Publications by authors named "Remo Panaccione"

266 Publications

Association of Circulating Fibrocytes With Fibrostenotic Small Bowel Crohn's Disease.

Inflamm Bowel Dis 2021 Aug 24. Epub 2021 Aug 24.

Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada.

Background: Fibrocytes are hematopoietic cells with features of mesenchymal cells found in the circulation and inflammatory sites implicated in promoting fibrosis in many fibroinflammatory diseases. However, their role(s) in the development of intestinal fibrosis is poorly understood. Here, we investigated a potential role of fibrocytes in the development of fibrosis in Crohn's disease (CD) and sought factors that may impact their development and function.

Methods: Plasma and mononuclear cells were collected from patients with and without fibrostenotic CD. Fibrocytes defined as CD11b+, CD34+, and Collagen 1+ were correlated with clinical assessments of fibrosis, including evaluation using intestinal ultrasound. We measured the levels of relevant circulating molecules via Luminex and studied the effect of patient plasma proteins on fibrocyte differentiation.

Results: Fibrocyte numbers were increased in CD patients with stricturing Crohn's disease compared with patients with an inflammatory phenotype (P = .0013), with strong correlation between fibrocyte numbers and acoustic radiation force impulse (ARFI), a measure of bowel elasticity on intestinal ultrasound (R = .8383, P = .0127). Fibrostenotic plasma was a more potent inducer of fibrocyte differentiation in both primary human monocytes and cell line and contained increased levels of cytokines implicated in fibrocyte differentiation compared with plasma from inflammatory patients. Interestingly, increased fibrocyte numbers at time of ultrasound were associated with escalation of medical therapy and endoscopic/surgical management of small bowel strictures at 30 months follow-up.

Conclusions: Circulating fibrocytes strongly correlate with fibrostenotic disease in CD, and they may serve as predictors for escalation of medical +/- surgical therapy.
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http://dx.doi.org/10.1093/ibd/izab157DOI Listing
August 2021

Early Serum Infliximab Levels in Pediatric Ulcerative Colitis.

Front Pediatr 2021 29;9:668978. Epub 2021 Jul 29.

Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.

Data on serum infliximab concentrations during induction in pediatric ulcerative colitis are limited. The study aim is to evaluate the relationship between serum infliximab concentrations during induction and short-term clinical remission in children with ulcerative colitis. We carried out a prospective, multi-center cohort study in pediatric patients with ulcerative colitis. Serum infliximab concentrations were collected at peak dose #1, week 1, trough pre-dose #2, and trough pre-dose #3. Infliximab dosing was left to investigator discretion. Clinical remission was defined by pediatric ulcerative colitis activity index <10 at week 8. Twenty-four of thirty-four subjects (71%) achieved clinical remission at week 8. The median infliximab concentrations were 33.0 μg/mL (interquartile range: 26.5-52.1 μg/mL) pre-dose #2 and 22.5 μg/mL (interquartile range:15.9-32.3 μg/mL) pre-dose #3. Trough pre-dose #2 infliximab concentration yielded area under receiver operator characteristic curve 0.7, 95% CI: 0.5-0.9 in predicting week 8 clinical remission; a cut-off of 33.0 μg/mL yielded 62.5% sensitivity, 66.7% specificity. Trough pre-dose #3 infliximab concentrations were lower for subjects <10 years compared to ≥ 10 years [median 15.9 μg/mL, interquartile range (IQR) 8.5-21.8 μg/mL vs. 27.7 μg/mL, IQR 17.2-46.7 μg/mL, = 0.01] and correlated with baseline weight (Spearman's rank correlation coefficient 0.45, = 0.01). The median half-life following first IFX dose was 6.04 days (IQR 5.3-7.9 days). Infliximab concentrations ≥33 μg/mL prior to the second dose were associated with week 8 clinical remission. As young age and low body weight impact infliximab concentration, prospective studies with proactive adjustment in pediatric patients with ulcerative colitis should be carried out. Clinicians caring for children with UC should diligently adjust and monitor infliximab to optimize response.
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http://dx.doi.org/10.3389/fped.2021.668978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358797PMC
July 2021

Anti-Microbial Antibody Response is Associated With Future Onset of Crohn's Disease Independent of Biomarkers of Altered Gut Barrier Function, Subclinical Inflammation, and Genetic Risk.

Gastroenterology 2021 Jul 20. Epub 2021 Jul 20.

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology & Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background And Aims: Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDRs) of CD patients is an independent risk factor for future CD development.

Methods: We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS). We used samples at enrollment of prospectively followed healthy FDRs from a nested case-control cohort of the Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic location with control FDRs remaining healthy (n = 307). To address our research aims, we fitted a multivariable conditional logistic regression model and performed causal mediation analysis.

Results: High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted odds ratio, 6.5; 95% confidence interval, 3.4-12.7; P < .001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation.

