Postoperative Ustekinumab Drug Levels and Disease Activity in Patients with Crohn's Disease.

AIMS: This study investigated how post-operative ustekinumab levels relate to surgery type, endoscopic, biochemical, and clinical outcomes in patients with Crohn's Disease. METHODS: A retrospective study of patients with Crohn's Disease with a disease-related operation between 2016 and 2022 assessed outcomes based on ustekinumab levels. Patients were included if they had an ustekinumab trough level within two years post-operatively. Patients were separated into groups based on whether their ustekinumab trough levels were adequate, defined as ≥ 4 µg/mL, or suboptimal < 4 µg/mL. A subset of patients with ustekinumab levels taken within two years both before and after surgery was compared to non-surgical treatment-escalated controls outside the initial patient set. Harvey-Bradshaw index was used to evaluate clinical disease activity. Rutgeert's and Simple Endoscopic Score for Crohn's Disease was used to evaluate endoscopic disease activity. C-reactive protein and fecal calprotectin values were collected to evaluate the molecular inflammatory disease state. CBC data were used to evaluate anemia. RESULTS: Forty-four patients were identified, which had ustekinumab levels after Crohn's Disease-related surgery. Twelve of these patients had pre-operative levels and were compared to 26 non-surgical treatment-escalated controls. No relationship between ustekinumab levels and endoscopic or clinical disease activity post-operatively was found. This also held true when looking at different surgery types. Adequate levels of ustekinumab post-operatively yielded lower risk of anemia. Surgery itself did not have an impact on ustekinumab levels. CONCLUSIONS: This study provided new insights into how post-operative ustekinumab levels impact several factors in patients having undergone Crohn's disease-related surgery.

Therapeutic drug monitoring in inflammatory bowel disease patients on vedolizumab.

OBJECTIVE: We aimed to investigate whether vedolizumab (VDZ) levels were associated with inflammatory markers or clinical or endoscopic scoring in inflammatory bowel disease (IBD). METHODS: Besides demographic data, clinical scoring, endoscopic data, and laboratory markers of IBD patients treated with VDZ from 2015 to 2020 who had trough levels drawn on maintenance therapy were collected at baseline and at follow-up (after at least 8 weeks on VDZ therapy or after change in dose frequency). Low drug levels were defined as VDZ trough <20 µg/mL. RESULTS: We identified 89 patients with a mean age of 42.9 years. Of the 90 total trough levels drawn, 61.1% were low. Among patients on every 8 week (Q8 week) VDZ dosing, 81.5% had low troughs. After increasing dosing frequency to Q4 weeks, all patients showed improvement in VDZ levels, but 30.6% remained <20 µg/mL. Higher VDZ levels on Q8 week dosing were associated with higher albumin levels (P = 0.01). While higher VDZ levels on Q4 week dosing were associated with higher albumin (P = 0.02), lower erythrocyte sedimentation rate (P = 0.04) and higher likelihood of having mild disease or endoscopic remission (P = 0.01). No significant association was found between VDZ levels and clinical scoring, body mass index, hemoglobin, vitamin D or platelet levels on either Q8 or Q4 week dosing. CONCLUSIONS: Higher VDZ troughs were associated with higher albumin, mild endoscopic disease or endoscopic remission. Patients who continue to have low VDZ troughs despite Q4 week dosing may require a change in therapy.

Therapeutic drug monitoring in patients with inflammatory bowel disease on ustekinumab.

OBJECTIVE: Therapeutic drug monitoring is used clinically to guide anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD), but its use for ustekinumab (UST) remains unclear. This study aimed to determine predictive variables of UST levels. METHODS: In this retrospective cohort of patients with IBD, UST trough levels were drawn at maintenance dosing. Relationships between UST trough levels and demographics, therapy, and outcomes were analyzed. Machine-learning models were used to infer combinatorial traits predictive of UST levels. RESULTS: Altogether 177 patients with IBD on UST had a mean UST trough level of 4.742 µg/mL. The injection schedule correlated significantly (P < 0.001) with UST levels. Naiveté to anti-TNFs correlated with higher UST levels (P = 0.048). Univariate analysis revealed that higher inflammatory biomarkers significantly correlated to lower UST levels and a lower Simple Endoscopic Score to Crohn's Disease to adequate UST levels (P = 0.018). Multivariate analysis identified body mass index (BMI), previous anti-TNF failure, and laboratory flare as predictors of UST levels with an area under the receiver operating characteristic curve (AUROC) of 0.72. The UST cut-off level of 5.77 µg/mL yielded a 0.79 AUROC, 80% sensitivity, and 81% specificity for predicting endoscopic remission of Crohn's disease. For the clinical remission end-point in ulcerative colitis, UST level of 4.73 µg/mL yielded a 0.69 AUROC, 53% sensitivity, and 86% specificity. CONCLUSIONS: Higher UST levels correlated with less disease activity. BMI was an important consideration for UST response as well. Therefore, UST dose adjustments to reach target levels may optimize response.

