bluuebunny/crossref_metadata_2025 huggingface dataset:
ADEQUACY OF SIGMOIDOSCOPY IN COMPARISION TO COLONOSCOPY TO ASSESS DISEASE ACTIVITY DURING FOLLOW UP IN PATIENTS WITH ULCERATIVE COLITIS
Authors: Patel Sameet , Jain Shubham , Chandnani Sanjay , Debnath Prasanta , Contractor Qais , Kahmei Seemily , Kamat Rima , Rathi Pravin
Published: January 2022

BACKGROUND

Endoscopic remission is the current treatment target in patients with Ulcerative Colitis (UC). Literature on adequacy of sigmoidoscopy in comparison to colonoscopy to assess endoscopic and histologic activity during follow up is sparse.

METHODS

This is an interim analysis of a prospective study of patients diagnosed with UC with disease extent proximal to the sigmoid colon. Fifty adult patients underwent a complete colonoscopy with segmental biopsies. Endoscopic disease activity was graded using Mayo Endoscopic Subscore (MES) and the Ulcerative Colitis Endoscopic Index of Severity score (UCEIS). The histological grading was done using the Nancy score, Robarts Histopathology Index (RHI) and Simplified Geboes Score (SGS). The maximum rectosigmoid disease activity was compared with the maximum disease activity in the rest of the colon.

RESULTS

Endoscopic Correlation: Sigmoidoscopic evaluation using MES showed good correlation with pan colonoscopic evaluation for disease activity with a sensitivity of 92.11%, specificity of 66.67%, accuracy of 86% (95% CI – 73.26% to 94.18%), kappa value (k) of 0.58 (p value < 0.001) and Area under curve (AUC) of 0.82 (95% CI- 0.74 to 0.942). Similarly, sigmoidoscopic evaluation using UCEIS score showed good correlation with pan colonoscopic evaluation for disease activity with a sensitivity of 95.0%, specificity of 70%, accuracy of 90% (95% CI – 78.19% to 96.67%), k of 0.68 (p value < 0.001) and AUC of 0.895 (95% CI- 0.805 to 0.924). Disease activity in the colon missed by performing a sigmoidoscopy using MES and UCEIS score is only 6% and 4% respectively. Histological Correlation: Histologic findings in rectosigmoid showed good correlation with histologic findings in rest of the colon using Nancy’s score [Sensitivity of 97.96%, specificity of 100%, accuracy of 98% (95% CI – 89.35% to 99.95%), k of 0.658 (p value < 0.001) and AUC of 0.99 (95% CI- 0.959 to 1.0)], Simplified Geboes Score [Sensitivity of 97.92%, specificity of 100%, accuracy of 98% (95% CI – 89.35% to 99.95%), k of 0.79 (p value < 0.001) and AUC of 0.99 (95% CI- 0.962 to 1.0)], and Robarts Histopathology Index [Sensitivity of 95.56%, specificity of 80%, accuracy of 94% (95% CI – 83.45% to 98.75%), k of 0.694 (p value < 0.001) and AUC of 0.878 (95% CI- 0.667 to 1.0) ]. Histologic disease activity in the colon missed by performing a sigmoidoscopy using Nancy score, SGS and RHI is only 2%, 2% and 4% respectively.

CONCLUSION

In patients diagnosed with UC and having disease extent proximal to the sigmoid colon, sigmoidoscopic evaluation has good correlation with pan colonoscopic evaluation for grading endoscopic and histological disease activity. A sigmoidoscopic examination is adequate to assess the disease activity in patients with disease extent proximal to the sigmoid colon.
CORRELATION OF FECAL, PLASMA, SERUM, AND SALIVARY CALPROTECTIN TO ENDOSCOPIC AND HISTOLOGIC OUTCOMES IN PATIENTS WITH CROHN’S DISEASE
Authors: Kamp Kendra , Clark-Snustad Kindra , Saad Kamil , Tolentino Ernie , Heitkemper Margaret , Dey Neelendu , Gui Sean , Lee Scott D
Published: January 2022

BACKGROUND

Monitoring disease activity in Crohn’s disease is important as achieving endoscopic remission significantly improves clinical outcomes. Fecal calprotectin is a common non-invasive biomarker for monitoring disease activity. However, fecal calprotectin does not always correlate with other disease activity assessments and stool samples can be difficult to collect and inconvenient to return. Thus, we aimed to compare the association between calprotectin levels in stool, saliva, and blood, and assess to their correlation with endoscopic and histologic outcomes among patients with Crohn’s disease.

METHODS

Nineteen patients with Crohn’s disease were included in the data analysis. Patients collected stool, blood and saliva samples within 2 days of colonoscopy. Samples were processed and stored at -80C, then assessed for calprotectin via ELISA. The Simple Endoscopic Score – Crohn’s Disease (SES-CD) was scored at the time of colonoscopy. The biopsy sample with the most severe disease activity was assessed by a single pathologist for the Robarts Histological Index (RHI).

RESULTS

All participants had endoscopic data and blood samples (n=19), 18 had saliva samples, and 18 had stool samples. Participants had a mean age of 32.4 (SD: 7.4). Seventy percent (n=14) were female and 45% were on biologics. The median calprotectin levels were 65.4 ug/g (IQR: 8.5, 385.0) for fecal calprotectin, 23.9 ng/ml (IQR: 15.9, 40.8) for plasma calprotectin, 977.7 ng/ml (IQR: 733.3, 1207.5) for serum calprotectin, and 3761.6 ng/ml (IQR: 874.0, 8267.2) for salivary calprotectin. Correlations (as represented by Pearson’s correlation coefficients) with endoscopic disease activity (SES-CD) were 0.83 for fecal calprotectin, 0.28 for plasma calprotectin, 0.24 for serum calprotectin, and 0.02 for salivary calprotectin. Correlations with histologic disease activity (RHI) were 0.80 for fecal calprotectin, 0.56 for plasma calprotectin, 0.16 for serum calprotectin, and -0.03 for salivary calprotectin.

