Provider Specialization in Inflammatory Bowel Diseases: Quality of Care and Outcomes.

BACKGROUND & AIMS: Management of inflammatory bowel diseases (IBD) is complex and variation in care has been well-documented. However, the drivers of practice variation remain unexplored. We examined variation based on the treating gastroenterologist's IBD focus (proportion of outpatient visits for IBD). METHODS: We conducted a retrospective cohort of newly diagnosed patients with IBD using data from Optum's deidentified Clinformatics Data Mart Database (2000-2020). The exposure variable was whether the treating gastroenterologist had an IBD focus (>90th percentile of IBD visits/total outpatient visits). We used adjusted regression models to evaluate associations between provider IBD focus and process measures (use of mesalamine, corticosteroid, biologic, and narcotic medications and endoscopic or radiographic imaging) and clinical outcomes (time to IBD-related hospitalization and bowel resection surgery). We tested for change in treatment patterns over time by including an interaction term for study era (2004-2012 vs 2013-2020). RESULTS: The study included 772 children treated by 493 providers and 2864 adults treated by 2076 providers. In children, none of the associations between provider focus and process or outcome measures were significant. In adults, care from an IBD-focused provider was associated with more use of biologics, combination therapy, and imaging and endoscopy, and less mesalamine use for Crohn's disease (P < .05 for all comparisons) but not with other process measures. Biologics were prescribed more frequently and narcotics less frequently during the later era (P < .05 for both). Hospitalization and surgery rates were not associated with IBD focus or era. CONCLUSIONS: IBD care for adults varies by provider specialization. Given the evolving complexity, novel methods may be needed to standardize care.

Challenges in IBD Research 2024: Environmental Triggers.

Environmental factors play an important role in inflammatory bowel diseases (IBD; Crohn's disease, [CD], ulcerative colitis [UC]). As part of the Crohn's & Colitis Challenges 2024 agenda, the Environmental Triggers workgroup summarized the progress made in the field of environmental impact on IBD since the last Challenges cycle in this document. The workgroup identified 4 unmet gaps in this content area pertaining to 4 broad categories: (1) Epidemiology; (2) Exposomics and environmental measurement; (3) Biologic mechanisms; and (4) Interventions and Implementation. Within epidemiology, the biggest unmet gaps were in the study of environmental factors in understudied populations including racial and ethnic minority groups and in populations witnessing rapid rise in disease incidence globally. The workgroup also identified a lack of robust knowledge of how environmental factors may impact difference stages of the disease and for different disease-related end points. Leveraging existing cohorts and targeted new prospective studies were felt to be an important need for the field. The workgroup identified the limitations of traditional questionnaire-based assessment of environmental exposure and placed high priority on the identification of measurable biomarkers that can quantify cross-sectional and longitudinal environmental exposure. This would, in turn, allow for identifying the biologic mechanisms of influence of environmental factors on IBD and understand the heterogeneity in effect of such influences. Finally, the working group emphasized the importance of generating high-quality data on effective environmental modification on an individual and societal level, and the importance of scalable and sustainable methods to deliver such changes.

Environmental factors are important in inflammatory bowel diseases. It is a high priority to identify environmental factors impacting different disease stages and in different populations, develop biomarkers for such exposures, and generate evidence for modifying them to improve outcomes.

Challenges in IBD Research 2024: Preclinical Human IBD Mechanisms.

Preclinical human inflammatory bowel disease (IBD) mechanisms is one of 5 focus areas of the Challenges in IBD Research 2024 document, which also includes environmental triggers, novel technologies, precision medicine, and pragmatic clinical research. Herein, we provide a comprehensive overview of current gaps in inflammatory bowel diseases research that relate to preclinical research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in IBD interception, remission, and restoration. The document is the result of multidisciplinary input from scientists, clinicians, patients, and funders and represents a valuable resource for patient-centric research prioritization. This preclinical human IBD mechanisms section identifies major research gaps whose investigation will elucidate pathways and mechanisms that can be targeted to address unmet medical needs in IBD. Research gaps were identified in the following areas: genetics, risk alleles, and epigenetics; the microbiome; cell states and interactions; barrier function; IBD complications (specifically fibrosis and stricturing); and extraintestinal manifestations. To address these gaps, we share specific opportunities for investigation for basic and translational scientists and identify priority actions.

