bluuebunny/crossref_metadata_2025_split huggingface dataset:
ARTHRITIS AND ARTHRALGIA AS EXTRAINTESTINAL MANIFESTATIONS IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE TREATED WITH VEDOLIZUMAB: A META-ANALYSIS
Authors: dos Anjos Gabriele Alves , Gomes Cintia Pavao , Oliveira Diego Brandão , Maia Julia de Carvalho , Dalfovo Milena Prigol , Carvalho Gabriela Domingues , Falcon Bruna Thaytala Quintino 
Published: January 2023

Abstract

BACKGROUND
Vedolizumab is a humanized gut selective drug that specifically targets α4β7 integrin and has been used successfully in the treatment of Inflammatory Bowel Disease (IBD). Although Vedolizumab is an effective treatment for IBD and acts specifically on the gastrointestinal system, some studies have reported extraintestinal manifestations as adverse events. One of the most frequently reported non-infectious adverse events is articular manifestations. However, it is difficult to know for sure whether the joint symptoms are due to the vedolizumab adverse event or due to extraintestinal symptoms of the disease itself.

AIMS
This systematic review and meta-analysis aimed to assess the incidence of extraintestinal manifestations in patients receiving Vedolizumab and to investigate whether these adverse events are indeed drug-related.

METHODS
Pubmed, Cochrane, and Scopus were searched for randomized clinical trials reporting the incidence of articular events in patients with Crohn’s Disease or Ulcerative Colitis who were treated with Vedolizumab. The considered outcomes were new-onset or worsening of pre-existing joint manifestations. We used Revman to calculate the pooled incidence of the reported outcomes and their corresponding 95% confidence intervals (95% CI).

RESULTS
The search strategy yielded 4.206 articles. After removal of duplicates and screening of results, 4 randomized studies met the inclusion criteria (Figure 1).
A total of 2.466 patients with moderately to severe IBD were included. Of those, 1822 were randomized to intervention group, with Vedolizumab administration, and 644 to placebo. In the intervention group, 232 patients developed arthritis or arthralgia of any kind, versus 66 patients of placebo group (95% CI 0.7%-1.3%; Figure 2). Of those patients, 73,8% and 33% had prior treatment with anti-TNF and immunomodulators, respectively. 63% and 15% also had prior anti-TNF and immunomodulators previous failure, respectively.

CONCLUSION
The meta-analysis presented above shows a result without statistical significance to say that vedolizumab is responsible for the manifestations previously described. Therefore, it is necessary to hypothesize that the new onset of worsening arthritis and arthralgia may be associated with the course of the disease itself, the body's response to the drugs or the exclusion of corticosteroids or anti-TNF from concomitant treatment with Vedolizumab. More studies with larger samples are needed, especially randomized clinical trials comparing Anti-TNF, corticosteroids and immunomodulators to assess the incidence of joint manifestations and even other rheumatologic manifestations in patients with Inflammatory Bowel Disease.
A PRECLINICAL MODEL OF STENOTIC CROHN’S DISEASE FOR THE STUDY OF MECHANISMS OF MOTILITY DYSFUNCTION IN IBD
Authors: Johnson John , Geesala Ramasatyaveni , Zhang Ke , Shi Xuan-Zheng 
Published: January 2023

Abstract

BACKGROUND AND AIMS
Motility dysfunction is present in patients with stenotic Crohn’s disease (CD) and contributes to cramps, diarrhea and constipation. However, mechanisms for motility dysfunction in CD are incompletely understood. Mechanical stress, i.e. inflammatory infiltration, edema, stenosis, and distention, is commonly encountered in CD. We tested the hypothesis in a rat model of stenotic CD that mechanical stress-induced expression of mechano-sensitive genes such as cyclo-oxygenase-2 (COX-2) may account for motility dysfunction in the inflammation site and the mechanically distended site prior to inflammation.