Conclusions: Our results suggest that increased anti-microbial antibody responses are associated with risk of future development of CD, independent of biomarkers of abnormal gut barrier function, subclinical inflammation, and CD-related genetic risks. This suggests that anti-microbial antibody responses are an early predisease event in the development of CD.
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http://dx.doi.org/10.1053/j.gastro.2021.07.009DOI Listing
July 2021

Evaluation of an integrated yoga program in patients with inflammatory bowel disease: A pilot study.

Explore (NY) 2021 May 4. Epub 2021 May 4.

Department of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada. Electronic address:

Background: The effects of integrated yoga programs on mental health outcomes in inflammatory bowel disease (IBD) have not been well explored. To explore the acceptability, implementation and effectiveness of an integrated eight-week yoga program plus aromatherapy massage in patients with IBD.

Methods: Nine participants with documented IBD were recruited from a gastroenterology clinic in Calgary, Alberta, Canada to participate in an integrated yoga program weekly for eight weeks with outcomes assessed at baseline and week 8. Primary outcomes were assessed using Theory of Planned Behaviour as a guiding theory to identify salient beliefs from qualitative analysis of a semi-structured interview, survey items measuring the strength of beliefs and a daily log was used to capture adherence and adverse events. Secondary outcomes were collected using validated survey tools examining anxiety, depression, stress, sleep quality, and physical and mental quality of life.

Results: Attitude, subjective norm and perceived behavioral control beliefs pertinent to the yoga intervention and daily practice were identified. Participants reported feeling the intervention was very helpful; however, felt guilt about not completing daily practices which decreased confidence and intention to continue with the practice. An average of 55.6% of in-person sessions were attended and decreased over time. Participants practiced on average of 5.4 days per week. Depression and mental health scores improved at week 8 from baseline.

Conclusions: We were able to identify key salient beliefs of IBD patients in regard to an integrated yoga plus aromatherapy massage intervention. This intervention appears to be acceptable and further research should explore its potential to improve mental and physical health outcomes including IBD symptoms.
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http://dx.doi.org/10.1016/j.explore.2021.04.006DOI Listing
May 2021

Relevance of monitoring transmural disease activity in patients with Crohn's disease: current status and future perspectives.

Therap Adv Gastroenterol 2021 16;14:17562848211006672. Epub 2021 Apr 16.

Department of Gastroenterology, University Teaching Hospital Lueneburg, Bögelstraße 1, Lueneburg 21339, Germany.

Treatment targets of inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn's disease (CD) have evolved over the last decade. Goals of therapy consisting of symptom control and steroid sparing have shifted to control of disease activity with endoscopic remission being an important endpoint. Unfortunately, this requires ileocolonoscopy, an invasive procedure. Biomarkers [C-reactive protein (CRP) and fecal calprotectin (FCP)] have emerged as surrogates for endoscopic remission and disease activity, but also have limitations. Despite this evolution, we must not lose sight that CD involves transmural inflammation, not fully appreciated with ileocolonoscopy. Therefore, transmural assessment of disease activity by cross-sectional imaging, in particular with magnetic resonance enterography (MRE) and intestinal ultrasonography (IUS), is vital to fully understand disease control. Bowel-wall thickness (BWT) is the cornerstone in assessment of transmural inflammation and BWT normalization, with or without bloodflow normalization, the key element demonstrating resolution of transmural inflammation, namely transmural healing (TH) or transmural remission (TR). In small studies, achievement of TR has been associated with improved long-term clinical outcomes, including reduced hospitalization, surgery, escalation of treatment, and a decrease in clinical relapse over endoscopic remission alone. This review will focus on the existing literature investigating the concept of TR or residual transmural disease and its relation to other existing treatment targets. Current data suggest that TR may be the next logical step in the evolution of treatment targets.
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http://dx.doi.org/10.1177/17562848211006672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053830PMC
April 2021

Drug development for ulcerative proctitis: current concepts.

Gut 2021 Jul 31;70(7):1203-1209. Epub 2021 Mar 31.

Department of Gastroenterology and Inserm NGERE U1256, Nancy University Hospital, University of Lorraine, Vandoeuvre-lès-Nancy, France

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http://dx.doi.org/10.1136/gutjnl-2021-324108DOI Listing
July 2021

Suboptimal Vaccination Administration in Mothers With Inflammatory Bowel Disease and Their Biologic-Exposed Infants.

Inflamm Bowel Dis 2021 Feb 20. Epub 2021 Feb 20.

Department of Community Health Sciences, University of Calgary, Alberta, Canada.

Background: Pregnant women with inflammatory bowel disease (IBD) are at increased risk of developing complications from vaccine-preventable infections. We investigated the factors influencing vaccine administration in pregnant women with IBD and their infants, in addition to the safety of vaccination in the infants.

