The Real-World Effectiveness and Safety of Ustekinumab in the Treatment of Crohn's Disease: Results From the SUCCESS Consortium.

INTRODUCTION: We evaluated the real-world effectiveness and safety of ustekinumab (UST) in patients with Crohn's disease (CD). METHODS: This study used a retrospective, multicenter, multinational consortium of UST-treated CD patients. Data included patient demographics, disease phenotype, disease activity, treatment history, and concomitant medications. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions were assessed using time-to-event analysis, and clinical predictors were assessed by using multivariate Cox proportional hazard analyses. Serious infections and adverse events were defined as those requiring hospitalization or treatment discontinuation. RESULTS: A total of 1,113 patients (51.8% female, 90% prior antitumor necrosis factor exposure) were included, with a median follow-up of 386 days. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions at 12 months were 40%, 32%, 39%, and 30%, respectively. Biologic-naive patients achieved significantly higher rates of clinical and endoscopic remissions at 63% and 55%, respectively. On multivariable analyses, prior antitumor necrosis factor (hazard ratio, 0.72; 95% confidence interval, 0.49-0.99) and vedolizumab exposure (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88) were independently associated with lower likelihoods of achieving endoscopic remission. In patients who experienced loss of remission, 77 of 102 (75%) underwent dose optimization, and 44 of 77 (57%) achieved clinical response. An additional 152 of 681 patients (22.3%) were dose-optimized because of primary nonresponse incomplete response to UST, of whom 40.1% (61 of 152) responded. Serious infections occurred in 3.4% of patients while other noninfectious adverse events (lymphoma [n = 1], arthralgia [n = 6], rash [n = 6], headache [n = 3], hepatitis [n = 3], hair loss [n = 3], neuropathy [n = 1], and vasculitis [n = 1]) occurred in 2.4% of patients. DISCUSSION: UST represents a safe and effective treatment option for CD, with 40% of patients from a highly refractory cohort achieving clinical remission by 12 months. The greatest treatment effect of UST was seen in biologic-naive patients, and dose escalation may recapture clinical response.

Risk of gastrointestinal cancers in patients with cystic fibrosis: a systematic review and meta-analysis.

BACKGROUND: The management and life expectancy of patients with cystic fibrosis have improved substantially in the past three decades, which has resulted in an increased number of these patients being diagnosed with malignancies. Our aim was to assess the risk of gastrointestinal cancers in patients with cystic fibrosis. METHODS: In this systematic review and meta-analysis, we searched PubMed, MEDLINE, Google Scholar, Scopus, Embase, and Cochrane databases with no language restrictions for studies published from inception of the databases to Aug 1, 2017, assessing the risk of gastrointestinal cancers in patients with cystic fibrosis. We also searched abstracts from scientific meetings and the bibliographies of identified articles for additional references. Studies were included if they reported the standardised incidence ratio (SIR) or incidence ratio per person-years. No exclusion criteria with regard to patient characteristics (age, sex, comorbidities, cystic fibrosis mutation type), study setting (location and time period), or method of reporting cancer diagnoses were applied. The primary outcome was risk of gastrointestinal cancer and site-specific gastrointestinal cancers in patients with cystic fibrosis compared with the general population. Pooled summary estimates were calculated using a random-effects model, and subgroup analyses were done to establish whether risk of gastrointestinal cancer varied according to patient lung transplant status. The study is registered with PROSPERO, number CRD42017075396. FINDINGS: Our search identified 95 681 records, of which six cohort studies including 99 925 patients (544 695 person-years) were eligible for the meta-analysis. The overall risk of gastrointestinal cancer was significantly higher in patients with cystic fibrosis than in the general population (pooled SIR 8·13, 95% CI 6·48-10·21; p<0·0001; log SIR 2·10, 95% CI 1·87-2·32; p<0·0001, I2=93·93%). Subgroup analyses showed that the risk of gastrointestinal cancer among patients with cystic fibrosis who had a lung transplant was increased compared with that of patients who did not receive a transplant (pooled SIR 21·13, 95% CI 14·82-30·14; p<0·0001; log SIR 3·05, 95% CI 2·70-3·41; p<0·0001, I2=28·52% vs pooled SIR 4·18, 3·10-5·62; p<0·0001; log SIR 1·43, 1·13-1·73; p<0·0001, I2=22·66%). The risk for the following site-specific cancers was also significantly increased in patients with cystic fibrosis compared with the general population: small bowel cancer (pooled SIR 18·94, 95% CI 9·37-38·27; p<0·0001; log SIR 2·94, 95% CI 2·24-3·64; p<0·0001, I2=38·61%), colon cancer (10·91, 8·42-14·11; p<0·0001; log SIR 2·39, 2·13-2·65; p<0·0001, I2=88·09%), biliary tract cancer (17·87, 8·55-37·36; p<0·0001; log SIR 2·88, 2·15-3·62; p<0·0001, I2=10·16%), and pancreatic cancer (6·18, 1·31-29·27; p=0·022; log SIR 1·82, 0·27-3·38; p<0·0001, I2=62·57%). INTERPRETATION: Our study suggests that patients with cystic fibrosis had a significantly increased risk of gastrointestinal cancer compared with the general population, including small bowel, colon, biliary tract, and pancreatic cancers. These findings highlight the need to develop individualised screening strategies for site-specific gastrointestinal cancers in patients with cystic fibrosis. FUNDING: None.