To address the unmet medical needs of patients with inflammatory bowel diseases (IBD) and move toward cures, preclinical human-relevant research must center on mechanistic questions pertinent to patients with IBD in the 3 areas of disease interception, remission, and restoration.

Incidence, Prevalence, and Racial and Ethnic Distribution of Inflammatory Bowel Disease in the United States.

BACKGROUND & AIMS: We sought to estimate the incidence, prevalence, and racial-ethnic distribution of physician-diagnosed inflammatory bowel disease (IBD) in the United States. METHODS: The study used 4 administrative claims data sets: a 20% random sample of national fee-for-service Medicare data (2007 to 2017); Medicaid data from Florida, New York, Pennsylvania, Ohio, and California (1999 to 2012); and commercial health insurance data from Anthem beneficiaries (2006 to 2018) and Optum's deidentified Clinformatics Data Mart (2000 to 2017). We used validated combinations of medical diagnoses, diagnostic procedures, and prescription medications to identify incident and prevalent diagnoses. We computed pooled age-, sex-, and race/ethnicity-specific insurance-weighted estimates and pooled estimates standardized to 2018 United States Census estimates with 95% confidence intervals (CIs). RESULTS: The age- and sex-standardized incidence of IBD per 100,000 person-years was 10.9 (95% CI, 10.6-11.2). The incidence of IBD peaked in the third decade of life, decreased to a relatively stable level across the fourth to eighth decades, and declined further. The age-, sex- and insurance-standardized prevalence of IBD was 721 per 100,000 population (95% CI, 717-726). Extrapolated to the 2020 United States Census, an estimated 2.39 million Americans are diagnosed with IBD. The prevalence of IBD per 100,000 population was 812 (95% CI, 802-823) in White, 504 (95% CI, 482-526) in Black, 403 (95% CI, 373-433) in Asian, and 458 (95% CI, 440-476) in Hispanic Americans. CONCLUSIONS: IBD is diagnosed in >0.7% of Americans. The incidence peaks in early adulthood and then plateaus at a lower rate. The disease is less commonly diagnosed in Black, Asian, and Hispanic Americans.

Development and Validation of Claims-Based Definitions to Identify Incident and Prevalent Inflammatory Bowel Disease in Administrative Healthcare Databases.

BACKGROUND: To facilitate inflammatory bowel disease (IBD) research in the United States, we developed and validated claims-based definitions to identify incident and prevalent IBD diagnoses using administrative healthcare claims data among multiple payers. METHODS: We used data from Medicare, Medicaid, and the HealthCore Integrated Research Database (Anthem commercial and Medicare Advantage claims). The gold standard for validation was review of medical records. We evaluated 1 incidence and 4 prevalence algorithms based on a combination of International Classification of Diseases codes, National Drug Codes, and Current Procedural Terminology codes. The claims-based incident diagnosis date needed to be within ±90 days of that recorded in the medical record to be valid. RESULTS: We reviewed 111 charts of patients with a potentially incident diagnosis. The positive predictive value (PPV) of the claims algorithm was 91% (95% confidence interval [CI], 81%-97%). We reviewed 332 charts to validate prevalent case definition algorithms. The PPV was 94% (95% CI, 86%-98%) for ≥2 IBD diagnoses and presence of prescriptions for IBD medications, 92% (95% CI, 85%-97%) for ≥2 diagnoses without any medications, 78% (95% CI, 67%-87%) for a single diagnosis and presence of an IBD medication, and 35% (95% CI, 25%-46%) for 1 physician diagnosis and no IBD medications. CONCLUSIONS: Through a combination of diagnosis, procedural, and medication codes in insurance claims data, we were able to identify incident and prevalent IBD cases with high accuracy. These algorithms can be useful for the ascertainment of IBD cases in future studies.