Methods: This retrospective cohort study identified individuals from a tertiary referral clinic whose records were linked to a provincial vaccine database. We conducted χ 2 tests, Fisher exact tests, and logistic regression adjusting for age and disease duration to compare vaccine administration by medication class. Potential rotavirus vaccine adverse events were determined in infants of women with IBD.

Results: We included 303 pregnant women and 262 infants. Vaccines were administered to women on biologic therapy as follows: hepatitis B virus (82.9%), diphtheria-tetanus-pertussis (82.1%), and hepatitis A virus (49.3%). The influenza vaccination was provided peripartum in 50.7% of patients. The measles-mumps-rubella-varicella vaccine was provided to 89.3% of women before biologic initiation. Women treated with a biologic (adjusted odds ratio, 2.50; 95% confidence interval, 1.39-4.35) or immunomodulator (adjusted odds ratio, 4.00; 95% confidence interval, 2.22-7.69) were more likely to receive the Prevnar 13 and Pneumovax 23 vaccines than were unexposed individuals, but the overall proportion vaccinated was low (Prevnar 13, 35.7%; Pneumovax 23, 39.3%). At least 90% of infants received the measles-mumps-rubella-varicella vaccine and inactivated vaccines. Fourteen biologic-exposed children (19.2%) received the live rotavirus vaccine with no significant differences in adverse events compared with biologic-unexposed infants (7.1% vs 8.2%, P = 0.99).

Conclusions: Better education surrounding vaccine recommendations is required for both health care providers and individuals with IBD given poor pneumococcal, hepatitis A virus, and influenza vaccination rates. Inadvertent administration of the rotavirus vaccine in biologic-exposed infants did not result in more adverse events, raising the possibility of safety.
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http://dx.doi.org/10.1093/ibd/izab033DOI Listing
February 2021

Dietary patterns, food groups and nutrients in Crohn's disease: associations with gut and systemic inflammation.

Sci Rep 2021 01 18;11(1):1674. Epub 2021 Jan 18.

Department of Medicine, University of Calgary, Room 6D60, TRW Building, 3280 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.

This study examined associations between dietary intake and gut and systemic inflammation assessed by fecal calprotectin ≤ or > 100 μg/mg (FCP), C-reactive protein ≤ or > 5 mg/L (CRP) and serum cytokine profiles in Crohn's disease (CD) patients in clinical remission. A 3-month observational study was conducted at the University of Calgary in Calgary, Alberta, Canada between 2016 and 2018 in 66 outpatients with CD in clinical remission. FCP was obtained from stool samples at baseline and 3-months and serum CRP and serum cytokines were assessed at 3-months only (n = 41). Dietary intakes were collected using 3-day food records at baseline and 3-months and categorized as: PREDIMED Mediterranean diet scores (pMDS) total and individual components, the dietary inflammatory index (DII), food groups, and common micro- and macro-nutrients. Statistical models were developed to identify relationships between dietary factors and FCP, CRP and cytokine levels. Daily intake of leafy green vegetables was associated with FCP ≤ 100 μg/mg (p < 0.05). Increasing omega 6:3 ratio was associated with CRP ≤ 5 mg/L (p = 0.02). Different cytokines were significantly associated with various dietary variables. Future studies in patients with greater disease activity should be undertaken to explore these relationships.
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http://dx.doi.org/10.1038/s41598-020-80924-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814046PMC
January 2021

An International Multicenter Real-Life Prospective Study of Electronic Chromoendoscopy Score PICaSSO in Ulcerative Colitis.

Gastroenterology 2021 04 6;160(5):1558-1569.e8. Epub 2021 Feb 6.

Institute of Immunology and Immunotherapy, NIHR Wellcome Trust Clinical Research Facilities, University of Birmingham, and University Hospitals Birmingham NHS Trust, Birmingham, United Kingdom; National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, United Kingdom; Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Canada.

Background & Aims: Endoscopic and histologic remission are important goals in the treatment of ulcerative colitis (UC). We investigated the correlation of the recently developed Paddington International Virtual ChromoendoScopy ScOre (PICaSSO) and other established endoscopic scores against multiple histological indices and prospectively assessed outcomes.

Methods: In this prospective multicenter international study, inflammatory activity was assessed with high-definition and virtual chromoendoscopy in the rectum and sigmoid using the Mayo Endoscopic Score (MES), UC Endoscopic Index of Severity (UCEIS), and PICaSSO. Targeted biopsies were taken for assessment using Robarts Histological Index (RHI), Nancy Histological index (NHI), ECAP (Extent, Chronicity, Activity, Plus score), Geboes, and Villanacci. Follow-up data were obtained at 6 and 12 months after colonoscopy.