ANIMAL MODEL AND METHODS
Rat model of CD-like colitis was induced by intracolonic instillation of TNBS 65 mg/kg in 250 µL of 40% ethanol. Control rats were treated with intracolonic saline instillation. When rats were fed with regular pellet food, instillation of TNBS led to localized transmural inflammation with stenosis in the instillation site (site I) and lumen distention in the colon segment proximal to inflammation (site P). However, when rats were fed exclusively with liquid diet, inflammation-associated stenosis and mechanical distention was eliminated. Rats were euthanized by 7 days.

RESULTS
1) Compared to controls, COX-2 mRNA expression was increased by 13.1(± 2.5)-fold in site I and 16.6(±4.3)-fold in the mechanically distended site P, but not in the non-distended site D. This data indicates a mechanosensitive mechanism in COX-2 expression. If mechanical distention in CD was prevented by feeding rats exclusively with clear liquid diet, the increase of COX-2 mRNA expression was attenuated in sites I and P. Further investigation showed that increased expression of COX-2 occurs mainly in the colonic smooth muscle cells (SMC) of the distended colon. 2) We found that COX-2 expression was robustly induced by mechanical stretch (18% static stretch) in vitro in rat colonic smooth muscle cells (SMC). 3) Inflammation led to significant suppression of colon circular muscle contractility not only in site I but also in distended site P of CD-like rats. Muscle contractility in site D was not significantly affected by inflammation. Moreover, clear liquid diet treatment significantly improved muscle contractility in sites P and I. 4) To determine the role of COX-2 in smooth muscle dysfunction in the CD model, COX-2 inhibitor NS-398 (5 mg/kg, i.p. daily) was administered in control and CD rats. We found that NS-398 significantly improved muscle contractility in CD rats in sites P and I.

CONCLUSIONS
Our study found that up-regulation of COX-2 expression in stenotic CD-like colitis is dependent on mechanical stress. COX-2 inhibitor improved colon smooth muscle contractility in colitis. Thus, mechanosensitive expression of COX-2 may play a critical role in smooth muscle dysfunction and dysmotility in CD.
LMT503, A NOVEL THERAPY FOR INFLAMMATORY BOWEL DISEASE THROUGH MACROPHAGE POLARIZATIONS BY METABOLIC REPROGRAMMING OF ACTIVATED MACROPHAGE
Authors: Lee Wheeseong , Chung Hyo Kyun , Kim Jusik , Ko Inseok , Yang Chul-Su , Kim Hyo Keun 
Published: January 2023

