bluuebunny/crossref_metadata_2025_split huggingface dataset:
INFLIXIMAB MARKET SHARE AND ASSOCIATED COST SAVINGS FOLLOWING BIOSIMILAR MARKET ENTRY
Authors: Paglinco Samantha , Abdel-Rasoul Mahmoud , McNicol Megan , Boyle Brendan , Dotson Jennifer , Michel Hilary , Maltz Ross 
Published: January 2024

Abstract

BACKGROUND
Biologic medications have transformed treatment for autoimmune conditions, including inflammatory bowel disease (IBD), but have also contributed to rising healthcare expenditures in the United States (US). Biosimilars, which are highly similar in safety and efficacy to the originator biologic, were introduced to create competition and reduce cost. Limited studies exist evaluating the impact biosimilars have had on biologic market share and cost savings. The objective of this study was to evaluate the impact infliximab biosimilars have had on the cost and market share of the infliximab originator product.

METHODS
Infliximab claims were reviewed and analyzed using the Merative MarketScan Commercial Claims and Encounters Database. Using only outpatient claims, both the infliximab originator and biosimilars were identified using Current Procedural Terminology codes from January 1, 2015, to December 31, 2021. Patients with commercial insurance, ages 0 to 64 years, and receiving infliximab for any indication were included. The Medical Care Consumer Price Index was used to adjust for inflation to December 2021 dollars. Outcomes of interest included market share of all infliximab products, cost per infliximab infusion, and cost per vial (one vial=100 mg) of the medication.

RESULTS
There were 471,748 claims for infliximab infusions that met our inclusion criteria, with 42,100 unique patients, 55% female, and a median age of 40 (inter-quartile range (IQR) 26 – 52) years old at the time of medication initiation. Indications for infliximab products included IBD (67%), rheumatoid arthrtiis (18%), psoriasis (9%), ankylosing spondylitis (5%), other (4%), with some patients receiving infliximab for multiple indications.
Utilization of infliximab biosimilars increased over time, reaching the highest utilization in December 2021, accounting for 24% of the market share. The median cost of the infliximab originator peaked at $1,491 per vial in December 2017, 13 months after market entry of the first biosimilar (infliximab-dyyb). The cost of the infliximab originator then decreased by 45% over time, reaching a low of $821 per vial in December 2021. Had infliximab biosimilars not been introduced to the market, the projected cost of the infliximab originator in December 2021 would have increased by 20% to $1793 per vial. Thus, infliximab biosimilars contributed to a theoretical decrease of 55% in the cost of infliximab originator during the time period studied.

CONCLUSIONS
The market share of infliximab biosimilars in the US has steadily increased since their introduction in 2016. The competition of infliximab biosimilars has contributed to the decrease in cost of both the infliximab originator and biosimilar products. Future studies are needed to determine if patients are seeing an out-of-pocket savings because of biosimilar introduction.
THE IMPACT OF TREATMENT SWITCH AMONG PATIENTS WITH ULCERATIVE COLITIS NEWLY TREATED WITH A BIOLOGIC – A JAPAN RETROSPECTIVE CLAIMS DATABASE STUDY
Authors: Garcia Ana Dubon , Sanon Myrlene , Tan Jin Yu , Miyazaki Celine , Yu DaeYoung , Jing Zhao 
Published: January 2024

Abstract

INTRODUCTION
Biologics have largely expanded treatment options for ulcerative colitis (UC) patients. Despite advanced treatments, up to 50% of patients treated with any biologic also suffer loss of response or intolerance. This study assessed the healthcare resource utilization (HCRU) associated with treatment switch as an indicator of suboptimal treatment of UC in patients newly treated with a biologic in a real-world setting in Japan.

METHODS
A retrospective cohort analysis was performed using the Japan Medical Data Center (JMDC) claims database for the period from 01/01/2016 through 09/30/2022. Adult patients with at least two UC diagnoses and newly treated with a biologic on or after the UC diagnosis were included. The index date was defined as the date of the first observed biologic prescription fill or injection after the UC diagnosis. Patients with a record of pregnancy one year before or one year after the index date and patients with at least two CD diagnosis were excluded. Patients were classified as switchers if they discontinued their index biologic treatment and switched to another biologic or 5-aminosalicylic acid or immunomodulator during a 12-month study period after the index date. All-cause HCRU during the study period were described and compared (unadjusted) between the 2 cohorts (switchers vs non-switchers).