Research-Based Product Innovation to Address Critical Unmet Needs of Patients with Inflammatory Bowel Diseases.

Despite progress in recent decades, patients with inflammatory bowel diseases face many critical unmet needs, demonstrating the limitations of available treatment options. Addressing these unmet needs will require interventions targeting multiple aspects of inflammatory bowel disease pathology, including disease drivers that are not targeted by available therapies. The vast majority of late-stage investigational therapies also focus primarily on a narrow range of fundamental mechanisms. Thus, there is a pressing need to advance to clinical stage differentiated investigational therapies directly targeting a broader range of key mechanistic drivers of inflammatory bowel diseases. In addition, innovations are critically needed to enable treatments to be tailored to the specific underlying abnormal biological pathways of patients; interventions with improved safety profiles; biomarkers to develop prognostic, predictive, and monitoring tests; novel devices for nonpharmacological approaches such as minimally invasive monitoring; and digital health technologies. To address these needs, the Crohn's & Colitis Foundation launched IBD Ventures, a venture philanthropy-funding mechanism, and IBD Innovate®, an innovative, product-focused scientific conference. This special IBD Innovate® supplement is a collection of articles reflecting the diverse and exciting research and development that is currently ongoing in the inflammatory bowel disease field to deliver innovative and differentiated products addressing critical unmet needs of patients. Here, we highlight the pipeline of new product opportunities currently advancing at the preclinical and early clinical development stages. We categorize and describe novel and differentiated potential product opportunities based on their potential to address the following critical unmet patient needs: (1) biomarkers for prognosis of disease course and prediction/monitoring of treatment response; (2) restoration of eubiosis; (3) restoration of barrier function and mucosal healing; (4) more effective and safer anti-inflammatories; (5) neuromodulatory and behavioral therapies; (6) management of disease complications; and (7) targeted drug delivery.

We highlight the pipeline of investigational therapies, diagnostics, and devices with potential to address pressing unmet needs of patients with inflammatory bowel diseases, including biomarkers for prognosis and treatment response, restoration of eubiosis and mucosal healing, neuromodulation, and improved control of inflammation and disease complications.

Immunoglobulin A Targets a Unique Subset of the Microbiota in Inflammatory Bowel Disease.

The immunopathogenesis of inflammatory bowel disease (IBD) has been attributed to a combination of host genetics and intestinal dysbiosis. Previous work in a small cohort of IBD patients suggested that pro-inflammatory bacterial taxa are highly coated with secretory immunoglobulin IgA. Using bacterial fluorescence-activated cell sorting coupled with 16S rRNA gene sequencing (IgA-SEQ), we profiled IgA coating of intestinal microbiota in a large cohort of IBD patients and identified bacteria associated with disease and treatment. Forty-three bacterial taxa displayed significantly higher IgA coating in IBD compared with controls, including 8 taxa exhibiting differential IgA coating but similar relative abundance. Patients treated with anti-TNF-α therapies exhibited dramatically altered microbiota-specific IgA responses compared with controls. Furthermore, increased IgA coating of Oscillospira was associated with a delay in time to surgery. These results demonstrate that investigating IgA responses to microbiota can uncover potential disease-modifying taxa and reveal improved biomarkers of clinical course in IBD.

Defining the Path Forward for Biomarkers to Address Unmet Needs in Inflammatory Bowel Diseases.