Abstract
Macrophages are the first line of defense against self-stimuli and non-self-pathogens and adopt diverse activation states by reprogramming their cell metabolism and thereby polarizing their phenotypes in order to drive their pro-inflammatory or pro-resolving responses. As the key gatekeeper of intestinal immune homeostasis, macrophage polarization has an important effect on maintaining tissue homeostasis with inducing resolution, and therefore macrophages phenotype alteration by modulating their cellular metabolism might be a novel therapeutic approach in IBD.
LMT503 is an orally available organic small molecule and exerted the macrophage polarization from M1-like inflammatory macrophage to M2-like anti-inflammatory macrophages in LPS-induced bone marrow-derived macrophage in vitro experiment. The expression level of M1-related intracellular functional marker iNOS was suppressed by LMT503, while Arg-1 which is M2-associated marker was increased. LMT503 also performed metabolic reprogramming with decreasing anabolic metabolism but enhancing catabolic metabolism including mitochondrial metabolism.
In the therapeutic settings using various IBD in vivo models such as DSS-induced acute/chronic mice models and adoptive T cell transfer mice model, LMT503 exerted macrophage polarization with showing reduced expression level of M1 markers such as iNOS, CD80, and CD86 but increased expression of M2 markers like Arg-1, CD168, and CD206. LMT503 mitigated inflammation with decreased production of inflammatory cytokines (TNF-a, IL-6, IL-1b, IL-18), increased anti-inflammatory cytokines (IL-10, IL-22), and reduced neutrophil infiltrations. In the addition to increased ratio of M2/M1 macrophages, LMT503 increased ratio of Treg/Th17.
LMT503 also induced epithelial restitution with increased number of goblet cells, and showed decreased bacterial translocation from gut to mesenteric lymph node.
In a chronic IBD mice model, LMT503 showed reduced intestinal fibrotic marker a-SMA which is one of critical complications for patients with long-term IBD.
Mode of action through macrophage polarization was proved by using a macrophage-depleted IBD in vivo model, and LMT503 did not improve the disease associate index or inflammation. Also LMT503 showed re-storing immunity in an in vivo study of challenging pathogen to LMT503-treated and washed-out model, which avoids the possibility of an opportunistic infections.
In summary, LMT503 was very efficacious in various IBD in vivo models with showing the resolution of intestinal inflammation and mucosal healing through improved epithelial restitution via macrophage polarizations, and this approach can be a very effective and safe therapy for multifaceted IBD. The first in human study with LMT503 will be initiating in 4Q 2022.
ACCELERATED INFLIXIMAB INFUSION SAFETY AND TOLERABILITY IS NON-INFERIOR TO STANDARD INFUSION PROTOCOL IN INFLAMMATORY BOWEL DISEASE PATIENTS – A RANDOMIZED CONTROLLED STUDY
Authors: Abushamma Suha , Walker Ted , Garza Kevin , Chen Chien-Huan 
Published: January 2023

Abstract

BACKGROUND & AIM
Infliximab is typically given over a standard infusion time of 2 hours, leading to a significant burden in inflammatory bowel disease (IBD) patients. Several retrospective and prospective studies have assessed the safety of accelerated infliximab infusions, but not in a randomized controlled setting. We aimed to determine the safety and cost-effectiveness of an accelerated infliximab infusion of 1 hour, compared to the standard 2 hour infusion.

METHODS
This open label randomized trial was done at a tertiary IBD center in the United States. Patients with an established diagnosis of IBD receiving maintenance infliximab infusions at one of our centers were eligible for inclusion. We excluded patients with a history of infusion reactions and those with known antidrug antibodies to infliximab. Patients were randomly assigned (1:1) to the 1 hour infusion (study) and 2 hour infusion (control) groups using an independent computerized randomization system. The primary outcome was to assess the rate of infusion reactions in the standard 2 hour compared to the accelerated 1 hour study groups. Secondary outcomes were assessment of the effect of pre-medications and concomitant immunomodulators on the rate of infusion reactions, and cost effectiveness analysis. Sample size calculation was based on an infusion reaction rate of 3%, as suggested by recent studies. In order to show a non-inferiority of the accelerated infusion time assuming an infusion reaction rate of 3% while allowing for a 4% non-inferiority limit, a total of 538 infusions would be needed. This would provide a power of 80% and significant alpha of 0.05. Non-inferiority was assessed using Farrington-Manning score test. This trial is registered with ClinicalTrials.gov, NCT05340764.

RESULTS
From November 2020 to November 2021, we assessed the eligibility of 448 patients, of whom 352 (78%) were excluded primarily due to infusions being received at an outside institution, or patient refusal. Thus, 96 (22%) patients were randomly assigned: 51 (53%) to the 1 hour infusion study group and 45 (47%) to the 2 hour infusion control group. Over a median time of 1 year, a total of 685 infusions were administered: 309 infusions in the control group, and 376 in the study group. 57 (18%) of 309 infusions in the control group and 45 (12%) of 376 infusions in the study group experienced an infusion reaction. The only infusion reaction experienced was hypotension, all of which were asymptomatic and none required infusion discontinuation. Diphenhydramine was associated with an increased rate of infusion reactions (OR 2.04 [95% CI 1.18 – 3.52], p=0.01). Average costs were estimated to reduce by 37% in the accelerated infusion group.