CONCLUSION

We present preliminary findings of the relationship between calprotectin from fecal, blood, and saliva samples with endoscopic and histologic outcomes in a small sample of patients with Crohn’s disease. Larger sample sizes are needed to further examine the possible role of blood-based calprotectin assessments. In the current study, only two participants had very high SES-CD scores which influenced our ability to understand the relationship of calprotectin to endoscopic disease activity in this subset. Of interest, plasma calprotectin had a higher correlation with histology than serum, which aligns with previous studies.
PAIN IN INFLAMMATORY BOWEL DISEASE (IBD): DOES OPIOID USE PREDICT WORSE HOSPITAL OUTCOMES?
Authors: Dasu Neethi , Khalid Yaser , Blair Brian , Foster C Jonathan
Published: January 2022

BACKGROUND

Opioid use has been hypothesized to be a marker for increased severity of (IBD) for patients because those patients are more likely to require surgical intervention and have uncontrolled pain. Previous studies have not compared outcomes between patients with opioid use and dependence with IBD compared to patients with IBD not using opioids. Our study aims to investigate hospital mortality, hospital length of stay (LOS), and total charges between both patient groups.

METHODS

Data were extracted from the National Inpatient Sample (NIS) 2016-2019 Database. The NIS was searched for hospitalizations for adult patients with IBD, including ulcerative colitis (UC) and Crohn’s (CD), as a principal discharge diagnosis with opioid use and dependence as a secondary diagnosis using ICD-10 codes. The primary outcome was inpatient mortality. Multivariate logistic and linear regression analysis was used accordingly to adjust for confounders. STATA software was used for analysis.

RESULTS

Among 1,165,075 patients who had IBD, 33,195 (2.8%) had concomitant opioid usage and dependence. The adjusted odds ratio (OR) for inpatient mortality (OR +2.8, p<0.018), LOS (+1.47 days, p<0.0001), and total hospital charges (+8,982, p<0.0001) for IBD and opioid use compared to those with only IBD were all statistically significant. Independent positive predictors of increased mortality were the following: fistula formation (OR 3.06), hematochezia (OR 2.85), electrolyte abnormalities (OR 1.48), bowel resection (OR 1.37), older age (OR 1.05) [p <0.0001 for all]. Interestingly, colonoscopy (OR 0.48, p<0.0001) and females (OR 0.79, p<0.0001) had less mortality. Independent positive predictors of increased LOS and total hospital charges were the following: fistula formation (+4.9 days, +$53,176 p<0.0001 for both), bowel obstruction (+1.2 days, +$9,228 p<0.0001 for both), hematochezia (+1.0, +14,977 days, p<0.0001 for both), electrolyte abnormalities (+2.0 days, +$16,793, p<0.0001, for both), colonoscopy (+1.9 days, +14,796, p<0.0001 for both), bowel resection (+4.5 days, +66,206, p<0.0001 for both). Total charges were also increased for Asian patients (+11,388, p<0.0001) and Hispanic patients (+10,177, p<0.0001).

CONCLUSION

Our study shows that there is significantly increased mortality, hospital LOS, and total charges for the subpopulation of IBD patients with opioid use and dependence. The presence of fistula formation, hematochezia, electrolyte abnormalities, older age, and prior bowel resection also portends higher mortality. Pain is a common complaint in patients with IBD and leads to increased morbidity. Our study is significant because it illustrates the importance of pain management in IBD and highlights the detrimental outcomes that come with opioid use and dependence. Further randomized trials would be helpful to study this patient population.
THE IMPACT OF CARDIAC ARRHYTHMIAS ON INFLAMMATORY BOWEL DISEASE (IBD)
Authors: Dasu Neethi , Khalid Yaser , Blair Brian , Derosa Justin , Chiesa Drew
Published: January 2022

BACKGROUND

Chronic inflammation in patients with IBD is theorized to be a trigger for cardiac arrhythmias in this patient population. There is a paucity of studies that study the risk factors and outcomes associated with cardiac arrhythmias in patients with IBD. Our study aims to investigate hospital mortality, hospital length of stay (LOS), and total charges between both patient groups.

METHODS

Data was extracted from the National Inpatient Sample (NIS) 2016-2019 Database using ICD -10 codes. The NIS was searched for hospitalizations involving adult patients with ulcerative colitis (UC) and Crohn’s disease (CD), as a principal discharge diagnosis. Cardiac arrhythmias, including atrial fibrillation, atrial flutter, ventricular tachycardia, ventricular fibrillation, cardiac arrest, and supraventricular tachycardias (SVT) was used as a secondary diagnosis. The primary outcome was inpatient mortality. Multivariate logistic and linear regression analysis was used accordingly to adjust for confounders. STATA software was used for analysis.

RESULTS

Among 1,165,075 patients who had IBD, 133,270 (11.4%) had cardiac arrhythmias. The adjusted odds ratio (OR) for inpatient mortality (OR 3.44, p<0.0001), hospital length of stay (LOS) (+1.78 days, p<0.0001), and total hospital charges (+25,727, p<0.0001) for IBD and cardiac arrhythmias compared to those patients with only IBD were all statistically significant. Independent positive predictors of increased mortality were the following: fistula formation (OR 3.02), hematochezia (OR 2.63), hypovolemia (OR 1.61), electrolyte abnormalities (OR 1.46), bowel resection (OR 1.37). Interestingly, patients undergoing colonoscopy (OR 0.48, p<0.0001) had less mortality. Independent positive predictors of increased LOS and total hospital charges were the following: fistula formation (+4.9 days, +$52,890 p<0.0001 for both), bowel obstruction (+1.3 days, +$10,000 p<0.0001 for both), hematochezia (+1.0 days, +13,736, p<0.0001 for both), electrolyte abnormalities (+1.9 days, +$15,999, p<0.0001, for both), colonoscopy (+1.9 days, +14,577, p<0.0001 for both), bowel resection (+4.5 days, +75,444, p<0.0001 for both).

