intervals of vedolizumab administration due to lack of response (P = .02). The vedolizumab CDST did not identify patients with corticosteroid-free remission during TNF antagonist therapy. CONCLUSIONS: We used data from a trial of patients with UC to develop a scoring system, called the CDST, which identified patients most likely to enter corticosteroid-free remission during vedolizumab therapy, but not anti-TNF therapy. We validated the vedolizumab CDST in a separate cohort of patients in clinical practice. The CDST identified patients most likely to benefited from reducing intervals of vedolizumab administration due to lack of initial response. ClinicalTrials.gov no: NCT00783718.

Systematic review: hepatosplenic T-cell lymphoma on biologic therapy for inflammatory bowel disease, including data from the Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: Hepatosplenic T-cell lymphoma (HSTCL) is a rare, poorly treatable malignancy associated with therapy for IBD. Current knowledge of HSTCL risk in IBD comes from an era of step-up therapy, before earlier use of biologics or combination therapy was advocated to achieve deep mucosal healing. HSTCL risk among newer biologic classes has also not been evaluated. AIMS: To systematically characterise the association of HSTCL with biologic therapy for IBD. METHODS: We conducted a literature search and query of the Food and Drug Administration Adverse Event Reporting System to summarise HSTCL cases among IBD patients with prior biologic exposure. Demographics and immunosuppression exposure were extracted. Patients were stratified by current regimen (combination therapy, biologic monotherapy or no biologic), and biologic class (anti-TNF, anti-integrin, anti-interleukin 12/23). RESULTS: Sixty-two cases of HSTCL were identified from 2486 abstracts and 181 FDA Adverse Events Reporting System reports. The median age of affected patients was 28 years (range 12-81), and 83.6% were male, 84.7% had Crohn's disease. Five of 62 patients had no reported azathioprine/mercaptopurine exposure. Three patients within the cohort developed HSTCL after exposure to natalizumab, vedolizumab or ustekinumab; all three also had anti-TNF and azathioprine/mercaptopurine exposure. Forty-three of 49 (87.8%) patients with known outcomes died with a median survival of 5 months. CONCLUSIONS: Consistent with existing data, almost all identified HSTCL cases among IBD patients on biologic therapy had azathioprine/mercaptopurine exposure, and all cases on patients exposed to biologics had anti-TNF exposure. These data suggest initiating a patient-centred discussion before starting anti-TNF therapy or other biologics.

Patients' Perceive Biologics to Be Riskier and More Dreadful Than Other IBD Medications.

BACKGROUND: Biologic medications have advanced the management of inflammatory bowel diseases (IBD) but are underutilized in the treatment algorithm. One reason may be related to patients' concerns about adverse events and their perceptions of risk. The aim of this study was to compare patients' perceptions of risk of IBD treatment with their perceived risk of everyday occurrences and other medications and how these perceptions may be influenced by personality traits. METHODS: A cross-sectional study of consecutive IBD patients was conducted at a single tertiary care center. Participants were asked to report about their perception of risk of IBD medications, non-IBD medications, invasive procedures, and everyday life occurrences. Participants responded also to the Multidimensional Health Locus of Control (MHLC) scale to characterize beliefs about control over health outcomes. RESULTS: A total of 130 patients with IBD completed the questionnaires. There was a broad range of disease severity and prior medication use. Biologics elicited the highest dread of all IBD medications, but this was still lower than their fear of surgery. Patients believed that biologics were of higher benefit than immunomodulators and mesalamines, but riskier. Having the personality trait of an internally developed locus of control was associated with the perception that biologics are less dreadful. CONCLUSIONS: Patients with IBD perceive biologics to be of higher benefit but riskier and more dreadful as compared with immunomodulators. Risk perception may be about more than their knowledge base but also about how much control patients typically believe they have over their daily lives.

Changes in Vedolizumab Utilization Across US Academic Centers and Community Practice Are Associated With Improved Effectiveness and Disease Outcomes.