Results: A total of 307 patients were recruited. There was strong correlation between PICaSSO and histology scores, significantly superior to correlation coefficients of MES and UCEIS with histology scores. A PICaSSO score of ≤3 detected histologic remission by RHI (≤3 + absence of neutrophils) with area under the receiver operating characteristic curve (AUROC) 0.90 (95% confidence interval [CI] 0.86-0.94) and NHI (≤1) AUROC 0.82 (95% CI 0.77-0.87). The interobserver agreement for PICaSSO was 0.88 (95% CI 0.83-0.92). At 6- and 12-months follow-up, PICaSSO score ≤3 predicted better outcomes than PICaSSO >3 (hazard ratio [HR] 0.19 [0.11-0.33] and 0.22 [0.13-0.34], respectively),} as well as PICaSSO 4-8 (HR 0.25 [0.12-0.53] and 0.22 (0.12-0.39), respectively) and similar to histologic remission.

Conclusion: In this first real-life multicenter study, the PICaSSO score correlated strongly with multiple histological indices. Furthermore, PICaSSO score predicted specified clinical outcomes at 6 and 12 months, similar to histology. Thus, PICaSSO can be a useful endoscopic tool in the therapeutic management of UC.
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http://dx.doi.org/10.1053/j.gastro.2020.12.024DOI Listing
April 2021

Ustekinumab is effective and safe for ulcerative colitis through 2 years of maintenance therapy.

Aliment Pharmacol Ther 2020 12 21;52(11-12):1658-1675. Epub 2020 Oct 21.

Spring House, PA, USA.

Background: The ongoing UNIFI long-term extension evaluates subcutaneous ustekinumab for moderate-to-severe ulcerative colitis (UC) from weeks 44 through 220.

Aims: To assess efficacy (through week 92) and safety (through week 96) during the long-term extension METHODS: Overall, 399 responders to intravenous ustekinumab induction and who were randomised to maintenance therapy were treated in the long-term extension (115 received subcutaneous placebo, 141 received ustekinumab 90 mg every 12 weeks [q12w], and 143 received ustekinumab 90 mg q8w). Placebo treatment was discontinued at unblinding after week 44. Partial Mayo scores were collected every 12 weeks and at each dosing visit after unblinding. Safety was evaluated throughout.

Results: Among all patients randomised in maintenance, symptomatic remission rates (stool frequency = 0/1; rectal bleeding = 0) at week 92 were, 64.5% and 67.6% in the ustekinumab q12w and q8w groups, respectively. Among randomised patients treated in the long-term extension, 78.7% and 83.2% of patients receiving q12w and q8w, respectively, attained symptomatic remission at week 92; >95% of patients in symptomatic remission at week 92 were corticosteroid-free. Both ustekinumab groups maintained efficacy through week 92. From weeks 44 to 96, adverse events (AEs) per hundred patient-years (PY) of follow-up for combined ustekinumab vs placebo were: 255.68 vs 267.93; serious AEs, 9.34 vs 12.69; malignancies (including non-melanoma skin cancers), 0.93 vs 1.49; and serious infections, 2.33 vs 2.99. One patient with multiple comorbidities who received one ustekinumab dose after dose adjusting from placebo experienced a fatal cardiac arrest.

Conclusions: The efficacy of ustekinumab in patients with UC was sustained through 92 weeks. No new safety signals were observed (ClinicalTrials.gov number, NCT02407236).
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http://dx.doi.org/10.1111/apt.16119DOI Listing
December 2020

Editorial: is age just a number when it comes to treatment of inflammatory bowel disease?

Aliment Pharmacol Ther 2020 11;52(10):1615-1616

Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, AB, Canada.

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http://dx.doi.org/10.1111/apt.16098DOI Listing
November 2020

Associations of NOD2 polymorphisms with Erysipelotrichaceae in stool of in healthy first degree relatives of Crohn's disease subjects.

BMC Med Genet 2020 10 15;21(1):204. Epub 2020 Oct 15.

Department of Medicine, University of Toronto, Toronto, ON, Canada.

Background: Genetic analyses have identified many variants associated with the risk of inflammatory bowel disease (IBD) development. Among these variants, the ones located within the NOD2 gene have the highest odds ratio of all IBD genetic risk variants. Also, patients with Crohn's disease (CD) have been shown to have an altered gut microbiome, which might be a reflection of inflammation itself or an effect of other parameters that contribute to the risk of the disease. Since NOD2 is an intracellular pattern recognition receptor that senses bacterial peptidoglycan in the cytosol and stimulates the host immune response (Al Nabhani et al., PLoS Pathog 13:e1006177, 2017), it is hypothesized that NOD2 variants represent perfect candidates for influencing host-microbiome interactions. We hypothesized that NOD2 risk variants affect the microbiome composition of healthy first degree relative (FDR) of CD patients and thus potentially contribute to an altered microbiome state before disease onset.

