Longitudinal assessment of sweat-based TNF-alpha in inflammatory bowel disease using a wearable device.

Wearable devices can non-invasively monitor patients with chronic diseases. Sweat is an easily accessible biofluid for continuous sampling of analytes, including inflammatory markers and cytokines. We evaluated a sweat sensing wearable device in subjects with and without inflammatory bowel disease (IBD), a chronic inflammatory condition of the gastrointestinal tract. Participants with an IBD related hospital admission and a C-reactive protein level above 5 mg/L wore a sweat sensing wearable device for up to 5 days. Tumor necrosis factor-alpha (TNF-α) levels were continually assessed in the sweat via the sensor, and daily in the blood. A second cohort of healthy subjects without chronic diseases wore the device for up to 48 h. Twenty-eight subjects were enrolled. In the 16 subjects with IBD, a moderate linear relationship between serum and sweat TNF-α levels was observed (R2 = 0.72). Subjects with IBD were found to have a mean sweat TNF-α level of 2.11 pg/mL, compared to a mean value of 0.19 pg/mL in 12 healthy controls (p < 0.0001). Sweat TNF-α measurements differentiated subjects with active IBD from healthy subjects with an AUC of 0.962 (95% CI 0.894-1.000). A sweat sensing wearable device can longitudinally measure key sweat-based markers of IBD. TNF-α levels in the sweat of subjects with IBD correlate with serum values, suggesting feasibility in non-invasive disease monitoring.

Reliability and Responsiveness of Histologic Indices for the Assessment of Crohn's Disease Activity.

BACKGROUND & AIMS: The operating properties of histologic indices for evaluating Crohn's disease (CD) activity are poorly characterized. We assessed the reliability and responsiveness of existing histologic indices/items used in CD and ulcerative colitis (UC), in addition to 3 novel items, and developed exploratory ileal, colonic, and colonic-ileal CD instruments. METHODS: Blinded central readers independently reviewed paired baseline and week 12 image sets from the EXTEND trial. Disease activity was scored using 4 indices (the Global Histologic Activity Score, Geboes Score, Nancy Histological Index, and Robarts Histopathology Index) and 3 items identified by an expert panel (mucin depletion, basal plasmacytosis, and ileal pyloric gland metaplasia). Reliability and responsiveness were quantified using the intraclass correlation coefficient (ICC) and area under the receiver operating curve (AUC), respectively. Exploratory indices were developed using backward stepwise linear regression analysis. Candidate independent variables were items with an inter-rater ICC ≥0.40 and AUC ≥0.56. The dependent variable was histologic disease activity measured by a 100-mm visual analogue scale. RESULTS: Paired image sets were available from 55 patients. Substantial to almost perfect inter-rater reliability (ICC, 0.63-0.87) and some responsiveness (AUC, 0.57-0.94) were observed for all existing indices regardless of whether individual colonic and ileal segments, combined colonic segments, or combined colonic and ileal segments were assessed and the calculation method used. Five items were tested as candidate items, and exploratory colonic, ileal, and colonic-ileal indices were developed. CONCLUSIONS: CD and UC indices were similarly reliable and responsive in measuring histologic CD activity. Exploratory index development did not offer benefit over current histologic instruments.

Review article: Putting some muscle into sarcopenia-the pathogenesis, assessment and clinical impact of muscle loss in patients with inflammatory bowel disease.

BACKGROUND: Sarcopenia, a loss of skeletal muscle mass or function, affects up to 50% of patients with inflammatory bowel disease (IBD) and is associated with poor clinical outcomes including increased hospitalizations, need for surgery and post-operative complications. Despite the high prevalence and clinical significance of sarcopenia in patients with IBD, few patients undergo routine muscle evaluation. AIM: The goal of this study was to review the mechanisms of sarcopenia in patients with IBD and understand novel modalities to assess and treat impaired muscle mass or function. METHODS: Pubmed and Cochrane databases were searched including articles published up to February 2023 utilizing the following keywords: "inflammatory bowel disease", "IBD", "Crohn's disease", "ulcerative colitis", "sarcopenia", "myosteatosis", "muscle health", and "frailty". RESULTS: The pathogenesis of sarcopenia in IBD is not well defined, however, there is evidence supporting the role of malabsorption, reduced protein intake, chronic inflammation, dysbiosis, decreased physical activity, medication effects and hormone signaling from visceral adiposity. Traditional sarcopenia assessment techniques include direct measurements on cross sectional imaging. However, given the time, cost and radiation exposure associated with cross sectional imaging, new bedside tools are now available to estimate muscle mass, including assessment of grip strength, mid upper arm circumference and body composition utilizing bioelectrical impedance analysis. In addition, novel biomarkers for assessing muscle mass and techniques utilizing point of care ultrasound have been proposed to make sarcopenia evaluation more streamlined in the IBD clinic. CONCLUSION: Sarcopenia is associated with poor clinical outcomes independent of IBD activity and therefore muscle health should be assessed in all IBD patients at routine intervals. Future studies to better our understanding of the pathophysiology as well as most effective management of sarcopenia in IBD will help guide clinical care and reduce disease related complications.