CONCLUSION

Our population-based study provides evidence that there is a significant increase in mortality, hospital LOS, and total charges for the subpopulation of IBD patients with cardiac arrhythmias. It is important to note that many patients in the IBD population have concomitant cardiac arrhythmias (>10% in this study) which leads to an increased burden on the healthcare system. It is important for practitioners to recognize the risk factors associated with worsening outcomes in this patient subpopulation as early intervention can help mitigate negative outcomes. The management of IBD is complex and this study illustrates the importance of a multidisciplinary team to help maximize patient care.
COST-EFFECTIVENESS OF TOFACITINIB FOR THE TREATMENT OF MODERATE TO SEVERE ACTIVE ULCERATIVE COLITIS IN COLOMBIA
Authors: Gil Fabio , Julian-Banos Fabian , Amador Luisa , Castano Natalia , Reyes Juan
Published: January 2022

OBJECTIVE

To evaluate the cost-effectiveness of tofacitinib versus other treatment options currently available in Colombia for the management of adult patients with moderate-to-severe ulcerative colitis in naïve to biologics (first line) and exposed to biologics (second line).

METHODS

A Markov model was constructed with 8 weeks cycles. It simulates a cohort of patients with moderate-to-severe ulcerative colitis from a payer perspective in a 5-year horizon. The health states include remission, treatment response (without remission), active UC, and colectomy. The transition probabilities for the induction and maintenance phase were obtained from a network meta-analysis. Effectiveness was measured from quality-adjusted life-year (QALY) and the utilities were obtained from the literature. Unit costs were derived from official national sources, and these were expressed in US dollars 2021 at the average exchange rate of $3 693 COP/US. Probabilistic and deterministic sensitivity analyses were conducted. The threshold was defined as one gross domestic product ($5 391) per capita.

RESULTS

For first line, the incremental cost-effectiveness ratio (ICER) per QALY was for tofacitinib $2 611 and for infliximab $7 652 compared to adalimumab. Sensitivity analysis showed that tofacitinib is shown as cost-effective in 52% of the iterations, followed by adalimumab 25% and infliximab 23% patients. Meanwhile, adalimumab was $27 527 compared to tofacitinib in second line. Tofacitinib was cost-effective 72% of the iterations, followed by adalimumab 28% in the sensitivity analysis. Infliximab and golimumab were not included due to data limitation in network metanalysis in second line. For both lines vedolizumab was not a cost-effective alternative under the threshold assessed.

CONCLUSION

The analysis suggests that, in Colombia, the treatment with tofacitinib for moderate-to-severe UC patients is a cost-effective option in both lines, compare with other treatment options available.
GEOGRAPHIC DIFFERENCES IN THE RISK OF SURGERY IN INFLAMMATORY BOWEL DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Hansen Tawnya , Mak Joyce , Underwood Fox , Windsor Joseph , King James , Quan Joshua , Buie Michael , Coward Stephanie , Frolkis Alex , Leung Alexander , Ma Christopher , Novak Kerri , Panaccione Remo , Qian Yiming , Burisch Johan , Gearry Richard , Ng Siew , Kaplan Gilaad
Published: January 2022

BACKGROUND

The management of inflammatory bowel disease (IBD) is associated with considerable healthcare and societal cost. A key driver of direct medical cost, remains surgery. Although the cumulative risks of surgery have been well described in countries of the Western world, surgical risk data from Asia, where IBD is rapidly emerging, is lacking.

OBJECTIVES

The primary objective was to compare the cumulative risk of surgery at 1-year after a diagnosis of Crohn’s disease (CD) and ulcerative colitis (UC) between contemporary adult population-based cohorts from the Western world and Asia. Secondarily, we estimated 5- and 10-year risks of IBD-related surgery.

METHODS

MEDLINE and EMBASE were searched for population-based studies published on or after January 1, 2000, that reported 1-, 5-, and 10-year risks of IBD-related surgery. Authors were contacted to provide previously unpublished data. Random effects models were performed to analyze temporal and regional risks of surgery for cohorts diagnosed with IBD in the year 1998 and later.

RESULTS

The initial search yielded 10,358 citations. Of those, 37 studies were used in analyses. For UC, the 1-, 5-, and 10-year risk of surgery were 1.71% (95% confidence intervals [CI]: 1.13, 2.29), 3.77% (95% CI: 2.41, 5.13), and 8.33% (95% CI: 5.03, 11.63), respectively. For CD, the 1-, 5-, and 10-year risk of surgery were 7.17% (95% CI: 5.92, 8.42), 13.63% (95% CI: 11.26, 16.00), and 24.57% (95% CI: 19.21, 29.93), respectively (Table 1; Figure 1). For CD, the 1-year risk of surgery was 7.44% (95% CI: 6.07, 8.80) and 7.22% (95% CI: 2.65, 11.78) for countries in the Western world and countries in Asia, respectively (p= 0.93). The Western 5-year risk of CD surgery (13.52%, 95% CI: 10.85, 16.19) was similar to Asia (15.95%, 95% CI: 5.48, 26.43) (p=0.66). The 1-year risk of surgery for UC was not significantly different between Western world countries (1.87%, 95% CI: 1.27, 2.47) and Asia (0.74%, 95% CI: -0.48, 1.97) (p=0.13). The pooled 5-year risk of surgery was significantly higher in countries of the Western world (4.13%, 95% CI: 2.71, 5.55) as compared to Asia (2.11%, 95% CI: 1.88, 2.33) (p=0.02). Comparison of pooled 10-year risk between countries of the Western world and Asia was not possible as there was only one Asian study published on risk of surgery 10-years after CD and UC diagnosis each.