Methods: Based on this, we studied a large cohort of 1546 healthy FDR of CD patients and performed a focused analysis of the association of three major CD SNPs in the coding region of the NOD2 gene, which are known to confer a 15-40-fold increased risk of developing CD in homozygous or compound heterozygous individuals.

Results: Our results show that carriers of the C allele at rs2066845 was significantly associated with an increase in relative abundance in the fecal bacterial family Erysipelotrichaceae.

Conclusions: This result suggests that NOD2 polymorphisms contribute to fecal microbiome composition in asymptomatic individuals. Whether this modulation of the microbiome influences the future development of CD remains to be assessed.
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http://dx.doi.org/10.1186/s12881-020-01115-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566148PMC
October 2020

Ulcerative Colitis Narrative Global Survey Findings: Communication Gaps and Agreements Between Patients and Physicians.

Inflamm Bowel Dis 2021 06;27(7):1096-1106

Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany.

Background: The Ulcerative Colitis (UC) Narrative global surveys examined patient and physician perspectives on living with UC and tried to identify gaps in optimal care. Questions explored patient-physician interactions, UC management goals, and resources for improving communication.

Methods: Questionnaires were conducted across 10 countries, covering aspects of UC including diagnosis, treatment, and impact on patient quality of life, in addition to standard demographic information. Descriptive statistics were calculated.

Results: Globally, 2100 patients and 1254 physicians were surveyed (from August 2017 to February 2018). Results showed 85% of patients were satisfied with the communication they had with their physician, including discussions relating to symptoms (86%) and medication options (81%). However, 72% of patients wished for more information and support at initial diagnosis, and 48% did not feel comfortable talking to their physician about emotional concerns. Most patients (71%) set UC management goals with their physician. Both patients (63%) and physicians (79%) wished for longer appointments. Although 84% of physicians believed patient advocacy organizations to be important in UC management, more than half (54%) never discussed them with patients.

Conclusions: These survey results highlight overall patient satisfaction with patient-physician communication but emphasize areas for improvement, such as patient desire to have more information earlier in their disease course. There is an unmet need for better information, materials, and support. Physicians need to consider which of the available tools and resources can help patients talk more openly, and accurately, because informed patients are more likely to engage with physicians in a shared decision-making process.
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http://dx.doi.org/10.1093/ibd/izaa257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214018PMC
June 2021

Harnessing localised delivery of gut-selective therapy for ulcerative colitis.

Lancet Gastroenterol Hepatol 2020 12 5;5(12):1031-1032. Epub 2020 Oct 5.

Division of Gastroenterology and Hepatology, University of Calgary, Calgary, AB T2N 4Z6, Canada.

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http://dx.doi.org/10.1016/S2468-1253(20)30292-2DOI Listing
December 2020

Best Practice Guidance for Adult Infusion Centres during the COVID-19 Pandemic: Report from the COVID-19 International Organization for the Study of IBD [IOIBD] Task Force.

J Crohns Colitis 2020 Oct;14(14 Suppl 3):S785-S790

Crohn's and Colitis Center, Professor of Medicine, Professor of Microbiology and Immunology, Division of Gastroenterology and Hepatology, University of Miami Miller School of Medicine, Miami, FL, USA.

Infusion centres are a central part in the management of patients with inflammatory bowel disease [IBD] and could be a source of transmission of SARS-COV-2. Here we aimed to develop global guidance for best practices of infusion centres for IBD patients and to determine the impact of the COVID-19 pandemic on these centres. Under the auspices of the International Organization for the Study of Inflammatory Bowel Disease [IOIBD], a task force [TF] was formed, an online survey was developed to query infusion centre protocols during COVID-19, and recommendations were made, based on TF experience and opinion. Recommendations focus mainly on patients screening, infusion centres re-organization, personnel protection, and protocol modifications such as shortening infusion duration or replacing it with subcutaneous alternatives. Implementing these recommendations will hopefully reduce exposure of both IBD patients and care givers to SARS-COV-2 and improve the function and safety of infusion centres during the COVID-19 pandemic as well as potential future threats.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543377PMC
October 2020

The Argument Against a Biosimilar Switch Policy for Infliximab in Patients with Inflammatory Bowel Disease Living in Alberta.

J Can Assoc Gastroenterol 2020 Oct 24;3(5):234-242. Epub 2020 Jan 24.

Inflammatory Bowel Disease Clinic, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.