Impact of Care in an Interdisciplinary Inflammatory Bowel Disease Specialty Clinic on Outcomes in Patients Insured with Medicaid.

BACKGROUND: Inflammatory bowel disease (IBD) patients are known to benefit from care delivered in a specialized, interdisciplinary setting. We aimed to evaluate the impact of this model on health outcomes, quality metrics, and health care resource utilization (HRU) in IBD patients insured with Medicaid. MATERIALS AND METHODS: In July 2017, IBD patients at our tertiary hospital were transitioned from a fellows' general gastroenterology (GI) clinic to a fellows' interdisciplinary IBD clinic. IBD patients were included if they were insured with Medicaid, had at least 1 visit in the general GI clinic between July 1, 2016 and June 30, 2017, and at least 1 visit between July 1, 2017 and June 30, 2018 in the IBD clinic. Characteristics related to patients' IBD course, overall health care maintenance, and HRU were compared. RESULTS: A total of 170 patients (51% male, mean age 39 y) were included. After the transition to the IBD clinic, use of corticosteroids (37% vs. 25%; P =0.004) and combination therapy were significantly lower (55% vs. 38%; P =0.0004), although use of high-dose biologics numerically increased (58.5% vs. 67%; P =0.05). Posttransition, patients showed significantly lower levels of mean C-reactive protein ( P =0.04). After the transition, patients attended significantly fewer outpatient GI visits ( P =0.0008) but were more often seen by other health care specialists ( P =0.0003), and experienced a numeric decrease in HRU with fewer emergency department visits, hospitalizations, and surgeries. CONCLUSIONS: Care in an interdisciplinary, IBD specialty setting is associated with significantly decreased corticosteroid use, decreased C-reactive protein levels, and improved access to ancillary services in Medicaid patients.

Objective disease activity assessment and therapeutic drug monitoring prior to biologic therapy changes in routine inflammatory bowel disease clinical practice: TARGET-IBD.

BACKGROUND: Inflammatory bowel disease (IBD) treatment paradigms recommend objective disease activity assessment and reactive therapeutic drug monitoring (TDM) prior to changes in biologic therapy. We aimed to describe objective marker and TDM assessment in routine clinical practice prior to biologic therapeutic changes in adult IBD patients. METHODS: TARGET-IBD is a prospective longitudinal cohort of over 2100 IBD patients receiving usual care at 34 US academic or community centers enrolled between June 2017 and October 2019 who received biologic therapy and had a dose change or biologic discontinuation for lack of efficacy. Objective markers of disease activity within 12 weeks prior included fecal calprotectin, C-reactive protein (CRP), endoscopy, computed tomography (CT) and magnetic resonance imaging (MRI). TDM data for infliximab or adalimumab was obtained. RESULTS: 525 patients (71.4% Crohn's disease [CD], 28.6% ulcerative colitis [UC]) receiving biologic therapy underwent dose change (55.6%) or discontinuation (44.4%) for lack of efficacy. The majority were Caucasian (85.7%), 18-39 years old (52.2%), privately insured (81.5%), and at academic centers (73.7%). For dose changes, 67.5% had at least one objective disease activity assessment or TDM in the 12 weeks prior (CD 67.9%, UC 66.2%; P = 0.79). The most common objective marker was CRP in both CD (39.1%) and UC (54.5%). CRP and calprotectin were used significantly more in UC (P = 0.02 and P = 0.03). TDM was obtained in 30.7% (28.8% UC, 31.4% CD; P = 0.72) prior to dose change. For biologic discontinuation, 79.4% patients underwent objective assessment or TDM prior. In CD, CRP (46.3%) was most common, and CT (P = 0.03) and MRI (P < 0.001) were significantly more frequent than in UC. TDM was performed in 40.1% of patients (43.5% UC, 38.0% CD, P = 0.49) prior to discontinuation. Among all participants with dose change or discontinuation, endoscopy was performed in 29.3% with CD and 31.3% with UC. Academic care setting was associated with objective assessment before therapy change (OR 1.59, 95% CI 1.01-2.50). CONCLUSION: Nearly one-third of patients undergoing a biologic dose change or discontinuation do not undergo objective disease activity assessment or TDM. Assessment choice differs by disease. Future studies assessing the impact of such practices on long-term outcomes are needed.