CONCLUSION
Accelerated 1 hour infliximab infusions are non-inferior in safety and superior in cost-effectiveness compared to standard 2 hour infusions in IBD patients.
CURCUMIN-QINGDAI COMBINATION FOR PATIENTS WITH ACTIVE ULCERATIVE COLITIS: A RANDOMIZED DOUBLE-BLINDED PLACEBO-CONTROLLED CLINICAL TRIAL
Authors: Ben-Horin Shomron , Salomon Nir , Karampekos Georgios , Viazis Nikos , Lahat Adi , Ungar Bella , Eliakim Rami , Kriger-Sharabi Ofra , Reiss-Mintz Hilla , Yanai Henit , Dotan Iris , Zittan Eran , Hirsch Ayal , Maharshak Nitsan , Mantzaris Gerassimos , Kopylov Uri 
Published: January 2023

Abstract

BACKGROUND
The herbal extracts Curcumin and QingDai were previously shown to be effective in mild-moderate and in moderate-severe ulcerative colitis (UC), respectively. We evaluated the efficacy and safety of a combination of curcumin-QingDai (CurQD) in patients with active UC.

METHODS
This was a two parts trial. Part 1 was an open label study of 4 weeks CurQD in patients with active UC, defined by a Simple Clinical Colitis Activity Index (SCCAI) score ≥5 and a modified Mayo endoscopic sub-score≥2. Part 2 was a placebo-controlled trial conducted in two centers in Israel and Greece, that randomized active UC patients at a 2:1 ratio to either enteric-coated CurQD 3gr/day or an identical placebo for eight weeks. The co-primary outcome at week 8 was clinical response (reduction in SCCAI of ≥3 points) and an objective evidence of response (Mayo endoscopic subscore improvement of ≥1 or 50% calprotectin reduction from baseline). Responding patients continued either Curcumin or placebo alone for additional 8 weeks as maintenance treatment. Expression of Cyp1A1 in rectal mucosa was assessed as a measure of aryl-hydrocarbon receptor (AhR) pathway activation. Curcumin purity, and indigo and indirubin content in CurQD were confirmed by LC-MS/MS.

RESULTS
59 patients were enrolled in the two study parts. In efficacy analysis of part 1, 7/10 responded including 3/10 who achieved clinical remission. For part 2, 95 patients were screened and 42 were included and randomized. The co-primary outcome was achieved in 43% and 8% of CurQD and placebo patients, respectively (p=0.033). Clinical response was observed in 85.7% versus 30.7% (p&lt;0.001), 50% calprotectin-reduction in 46.4% versus 15.4% (p=0.08) and endoscopic improvement in 75% versus 20% (p=0.036), in the CurQD and placebo groups, respectively. The overall rate of adverse events was comparable between the groups. Among week-8 responders to CurQD, additional 8 weeks of treatment with curcumin alone resulted in 93%, 80% and 40% with maintained clinical response, clinical remission and clinic-biomarker response, respectively, at week 16. CurQD treatment uniquely resulted in activation of the AhR pathway, as gauged by up-regulated expression of CYP1A1 in the rectal mucosa, which was not observed among patients receiving placebo, nor was it observed in patients responding to 5ASA or biologic drugs.

CONCLUSION
In this randomized controlled trial, combination CurQD was found to be effective for inducing remission in active UC patients. Induction of AhR may merit further study as a potential treatment target in active UC.
FEASIBILITY OF A NURSE AND DIETITIAN-LED IBD SURGICAL PREHABILITATION PROGRAM
Authors: Banty Andrea , Issokson Kelly , Fleshner Phil , Melmed Gil , Zaghiyan Karen , Ha Christina 
Published: January 2023

Abstract

BACKGROUND
Surgery activates catabolic pathways that lead to loss of lean body mass and physical deconditioning, which can predispose to complications and delayed healing. Prehabilitation addresses modifiable risk factors, provides nutrition and functional status optimization, and has been shown to optimize surgical outcomes after cancer and/or orthopedic surgery. This includes decreased hospital length of stay (LOS), postoperative complications, readmission rates, and accelerated return to pre-surgical functional capacity. We assessed the feasibility of a structured, multidisciplinary prehabilitation program for patients with inflammatory bowel disease (IBD) undergoing abdominal surgery.