RESULTS
Among 47,572 patients diagnosed with UC, 1,214 met criteria for inclusion, of which 261 (21.5%) were in the switchers cohort and 953 (78.5%) in the non-switchers cohort. Overall, the mean age (SD) was 41.3 (12.4) years old and 31% (n=376) were female. In the switchers group, 85.8% (n=224) discontinued index treatment and switched to another biologic, 5.0% (n=13) to a 5-ASA and 11.1% (n=29) to an immunomodulator. Among switchers, 59.0% (n=154) of switching occurred during the first 6 months after index treatment.
During the 12-months follow-up period, the mean number of outpatient visits were similar between cohorts (15.5 visits vs 14.3 visits, p = 0.01). However, a greater proportion of the switchers cohort experienced inpatient hospitalization compared to non-switchers (43.7% [n=114] vs 19.6% [n=187], p&lt;0.001). In addition, the inpatient hospitalizations had a longer mean length of stay in the switchers group vs non-switchers (12.9 days vs 4.5 days, p&lt;0.001).

CONCLUSION
This real-world analysis using the JMDC database showed that roughly one out of five patients newly treated with a biologic switched to another treatment within 12 months of the treatment initiation. Those who experience treatment switch were also more likely to be hospitalized and had a longer length of stay versus patients who did not switch treatment. These findings highlight the continued burden of non-remission associated with treatment switch and the need for more efficacious and safe treatment interventions early in disease management.
UNCOVERING UNIQUE NEEDS AND BARRIERS TO CARE AMONG LGBTQ+ PATIENTS WITH IBD: INSIGHTS FROM A COMMUNITY SURVEY TO INFORM INCLUSIVE PRACTICES
Authors: Chedid Victor , Aiello Alicia , Chadha Chelsie Anderson , Carter Jeffrey , Simone Laura , Balmer Jennifer 
Published: January 2024

Abstract

INTRODUCTION
Lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ+) individuals face a myriad of disparities and unique challenges that impact their clinical care and outcomes, however, less is known regarding the specific needs of sexual and gender minorities with inflammatory bowel disease (IBD). Methods: The aim of this study was to better understand the unmet needs and potential barriers to care that LGBTQ+ persons with IBD experience. A survey was disseminated in March 2023 via email distribution by Girls with Guts and the AIDS Institute to individuals with IBD who identify as LGBTQ+. The data was analyzed with descriptive analysis with frequencies and percentages (%). Results: A total of 217 people completed the survey, including 165 cisgender, 34 transgender, and 18 gender nonbinary individuals with IBD. The majority of respondents identified as lesbian or gay (56%) or bisexual (27%), and most reported an IBD diagnosis of Crohn’s Disease (61%). Most indicated their IBD care team was aware of their gender identity (76%) and sexual orientation (75%), either through direct discussions or being asked on medical forms, however nearly half report that they sometimes to very frequently delay seeking IBD care (49%) or refrain from sharing information with their IBD care team (63%) because of worry or fear of mistreatment or judgement (Figure 1). Only 37% of individuals agreed their IBD care team meets their unique needs as an LGBTQ+ person, and respondents reported most commonly turning to online sources of health information (55%) and other members of the LGBTQ+ community (42%) rather than their IBD care team (26%) for information on IBD as it relates to their gender, sexual orientation, and/or sexual practices. Overall, respondents most frequently cited worry about judgement or mistreatment (40%) as a barrier to discussing sexual orientation and gender identify (SOGI) with their IBD care team, however, this concern was more frequently reported by transgender (65%) and gender nonbinary (72%) individuals than cisgender persons (33%) (Figure 2). Nearly half (46%) agreed the clinic where they receive their IBD care could be described as LGBTQ+ safe and inclusive, however, this percentage varied by location, with individuals living in small towns or rural areas expressing more disagreement. Overall, respondents identified their IBD care teams could most improve by becoming more knowledgeable in LGBTQ+ concerns related to IBD (46%), initiating conversations related to SOGI and sexual practices (30%), and displaying visible signs of LGBTQ+ acceptance (29%).