A nonmedical switch policy is currently being considered in Alberta, which would force patients on originator biologics to biosimilar alternatives with the hypothetical aim of reducing costs to the health care system. The evidence to support the safety of nonmedical switching in patients with inflammatory bowel disease (IBD) is of low to very low quality; in fact, existing data suggest a potential risk of harm. In a pooled analysis of randomized controlled trials, one patient would lose response to infliximab for every 11 patients undergoing nonmedical switching. Switching to a biosimilar has important logistical and ethical implications including potential forced treatment changes without appropriate patient consent and unfairly penalizing patients living in rural areas and those without private drug insurance. Even in the best-case scenario, assuming perfectly executed switching without logistical delays, we predict switching 2,000 patients with Remicade will lead to over 60 avoidable surgeries in Alberta. Furthermore, nonmedical switching has not been adequately studied in vulnerable populations such as children, pregnant women, and elderly patients. While the crux of the argument for nonmedical switching is cost savings, biosimilar switching may not be cost effective: Particularly when originator therapies are being offered at the same price as biosimilars. Canadian patients with IBD have been surveyed, and their response is clear: They are not in support of nonmedical switching. Policies that directly influence patient health need to consider patient perspectives. Solutions to improve cost efficiency in health care exist but open, transparent collaboration between all involved stakeholders is required.
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http://dx.doi.org/10.1093/jcag/gwz044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465546PMC
October 2020

Long-term safety of vedolizumab for inflammatory bowel disease.

Aliment Pharmacol Ther 2020 10 2;52(8):1353-1365. Epub 2020 Sep 2.

Leuven, Belgium.

Background: Vedolizumab, a gut-selective α β integrin antibody, is approved for moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD).

Aim: To report the final results from the vedolizumab GEMINI long-term safety (LTS) study.

Methods: The phase 3, open-label GEMINI LTS study (initiated May 2009) enrolled patients with UC or CD from four prior clinical trials and vedolizumab-naïve patients. Vedolizumab LTS was evaluated; efficacy and patient-reported outcomes were exploratory endpoints.

Results: Enrolled patients (UC, n = 894; CD, n = 1349) received vedolizumab 300 mg IV every 4 weeks; median cumulative exposure was 42.4 months (range: 0.03-112.2) for UC and 31.5 months (range: 0.03-100.3) for CD. Over 8 years, adverse events (AEs) occurred in 93% (UC) and 96% (CD) of patients, with UC (36%) and CD (35%) exacerbations most frequent. Serious AEs were reported for 31% (UC) and 41% (CD) of patients. Vedolizumab discontinuation due to AEs occurred in 15% (UC) and 17% (CD) of patients. There were no new trends for infections, malignancies, infusion-related reactions, or hepatic events, and no cases of progressive multifocal leukoencephalopathy. Of the ten deaths (UC, n = 4; CD, n = 6), two were considered drug-related by local investigators (West Nile virus infection-related encephalitis and hepatocellular carcinoma). Continuous vedolizumab maintained clinical response long-term, with 33% (UC) and 28% (CD) of patients in clinical remission at 400 treatment weeks.

Conclusions: The safety profile of vedolizumab remains favourable with no unexpected or new safety concerns. These results further establish the safety of vedolizumab and support its long-term use (NCT00790933/EudraCT 2008-002784-14).
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http://dx.doi.org/10.1111/apt.16060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540482PMC
October 2020

Characterization of Creatine Kinase Levels in Tofacitinib-Treated Patients with Ulcerative Colitis: Results from Clinical Trials.

Dig Dis Sci 2021 08 20;66(8):2732-2743. Epub 2020 Aug 20.

Inflammation and Immunology, Pfizer Inc, Collegeville, PA, USA.

Background: Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Creatine kinase (CK) levels and CK-related adverse events (AEs) in tofacitinib-treated patients with UC were evaluated.

Methods: Data were analyzed for three UC cohorts: Induction (phase 2 and 3 induction studies); Maintenance (phase 3 maintenance study); Overall [patients who received tofacitinib 5 or 10 mg twice daily (b.d.) in phase 2, phase 3, or open-label, long-term extension studies; data at November 2017]. Clinical trial data for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis are presented for contextualization.

Results: Week 8 mean change from baseline CK with tofacitinib 10 mg b.d. induction therapy was 91.1 U/L (95% CI, 48.1-134.1) versus 19.2 U/L (8.5-29.9) with placebo. Among patients completing induction with 10 mg b.d. and re-randomized to 52 weeks of maintenance therapy, mean increases from induction baseline to the end of maintenance were 35.9 (8.1-63.7), 90.3 (51.9-128.7), and 115.6 U/L (91.6-139.7), with placebo, 5 and 10 mg b.d., respectively. The incidence rate (unique patients with events per 100 patient-years) for AEs of CK elevation in the tofacitinib-treated UC Overall cohort was 6.6 versus 2.2, 6.5, and 3.7 for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis, respectively. No serious AEs of CK elevation or AEs of myopathy occurred in UC studies.

Conclusions: In patients with UC, CK elevations with tofacitinib appeared reversible and not associated with clinically significant AEs. UC findings were consistent with tofacitinib use in other inflammatory diseases.