METHODS
We developed a nurse-practitioner and dietitian-led IBD prehabilitation program for patients undergoing ileal-cecal resection (ICR) or colectomy. Perioperative nutrition and medications were addressed during two clinic visits (4 weeks before and after surgery). The Global Leadership Initiative on Malnutrition (GLIM) criteria were used to define malnutrition. Sarcopenia was defined as either (1) two standard deviations below the norm for age and gender as assessed by dynamometry or (2) skeletal muscle index (SMI) &lt;55 cm2/m2 for males and &lt;39 cm2/m2 for females at the L3 region as assessed by computerized tomography. Micronutrients (iron profile, vitamin D, B6, zinc) were assessed and corrected if a deficiency was found. Patients were provided personalized diet recommendations for optimizing nutrition and were counseled on preoperative carbohydrate loading, and pre- and post-operative immunonutrition (IN). We assessed post-operative outcomes including post-operative length-of-stay (LOS), 30-day readmission, and perioperative complications of infection, abscess, and leak.

RESULTS
Ten patients (70% female, mean age 41 years) completed the program between 3/2021 and 5/2022. 9 underwent ICR and 1 underwent colectomy. 9 completed IN pre-operatively (90%); 9 (90%) completed carbohydrate loading pre-operatively, and 4 (40%) completed IN post-operatively. Upon initial assessment, 6 patients (60%) had malnutrition, and among the 4 patients with sarcopenia assessments, all 4 met criteria for sarcopenia. Forty percent had at least one micronutrient deficiency. Median post-operative LOS was 3.5 days. There were no readmissions within 30 days, and one patient had a postoperative infection.

CONCLUSION
A nurse practitioner- and dietician-led structured prehabilitation program is feasible. We hypothesize that low compliance with post-operative IN was due to formula not being available for inpatients at our facility; the impact of IN on post-operative outcomes should be evaluated in future studies. Further evaluation of outcomes associated with structured, multidisciplinary prehabilitation in IBD relative to usual care is warranted.
USING R TO ADVANCE PATIENT-CENTRIC RESEARCH IN THE STUDY OF A PROSPECTIVE ADULT RESEARCH COHORT
Authors: Fehlmann Tara , Harvey Sarah , Deepak Parakkal , O'Charoen Sirimon 
Published: January 2023

Abstract

OBJECTIVE
IBD Plexus is a data exchange platform that houses four cohorts, including The Study of a Prospective Adult Research Cohort with IBD (SPARC IBD). SPARC IBD is a multicentered, longitudinal cohort that follows patients through their standard of care. In IBD Plexus, patient reported data (eCRF) is linked with clinical and electronic medical record (EMR) data. Biospecimens are continuously collected and have been used to generate a myriad of molecular and biomarker data. To facilitate inflammatory bowel disease (IBD) research, we built an R package ‘ibdplexus’ (https://github.com/ccf-tfehlmann/ibdplexus), with multiple functions to load, filter and subset the data in IBD Plexus. Currently, this R package focuses primarily on SPARC IBD, with a future goal to expand to incorporate other studies. Each function is designed to help understand an IBD patient’s journey including their treatment use and disease activity over time.