Long-term Safety and Efficacy of Etrasimod for Ulcerative Colitis: Results from the Open-label Extension of the OASIS Study.

BACKGROUND AND AIMS: Etrasimod is an oral, selective, sphingosine 1-phosphate receptor modulator. In a phase 2, randomised, double-blind, placebo-controlled trial in adults with moderately-to-severely active ulcerative colitis [OASIS], etrasimod 2 mg provided significant benefit versus placebo and was generally well tolerated. This open-label extension [OLE] evaluated safety and efficacy of etrasimod for up to 52 weeks. METHODS: In OASIS, 156 patients received etrasimod 1 mg, etrasimod 2 mg, or placebo, once daily for 12 weeks. After completing OASIS, patients could enrol in the OLE and receive etrasimod 2 mg for an additional 34-40 weeks. RESULTS: In all, 118 patients enrolled in the OLE; 112 patients received etrasimod 2 mg at any point and were evaluated for safety and efficacy. A total of 92 [82%] patients who received etrasimod 2 mg in the OLE completed the study. Treatment-emergent adverse events occurred in 60% [67/112] of patients receiving etrasimod 2 mg at any time, most commonly worsening ulcerative colitis and anaemia; 94% of adverse events were mild/moderate. At end of treatment, 64% of patients met the criteria for clinical response, 33% for clinical remission, and 43% for endoscopic improvement. Week 12 clinical response, clinical remission, or endoscopic improvement was maintained to end of treatment in 85%, 60%, or 69% of patients, respectively. Steroid-free clinical remission occurred in 22% of overall patients. CONCLUSIONS: In this long-term extension study, etrasimod 2 mg demonstrated a favourable safety profile. Most patients with clinical response, clinical remission, or endoscopic improvement at Week 12 maintained that status to end of treatment.

The Impact of Clinical Information on the Assessment of Endoscopic Activity: Characteristics of the Ulcerative Colitis Endoscopic Index Of Severity [UCEIS].

BACKGROUND AND AIMS: To determine whether clinical information influences endoscopic scoring by central readers using the Ulcerative Colitis Endoscopic Index of Severity [UCEIS; comprising 'vascular pattern', 'bleeding', 'erosions and ulcers']. METHODS: Forty central readers performed 28 evaluations, including 2 repeats, from a library of 44 video sigmoidoscopies stratified by Mayo Clinic Score. Following training, readers were randomised to scoring with ['unblinded', n = 20, including 4 control videos with misleading information] or without ['blinded', n 20] clinical information. A total of 21 virtual Central Reader Groups [CRGs], of three blinded readers, were created. Agreement criteria were pre-specified. Kappa [κ] statistics quantified intra- and inter-reader variability. RESULTS: Mean UCEIS scores did not differ between blinded and unblinded readers for any of the 40 main videos. UCEIS standard deviations [SD] were similar [median blinded 0.94, unblinded 0.93; p = 0.97]. Correlation between UCEIS and visual analogue scale [VAS] assessment of overall severity was high [r blinded = 0.90, unblinded = 0.93; p = 0.02]. Scores for control videos were similar [UCEIS: p ≥ 0.55; VAS: p ≥ 0.07]. Intra- [κ 0.47-0.74] and inter-reader [κ 0.40-0.53] variability for items and full UCEIS was 'moderate'-to-'substantial', with no significant differences except for intra-reader variability for erosions and ulcers [κ blinded: 0.47 vs unblinded: 0.74; p 0.047]. The SD of CRGs was lower than for individual central readers [0.54 vs 0.95; p < 0.001]. Correlation between blinded UCEIS and patient-reported symptoms was high [stool frequency: 0.76; rectal bleeding: 0.82; both: 0.81]. CONCLUSIONS: The UCEIS is minimally affected by knowledge of clinical details, strongly correlates with patient-reported symptoms, and is a suitable instrument for trials. CRGs performed better than individuals.