Despite major advances in the inflammatory bowel diseases field, biomarkers to enable personalized and effective management are inadequate. Disease course and treatment response are highly variable, with some patients experiencing mild disease progression, whereas other patients experience severe or complicated disease. Periodic endoscopy is performed to assess disease activity; as a result, it takes months to ascertain whether a treatment is having a positive impact on disease progression. Minimally invasive biomarkers for prognosis of disease course, prediction of treatment response, monitoring of disease activity, and accurate diagnosis based on improved disease phenotyping and classification could improve outcomes and accelerate the development of novel therapeutics. Rapidly developing technologies have great potential in this regard; however, the discovery, validation, and qualification of biomarkers will require partnerships including academia, industry, funders, and regulators. The Crohn's & Colitis Foundation launched the IBD Biomarker Summit to bring together key stakeholders to identify and prioritize critical unmet needs; prioritize promising technologies and consortium approaches to address these needs; and propose harmonization approaches to improve comparability of data across studies. Here, we summarize the outcomes of the 2018 and 2019 meetings, including consensus-based unmet needs in the clinical and drug development context. We highlight ongoing consortium efforts and promising technologies with the potential to address these needs in the near term. Finally, we summarize actionable recommendations for harmonization, including data collection tools for improved consistency in disease phenotyping; standardization of informed consenting; and development of guidelines for sample management and assay validation. Taken together, these outcomes demonstrate that there is an exceptional alignment of priorities across stakeholders for a coordinated effort to address unmet needs of patients with inflammatory bowel diseases through biomarker science.

Challenges in IBD Research: Precision Medicine.

Precision medicine is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, environmental triggers, novel technologies, and pragmatic clinical research. The Challenges in IBD Research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the precision medicine section is focused on highlighting the main gap areas that must be addressed to get closer to treatments tailored to the biological and clinical characteristics of each patient, which is the aim of precision medicine. The main gaps were identified in: 1) understanding and predicting the natural history of IBD: disease susceptibility, activity, and behavior; 2) predicting disease course and treatment response; and 3) optimizing current and developing new molecular technologies. Suggested approaches to bridge these gaps include prospective longitudinal cohort studies to identify and validate precision biomarkers for prognostication of disease course, and prediction and monitoring of treatment response. To achieve this, harmonization across studies is key as well as development of standardized methods and infrastructure. The implementation of state-of-the-art molecular technologies, systems biology and machine learning approaches for multi-omics and clinical data integration and analysis will be also fundamental. Finally, randomized biomarker-stratified trials will be critical to evaluate the clinical utility of validated signatures and biomarkers in improving patient outcomes and cost-effective care.

Challenges in IBD Research: Novel Technologies.

Novel technologies is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, environmental triggers, precision medicine and pragmatic clinical research. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the novel technologies section is focused on prioritizing unmet clinical needs in IBD that will benefit from novel technologies applied to: 1) non-invasive detection and monitoring of active inflammation and assessment of treatment response; 2) mucosal targeted drug delivery systems; and 3) prevention of post-operative septic complications and treatment of fistulizing complications. Proposed approaches include development of multiparametric imaging modalities and biosensors, to enable non invasive or minimally invasive detection of pro-inflammatory signals to monitor disease activity and treatment responses. Additionally, technologies for local drug delivery to control unremitting disease and increase treatment efficacy while decreasing systemic exposure are also proposed. Finally, research on biopolymers and other sealant technologies to promote post-surgical healing; and devices to control anastomotic leakage and prevent post-surgical complications and recurrences are also needed.

Challenges in IBD Research: Environmental Triggers.

Environmental triggers is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, novel technologies, precision medicine and pragmatic clinical research. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the environmental triggers section is focused on the main research gaps in elucidating causality of environmental factors in IBD. Research gaps were identified in: 1) epidemiology of exposures; 2) identification of signatures of biological response to exposures; and 3) mechanisms of how environmental exposures drive IBD. To address these gaps, the implementation of longitudinal prospective studies to determine disease evolution and identify sub-clinical changes in response to exposures is proposed. This can help define critical windows of vulnerability and risk prediction. In addition, systems biology analysis and in silico modeling were proposed as approaches to integrate the IBD exposome for the identification of biological signatures of response to exposures, and to develop prediction models of the effects of environmental factors in driving disease activity and response to therapy. This research could lead to identification of biomarkers of exposures and new modalities for therapeutic intervention. Finally, hypothesis-driven mechanistic studies to understand gene-environment interactions and to validate causality of priority factors should be performed to determine how environment influences clinical outcomes.