Development of Shingles on Tofacitinib Despite Completion of Recombinant Varicella-Zoster Virus Vaccine Series.

Shingles, also known as herpes zoster, is caused by the reactivation of the varicella-zoster virus (VZV). The risk of developing shingles increases with age, as well as in patients with weakened immune systems. Tofacitinib is a reversible Janus kinase inhibitor that suppresses the immune system and is used to treat autoimmune diseases, such as ulcerative colitis. Recombinant VZV vaccine is recommended for individuals taking tofacitinib and is highly effective at reducing the risk of shingles. This case report describes a patient with severe, refractory ulcerative colitis who developed shingles while on tofacitinib, despite prior vaccination with the recombinant VZV vaccine.

Patient Attitudes and Barriers to Endoscopy During the COVID-19 Pandemic.

BACKGROUND: After COVID-19 restrictions on nonessential procedures were lifted and safety protocols established, utilization rates of endoscopic procedures remained reduced. AIMS: This study assessed patient attitudes and barriers to scheduling endoscopy during the pandemic. METHODS: A survey was administered to patients with ordered procedures at a hospital-based setting (7/21/2020-2/19/2021) collecting demographic data, body mass index, COVID-19 relevant comorbidities, level of procedural urgency (defined by recommended scheduling window), scheduling and attendance, concerns, and awareness of safety measures. RESULTS: The average respondent was female (63.8%), age 57.6 ± 14, White (72.3%), married (76.7%), insured (99.3%), affluent English speakers (92.3%) and highly educated (at least college 90.2%). Most reported moderate to excellent COVID-19 knowledge (96.6%). Of 1039 procedures scheduled, emergent cases accounted for 5.1%, urgent 55.3% and elective 39.4%. Respondents identified appointment convenience (48.53%) as the most frequent factor impacting scheduling, also noting concern for results (28.4%). Age (p = .022), native language (p = .04), education (p = .007), self-reported COVID knowledge (p = .002), and a desire to be COVID tested pre-procedure (p = .023) were associated with arrival, more commonly in an ambulatory surgical center than hospital (p = .008). Diabetes mellitus (p = .004) and an immunocompromised state (p = .009) were adversely related to attendance. Attitudes towards safety protocols did not affect scheduling. Multivariate analysis demonstrated age, education and COVID knowledgeability were associated with procedure completion. CONCLUSIONS: Safety protocols and urgency levels were not associated with procedure completion. Pre-pandemic barriers to endoscopy persisted as dominant factors amid pandemic concerns.

Clinical Evaluation of Upadacitinib in the Treatment of Adults with Moderately to Severely Active Ulcerative Colitis (UC): Patient Selection and Reported Outcomes.

This review addresses appropriate patient selection for upadacitinib, a Janus kinase inhibitor approved by the FDA and EMA for treatment of moderately to severely active ulcerative colitis (UC). Janus kinase molecules can contribute to the inflammatory pathway, so inhibiting certain of them may prove efficacious in treating UC and may reduce safety concerns. Upadacitinib is the newest Janus kinase inhibitor to be approved for UC, so it is timely and relevant to review patient selection and when to consider this medication. We will discuss efficacy and safety data from the pivotal clinical trials on upadacitinib. These data can be shared with patients and can inform the use of these agents in clinical practice.

Biological Therapies for the Management of Enteric Disease: Considerations for the Clinician.

Several biologic therapies have been approved for enteric diseases. We evaluate each biologic's role based on their mechanism of action in treating these conditions. This review examines data on efficacy and safety, as well as considerations for using these therapies in clinical practice in inflammatory bowel diseases, enteric infections-specifically Clostridioides difficile colitis-and potentially in the increasingly prevalent disorder of eosinophilic esophagitis. When choosing an appropriate therapy, it is important to assess patient severity, as most biologics are approved for those with moderate to severe disease activity. With many years of data from clinical trials and real-world experience, these therapies have been shown to improve outcomes overall in enteric diseases, contributing to more options for our patients.

Systematic Review With Meta-analysis: Safety and Effectiveness of Combining Biologics and Small Molecules in Inflammatory Bowel Disease.