CONCLUSIONS

During the 21st century the risk of early surgery 1-year after the diagnosis for CD and UC was similar in countries of the Western world as compared to Asia. Long-term (10-year data) was lacking for Asian countries. Future studies are needed to generate more robust long-term estimates for risks of IBD-surgery in Asia.
NOVEL CONTRIBUTIONS OF CLAUDIN-4 TO EPITHELIAL BARRIER REGULATION AND COLITIS
Authors: Shashikanth Nitesh , Liu Yunuo , Xing Tiaosi , Turner Jerrold
Published: January 2022

Intestinal barrier dysfunction is linked to human IBD and contributes to progression of experimental, immune-mediated colitis. Claudin family tight junction proteins are critical determinants of epithelial paracellular permeability and barrier function. Expression of one of these, claudin-2, a pore-forming claudin, is specifically upregulated in IBD. We have shown that claudin-2 overexpression or, conversely, channel inhibition, augment or attenuate, respectively, immune-mediated colitis severity. We sought to understand claudin contributions to barrier function using in vitro and in vivo models.

Claudin-4 overexpression has been shown to reduce cation permeability in vitro, leading to the conclusion that this protein is a barrier-forming claudin. We found, however, that, in the absence of claudin-2 expression, neither knockout nor overexpression of claudin-4 affected barrier function. Instead, claudin-4 specifically suppressed claudin-2 pore function by destabilizing claudin-2 polymers and disrupting claudin-2 anchoring at the tight junction. Thus, claudin-4 is not barrier-forming but is the first pore-regulating claudin.

Together with observations that claudin-2 exacerbates colitis in vivo and that claudin-4 antagonizes claudin-2 function in vitro led us to hypothesize that intestinal epithelial claudin-4 knockout would exacerbate colitis. Knockout mice were, however, protected from both immune-mediated and DSS-induced chemical colitis. Conversely, transgenic claudin-4 overexpression exacerbated colitis. Preliminary in vitro studies suggest that claudin-4 may limit collective migration and epithelial wound repair.

As a whole, our studies require a reconsideration of claudin functional classifications and reveal unanticipated contributions of claudin-4 to barrier regulation and epithelial wound repair. The relationship between these functions and claudin-4 downregulation in human IBD remains to be explored.
PLIN2 IS AN ARYL HYDROCARBON RECEPTOR TRANSCRIPTIONAL TARGET AND MAY CONTRIBUTE TO MUCOSAL RESTITUTION
Authors: Davis Deanna , Ciorba Matthew , Alvarado David
Published: January 2022

INTRODUCTION

Dysregulated barrier function contributes to the pathogenesis in inflammatory bowel diseases (Crohn’s (CD) and ulcerative colitis (UC)). The cytosolic transcription factor aryl hydrocarbon receptor (AHR) is activated by both endogenous and exogenous ligands, and functionally contributes to maintaining mucosal homeostasis. Recently, we demonstrated that AHR activity promotes a pro-restitutive program in small intestine, but this pathway is disrupted in Crohn’s disease. In this study, we sought to identify genetic loci associated with AHR pathway dysfunction and to identify candidate downstream effectors linking AHR activity to mucosal healing.

METHODS

Organoid lines were established with biopsies from healthy patients (N=4) and patients with IBD (CD=4, UC=5) and from mice with intact Ahr (WT) or Ahr null (KO). Genomic DNA was isolated and genotyped with a custom GSA SNP chip. Organoids were differentiated and treated with AHR agonist 6-Formylindolo[3,2-b]carbazole (FICZ) or vehicle. Expression of AHR transcriptional target cytochrome P450 1A1 (CYP1A1) was determined by quantitative realtime (qRT) PCR and was used to measure AHR activity. Genomic association analysis was performed using PLINK with cell lines with high (>3 fold) CYP1A1 expression as controls and cells with low CYP1A1 expression as cases.

RESULTS

Using human organoids, nine genetic variants were associated with low AHR activity (p<5x10-8). One variant, rs12338361, has been identified as an expression quantitative trait locus (eQTL) for Perilipin 2 (PLIN2) in other tissues. PLIN2 is involved in lipid droplet formation and trafficking in the liver, but has also been shown to be a PPARγ effector and reduce inflammation by lowering the release of TNFa in the intestine. In WT mouse organoids, expression of Plin2 was increased in response to FICZ treatment (∼50% increase). This upregulation was dependent on Ahr, as Plin2 expression did not increase in KO mouse organoids (∼7% increase). Expression of PLIN2 was assessed in human organoids treated with FICZ and was found to correlate with AHR activity (r=0.953, p=4.896 x 10-7).

CONCLUSIONS

PLIN2 is a transcriptional target of AHR and may contribute to AHR-mediated epithelial restitution through activation of the PPARγ pathway. This may represent a novel method of controlling inflammation in the intestinal epithelium.
A NEWLY DISCOVERED REGULATORY CD8 T CELL NETWORK HAS THE POTENTIAL TO REGULATE AND ELIMINATE PATHOGENIC CD4 T CELLS IN AUTOIMMUNE MEDIATED DISEASE OF THE GUT
Authors: Crane Courtney , Bowser Justin , Fasnacht Rachael , Gardell Jennifer , Maurer Meghan , Julien Susan , Templeton Megan , Therriault Jon Henry , Swiderek Kristine
Published: January 2022

INTRODUCTION

Several groups have described a subset of CD8 T cells with immunosuppressive characteristics in inflammatory disease settings. The increased prevalence of a defined subset of CD8 T cells and correlation to disease has been reported in mouse and human autoimmune diseases, suggesting a protective role for select CD8 T cells in autoimmunity. We hypothesized that a dysregulated regulatory CD8 T cell (CD8 Treg) network was similarly involved in the pathology of autoimmune diseases of the gut, including Celiac disease, Crohn’s, and Ulcerative Colitis. Recently, investigators have described CD8 Treg activation through a canonical T cell receptor that results in oligoclonal expansion and perforin dependent elimination of pathogenic CD4 T cells in animal models. Here, we have demonstrated the presence of this CD8 Treg cell network in Celiac patients and its potential to regulate and eliminate pathogenic CD4 T cells.