Risk Factors for Vitamin D Deficiency and Impact of Repletion in a Tertiary Care Inflammatory Bowel Disease Population.

INTRODUCTION: Many patients with inflammatory bowel disease (IBD) are vitamin D deficient. The purpose of our study was to identify risk factors for vitamin D deficiency in IBD and to assess the impact of vitamin D repletion on disease activity and quality of life (QOL). METHODS: Patients with at least one 25-OH vitamin D level measured between 2004 and 2011 were included. Patients with a level <30 ng/ml at baseline were followed until the time of repletion. QOL and disease activity scores were measured at baseline and repletion. RESULTS: A total of 255 patients were identified. 33, 29, and 39% had a vitamin D level of ≥30, 20-29, and <20 ng/ml, respectively. When adjusting for disease type and duration, gender, smoking, and race, non-Caucasians had 5.3 (2.3-12.3) and UC patients had a 0.59 (0.33-1.03) odds of having a vitamin D <30 ng/ml. Women were 1.7 times more likely to have a 25-OH vitamin D level <20 ng/ml than men. 55 patients underwent repletion. In CD patients, the HBI and SIBDQ prior to repletion was 5.5 ± 4.9 and 44.3 ± 16.4, respectively; these improved to 3.6 ± 3.4 and 48.6 ± 14.2 after repletion (p = 0.0154 and p = 0.0684). CONCLUSIONS: In this tertiary care IBD cohort, the majority of patients have low vitamin D levels. Non-Caucasian race and female gender are associated with low vitamin D. UC was associated with lower risk of vitamin D insufficiency. In CD, vitamin D repletion is associated with decreased disease activity and increased QOL.

Proactive Therapeutic Drug Monitoring Is Associated With Increased Drug Persistence in Patients With Inflammatory Bowel Disease Treated With Intravenous Vedolizumab.

BACKGROUND: There are limited data regarding therapeutic drug monitoring (TDM) of non-anti-tumor necrosis factor therapy in inflammatory bowel disease (IBD). This study aimed to evaluate the efficacy of proactive TDM in IBD patients treated with intravenous (iv) vedolizumab (VDZ). METHODS: This single-center retrospective cohort study included consecutive IBD patients treated with maintenance iv VDZ therapy undergoing TDM from November 2016 to March 2023. Patients were followed through June 2023 and were divided in to 2 groups: those who had at least 1 proactive TDM vs those who underwent only reactive TDM. A survival analysis was performed to evaluate drug persistence, defined as no need for drug discontinuation due to loss of response, serious adverse event, or an IBD-related surgery. RESULTS: The study population consisted of 94 patients (proactive TDM, n = 72) with IBD (ulcerative colitis, n = 53). Patients undergoing at least 1 proactive TDM compared with patients having only reactive TDM demonstrated a higher cumulative probability of drug persistence (Log-rank P < .001). In multivariable Cox proportional hazard regression analysis, at least 1 proactive TDM was the only factor associated with drug persistence (hazard ratio, 14.3; 95% confidence interval [CI], 3.8-50; P < .001). A ROC analysis identified a VDZ concentration of 12.5 µg/mL as the optimal drug concentration threshold associated with drug persistence (area under the ROC curve: 0.691; 95% CI, 0.517-0.865; P = .049). CONCLUSION: In this single-center retrospective study reflecting real-life clinical practice, proactive TDM was associated with increased drug persistence in patients with IBD treated with iv VDZ.