BACKGROUND: Vedolizumab effectiveness estimates immediately after Food and Drug Administration (FDA) approval for ulcerative colitis (UC) and Crohn's disease (CD) are limited by use in refractory populations. We aimed to compare treatment patterns and outcomes of vedolizumab in 2 time frames after FDA approval. METHODS: We used 2 data sets for time trend analysis, an academic multicenter vedolizumab consortium (VICTORY) and the Truven MarketScan database, and 2 time periods, May 2014-June 2015 (Era 1) and July 2015-June 2017 (Era 2). VICTORY cumulative 12-month clinical remission, corticosteroid-free remission, and mucosal healing rates, and Truven 12-month hospitalization and surgery rates, were compared between Eras 1 and 2 using time-to-event analyses. RESULTS: A total of 3661 vedolizumab-treated patients were included (n = 1087 VICTORY, n = 2574 Truven). In both cohorts, CD and UC patients treated during Era 2 were more likely to be biologic naïve. Compared with Era 1, Era 2 CD patients in the VICTORY consortium had higher rates of clinical remission (31% vs 40%, P = 0.03) and mucosal healing (42% vs 58%, P < 0.01). These trends were not observed for UC. In the Truven database, UC patients treated during Era 2 had lower rates of inflammatory bowel disease-related hospitalization (22.4% vs 9.6%, P < 0.001) and surgery (17.2% vs 9.4%, P = 0.008), which was not observed for CD. CONCLUSION: Since FDA approval, remission and mucosal healing rates have increased for vedolizumab-treated CD patients, and vedolizumab-treated UC patients have had fewer hospitalizations and surgeries. This is likely due to differences between patient populations treated immediately after drug approval and those treated later.

Prognosticating the Course of Inflammatory Bowel Disease.

Both Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBD) that can lead to progressive irreversible bowel damage. Selecting the most appropriate therapy for patients is a challenge because not all patients diagnosed with IBD have complications, and the amount of time to develop a complication is different for individuals. Models using patient characteristics, genetics, and immune responses help identify those patients who require early aggressive therapy with a goal to modify their disease course. Future research will help identify the role that the microbiome, metagenomics, metaproteomics, and microRNAs play in a patient prognosis.

Shorter Disease Duration Is Associated With Higher Rates of Response to Vedolizumab in Patients With Crohn's Disease But Not Ulcerative Colitis.

BACKGROUND & AIMS: Patients with Crohn's disease (CD), but not ulcerative colitis (UC), of shorter duration have higher rates of response to tumor necrosis factor (TNF) antagonists than patients with longer disease duration. Little is known about the association between disease duration and response to other biologic agents. We aimed to evaluate response of patients with CD or UC to vedolizumab, stratified by disease duration. METHODS: We analyzed data from a retrospective, multicenter, consortium of patients with CD (n = 650) or UC (n = 437) treated with vedolizumab from May 2014 through December 2016. Using time to event analyses, we compared rates of clinical remission, corticosteroid-free remission (CSFR), and endoscopic remission between patients with early-stage (≤2 years duration) and later-stage (>2 years) CD or UC. We used Cox proportional hazards models to identify factors associated with outcomes. RESULTS: Within 6 months initiation of treatment with vedolizumab, significantly higher proportions of patients with early-stage CD, vs later-stage CD, achieved clinical remission (38% vs 23%), CSFR (43% vs 14%), and endoscopic remission (29% vs 13%) (P < .05 for all comparisons). After adjusting for disease-related factors including previous exposure to TNF antagonists, patients with early-stage CD were significantly more likely than patients with later-stage CD to achieve clinical remission (adjusted hazard ratio [aHR], 1.59; 95% CI, 1.02-2.49), CSFR (aHR, 3.39; 95% CI, 1.66-6.92), and endoscopic remission (aHR, 1.90; 95% CI, 1.06-3.39). In contrast, disease duration was not a significant predictor of response among patients with UC. CONCLUSIONS: Patients with CD for 2 years or less are significantly more likely to achieve a complete response, CSFR, or endoscopic response to vedolizumab than patients with longer disease duration. Disease duration does not associate with response vedolizumab in patients with UC.

Effects of Medical Cannabis on Use of Opioids and Hospital Visits by Patients With Painful Chronic Pancreatitis.

Pain is the most common and most debilitating aspect of chronic pancreatitis and is difficult to treat.1-3 Clinical management of painful chronic pancreatitis includes abstinence from alcohol and tobacco products, analgesic medications (including opioids), antidepressant medications, and pancreatic enzyme replacement.4-8 Medical cannabis has been proposed as a therapy for chronic pain and has shown some efficacy in neuropathic and cancer pain. In this study, we investigated the efficacy of medical cannabis on pain control for chronic pancreatitis.