Trial Registration: NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612; NCT01262118; NCT01484561; NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01059864; NCT01164579; NCT00976599; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT00413699; NCT00661661; NCT01710046; NCT00678210; NCT01276639; NCT01309737; NCT01241591; NCT01186744; NCT01163253; NCT01877668; NCT01882439; NCT01976364.
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http://dx.doi.org/10.1007/s10620-020-06560-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298233PMC
August 2021

Frequency of Opioid Prescription at Emergency Department Discharge in Patients with Inflammatory Bowel Disease: A Nationwide Analysis.

Clin Gastroenterol Hepatol 2021 Oct 16;19(10):2064-2071.e1. Epub 2020 Jul 16.

Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alimentiv (formerly Robarts Clinical Trials, Inc), London, Ontario, Canada. Electronic address:

Background & Aims: Patients with inflammatory bowel disease (IBD) frequently experience chronic pain. Patients will often seek out care in the emergency department (ED) where short-term opioid use may be associated with potential treatment-related complications. We aimed to assess the rate and factors associated with opioid prescription in IBD patients discharged from the ED.

Methods: We conducted a cross-sectional analysis of data collected in the US National Hospital Ambulatory Medical Care Survey (NHAMCS) from 2006-2017. We determined the proportion of adult patients (≥18 years) with IBD prescribed an opioid in ED or at ED discharge. Logistic regression was used to evaluate predictors of opioid prescription. Time-trend analysis was performed to evaluate temporal patterns in opioid use. All analyses were adjusted for complex survey design.

Results: We identified ∼965,000 weighted discharges from the ED for patients with IBD. In total, 51.9% [95% CI: 42.2% -61.6%] of visits resulted in opioid administration in ED and 35.3% [95% CI: 26.5% -45.2%] of IBD-related ED discharges were associated with an opioid prescription. IBD patients with moderate/severe pain (adjusted odds ratio aOR 5.06 [95% CI: 1.72 -14.90], p < 0.01) were more likely to receive opioids whereas older age (aOR 0.73 per decade [95% CI: 0.55 -0.98], p = 0.04) were less likely. In temporal analysis, a trend towards decreasing opioid use in ED and opioid prescriptions at discharge was observed in 2015-2017.

Conclusions: More than one third of IBD patients are prescribed an opioid at discharge from ED, highlighting a potential gap in care for accessing effective pain management solutions in this population.
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http://dx.doi.org/10.1016/j.cgh.2020.07.020DOI Listing
October 2021

Combination Therapy Does Not Improve Rate of Clinical or Endoscopic Remission in Patients with Inflammatory Bowel Diseases Treated With Vedolizumab or Ustekinumab.

Clin Gastroenterol Hepatol 2021 07 12;19(7):1366-1376.e2. Epub 2020 Jul 12.

Department of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background & Aims: Patients with Crohn's disease (CD) or ulcerative colitis (UC) often receive combination therapy with an immunomodulator and tumor necrosis factor antagonists, especially infliximab. However, the benefits of combination therapy with vedolizumab and ustekinumab are unclear.

Methods: We performed a retrospective study of patients with CD or UC initiating vedolizumab or ustekinumab therapy at Massachusetts General Hospital (USA), Alberta Health Sciences (Canada), or Nancy University Hospital (France) with at least 1 year of follow up. The primary outcome was clinical remission or response at week 14, based on the Harvey Bradshaw index for CD or simple clinical colitis index or partial Mayo score for UC. We separately examined week 30 and week 54 clinical outcomes, endoscopic response, and durability of therapy using multivariable regression models and adjusting for relevant confounders.

Results: Our study included 549 patients (263 with UC, 286 with CD) receiving maintenance therapy with vedolizumab and 363 patients (4 with UC, 359 with CD) receiving maintenance therapy with ustekinumab with 1 year of follow up. The mean disease duration was 13-15 years. One-hundred thirty-one patients receiving vedolizumab (23.9%; 78 receiving thiopurine, 53 receiving methotrexate) and 120 patients receiving ustekinumab (33.1%, 57 receiving thiopurine, 63 receiving methotrexate) were receiving combination therapy. For vedolizumab, there was no difference in clinical response or remission with combination therapy vs monotherapy at week 14 (68.2% vs 74.1%; P = .22), week 30 (74.3% vs 75.6%; P = .78) or week 54 (78.3% vs 72.9%, P = .33). For ustekinumab, there was no difference in clinical response or remission with combination therapy vs monotherapy at week 14 (54.6% vs 65.8%; P = .08), week 30 (71.6% vs 77.4%; P = .33) or week 54 (62.1% vs 67.0%; P = .52). There were similar proportions of patients remaining on treatment or with endoscopic response at 1 year among patients receiving combination or monotherapy with vedolizumab or ustekinumab.