Challenges in IBD Research: Pragmatic Clinical Research.

Pragmatic clinical research is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, environmental triggers, novel technologies, and precision medicine. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the pragmatic clinical research section is focused on highlighting gaps that need to be addressed in order to optimize and standardize IBD care. Identified gaps include: 1) understanding the incidence and prevalence of IBD; 2) evaluating medication positioning to increase therapeutic effectiveness; 3) understanding the utility of therapeutic drug monitoring (TDM); 4) studying pain management; and 5) understanding healthcare economics and resources utilization. To address these gaps, there is a need to emphasize the use of emerging data sources and real-world evidence to better understand epidemiologic and therapeutic trends in IBD, expanding on existing data to better understand how and where we should improve care. Proposed approaches include epidemiological studies in ethnically and geographically diverse cohorts to estimate incidence and prevalence of IBD and impact of diversity on treatment patterns and outcomes. The implementation of new clinical trial design and methodologies will be essential to evaluate optimal medication positioning, appropriate use of TDM in adults and children, and multidisciplinary approaches to IBD pain management and its impact on healthcare resources.

Challenges in IBD Research: Preclinical Human IBD Mechanisms.

Preclinical human IBD mechanisms is part of five focus areas of the Challenges in IBD research document, which also include environmental triggers, novel technologies, precision medicine and pragmatic clinical research. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the preclinical human IBD mechanisms manuscript is focused on highlighting the main research gaps in the pathophysiological understanding of human IBD. These research gap areas include: 1) triggers of immune responses; 2) intestinal epithelial homeostasis and wound repair; 3) age-specific pathophysiology; 4) disease complications; 5) heterogeneous response to treatments; and 6) determination of disease location. As an approach to address these research gaps, the prioritization of reverse translation studies is proposed in which clinical observations are the foundation for experimental IBD research in the lab, and for the identification of new therapeutic targets and biomarkers. The use of human samples in validating basic research findings and development of precision medicine solutions is also proposed. This prioritization aims to put emphasis on relevant biochemical pathways and humanized in vitro and in vivo models that extrapolate meaningfully to human IBD, to eventually yield first-in-class and effective therapies.

Phosphoproteomic evaluation of pharmacological inhibition of leucine-rich repeat kinase 2 reveals significant off-target effects of LRRK-2-IN-1.

Genetic mutations in leucine-rich repeat kinase 2 (LRRK2) have been linked to autosomal dominant Parkinson's disease. The most prevalent mutation, G2019S, results in enhanced LRRK2 kinase activity that potentially contributes to the etiology of Parkinson's disease. Consequently, disease progression is potentially mediated by poorly characterized phosphorylation-dependent LRRK2 substrate pathways. To address this gap in knowledge, we transduced SH-SY5Y neuroblastoma cells with LRRK2 G2019S via adenovirus, then determined quantitative changes in the phosphoproteome upon LRRK2 kinase inhibition (LRRK2-IN-1 treatment) using stable isotope labeling of amino acids in culture combined with phosphopeptide enrichment and LC-MS/MS analysis. We identified 776 phosphorylation sites that were increased or decreased at least 50% in response to LRRK2-IN-1 treatment, including sites on proteins previously known to associate with LRRK2. Bioinformatic analysis of those phosphoproteins suggested a potential role for LRRK2 kinase activity in regulating pro-inflammatory responses and neurite morphology, among other pathways. In follow-up experiments, LRRK2-IN-1 inhibited lipopolysaccharide-induced tumor necrosis factor alpha (TNFα) and C-X-C motif chemokine 10 (CXCL10) levels in astrocytes and also enhanced multiple neurite characteristics in primary neuronal cultures. However, LRRK2-IN-1 had almost identical effects in primary glial and neuronal cultures from LRRK2 knockout mice. These data suggest LRRK2-IN-1 may inhibit pathways of perceived LRRK2 pathophysiological function independently of LRRK2 highlighting the need to use multiple pharmacological tools and genetic approaches in studies determining LRRK2 function.