Background: Combining biologics and small molecules could potentially overcome the plateau of drug efficacy in inflammatory bowel disease (IBD). We conducted a systematic review and meta-analysis to assess the safety and effectiveness of dual biologic therapy (DBT), or small molecule combined with a biologic therapy (SBT) in IBD patients. Methods: We searched MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews, and Clinical trials.gov until November 3, 2020, including studies with 2 or more IBD patients on DBT or SBT. Main outcome was safety assessed as pooled rates of adverse events (AEs) and serious AEs (SAEs) for each combination. Effectiveness was reported as pooled rates of clinical, endoscopic, and/or radiographic response and remission. The certainty of evidence was rated according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. Results: Of the 3688 publications identified, 13 studies (1 clinical trial, 12 observational studies) involving 266 patients on 7 different combinations were included. Median number of prior biologics ranged from 0 to 4, and median duration of follow-up was 16-68 weeks. Most common DBT and SBT were vedolizumab (VDZ) with anti-tumor necrosis factor (aTNF, n = 56) or tofacitinib (Tofa, n = 57), respectively. Pooled rates of SAE for these were 9.6% (95% confidence interval [CI], 1.5-21.4) for VDZ-aTNF and 1.0% (95% CI, 0.0-7.6) for Tofa-VDZ. The overall certainty of evidence was very low due to the observational nature of the studies, and very serious imprecision and inconsistency. Conclusions: DBT or SBT appears to be generally safe and may be effective in IBD patients, but the evidence is very uncertain.

Inflammatory bowel disease and atherosclerotic cardiovascular disease in U.S. adults-A population-level analysis in the national health interview survey.

OBJECTIVES: To evaluate the association between inflammatory bowel disease (IBD) and atherosclerotic cardiovascular disease (ASCVD) and whether this association is modified by age or sex. METHODS: We conducted a cross-sectional analysis using data from the 2015-2016 National Health Interview Survey (NHIS). The exposure of interest was self-reported IBD. The outcome of interest was prevalent ASCVD, which included a history of angina, myocardial infarction or stroke. We used survey-specific descriptive statistics to obtain weighted national estimates for IBD and ASCVD prevalence. Logistic regression models were used to assess the association between IBD and ASCVD, progressively adjusting for demographics and traditional risk factors. Effect modification by age and sex was evaluated. RESULTS: Among participants with IBD, the age-adjusted prevalence of ASCVD was 12.0% compared to 6.9% among those without IBD (p < 0.001). In multivariable regression analyses IBD was associated with increased odds of having ASCVD, even after adjustment for demographics and traditional risk factors (odds ratio 1.58, 95% CI 1.17-2.13). We found statistically significant interaction by age (p < 0.001) whereby those in the younger age strata had the strongest association (fully adjusted odds ratio among 18- to 44-year-olds 3.35, 95% CI 1.75, 6.40) while the association was null in those ≥65 years. Effect modification by sex was not observed. CONCLUSION: Our analysis confirms an independent association between IBD and ASCVD in the U.S., particularly among young adults. Further studies are needed to fully establish a causal relationship between IBD and ASCVD, characterize the mechanisms underlying these associations, and identify tailored opportunities for ASCVD prevention in young and middle-aged adults with IBD.

Prevalence of cardiovascular risk factors in a nationally representative adult population with inflammatory bowel disease without atherosclerotic cardiovascular disease.

BACKGROUND AND AIMS: Chronic inflammation is associated with premature atherosclerotic cardiovascular disease (ASCVD). We studied the prevalence of cardiovascular risk factors (CRFs) amongst individuals with IBD who have not developed ASCVD. METHODS: Our study population was derived from the 2015 - 2016 National Health Interview Survey. Those with ASCVD (defined as myocardial infarction, angina or stroke) were excluded. The prevalence of CRFs among individuals with IBD was compared with those without IBD. The odds CRFs among adults with IBD was assessed using logistic regression models. RESULTS: In our study population of 60,155 individuals, 786 (1.3%) had IBD. IBD was associated with increased odds hypertension (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.39-2.09), diabetes (OR 1.68, 95% CI 1.22-2.32), hypercholesterolemia (OR 1.62, 95% CI 1.32-2.99) and insufficient physical activity (OR 1.38, 95% CI 1.16-1.66). CONCLUSION: IBD is associated with higher prevalence of CRFs. Early screening and risk mitigation strategies are warranted.

Risk Factors for and Frequency of CT Scans, Steroid Use, and Repeat Visits in Inflammatory Bowel Disease Patients Seen at a Single-Center Emergency Department: A Retrospective Cohort Study.