Can endoscopy be avoided in the assessment of ulcerative colitis in clinical trials?

BACKGROUND: There is no gold standard index in the measurement of ulcerative colitis (UC) disease activity in clinical trials. Mucosal healing has been described as an important clinical endpoint requiring endoscopic assessment, which is unpleasant for the patient and may hamper recruitment to trials. The aim of this study was to determine whether endoscopy is necessary in the assessment of UC disease activity and whether a noninvasive disease activity index (partial Mayo score) could be used to predict the Mayo score. METHODS: In all, 149 subjects with moderate to severe UC enrolled in a clinical trial were assessed using total and partial Mayo scores. Histologic assessment of biopsies was performed. A regression model was constructed to predict total Mayo score from the partial Mayo score and histology score from the Mayo score. A Bland-Altman test of agreement was performed. RESULTS: The partial Mayo score correlated closely with the total Mayo score at week 4 (rho = 0.97) and week 8 (rho = 0.98). The model to predict total from partial Mayo score showed excellent correlation (rho = 0.97) and good agreement with the total Mayo score at week 4 and the week 8 validation set (rho = 0.97) and accurately classified disease severity (kappa = 0.82). The model to predict histology score from the Mayo score correlated only moderately with the actual histology score at week 4 (rho = 0.59) and week 8 (rho = 0.36). CONCLUSIONS: The Mayo score can be accurately predicted from the partial Mayo score. A noninvasive index can replace the Mayo score in future clinical trials.

Adverse events do not outweigh benefits of combination therapy for Crohn's disease in a decision analytic model.

BACKGROUND & AIMS: The Study of Biologic and Immunomodulator-Naïve Patients With Crohn's Disease (SONIC) showed that combination therapy with infliximab and azathioprine (IFX/AZA) is more effective than treatment with IFX alone. Numbers and types of adverse events were roughly equivalent among groups, although enrollment was limited, so it was not clear how rare adverse events might affect overall outcomes in practice. We sought to define the frequency at which a rare adverse event would have to occur for the risks of combination therapy to outweigh the benefits of treatment. METHODS: We constructed a decision model to compare the risks and benefits of IFX/AZA with IFX monotherapy. Model parameters were taken from SONIC and other published literature. The base-case analysis was patients with active Crohn's disease who are naïve to both medications (similar to those in SONIC) who were treated for 1 year. We used sensitivity analyses to determine the thresholds at which the risks of side effects from IFX/AZA outweigh its benefits. RESULTS: During 1 year, the benefits of IFX/AZA would outweigh the risks, unless serious infections occurred in 20% or more of the population or lymphoma in 3.9% or more. These thresholds are 5-fold and 65-fold higher than base-case estimates, respectively. CONCLUSIONS: On the basis of data from 1 year of SONIC, the combination of IFX/AZA was more effective than IFX alone in patients with Crohn's disease who are naïve to either drug. For the risks of combination therapy to outweigh the benefits in this time frame, the incidence of serious adverse events would have to be higher than seems clinically realistic.

Validation of interactive voice response system administration of the Short Inflammatory Bowel Disease Questionnaire.

BACKGROUND: The Short Inflammatory Bowel Disease Questionnaire (SIBDQ) is a written, self-administered instrument measuring quality of life in IBD. We assessed the validity of an interactive voice response system (IVRS) as a new mode of administering the SIBDQ. METHODS: An IVRS was designed using prerecorded questions to collect data via touchtone telephone. Subjects with Crohn's disease (CD) or ulcerative colitis (UC) were randomized into 2 groups with different orders of administration: written, self-administered followed by IVRS (S-I) or IVRS followed by written, self-administered (I-S). Half of the S-I group was also randomized to receive a second IVRS. Sixty-four subjects were studied: 30 in S-I, 34 in I-S. RESULTS: The mean SIBDQ scores were not different between written and IVRS modes (P = 0.26) with r = 0.93. IVRS scores were lower in active than inactive CD (36.1 +/- 9.6 versus 54.7 +/- 8.6, P < 0.001) and lower in active than inactive UC (40.8 +/- 9.6 versus 59.8 +/- 10.0, P < 0.001). Mean scores correlated highly with disease activity indices, and were not different between first and second IVRS administrations (P = 0.85) with r = 0.92. IVRS had excellent internal consistency (Cronbach alpha = 0.90). CONCLUSIONS: IVRS administration of the SIBDQ yields results similar to written self-administration, with excellent procedural validity, test-retest reliability, and internal consistency.