Aldolase directly interacts with ARNO and modulates cell morphology and acidic vesicle distribution.

Previously, we demonstrated that the vacuolar-type H(+)-ATPase (V-ATPase) a2-subunit functions as an endosomal pH sensor that interacts with the ADP-ribosylation factor (Arf) guanine nucleotide exchange factor, ARNO. In the present study, we showed that ARNO directly interacts not only with the a2-subunit but with all a-isoforms (a1-a4) of the V-ATPase, indicating a widespread regulatory interaction between V-ATPase and Arf GTPases. We then extended our search for other ARNO effectors that may modulate V-ATPase-dependent vesicular trafficking events and actin cytoskeleton remodeling. Pull-down experiments using cytosol of mouse proximal tubule cells (MTCs) showed that ARNO interacts with aldolase, but not with other enzymes of the glycolytic pathway. Direct interaction of aldolase with the pleckstrin homology domain of ARNO was revealed by pull-down assays using recombinant proteins, and surface plasmon resonance revealed their high avidity interaction with a dissociation constant: K(D) = 2.84 × 10(-10) M. MTC cell fractionation revealed that aldolase is also associated with membranes of early endosomes. Functionally, aldolase knockdown in HeLa cells produced striking morphological changes accompanied by long filamentous cell protrusions and acidic vesicle redistribution. However, the 50% knockdown we achieved did not modulate the acidification capacity of endosomal/lysosomal compartments. Finally, a combination of small interfering RNA knockdown and overexpression revealed that the expression of aldolase is inversely correlated with gelsolin levels in HeLa cells. In summary, we have shown that aldolase forms a complex with ARNO/Arf6 and the V-ATPase and that it may contribute to remodeling of the actin cytoskeleton and/or the trafficking and redistribution of V-ATPase-dependent acidic compartments via a combination of protein-protein interaction and gene expression mechanisms.

The phospholipase D1 pathway modulates macroautophagy.

Although macroautophagy is known to be an essential degradative process whereby autophagosomes mediate the engulfment and delivery of cytoplasmic components into lysosomes, the lipid changes underlying autophagosomal membrane dynamics are undetermined. Here, we show that phospholipase D1 (PLD1), which is primarily associated with the endosomal system, partially relocalizes to the outer membrane of autophagosome-like structures upon nutrient starvation. The localization of PLD1, as well as the starvation-induced increase in PLD activity, are altered by wortmannin, a phosphatidylinositol 3-kinase inhibitor, suggesting PLD1 may act downstream of Vps34. Pharmacological inhibition of PLD and genetic ablation of PLD1 in mouse cells decreased the starvation-induced expansion of LC3-positive compartments, consistent with a role of PLD1 in the regulation of autophagy. Furthermore, inhibition of PLD results in higher levels of Tau and p62 aggregates in organotypic brain slices. Our in vitro and in vivo findings establish a role for PLD1 in autophagy.

V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway.

The recruitment of the small GTPase Arf6 and ARNO from cytosol to endosomal membranes is driven by V-ATPase-dependent intra-endosomal acidification. The molecular mechanism that mediates this pH-sensitive recruitment and its role are unknown. Here, we demonstrate that Arf6 interacts with the c-subunit, and ARNO with the a2-isoform of V-ATPase. The a2-isoform is targeted to early endosomes, interacts with ARNO in an intra-endosomal acidification-dependent manner, and disruption of this interaction results in reversible inhibition of endocytosis. Inhibition of endosomal acidification abrogates protein trafficking between early and late endosomal compartments. These data demonstrate the crucial role of early endosomal acidification and V-ATPase/ARNO/Arf6 interactions in the regulation of the endocytic degradative pathway. They also indicate that V-ATPase could modulate membrane trafficking by recruiting and interacting with ARNO and Arf6; characteristics that are consistent with the role of V-ATPase as an essential component of the endosomal pH-sensing machinery.