Retrospective Analysis of Safety of Vedolizumab in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: There are few real-world data on the safety of vedolizumab for treatment of Crohn's disease (CD) or ulcerative colitis (UC). We quantified rates and identified factors significantly associated with infectious and non-infectious adverse events in clinical practice. METHODS: We performed a retrospective review of data from a multicenter consortium database (from May 2014 through June 2017). Infectious and non-infectious adverse events were defined as those requiring antibiotics, hospitalization, vedolizumab discontinuation, or resulting in death. Rates were quantified as proportions and events per 100 patient years of exposure (PYE) or follow up (PYF). We performed multivariable logistic regression analyses to identify factors significantly associated with events and reported as odds ratios (OR) with 95% CIs. RESULTS: Our analysis comprised 1087 patients (650 with CD and 437 with UC; 55% female; median age, 37 years) with 861 PYE and 955 PYF. Infections were observed in 68 patients (6.3%; 7.9 per 100 PYE, 7.1 per 100 PYF); gastrointestinal infections (n = 31, 2.4 per 100 PYE, 2.2 per 100 PYF) and respiratory infections (n = 14, 1.6 per 100 PYE, 1.5 per 100 PYF) were the most common. Arthralgias were the most common non-infectious adverse events (n = 31, 2.9%; 3.6 per 100 PYE). Two patients developed malignancies (squamous cell skin cancer and colorectal cancer; 0.23 per 100 PYE, 0.21 per 100 PYF). Active smoker status (OR, 3.39) and number of concomitant immunosuppressive agents (corticosteroids or immunomodulators; OR, 1.72 per agent) used were independently associated with infections. CONCLUSION: In a retrospective cohort study of patients with IBD, we found vedolizumab to be well tolerated with an overall favorable safety profile. Active smoking and concomitant use of immunosuppressive agents were independently associated with infections.

Correction: Vedolizumab for Ulcerative Colitis: Treatment Outcomes from the VICTORY Consortium.

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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 TNFα 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 TNFα 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 TNFα antagonist therapy (2%) than those who had been exposed to TNFα antagonists (19%). CONCLUSION: In this large real-world cohort we observed that VDZ was well tolerated and effective in achieving key clinical outcomes.

Development and Validation of a Scoring System to Predict Outcomes of Vedolizumab Treatment in Patients With Crohn's Disease.

BACKGROUND & AIMS: As more treatment options for inflammatory bowel diseases become available, it is important to identify patients most likely to respond to different therapies. We created and validated a scoring system to identify patients with Crohn's disease (CD) who respond to vedolizumab. METHODS: We collected data from the GEMINI 2 phase 3 trial of patients with active CD treated with vedolizumab for 26 weeks (n = 814) and performed logistic regression analysis to identify factors associated with clinical, steroid-free, and durable remission (derivation set). We used these data to develop a clinical decision support tool, which we validated using data from 366 participants in a separate clinical practice observational cohort of patients with active CD treated with vedolizumab for 26 weeks (the VICTORY cohort). We evaluated the ability of this tool to identify patients in clinical remission or corticosteroid-free remission, or those with mucosal healing (MH), clinical remission with MH, or corticosteroid-free remission with MH after vedolizumab therapy using receiver operating characteristic area under the curve (AUC) analyses. The primary outcome was to develop and validate a list of factors associated with achieving remission by vedolizumab in patients with active CD. RESULTS: In the derivation analysis, we identified absence of previous treatment with a tumor necrosis factor antagonist (+3 points), absence of prior bowel surgery (+2 points), absence of prior fistulizing disease (+2 points), baseline level of albumin (+0.4 points per g/L), and baseline concentration of C-reactive protein (reduction of 0.5 points for values between 3.0 and 10.0 mg/L and 3.0 points for values >10.0 mg/L) as factors associated with remission. In the validation set, our model identified patients in clinical remission with an AUC of 0.67, patients in corticosteroid-free remission with an AUC of 0.66, patients with MH with an AUC of 0.72, patients in clinical remission with MH with an AUC of 0.73, and patients in corticosteroid-free clinical remission with MH with an AUC of 0.75. A cutoff value of 13 points identified patients in clinical remission after vedolizumab therapy with 92% sensitivity, patients in corticosteroid-free remission with 94% sensitivity, patients with MH with 98% sensitivity, patients with clinical remission and MH with 100% sensitivity, and patients with corticosteroid-free clinical remission with MH with 100% sensitivity. CONCLUSIONS: We developed and validated a scoring system to identify patients with CD most likely to respond to 26 weeks of vedolizumab therapy. Further studies are needed to optimize its accuracy in select populations and determine its cost-effectiveness.