Impact of hospital volume on postoperative morbidity and mortality following a colectomy for ulcerative colitis.

BACKGROUND & AIMS: Postoperative morbidity and mortality following a colectomy for ulcerative colitis (UC) has been primarily reported from tertiary care referral centers that perform a high volume of operations; however, the postoperative outcomes among nonselected hospitals are not known. We set out to evaluate postoperative morbidity and mortality using a nationally representative database and to determine the factors that influenced outcomes. METHODS: We analyzed the 1995-2005 Nationwide Inpatient Sample to identify 7108 discharges for UC patients who underwent a total abdominal colectomy. The effects of hospital volume on postoperative morbidity and mortality were evaluated in logistic regression models adjusting for demographic and clinical factors. RESULTS: Postoperative mortality and morbidity rates were 2.3% and 30.8%, respectively. Most operations were performed in low-volume hospitals that had an increased risk of death (adjusted odds ratio [aOR], 2.42; 95% confidence interval [CI]: 1.26-4.63). In-hospital mortality was increased in patients who were admitted emergently (aOR, 5.40; 95% CI: 3.48-8.40), aged 60-80 years (aOR, 8.70; 95% CI: 3.30-22.92), and those with Medicaid (aOR, 4.29; 95% CI: 2.13-8.66). Emergently admitted UC patients whose surgery was performed 6 days after their admission had significantly increased likelihood of in-hospital death (aOR, 2.12; 95% CI: 1.13-3.97). CONCLUSIONS: Postoperative mortality was lowest in hospitals that performed the highest volume of operations. Increasing the proportion of total colectomies performed in high-volume hospitals may improve clinical outcomes for patients with UC.

Variation in severity assessment and initial mesalamine dose selection for ulcerative colitis in community practice.

BACKGROUND AND AIMS: Ulcerative colitis treatment is based largely on anatomic extent of inflammation and severity. Clinical severity is designated by the terms mild, moderate, or severe. The aims of this study are to assess consistency between: (1) community physicians and established treatment guidelines in their respective operational definitions of severity and (2) clinical severity ratings and resulting treatment. METHODS: Medical records of 411 patients who were successfully treated with mesalamine delayed release tablets without requiring steroids were reviewed. Data recorded included the prescribed dose of mesalamine, clinical symptoms, and physician's global assessment (PGA). RESULTS: Physicians were moderately consistent with the American College of Gastroenterology Guidelines in their assignments of PGA (kappa=0.57, P<0.001). An alternative decision rule, which deviated from the guidelines by placing a higher proportion of patients in the mild category, yielded a significantly higher kappa of 0.69 (P<0.001). The associations between severity measures and mesalamine dose yielded tau statistics of 0.13, 0.16, and 0.14 (all P<0.001), respectively for PGA, number of stools per day and percentage of stools with blood. CONCLUSIONS: Ulcerative colitis treatment quality may be enhanced by promoting a more consistent terminology for disease severity and reducing the unexplained variation in treatment dosing.

Algorithms to identify colonic ischemia, complications of constipation and irritable bowel syndrome in medical claims data: development and validation.

PURPOSE: A challenge in the use of insurance claims databases for epidemiologic research is accurate identification and verification of medical conditions. This report describes the development and validation of claims-based algorithms to identify colonic ischemia, hospitalized complications of constipation, and irritable bowel syndrome (IBS). METHODS: From the research claims databases of a large healthcare company, we selected at random 120 potential cases of IBS and 59 potential cases each of colonic ischemia and hospitalized complications of constipation. We sought the written medical records and were able to abstract 107, 57, and 51 records, respectively. We established a 'true' case status for each subject by applying standard clinical criteria to the available chart data. Comparing the insurance claims histories to the assigned case status, we iteratively developed, tested, and refined claims-based algorithms that would capture the diagnoses obtained from the medical records. We set goals of high specificity for colonic ischemia and hospitalized complications of constipation, and high sensitivity for IBS. RESULTS: The resulting algorithms substantially improved on the accuracy achievable from a naïve acceptance of the diagnostic codes attached to insurance claims. The specificities for colonic ischemia and serious complications of constipation were 87.2 and 92.7%, respectively, and the sensitivity for IBS was 98.9%. CONCLUSIONS: U.S. commercial insurance claims data appear to be usable for the study of colonic ischemia, IBS, and serious complications of constipation.