METHODS

Using antigen induced animal models of autoimmunity, as well as PBMCs and tissues derived from patients with Celiac disease, we have developed assays to evaluate CD8 Tregs. Our approach integrates imaging, gene expression, flow cytometry, and quantification of soluble analytes following gluten exposure. This platform may be extended to evaluate the CD8 Treg network following exposure to an antigenic trigger resulting in disease flare, including in diseases with poorly defined antigenic triggers, such as Crohn’s and colitis.

RESULTS

We have characterized a surface and functional phenotype associated with CD8 Treg prevalence and activation via agonism of a native TCR. Using this phenotype, we then confirmed the presence and prevalence in Celiac patient PBMCs and duodenal tissues and distinct from CD8 T cells (Figure 1). Activation resulted in a rapid and specific cytolytic mechanism of action in mouse and human CD8 Treg cells. CD8 Treg in Celiac patients are not inherently dysfunctional, as activation of celiac patient CD8 Tregs resulted in the elimination of pathogenic CD4 T cells, which are responsible for the initiation and perpetuation of tissue destructive inflammation in Celiac disease and IBD. Using Celiac disease as platform to introduce a known antigenic trigger for autoimmunity, we have established a panel of phenotypic and functional markers to define CD8 Tregs and their activity in patients with other autoimmune diseases, including Crohn’s disease and Ulcerative Colitis.

CONCLUSION

We postulate the importance of a newly described regulatory network in autoimmune mediated gut disorders and other inflammatory disease. This network can potentially be targeted by immune-modulating biologics, to suppress pathogenic T cells, reduce disease severity & onset, as well as mitigate flare severity & frequency.
TNFAIP3 DRIVES COLITIS THROUGH DEATH CELL AND TNFα PRODUCTION
Authors: Huerta Alvaro Torres , Ruley-Haase Katelyn , Boger-May Antonia , Boone David
Published: January 2022

IBD is characterized by inflammation involving a complex interplay between innate and adaptive immunity, non-immune cells, and intestinal microbes. To understand the contributions of innate immunity to inflammation during colitis we have developed a chronic model of innate immune-mediated colitis wherein RAG1-/- mice are crossed with mice expressing TNFAIP3 in intestinal epithelial cells (villin-TNFAIP3 mice). These villin-TNFAIP3 x RAG1-/- (TRAG) mice develop early onset, 100% penetrant, chronic colitis driven by gut microbes. To understand the inflammatory signals that lead to innate colitis in this model, we crossed TRAG mice with TNFα-/- mice (FRAG mice) and compared the severity of colitis in TRAG vs. FRAG mice. In addition, we characterized TNFα-producing myeloid populations from the lamina propria of TRAG mice. Finally, we assessed the expression and localization of proteins involved in cell death pathways, to unravel the mechanisms driving innate-immune mediated colitis. Our results show that, compared to RAG1-/- mice, TRAG mice have significantly increased numbers of lamina propria leukocytes, including increased numbers of neutrophils, inflammatory monocytes, macrophages, dendritic cells, and innate lymphoid cells. TRAG mice lacking TNFα (FRAG mice) had significantly lower numbers of all these leukocyte subsets. Consistent with this, FRAG mice had significantly lower histological colitis scores, compared to TRAG mice. Inflammatory monocytes, monocytes, macrophages, and neutrophils were found to be the main sources of TNFα production, while TNFα production was null or minimal in dendritic cells, natural killer cells, ILC1, ILC3 and IC2. Macrophages and inflammatory monocytes in TRAG mice were characterized by the expression of iNOS, whereas macrophages and monocytes of FRAG and RAG1-/- mice were notably marked by Arginase1 expression. Localization of active caspase3, phosphor-MLKL and TUNEL positive cells indicated extensive epithelial crypt cell death in TRAG mice that was markedly suppressed in FRAG mice. Together our results show that TNFα drives innate immune mediated colitis, potentially through induction of IEC necroptosis. TNFAIP3 is well known as a negative regulator of receptor-mediated NFκB and MAPK activation and therefore attempts to increase TNFAIP3 expression are considered promising avenues for prevention of inflammation. The present study, indicating that intestinal epithelial cell expression of TNFAIP3 drives TNFα-induced IEC death and innate colitis, highlights potential tissue-specific roles for TNFAIP3 that should be considered in the paradigm of TNFAIP3 as a target for prevention of inflammation.
ACTIVATION OF MK2 IN CROHN’S DISEASE-ASSOCIATED FIBROSIS: NEW TARGET FOR ANTI-FIBROTIC THERAPY
Authors: Chulkina Marina , McAninch Steven , Ehudin Melanie , Cohen Claire , Dovat Sinisa , Koltun Walter , Yochum Gregory , Pinchuk Irina , Beswick Ellen
Published: January 2022

INTRODUCTION

Fibrosis is the major aggressive complication of Crohn’s disease (CD), causing intestinal obstruction. No targeted therapies are currently available to revert CD-associated fibrosis. While inflammatory mechanisms in CD have been extensively investigated, understanding the pathogenesis of fibrosis is relatively limited. Mesenchymal cells are believed to be the major effectors in profibrotic processes in CD. There is a dramatic increase in α-SMA expressing subsets of mesenchymal cells, also known as myofibroblasts (MF), and this is considered to be among the main hallmarks of profibrotic changes in CD. Thus, targeting the profibrotic reprogramming/increase of α-SMA+ MFs and/or fibrosis-driving signaling could lead to the development of novel anti-fibrotic approaches in CD. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a downstream substrate of p38 and is known to regulate pro-inflammatory cytokines. Moreover, MK2 is a regulator of downstream signaling in the profibrotic non-canonical TGF-β1/p38 pathway. However, the role of MK2 in CD-associated fibrosis and profibrotic reprogramming of MFs is not known. We hypothesize that hyperactivation of MK2 is critical to the profibrotic reprogramming of MF in CD and has potential as an anti-fibrotic therapeutic target.

METHODS

Human normal- and CD-derived MFs were analyzed using RNAseq, cytokine/chemokine multiplex array, FACS, and confocal microscopy. Chronic IL-10 KO colitis murine models relevant to CD were used in this study.