There are limited data regarding therapeutic drug monitoring (TDM) of non-anti-tumor necrosis factor therapy in inflammatory bowel disease (IBD). We found that proactive TDM was associated with drug persistence in patients with IBD treated with vedolizumab. Moreover, a vedolizumab concentration of 12.5 µg/mL was identified as the optimal drug concentration threshold associated with drug persistence.

Histologic Inflammation can Predict Future Clinical Relapse in Ulcerative Colitis Patients in Endoscopic Remission.

Background: In ulcerative colitis (UC), endoscopic improvement, defined as a Mayo Endoscopic Score (MES) of 0 or 1, is a target of treatment. The aim of our study was to evaluate the risk of clinical relapse between patients with an MES of 0 or 1 and determine if histologic activity using the Robarts Histopathologic Index (RHI) was predictive of clinical relapse. Methods: UC patients with an MES score of 0 or 1, no prior colectomy, and at least 1 year of outpatient follow-up after colonoscopy were included. Demographic, clinical characteristics, and clinical relapse were retrospectively collected. Biopsy specimens were read by a gastrointestinal pathologist. Primary outcome was defined as a composite of relapse requiring change in medical therapy, new steroid use, UC-related hospitalization, and/or colectomy. Results: Four hundred and forty-five UC patients were identified. Ninety-five percent of patients with MES 0 were in histologic remission by the RHI whereas only 35% of patients with MES 1 were in histologic remission. Twenty-six percent of patients experienced a clinical relapse; patients with MES 1 or RHI > 3 were significantly more likely to relapse (P < .01) compared to patients with MES 0 or RHI ≤ 3. When patients were stratified into 4 groups (MES 0, RHI ≤ 3; MES 0, RHI > 3; MES 1, RHI ≤ 3; MES 1, RHI > 3) and adjusted for age and sex, RHI > 3 was predictive of relapse (P = .008). Conclusions: UC patients with endoscopic improvement have a high rate of clinical relapse over time. Histologic activity is a predictor of clinical relapse.

Real-World Effectiveness and Safety of Ustekinumab for Ulcerative Colitis From 2 Tertiary IBD Centers in the United States.

Background: Ustekinumab has been recently approved for the treatment of moderately to severely active ulcerative colitis (UC). The registry trials for ustekinumab in UC demonstrated efficacy and safety, but data on real-world outcomes are limited. We describe the effectiveness and safety of ustekinumab in patients with UC from 2 US tertiary inflammatory bowel disease centers. Methods: Patients with moderately to severely active UC treated with ustekinumab at NYU Langone Health (New York, New York) and University of Chicago Medical Center (Chicago, Illinois) between January 2016 and March 2020 were retrospectively included. The primary outcome was clinical remission at 3 and 12 months, defined as a partial Mayo score of ≤2, with a combined rectal bleeding and stool frequency subscore of ≤1. Results: Sixty-six UC patients were included. Ninety-two percent of patients had prior exposure to biologics or tofacitinib. Forty-three percent and 45% of patients achieved clinical remission by 3 and 12 months, respectively. Anti-TNF nonresponse and endoscopic Mayo score of 3 were negative predictors of clinical remission. Thirty-three percent of those followed for a year achieved concurrent endoscopic and histologic healing, which was significantly associated with lower partial Mayo score (P < 0.01) and lower stool frequency (P = 0.02). Serious adverse events occurred in 4 (6%) patients (3 UC exacerbations, 1 vasculitis). Conclusions: In this cohort of mostly biologic-refractory UC patients, treatment with ustekinumab achieved remission in nearly half of them at 12 months, and was associated with an overall favorable safety profile. These results are modestly better than the pivotal trials.

Updates on vaccinating the inflammatory bowel disease patient.

INTRODUCTION: Many of the therapeutic options for patients with inflammatory bowel disease (IBD) suppress the immune system, which increases the risk of certain infections in these patients. Effective vaccines exist and offer protection against a number of infectious diseases. However, data has shown that IBD patients are inadequately vaccinated and, as a result, are at risk of developing certain preventable infections. Furthermore, gastroenterologists' knowledge regarding the appropriate immunizations to administer to their IBD patients is suboptimal. Areas covered: Over the past several years, there has been a considerable amount of research contributing to our knowledge regarding vaccination of patients with IBD. Expert opinion: This updated review article focuses on the current immunization schedule for the IBD patient and stresses the important role of the gastroenterologist as an active participant in the health maintenance of their IBD patients.