PRIMARY FUNCTIONS
Three main functions help navigate the prescription information from the eCRF and structured EMR data. ‘Sparc_medication_filter’ filters the prescription data to generate a dataset with medication(s) of interest from eCRF and EMR data. For long-term medications including biologics, aminosalicylates, and immunomodulators, `sparc_medication_starts’ extracts the first instance of a medication start date from eCRF and EMR data. Sparc_medication_at_index’ generates a dataset with each participant and their medication at a specified time-point (e.g., enrollment, at time of biosample collection, etc.). Another set of functions map out a patient’s disease activity over the course of their enrollment. ‘Calculate_disease_scores’ creates a list of dataframes and an optional spreadsheet containing multiple tabs with disease activity and endoscopy scores for participants. Calculations include the short Crohn’s Disease activity index and the patient reported outcome (PRO) derivations PRO2 and PRO3, as well as the simple endoscopic score for Crohn’s Disease. For ulcerative colitis patients, the disease activity measures include the 6 and 9-point Mayo score and Mayo endoscopy score. ’Sparc_scores’ generates a dataset with each SPARC participant and their disease activity scores at a specified time-point.

CONCLUSION
The ibdplexus R package has increased the speed and efficiency with which the SPARC IBD data can utilized for research projects. Twenty domains can now be easily collapsed into one table mapped to a date of interest. These reference tables are then used to complete multiple queries, reducing the time per query from up to a day to an hour. The results from the medication functions are well aligned with a subset of patients that underwent chart review. In the few cases where the medication at index date did not align, the information was only available in progress notes or other forms of unstructured EMR data.
AMINOSALICYLATE USE IN PEDIATRIC PATIENTS WITH CROHN’S DISEASE
Authors: Patel Perseus , Kaplan Jess , Moses Jonathan , Pasternak Brad , Samson Charles , Suskind David , Ali Sabina , Adler Jeremy 
Published: January 2023

Abstract

INTRODUCTION
Societal guidelines recommend against the use of 5-aminosalicylate (5-ASA) therapy for pediatric patients with Crohn’s Disease (pCD). Previous trials showed no benefit of 5-ASAs for inducing remission and similar one-year relapse rates when compared with placebo. Conversely, biologics are recommended as first-line therapy due to higher remission rates, corticosteroid-sparing effects, and potential to alter disease progression.

AIMS
We aimed to describe the use of 5-ASAs in pCD and the associated patterns of biologic and corticosteroid use in a large multi-center patient cohort.

METHODS
We used data from the Biologic dISContinUation sTudy (BISCUIT), a multi-center study in which retrospective medical record abstraction from 7 US centers supplemented prospectively collected data from the ImproveCareNow (ICN) Network Registry. We included patients newly diagnosed with pCD (&lt;18 years old) and compared patients who were prescribed a 5-ASA within 90 days of diagnosis to those who were not exposed to 5-ASAs. We used Student’s t-tests, chi-squared tests, and Wilcoxon rank sum to compare baseline characteristics, including demographics (age, gender, race, ethnicity, insurance status); disease characteristics (age at diagnosis, Paris classification, concomitant liver disease, extraintestinal manifestations); and disease activity measures (labs, disease activity indices, and extraintestinal manifestations).

RESULTS
Our study included 608 patients, 142 of whom (23.4%) were treated with 5-ASAs within 90 days after CD diagnosis. At baseline, younger patients (p&lt;0.01), those with colonic disease (L2) (p=0.03), and those with Medicaid as their primary insurance (p=0.05) were more likely to receive 5-ASAs (Table 1). There was no difference in 5-ASA use by disease severity (p=0.52). Those on 5-ASA therapy had an 84-day longer delay in initiation of their first biologic medication, with 56.1% of patients starting a biologic at least 90 days after diagnosis (p&lt;0.001). There were no differences in corticosteroid use (p=0.08) or dietary therapy (p=0.90) (Table 2).

CONCLUSIONS
We found 5-ASA use was common in pCD and was associated with a near 4-month delay in initiating biologic therapy. These results are a call-to-action to improve guideline dissemination and examine barriers such as insurance status in the evidence-based treatment of pCD. Our future work will evaluate differences in outcomes, biologic durability, and disease complication rates between these groups.