CONCLUSION
Collectively, these data provide insight into the unique challenges and needs of LGBTQ+ individuals with IBD and may be used to inform strategies that support equitable IBD care. Future studies should focus on the impact of such strategies on IBD-related outcomes.
ENHANCED MITOCHONDRIAL BIOGENESIS INCREASES ANTI-OXIDANT ENZYMES AND IMPROVES TISSUE INFLAMMATION IN HUMAN IBD TISSUE
Authors: Bhogoju Sarayu , Kapur Neeraj , Vekaria Hemendra , Goretsky Tatiana , Hassan Syed Adeel , Kim Jong Hyun , Awuah Samuel , Sullivan Patrick , Chaiswing Luksana , Barrett Terrence 
Published: January 2024

Abstract

BACKGROUND
In patients with inflammatory bowel disease (IBD), there exists a connection between mitochondrial dysfunction and two key issues: increased oxidative stress and attenuated ATP production. Previously we presented at this meeting the effect of a novel gold-based compound (AuPhos) on enhancing mitochondrial function in attenuating mice colitis (). In the present study we interrogate the effect of AuPhos on mitochondrial biogenesis in biopsies from control and active ulcerative colitis (UC) (Mayo 1-2) patients and normal human colonic epithelial cells (NCM460). We postulate that AuPhos-induced mitochondrial function enhances biogenesis and anti-oxidant levels and improves tissue inflammation in human IBD tissue.

METHODS
Effects of AuPhos on mitochondrial and anti-oxidant proteins were evaluated in NCM460 cells by western blot (WB) +/- low-dose TNF(1ng/ml). Human colonic biopsy samples (n=3) were collected and treated ex-vivo with vehicle or AuPhos (3h, 4oC), and processed for protein and mRNA analysis by WB and RT-qPCR, respectively. Flow cytometry of mitotracker green quantified mitochondrial mass in NCM460 and intestinal epithelial cells (IECs) from human control and UC tissues (n=3, Mayo 1-2).

RESULTS
AuPhos increased mitochondrial mass (mitotracker, Fig.1A,1B) and biogenesis protein levels PGC1α, NRF2 and TFAM (Fig.1C) in human intestinal epithelial cells (IECs), biopsies, and in NCM460 cells. Protein analysis in NCM460 cells show that AuPhos increases downstream antioxidant markers such as manganese superoxide dismutase (MnSOD), glutathione peroxidase 4 (GPX4), thioredoxin reductase2 (Trx2), and catalase expression when compared to the TNF or control samples. AuPhos substantially upregulates levels of mitochondria complex (mtCO1, mtCO2 Cox6A1, ATP5A1) and anti-oxidant enzyme (MnSOD, GPX, PRDX-2, -4, and -6) mRNA and protein levels in human colonic biopsies compared to vehicle and TNF treated samples (Fig. 1D). Furthermore, AuPhos reduces tissue cytokine and chemokine mRNA levels (IL1β, MCP1, RankL, and TNFα) in human UC tissues (Fig. 1E).

CONCLUSIONS
The current study reveals that AuPhos increases mitochondrial biogenesis, mitochondrial complex, and antioxidant enzyme levels in human IBD tissue. THE REDUCTION IN TISSUE CYTOKINES AND CHEMOKINES SUGGESTS THAT ENHANCED MITOCHONDRIAL FUNCTION IMPROVES TISSUE INFLAMMATION. This suggests the potential of AuPhos in treating IBD through the restoration of mitochondrial biogenesis.
MITOCHONDRIAL DYSFUNCTION CAUSES CECAL PATCH (CP) INFLAMMATION IN ULCERATIVE COLITIS
Authors: Patel Parth H , Hassan Syed Adeel , Kasem Ahmad , Wempe Lesley , Elsayed Mohamed , Bhogoju Sarayu , Goretsky Tatiana , Lee Goo , Barrett Terrence , Kapur Neeraj 
Published: January 2024

Abstract

BACKGROUND
Up to 17% of distal ulcerative colitis (UC) patients have discontinuous (proximal) inflammation referred to as Cecal Patch (CP), associated with greater abdominal pain, bleeding and diarrhea. Despite these known associations, the pathogenesis of CP lesions is poorly understood. Recent data suggest that reduced mitochondrial (Mito) function predicts unfavorable clinical outcomes in active UC (Haberman et al; Nat Comm 2019). We posit that inflammation and tissue injury induced in UC-associated CP involves Mito dysfunction.

METHOD
UC patients with/without cecal disease and normal controls were biopsied. Tissue from CP lesions or normal caecum were collected in Allprotect® (AP) and formalin. Total RNA from AP-preserved biopsies were used for cDNA synthesis and RT-qPCR for Mito complexes, cytokines, anti-oxidant and calcineurin (CaN) signaling genes and tissue processed for IHC for Mito complexes.