Patients with inflammatory bowel disease often present to the emergency department due to the chronic relapsing nature of the disease. Previous studies have shown younger patients to have an increased frequency of emergency department visits, resulting in repeated exposure to imaging studies and steroids, both of which are associated with risks. We performed a retrospective cohort analysis of inflammatory bowel disease patients seen at Houston Methodist Hospital's emergency department from January 2014 to December 2017 using ICD codes to identify patients with Crohn's disease, ulcerative colitis, or indeterminate colitis from the electronic medical record. Data were collected on demographics, medications, and imaging. Five hundred and fifty-nine patients were randomly selected for inclusion. Older age was associated with decreased risk of CT scan or steroid use. Patients with ulcerative colitis compared to Crohn's had decreased risk of CT scan, while there was an increased risk of CT in patients on a biologic, immunomodulator, or when steroids were given. Steroid use was also more common in those with inflammatory bowel disease as the primary reason for the visit. Patients in our study frequently received steroids and had CT scans performed. The increased risk of CT in those on a biologic, immunomodulator, or steroids suggests more severe disease may contribute. Guidelines are needed to reduce any unnecessary corticosteroid use and limit repeat CT scans in young inflammatory bowel disease patients to decrease the risk of radiation-associated malignancy over their lifetime.

Positioning biologics and small molecules in the management of moderate to severe ulcerative colitis.

PURPOSE OF REVIEW: This review addresses the selection of biologic and small molecule therapy for patients with moderate to severe ulcerative colitis (UC). With several new treatment options approved within the past few years, an update in positioning is timely and relevant. RECENT FINDINGS: Updates on the safety and comparative efficacy of approved therapeutic agents for UC are presented. Newly approved therapies including tofacitinib and ustekinumab, as well as where to position these treatments are discussed. Data on the first-ever head-to-head trial of biologic therapy in UC are examined. This review provides an evidence-based overview of the optimal management strategies of patients in both the inpatient and outpatient settings. SUMMARY: As we move closer towards the goal of personalized therapy for our patients with UC, we hope to better select appropriate and effective treatment options. Newly approved therapies provide us with additional options for management. Future advancements in predictive serologic, mucosal, genetic, and fecal markers can enable us to tailor therapy to an individual patient.

Inflammatory Bowel Disease and Atherosclerotic Cardiovascular Disease: JACC Review Topic of the Week.

Chronic inflammatory diseases including human immunodeficiency virus infection, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus predispose to atherosclerotic cardiovascular disease (ASCVD). Inflammatory bowel disease (IBD) is a common chronic inflammatory condition, and the United States has the highest prevalence worldwide. IBD has so far been overlooked as a contributor to the burden of ASCVD among young and middle-age adults, but meta-analyses of cohort studies suggest that IBD is an independent risk factor for ASCVD. This review discusses the epidemiological links between IBD and ASCVD and potential mechanisms underlying these associations. ASCVD risk management of patients with IBD is challenging because of their young age and the inability of current risk scores to fully capture their increased risk. The role of IBD in current primary prevention guidelines is evaluated, and strategies for enhanced ASCVD risk reduction in patients with IBD are outlined. Finally, the authors discuss knowledge gaps and future research directions in this innovative field.

The use of combination biological or small molecule therapy in inflammatory bowel disease: A retrospective cohort study.

OBJECTIVE: There are limited data on using more than one biologic or small molecule drug combined to treat patients with inflammatory bowel disease. The aim of our study was to determine the effectiveness and safety of combination biologic use in inflammatory bowel disease. METHODS: We identified patients with Crohn's disease or ulcerative colitis who received treatment with a combination of two biologics or a biologic and a small molecule drug from 2015 to 2019 for persistent disease activity or concomitant rheumatological or dermatological disease. The primary end-point was effectiveness, based on improvements in inflammatory markers, clinical, and endoscopic remission. The secondary end-point was safety. RESULTS: Of the 50 patients treated with combination therapy there were significantly more patients in clinical and endoscopic remission at follow-up compared to baseline (50% vs 14%, P = 0.0018, delta 36%, 95% confidence interval [CI] 0.13-0.53; and 34% vs 6%, P = 0.0039, delta 28%, 95% CI 0.09-0.47), respectively. Median erythrocyte sedimentation rate (17 mm/h vs 13 mm/h, P = 0.002) and C-reactive protein (5.00 mg/dL vs 2.35 mg/dL, P = 0.002) also decreased posttreatment. There were eight serious adverse events and no deaths CONCLUSIONS: Combination biologic therapy appears to be an effective option for patients with refractory inflammatory bowel disease or concomitant autoimmune disease that is inadequately controlled by biologic monotherapy. There was an increased risk of serious infection compared with biologic monotherapy; however, this risk might be minimized by discontinuing immunomodulators prior to initiating combination therapy. Large prospective studies are needed to confirm these findings.