Eosinophilic esophagitis, gastroenteritis, and colitis in a patient with prior parasite exposure.

Eosinophilic gastrointestinal disorders (EGID) comprise a spectrum of inflammatory diseases that can affect any segment of the gastrointestinal tract. The pathogenesis of these conditions is complex; differentiating between primary and secondary forms of these disorders can be clinically challenging. We report a case of primary EGID in a patient with remote parasite exposure, whose symptoms were initially attributed to irritable bowel syndrome. Endoscopy revealed the rare finding of EGID involving the entire gastrointestinal tract; symptoms improved with an elimination diet. This case raises the possibility of a link between prior parasite exposure and development of EGID, and underscores the necessity of exploring alternative diagnoses in patients with presumed IBS who present with severe symptoms.

Herpes Zoster Vaccine Response in Inflammatory Bowel Disease Patients on Low-dose Immunosuppression.

BACKGROUND: Inflammatory Bowel Disease (IBD) patients are at an increased risk of developing herpes zoster (HZ), especially when immunosuppressed. HZ may be preventable with the herpes zoster vaccine (HZV), but many patients are not offered vaccination over concern regarding efficacy and fear of adverse events. Although the Center for Disease Control and Prevention recommends that low-dose immunosuppression is not a contraindication, few IBD patients on these medications are receiving HZV. METHODS: This study was a prospective clinical trial to assess the safety and immunogenicity of HZV among 2 groups of IBD patients. Group A consisted of 14 patients on low-dose immunomodulators and group B consisted of 25 patients either on 5-aminosalicylic acid or no IBD therapy. Blood samples were obtained to measure immune responses. RESULTS: HZ specific immunoglobulin G rose significantly in both groups but the response was lower in the immunosuppressed group (P = 0.0002). Peripheral blood mononuclear cell secretion of Tumor necrosis factor-α in response to HZ antigen increased after HZV in group B, but not in group A. Interleukin-8 secretion increased in both groups, but the response was much higher in group B. There were no significant differences in adverse events between groups. No patients developed a HZ-like rash within 1 year after vaccination. CONCLUSIONS: IBD patients on low-dose immunosuppressive therapy have a blunted immune response to HZV as compared with nonimmunosuppressed subjects. Despite this, immunosuppressed IBD patients are able to mount a statistically significant immune response. There were no serious adverse events to HZV.

A Health Survey of Gastroenterologist Prescribing Practices of Adalimumab for Treatment of Crohn's Disease: Final Results.

Adalimumab (Humira, AbbVie) has efficacy in treatment-naive and infliximab (Remicade, Janssen)-exposed patients with Crohn's disease (CD). An e-survey was sent to US gastroenterologists who were members of the American Gastroenterological Association. A total of 398 gastroenterologists (3%) completed the survey. Seventy-two percent prescribed adalimumab more than a few times yearly, 58% followed more than 50 patients with CD, and 15% followed 200 or more patients with CD. Ninety percent of gastroenterologists felt that adalimumab had a moderately significant positive impact on patient care. Eighty-two percent correctly identified the US Food and Drug Administration-approved adalimumab induction and maintenance regimens. These gastroenterologists were more likely to follow 200 or more patients with CD (P=.045) and prescribe adalimumab more than a few times per year (P=.037). Years in practice, practice setting, gender, and region did not impact prescribing. Correct dosing was associated with higher prescribing frequency (P=.014) and volume of patients with CD (P=.025). The frequency of adalimumab prescribing and volume of patients with CD were predictive of the total number of correct survey answers (P=.014 and P=.017, respectively). Only 50% of gastroenterologists always administered loading doses when switching to adalimumab from another anti-tumor necrosis factor (TNF) agent; 43.5% reported unclear loading efficacy and 24.3% reported infection concerns from excess anti-TNF as reasons. Eighteen percent of gastroenterologists reported that pharmacies had reduced their prescribed adalimumab doses. To our knowledge, this is the only study evaluating prescribing patterns of adalimumab in patients with CD in the United States. Our findings demonstrate that many gastroenterologists are not using optimal adalimumab dosing strategies, which may lead to a decreased rate of response in patients with CD. Further research is needed to confirm our findings and identify barriers to optimal adalimumab use by gastroenterologists for treatment of CD.