RESULT
Transcriptomic analysis showed significant downregulation in genes associated with Mito biogenesis (PGC1α, TFAM, NRF2) and Mito complexes (Ndufa1, Ndufa4, Ndufb2, Ndufb6, mtCO1, mtCO2, Cox5B, Cox6A1, ATP5A1, ATP5B, ATP5E) in CP lesions compared to normal caecum from active patients. Major regulators of Mito biogenesis (PGC1α and TFAM) revealed ~39% and ~24% reductions of mRNA respectively, while NRF2 (anti-oxidant regulator) showed ~62% reduced mRNA in CP lesions compared to normal cecum from distal UC patients. Electron transport chain complex mRNAs showed 31%, 47%, and 48% reduction in complex I (Ndufa1, Ndufa4, Ndufb2, Ndufb6), complex IV (mtCO1, mtCO2, Cox5B, Cox6A1), and complex V (ATP5A1, ATP5B, ATP5E) levels, respectively in CP lesions compared to normal controls. Concomitantly, the IHC staining also showed significant reductions in Ndufb6, MTCO1 and Cox5A protein levels in CP lesions compared to normal cecum sections. The CP-related decreased markers of Mito biogenesis and function correlates with increased proinflammatory cytokine mRNA (IL-6: 2-fold; TGFβ1: 1.6-fold; IL-2: 2.6-fold) and decreased anti-inflammatory (IL10: 3.2-fold) gene expression in CP lesions. Further investigation demonstrated that repressed Mito function in CP lesions is associated with downregulation of anti-oxidant genes (SOD1, SOD2, Prdx3, Gpx4, Trx2) compared to normal cecum. Inflammation-induced Mito dysfunction in CP lesions also stimulates CaN signaling as demonstrated by significant increases in mRNA levels of CaN and downstream regulated genes (Cathepsin-L, Rel-A Glut4, CREB-BP and Igf-1r).

CONCLUSION
These data represent the first indication that Mito dysfunction occurs in CP associated with distal UC. Furthermore, we speculate that Mito dysfunction-induced CaN signaling promotes regional (CP) inflammatory responses. These important findings indicate that targeting Mito metabolism may be an important therapeutic goal of treating UC patients with CP.
NANOPARTICLE ENCAPSULATION OF THE SPECIALIZED PRO-RESOLVING MEDIATOR MARESIN-2: A NOVEL APPROACH FOR PROMOTING MUCOSAL REPAIR IN THE INTESTINE
Authors: Miranda-Guzman Jael , Morris Aaron , Quiros Miguel , Brazil Jennifer , Parkos Charles , Nusrat Asma 
Published: January 2024

Abstract
Epithelial cells form protective barriers at mucosal surfaces and play a critical role in maintaining tissue homeostasis. Active inflammation in inflammatory bowel disease (IBD) is associated with epithelial barrier disruption and mucosal erosions/wounds that contribute to the inflammatory response and disease symptoms. Therefore, efficient repair of epithelial erosions/wounds is crucial for restoring intestinal barrier function and resolving mucosal inflammation. In response to injury, epithelial cells proliferate and migrate to cover denuded surfaces and restore critical barrier properties. Resident and recruited immune cells at sites of injury release factors that play an important role in orchestrating mucosal repair. Bioactive lipid mediators released by leukocytes, including leukotrienes and specialized pro-resolving mediators (SPMs), regulate epithelial signaling pathways to influence mucosal repair processes. Liquid chromatography-mass spectrometry (LCMS) analyses of healing colonic mucosal wounds performed to detect SPMs identified high levels of MaR2 in healing colonic wounds. In vitro studies using primary colonic epithelial cells revealed MaR2-driven increases in epithelial wound repair that were potentiated by the pro-inflammatory cytokines TNFα and IFNγ. While MaR2 increased epithelial migration by activating cell matrix adhesion proteins, including Src-paxillin and focal adhesion kinase, we did not observe any influence of MaR2 on the activation of cyclin D1/D2 or on epithelial proliferation. Importantly, in vivo studies demonstrated enhanced colonic mucosal wound repair and recovery from dextran sulfate-induced colitis in mice administered MaR2. Given the thermolabile nature of MaR2 (and associated ultracold storage requirements), thermostable polylactic acid (PLA) nanoparticles (NP) containing MaR2 (PLA MaR2) were generated. PLA MaR2 nanoparticles retained bioactivity following extended storage at room temperature and exhibited potent effects on in vivo colonic biopsy induced wound repair. Taken together these data reveal that thermostable MaR2 containing nanoparticles represent a promising new therapeutic approach for regenerating epithelial barrier function and restoring mucosal homeostasis in individuals with IBD.
CD11B/CD18 SIALYLATION REGULATES NEUTROPHIL TRAFFICKING AND INFLAMMATORY FUNCTION IN THE INTESTINE
Authors: Brazil Jennifer , Azcutia Veronica , Kelm Matthias , Cummings Richard , Parkos Charles 
Published: January 2024