RESULTS

Increased expression of MK2 within α-SMA+ mesenchymal cells was observed in stricturing CD. Ex vivo treatment of the CD tissues with MK2 inhibitor PF-3644022 (10 μM) abrogated MK2 activity and decreased expression of fibrosis-related genes. An increase in MK2 activity within intestinal MFs was observed in vivo in IL-10KO murine colitis. Therapeutic use of the MK2 inhibitor PF-3644022 (0.2 mg/kg, daily for 10 days) in vivo significantly decreased the degree of intestinal fibrosis as measured by collagen deposition and reduced the expression of fibrosis-related genes. When compared to the WT murine-derived MFs, MK2-/- MFs showed low basal and TGF-β1 induced levels of pro-fibrotic genes expression in vitro. Using primary human MFs, we found that MK2 activity was associated with hallmark profibrotic genes in CD-MFs. Inhibition of MK2 activity with PF-3644022 reduced TGF-β1-induced overexpression of Col1α2, α-SMA, TNC, Fn1, and TGF-β1 genes. Profibrotic responses in MFs through SMAD2/3 and p38, but not MAPK signaling were mediated by MK2.

CONCLUSIONS

Our data provide evidence that activation of MK2 drives profibrotic reprogramming of mesenchymal cells in CD and it may be an attractive therapeutic target for the development of novel targeted strategies against CD-associated fibrosis.
ENHANCED RECOVERY PROGRAMS: HOW ARE WE BENEFITTING PATIENTS WITH IBD?
Authors: Shao Connie , McLeod Marshall , Gleason Lauren , Marques Isabel , Smith Burke , Chu Daniel
Published: January 2022

BACKGROUND

Enhanced Recovery Programs (ERPs) improve postoperative outcomes in colorectal surgery. Patients with IBD have been shown to benefit from use of ERP, but are immunosuppressed and chronically ill. We aimed to determine how patient outcomes under an ERP are affected by IBD.

METHODS

Patients undergoing colorectal surgery for IBD under an ERP from Oct 2015-May 2021 at a single institution were abstracted using ACS-NSQIP data, which was cross referenced with an internal health literacy database (BRIEF, 4-20). Adherence was defined as the sum of adherence to six components: pre-admission counseling, pre-op VTE prophylaxis, clear liquid diet pre-op, regional anesthesia, anti-emetic prophylaxis, and multi-modal pain management. Chi-square and two-sample t-test were used to compare patients with and without IBD. Multivariable linear and logistic regression were used to determine factors associated with IBD, SSI, and 30-day readmission.

RESULTS

Overall, patients (n=2,221) were 54% female, 76% White, 26% privately insured, 78% ASA Class 3, with mean age 57 yr, BMI 28.8 (SD=7.4). BRIEF scores were available for 644 patients, with a mean of 18.1. There were 308 patients (13.9%) undergoing surgery for IBD. Surgeries were 99.5% inpatient, 81.6% elective and 60% were laparoscopic. Procedure types included partial colectomy (69%), proctectomy (21%), total colectomy (6%), and total colectomy with proctectomy (4%). Overall ERP adherence was 59% (3.52 out of 6 components). Mean pLOS was 6.9 days (SD=7.7), SSI rate was 12.6%, readmission rate was 13.2%

On univariate analysis, patients with IBD were younger (41 vs 60 yr, p<0.001), healthier at the time of surgery (ASA2: 23% vs 12%, ASA3: 73% vs 79%, p<0.001), and more male (53% vs 45%, p=0.02), White (82% vs 75%, p=0.004), and privately insured (42% vs 23%, p<0.001). IBD patients had lower BMI (27.4 vs 29, p<0.001) and more frequently underwent total colectomy (16% vs 5%) and total colectomy with proctectomy (14% vs 2%, p<0.001), as well as laparoscopic surgery (65% vs 59%, p=0.04). Despite similar ERP adherence (60% vs 59%, p=0.6), patients with IBD had higher rates of SSI (17% vs 12%, p=0.008) and readmission (20.6% vs 12%, p<0.001).

On multivariable analysis, patients who were older (OR 0.92), Black (OR 0.25) or publicly insured (Medicaid OR 0.28, Medicare OR 0.53) we’re less like to have IBD. Those with IBD had greater health literacy scores (OR 1.11). Controlling for patient- and provider-level factors, patients with IBD were more likely to have post-operative SSI (OR 2.7) and readmission (OR 1.8).

CONCLUSION

Within an ERP, IBD is independently associated with greater rates of SSI and readmission despite factors associated with improved post-operative outcomes: younger age, private insurance, and greater health literacy. Additional research is needed to better adapt ERPs to the needs of patients with IBD.
EVALUATING THE IMPACT OF THE COVID-19 PANDEMIC ON URGENT MEDICAL ACCESS FOR PATIENTS WITH INFLAMMATORY BOWEL DISEASE AT A PRIVATE COMMUNITY GASTROENTEROLOGY PRACTICE
Authors: Kwon Michelle , Tse Chung Sang , van Deen Welmoed , Danielewicz Michael , Ward Christopher , Kogan Lawrence , Saeed Firrah , Shah Samir
Published: January 2022

BACKGROUND

Patients with inflammatory bowel disease (IBD) are subject to frequent emergency department (ED) visits. In order to decrease unnecessary ED utilization, we established an urgent care hotline (IBD URGENT) at a private community gastroenterology practice to triage pressing concerns from our patients with IBD. However, at the beginning of the Coronavirus disease 2019 (COVID-19) pandemic in Mar 2020, in-person visits were converted to telehealth visits, which could have adversly impacted patient care. Therefore, we examined the impact of the COVID-19 pandemic on the access and utilization of urgent healthcare by patients with IBD.