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 Crohn's 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 Crohn's 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.

Update on the Management of Chronic Constipation.

OPINION STATEMENT: Chronic constipation (CC) is a highly prevalent disorder encountered by health care providers of all specialties. The diagnosis can be confidently made by taking a careful history, evaluating for warning signs and symptoms, performing an examination, including a digital rectal exam, and using the Rome IV criteria. Treatment should begin at the first visit; most patients require few diagnostic tests to make, or confirm, the diagnosis of CC. Assuming that the patient has persistent symptoms of constipation, despite using traditional therapy (fiber, osmotic agents), then patients should be offered one of the newer treatments, rather than repeating prior treatments, which is a common practice. Lubiprostone, a chloride channel activator, has been shown to safely improve symptoms of CC. Its proven track record of success over the last decade is a common reason why many health care providers choose this as a first-line agent. Alternatively, linaclotide, which stimulates guanylate cyclase C receptors, and which has also been shown to improve symptoms of CC in large, randomized trials, is another logical choice. The decision of which agent to use first often depends upon the patient's co-payment or insurance plan. Either medication should be given a trial of at least 4-6 weeks. If a patient does not respond, then the patient should be treated with the other agent. If symptoms persist, the clinician should consider the possibility of overlapping, or predominant, pelvic floor dysfunction (PFD). The combination of high-resolution anorectal manometry and a balloon expulsion test can be used to make the diagnosis of PFD. If present, patients should be referred to a knowledgeable physical therapist for pelvic floor retraining. New treatment options are available to treat the multiple symptoms of CC. Co-existing pelvic floor dysfunction should be considered in those patients who fail medical therapy.

Utility of Emergency Department Use of Abdominal Pelvic Computed Tomography in the Management of Crohn's Disease.

GOAL: The primary aim of this study was to determine predictors of clinically significant computed tomography (CT) scans, paying particular attention to findings of previous CT scans. BACKGROUND: Use of CT to assess patients with Crohn's disease (CD) in the Emergency Department (ED) is both costly and exposes patients to high levels of ionizing radiation while not clearly improving outcomes. STUDY: Patients with CD who underwent CT scan in the Emergency Department from 2008 to 2011 at a tertiary referral center were assessed for clinically significant findings. A multivariable generalized estimating equation model with logit link and exchangeable working correlation structure was constructed to assess for independent predictors of CT scans with clinically significant findings. RESULTS: A total of 118 patients with CD underwent 194 CT scans. Ninety-two of 194 (47%) CT scans demonstrated clinically significant findings. Predictors of clinically significant CT scans included ileal disease involvement [odds ratios (OR) 3.47, P=0.01] and white blood cell count >12 (OR 2.1, P=0.03). Most notably, patients with a CT scan without clinically significant findings performed in the preceding month were significantly less likely to have a clinically significant CT scan (OR 0.23, P=0.005). CONCLUSIONS: Patients with CD who had a CT scan without significant findings the month prior are unlikely to have clinically significant CT findings. Ileal disease and an elevated white blood cell are predictive of clinically significant CT scans.

Is the Hype of Medical Marijuana All Smoke and Mirrors?

Being classified as a Schedule I drug by the Federal government has not prevented states from passing their own medical marijuana laws. While there is no denying that marijuana's euphoria makes people feel better, there is a lack of scientific data to support the efficacy of marijuana for gastrointestinal diseases. Marijuana, when used as a medical treatment, should be held to the same standards as any other drug coming to market including investigating the adverse event profile and ensuring a rigorous quality control program. Although we are not writing a prescription in the classic definition, we are signing state paperwork supporting the use as a treatment for a medical illness. Therefore, we have the obligation to our patients to ensure that we are recommending a safe and effective drug. More research needs to be conducted until we can reach that conclusion.