Abstract
Pathogen-triggered neutrophil (PMN) recruitment is critical for innate immunity, but excessive PMN influx and associated mucosal tissue damage is implicated in the pathogenesis of numerous human inflammatory disorders including inflammatory bowel disease (IBD). Critically in both ulcerative colitis and Crohn’s disease, disease flares requiring medical intervention are associated with migration of large numbers of PMNs across colonic epithelium resulting in mucosal injury/ulceration. Recent studies have shown that specific PMN glycans can be targeted to reduce transepithelial migration (TEpM) the critical final step in PMN intestinal trafficking. However the role of Sialic acid (Sia), the most abundant PMN expressed terminal glycan, in regulating PMN migration and inflammatory function in the gut is not well understood. Using sophisticated models of human and murine PMN intestinal migration, we show that blocking sialidase-mediated removal of alpha 2-3 linked sialic acid from CD11b/CD18 inhibits PMN TEpM in vitro and in vivo.Measurement of cytochrome C reduction revealed that inhibition of sialidases reduced bacterial peptide (fMLF) stimulated superoxide release by human and murine PMN. Flow cytometry analyses revealed that sialidase inhibition decreased fMLF mediated PMN degranulation and fMLF mediated CD11b/CD18 conformational activation. Highlighting the functional importance of individual Sia residues, inhibition of alpha 2-3 sialidase activity with 3’ Sialyllactose (3’SL) was found to inhibit PMN intestinal trafficking in vitro and in vivo and reduce PMN degranulation responses. Immunoblotting studies showed that sialidase inhibition deactivates spleen tyrosine kinase (Syk) and p38 MAP kinase, key intracellular mediators that signal downstream of PMN CD11b/CD18. Finally, inhibition of sialidase activity reduced adhesion of PMN to ICAM-1 (a major physiological substrate of CD11b/CD18) demonstrating that endogenous PMN sialidases regulate binding interactions between migrating PMN and intestinal epithelial receptors. Taken together data show that upon activation PMN sialidases remove alpha 2-3 Sia from CD11b/CD18 which leads to integrin activation and subsequent outside in signaling mediated by Syk to drive PMN inflammatory effector functions including migration, degranulation, and superoxide release. As such targeting CD11b/CD18 sialylation represents a promising new therapeutic strategy for reducing dysregulated PMN influx and associated mucosal tissue damage in IBD and other inflammatory disorders.
BREASTFEEDING STATUS AND DISEASE SEVERITY IN PEDIATRIC PATIENTS WITH ULCERATIVE COLITIS: AN EXPLORATORY RETROSPECTIVE COHORT STUDY
Authors: Glick Abigail , Horwitz Bruce , Snapper Scott , Ouahed Jodie 
Published: January 2024

Abstract

OBJECTIVE
While the protective effect of being breastfed on the development of ulcerative colitis has been well established, it is not known if being breastfed decreases colectomy rate and disease severity for pediatric patients. This work is designed to better understand the connection between breastfeeding status and disease severity of ulcerative colitis among pediatric patients.

METHODS
This exploratory retrospective cohort study analyzed the clinical and laboratory data of patients at Boston Children’s Hospital enrolled in a data registry and biorepository since 2012. Data was collected from charts and analyzed to determine if there is a significant difference in colectomy rate, pediatric ulcerative colitis activity index (PUCAI) score, ESR, or CRP, between not breastfed (n=56), breastfed (n=39), and mixed breastfed patients (n=31). Breastfed patients are defined as patients who were exclusively breastfed for greater than or equal to three months. Patients who were never breastfed were considered not breastfed. Patients who were exclusively breastfed for less than three months or received a mix of formula and breastfeeding were considered mixed breastfed. Statistical analysis of the groups was performed using a one-way ANOVA.

RESULTS
At disease diagnosis, the average PUCAI score of the not breastfed group (32.4) was significantly higher than the exclusively breastfed group (18.4) (p value = 0.0189). No significant difference was detected in the average PUCAI score of the mixed breastfed group (34.1) compared to the not breastfed group (32.4). Significant differences in the colectomy rate between all three groups were not detected, and likewise we did not find significant differences in markers of disease severity including ESR, CRP, and hemoglobin at diagnostic visit between groups.

CONCLUSION
These results suggest that children with ulcerative colitis who were exclusively breastfed have a lower average PUCAI score at the time of diagnosis than those who were not breastfed. Further investigation with larger data sets may be necessary to determine other benefits of exclusive breastfeeding in pediatric ulcerative colitis patients.