Herpes Simplex Virus-2 Hepatitis: A Case Report and Review of the Literature.

Herpes simplex virus (HSV) is a rare cause of hepatitis in pregnancy and the chronically immunosuppressed, with a high propensity to progress to acute liver failure (ALF) and death. Patients typically present with a nonspecific clinical picture that often delays diagnosis and treatment, contributing to the high mortality rate. We present a case of a young female on chronic prednisone and hydroxychloroquine for systemic lupus erythematosus (SLE) who was diagnosed with HSV-2 hepatitis after presenting with right-sided chest and abdominal discomfort. Despite early clinical deterioration, prompt initiation of therapy with intravenous acyclovir and methylprednisolone led to rapid improvement.

The microbiome and inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic immune-mediated disease affecting the gastrointestinal tract. IBD consists of 2 subtypes: ulcerative colitis and Crohn disease. IBD is thought to develop as a result of interactions between environmental, microbial, and immune-mediated factors in a genetically susceptible host. Of late, the potential role of the microbiome in the development, progression, and treatment of IBD has been a subject of considerable interest and enquiry. Indeed, studies in human subjects have shown that the gut microbiome is different in patients with IBD compared with that in healthy control subjects. Other evidence in support of a fundamental role for the microbiome in patients with IBD includes identification of mutations in genes involved in microbiome-immune interactions among patients with IBD and epidemiologic observations implicating such microbiota-modulating risk factors as antibiotic use, cigarette smoking, levels of sanitation, and diet in the pathogenesis of IBD. Consequently, there has been much interest in the possible benefits of microbiome-modulating interventions, such as probiotics, prebiotics, antibiotics, fecal microbiota transplantation, and gene manipulation in the treatment of IBD. In this review we will discuss the role of the gut microbiome in patients with IBD; our focus will be on human studies.

Autoimmune liver disease and the enteric microbiome.

The human enteric microbiome is highly complex and has more than 150 times more genes within it than its host. The host and the microbiome have a commensurate relationship that can evolve over time. The typically symbiotic relationship between the two can become pathogenic. The microbiome composition in adults reflects their history of exposure to bacteria and environmental factors during early life, their genetic background, age, interactions with the immune system, geographical location, and, most especially, their diet. Similarly, these factors are thought to contribute to the development of autoimmune disease. It is possible that alterations in the intestinal microbiome could lead to liver disease. There is emerging data for the contribution of the microbiome in development of primary sclerosing cholangitis, primary biliary cholangitis, and autoimmune hepatitis; liver disorders associated with aberrant immune function in genetically susceptible individuals.

Epidemiology and Risk Factors of Nonalcoholic Fatty Liver Disease Among Patients with Inflammatory Bowel Disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has been increasingly identified in patients with inflammatory bowel disease (IBD). We aimed to determine risk factors of NAFLD in patients with IBD. METHODS: We examined 3 groups of patients: IBD + NAFLD, IBD only, and NAFLD only. Data on demographics, body mass index, duration of IBD, type of medication use, laboratory data, and metabolic risk factors were collected. RESULTS: A total of 168 patients between the ages 19 and 82 were evaluated, 56 patients in each group. Patients with IBD + NAFLD were significantly older than IBD only patients 45.0 (±14.1) versus 35.0 (±13), P = 0.007, and their mean body mass index was higher 30.4 (±10.2) versus 25.6 (±6.4); P = 0.002. IBD + NAFLD patients in comparison with IBD only patients had significantly longer duration of IBD (20 [±12.2] versus 10 [±7.7], P = 0.004), had an increased risk of diabetes (16% versus 2%, P = 0.01), and obesity (40% versus 20%, P = 0.02). There were no differences in the mean age or the mean body mass index (32.6 versus 30.4, P = 0.07) between patients with IBD + NAFLD and NAFLD only. More patients were obese in the NAFLD only group compared with the IBD + NAFLD group (59% versus 40%, P = 0.03), had hypertension (55% versus 33%, P = 0.02), hyperlipidemia (53% versus 17.5%, P = 0.0001), and diabetes (40% versus 16%, P = 0.0001). CONCLUSIONS: IBD patients with NAFLD had longer disease duration of IBD and developed NAFLD with fewer metabolic risk factors than patients with NAFLD only. These findings suggest that there may be other factors that contribute to the development of NAFLD in the IBD population.