METHODS

In Jun 2018 we implemented a triage system involving gastroenterologists, nurses, and support staff to enable patients to contact our practice for urgent IBD issues with the goal of providing a plan of action from a provider within 4 hours of the call. Incoming patient calls were flagged with a red exclamation mark and labeled as “IBD URGENT” in our electronic medical record (eClinicalWorks) if they met any of the following criteria: new, severe abdominal pain; new, severe anal pain; fever greater than 101F; refractory emesis; or anything otherwise deemed urgent by the clinic nurses. Patients were then either advised to present to the ED for immediate evaluation, scheduled for same-day/next-day medical appointment +/- urgent labs, or received medical advice such as medication changes. The number (two-sample t-test) and triage (two-sample Z-test) of IBD URGENT calls were compared between pre-COVID (Jun 2018-Feb 2020) and post-COVID (Mar 2020-Sep 2021).

RESULTS

A total of 366 IBD URGENT calls were received and 91% had a response from a provider within 4 hours (Figure 1). The average number of IBD URGENT calls received per month were comparable pre- and post-COVID (10 vs 9, p=0.32). From Mar 2020 onwards, 40% of IBD URGENT calls were managed by urgent appointments, 51% medical advice, and only 9% ED visits, which was comparable to pre-COVID (Table 1).

CONCLUSION

It is reassuring that the COVID-19 pandemic did not cause any significant changes to the utilization and triage outcomes of the urgent IBD hotline system in our practice. Timely clinical operational changes to meet the needs of patients with the onset of the pandemic has allowed our proportion of ED visits to remain comparable to pre-COVID despite the decrease in in-person visits. As we return to normal operations, we plan to sustain our urgent hotline service by educating new staff and by reminding our patients of the IBD URGENT service. We believe this service improves quality of care for patients with IBD by avoiding unnecessary ED visits that often include overuse of Computer Tomography (CT) scans and prescription of steroids and narcotics—all associated with significant risks and financial costs.
LOCAL IBD-EXPERTS DISSATISFACTION WITH BIOLOGIC MEDICATION AUTHORIZATION DENIALS - A SURVEY OF SPECIFIC CLINICAL SCENARIOS
Authors: DeCoste Leah , Pellish Randall
Published: January 2022

BACKGROUND

Treatment with biologic medications for patients with inflammatory bowel disease (IBD) requires authorization by insurers. Insurance authorization denials are often a major obstacle in many clinical scenarios to use biologics, including specific denials of escalated dosing regimens directed by appropriate clinical indications. The objective of this study is to assess IBD-focused gastroenterologists’ (GIs) views and experiences on specific clinical scenarios resulting in biologic authorization denials.

METHODS

The survey was distributed by email to adult and pediatric IBD-focused GIs with 24 specific clinical scenarios, assessing experience and opinions on each authorization denial scenario. Survey data was recorded using REDCap software.

RESULTS

The survey was completed by 22 GIs including 17 adult GIs (81%), 4 pediatric GIs (19%), and one undisclosed provider. 70% or greater of participants disagreed with denials for (1) infliximab (IFX) dose-escalation, (2) Remicade in place of biosimilar, (3) facility-based IFX induction, (4) vedolizumab (VDZ) dose-escalation, (5) facility-based VDZ induction, (6) first-line ustekinumab (UST) therapy, (7) UST dose-escalation or re-induction, (8) UST maintenance after induction approval, (9) tofacitinib after mechanistic biologic failures, (10) VDZ or UST first-line in elderly or co-morbid patients, (11) facility-based biologic infusion for patients with prior acute infusion reactions. Variable experience was reported across the clinical scenarios ranging from 18.2% to 100%. In addition, variable experience was reported with the scenarios on whether specific denials were increasing in the past year, ranging from 16.7% to 90%.

CONCLUSION

This data portrays the collective experience of authorization denials as obstacles to using biologic medications, including escalated dosing, in multiple specific clinical scenarios. Many of these denial scenarios contradict treatment strategies that are utilized for optimal care of complex IBD patients. The data indicates many authorization denials reflect significant discrepancies between GIs and insurers on the clinical appropriateness of multiple different biologic treatment strategies. Broader survey data could better elucidate further experience with biologic treatment strategies that are being denied IBD patients, the nature of the obstacles created by insurers, and guide collaboration between physicians and insurers on best practices in the treatment of complex IBD patients.
MEDICAL DECISION-MAKING AND EDUCATION RELATED TO OSTOMY SURGERY IN PEDIATRIC PATIENTS WITH IBD: QUALITATIVE THEMES FROM MULTIDISCIPLINARY PROVIDER FOCUS GROUPS
Authors: David Jennie , Dotson Jennifer , Mackner Laura
Published: January 2022

INTRODUCTION

Pediatric patients with Inflammatory Bowel Disease (IBD) may undergo ostomy surgery, which surgically diverts stool to be collected in a bag worn on the abdomen. In addition to medical decision-making about ostomy surgery being innately complex and necessary to take a developmental approach, the medical decision also intersects with multiple disciplines and arguably requires nuanced coordination and collaboration for optimal medical decision-making and educational support.

METHODS

Multidisciplinary providers at a large, urban pediatric institution were recruited to participate in semi-scripted focus groups on medical decision-making and education related to ostomy surgery in pediatric patients with IBD. Focus groups occurred virtually and were recorded and transcribed for qualitative analysis of focus group content, with iterative analysis to generate qualitative themes.

RESULTS

Three focus groups were held, with a total of n=12 providers across all focus groups. Participants included pediatric GI providers (n=6), surgeons (n=2), GI nurse practitioner (n=1), GI social worker (n=1), and ostomy nurses (n=2). Participants reported providing care to patients at the institution for an average of 10 years (SD=9.7), and all worked with pediatric IBD patients. Focus group themes included 1) Ostomy surgery as a later treatment option for IBD patients, 2) Perception of “Defeat”/“failure,” 3) Differences between IBD patients (e.g., Crohn’s Disease versus ulcerative colitis), 4) Patients feeling unwell medically pre-operatively plays a role, 5) Psychosocial needs/support of patients, 6) Professional role issues/Provider Role considerations, 7) Provider perceptions of ostomies, 8) Provider Concerns/Needs, 10) Timing Considerations/Concerns, 11) Family Considerations/Challenges, and 12) Coordination/collaboration challenges.

CONCLUSIONS

The decision to consider ostomy surgery in pediatric IBD is often a complex decision that requires nuanced medical decision-making conversations and education for the patient and the parent/family. Further, this medical decision-making process often involves coordination and collaboration with multidisciplinary providers and often occurs over a period of time. This work assessed multidisciplinary providers’ perception of coordination and collaboration across specialties in supporting young people with IBD considering ostomy surgery. Qualitative themes identified psychosocial needs of patients and families throughout the process, various roles of multidisciplinary providers in the ostomy surgery decision, and logistical timing and coordination concerns during this medical decision. This work highlights the developmental and psychosocial considerations in supporting patients and parents through a complex medical decision.
INCREASED PREVALENCE OF ANXIETY IN HOSPITALIZED CROHN’S DISEASE PATIENTS IN THE UNITED STATES: INSIGHTS FROM NATIONAL INPATIENT DATABASE FROM 2009 TO 2018
Authors: Bhurwal Abhishek , Mutneja Hemant , Pimpinelli Sophia , Pimpinelli Marcella , Seril Darren
Published: January 2022

BACKGROUND

Patients with Crohn’s disease (CD) are at increased risk of developing anxiety and depression, and there is growing evidence that these patients would benefit from mental health screening. This study aimed to examine the temporal trends of anxiety and depression diagnoses in hospitalized CD patients in the United States.

METHODS

Using the National Inpatient Database (NIS) for the years 2009 to 2018, we analyzed all admissions for CD-related discharges using ICD 9 and ICD 10 CM codes. Besides the primary discharge diagnosis of CD, we also included discharges with a primary complication of CD or with a secondary diagnosis of CD. ICD CM codes were also utilized to identify associated comorbidities of depression and anxiety. Subsequently, we analyzed (1) the overall prevalence of depression and anxiety for CD related admissions, and (2) national temporal trends for depression and anxiety in hospitalized CD patients, from 2009 to 2018. All statistical analyses were performed using STATA software.

RESULTS

Using the NIS cohort for the years 2009 to 2018, a total of 585,867 CD-related discharges were identified. Overall, the prevalence of anxiety amongst CD-related admissions was 15.3%, and the prevalence of depression was 16.5%. The prevalence rate of anxiety increased from 7.7% in 2009 to 22.21% in 2018 (p<0.001). The prevalence of depression increased from 14.8% in 2009 to 17.3% in 2018 (p=0.15) (see Figure 1).

CONCLUSION

These results obtained utilizing the NIS indicate that the prevalence of psychiatric diagnosis, particularly anxiety, increased in hospitalized CD patients over time. The diagnosis of anxiety increased 3-fold during the time period studied. The prevalence of anxiety and depression have been reported to be higher in CD patients than in the general population. This study highlights the importance of incorporating psychological screening and mental health services in the management CD patients in both the outpatient and inpatient settings. Further studies are needed to examine the cause of the increased anxiety and depression rates observed in this patient population.
LONGITUDINAL STUDY OF THE IMPACT OF HEALTH CONFIDENCE ON INFLAMMATORY BOWEL DISEASE OUTCOMES AND HEALTHCARE UTILIZATION
Authors: Tse Chung Sang , Melmed Gil , Weng Chien-Hsiang , Shah Samir , Weaver Alandra , Oliver Brant , Elwyn Glyn , Siegel Corey , van Deen Welmoed
Published: January 2022

INTRODUCTION

A growing body of data from the primary care population demonstrates that health confidence (a patient’s belief of their ability and agency to manage their disease and impact the disease course) is an important psychosocial factor associated with chronic disease outcomes (e.g., blood pressure and glycemic control) and emergency department [ED] visits.[1] Health confidence has also been shown to be associated with inflammatory bowel disease (IBD) symptomatic burden, general well-being, and healthcare utilization.[2] We aim to explore factors that influence health confidence and examine its impact on IBD disease outcome and healthcare utilization in a longitudinal, multi-institutional cohort of adults with IBD.

METHODS

We surveyed adults (age >18) with IBD and their GI providers (verified IBD diagnosis phenotype) at 11 GI clinics across the U.S. as part of the Crohn’s and Colitis Foundation’s IBD Qorus Learning Health System. Included patients reported health confidence, disease activity, and healthcare utilization at baseline and on follow-up 6-12 months thereafter between 2018 and 2021. Health confidence was assessed using the validated Wasson’s health confidence Likert scale from 0 (‘not confident at all’) to 10 (‘very confident’).[1] We identified patient characteristics associated with health confidence using the Kruskal-Wallis test. A Fisher’s exact test was used to examine the associations between baseline low vs high health confidence (score <8 vs ≥8) and adverse IBD outcomes. P<.05 was considered statistically significant.

RESULTS

Adults with IBD (n=327; 62% Crohn’s disease, 35% ulcerative colitis; 47% in remission) had a median baseline health confidence score of 8 (IQR 7-10; Table 1). Patients with low health confidence (score <8; n=197, 60%) were more likely to have active IBD (p<.0001), use opioids (p=.0001), and have had an ED visit in the preceding 6 months (p=.04; Table 1). Notably, in the subsequent 6-12 months, patients with low baseline health confidence were more likely to have a CT scan (87% vs 13%, p=.03) and be on opioids (100% vs 0%, p=0.02) (Table 2). A higher proportion of patients with low baseline health confidence used steroids (91% vs 9%), had an ED visit (88% vs 11%), and were hospitalized (91% vs 9%) 6-12 months thereafter, though these differences did not reach statistical significance (Table 2).

CONCLUSION

Symptomatically active disease and ED visits may undermine patients’ confidence to manage their disease, which in turn increases the frequency of subsequent radiographic diagnostic testing. Opioid use was correlated with low health confidence both as a predictor and outcome in this cohort.

REFERENCES

1. Wasson, J. et al. Family practice management 21.5 (2014): 8-12.

2. Tse, C. S., et al. Gastroenterology 160.6 (2021): S-58.