Conclusions: In patients with CD or UC initiating ustekinumab or vedolizumab therapy, combination therapy with immunomodulators did not increase rates of clinical remission or response, endoscopic remission, or persistence of therapy at 1 year.
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http://dx.doi.org/10.1016/j.cgh.2020.07.012DOI Listing
July 2021

Letter: combination of biologics in inflammatory bowel diseases. Authors' reply.

Aliment Pharmacol Ther 2020 08;52(3):568-569

Division of Gastroenterology, Department of Medicine, UCSD Inflammatory Bowel Disease Center, La Jolla, CA, USA.

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http://dx.doi.org/10.1111/apt.15919DOI Listing
August 2020

Smoking May Reduce the Effectiveness of Anti-TNF Therapies to Induce Clinical Response and Remission in Crohn's Disease: A Systematic Review and Meta-analysis.

J Crohns Colitis 2021 Jan;15(1):74-87

Community Health Sciences, University of Calgary, Calgary, AB, Canada.

Background And Aims: Cigarette smoking worsens prognosis of Crohn's disease [CD]. We conducted a systematic review and meta-analysis to examine the association between smoking and induction of clinical response or remission with anti-tumour necrosis factor [TNF] therapy.

Methods: MEDLINE, EMBASE, PubMed, and Cochrane CENTRAL [June 2019] were searched for studies reporting the effect of smoking on short-term clinical response and remission to anti-TNF therapy [≤16 weeks following the first treatment] in patients with CD. Risk ratios [RR] with 95% confidence intervals [CI] were calculated using random-effects models.

Results: Eighteen observational studies and three randomised controlled trials [RCT] were included. Current smokers and non-smokers [never or former] had similar rates of clinical response [observational studies RR: 0.96; 95% CI: 0.88, 1.05; RCTs RR: 1.09; 95% CI: 0.84, 1.41]. When restricted to studies clearly defining the smoking exposure, smokers treated with anti-TNF were less likely to achieve clinical response than non-smokers [smokers defined as having ≥5 cigarettes/day for ≥6 months RR: 0.63; 95% CI: 0.48, 0.83; lifetime never smokers vs ever smokers excluding former smokers RR: 0.81; 95% CI: 0.71, 0.93]. Current smokers were also less likely to achieve clinical remission in observational studies [RR: 0.75; 95% CI: 0.57, 0.98], though this association was not seen in RCTs [RR: 1.04; 95% CI: 0.89, 1.21].

Conclusions: Smoking is significantly associated with a reduction in the ability of infliximab or adalimumab to induce short-term clinical response and remission when pooling studies where smoking status was clearly defined. When patients with CD are treated with highly effective therapy, including anti-TNF agents, concurrent smoking cessation may improve clinical outcomes.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa139DOI Listing
January 2021

Author Correction: Crohn's disease.

Nat Rev Dis Primers 2020 06 19;6(1):51. Epub 2020 Jun 19.

IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center - IRCCS -, Rozzano, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41572-020-0193-xDOI Listing
June 2020

Human interleukin-4-treated regulatory macrophages promote epithelial wound healing and reduce colitis in a mouse model.

Sci Adv 2020 Jun 5;6(23):eaba4376. Epub 2020 Jun 5.

Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.

Murine alternatively activated macrophages can exert anti-inflammatory effects. We sought to determine if IL-4-treated human macrophages [i.e., hM(IL4)] would promote epithelial wound repair and can serve as a cell transfer treatment for inflammatory bowel disease (IBD). Blood monocytes from healthy volunteers and patients with active and inactive IBD were converted to hM(IL4)s. IL-4 treatment of blood-derived macrophages from healthy volunteers and patients with inactive IBD resulted in a characteristic CD206CCL18CD14 phenotype (RNA-seq revealed IL-4 affected expression of 996 genes). Conditioned media from freshly generated or cryopreserved hM(IL4)s promoted epithelial wound healing in part by TGF, and reduced cytokine-driven loss of epithelial barrier function in vitro. Systemic delivery of hM(IL4) to dinitrobenzene sulphonic acid (DNBS)-treated mice significantly reduced disease. These findings from in vitro and in vivo analyses provide proof-of-concept support for the development of autologous M(IL4) transfer as a cellular immunotherapy for IBD.
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http://dx.doi.org/10.1126/sciadv.aba4376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274799PMC
June 2020

Author Correction: Crohn's disease.

Nat Rev Dis Primers 2020 05 20;6(1):42. Epub 2020 May 20.

IBD Center, Humanitas Research Hospital, Milan, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41572-020-0183-zDOI Listing
May 2020

Systematic review: medical therapy for fibrostenosing Crohn's disease.

Aliment Pharmacol Ther 2020 06 13;51(12):1233-1246. Epub 2020 May 13.

Cleveland, USA.

Background: Medical therapy and/or endoscopic balloon dilation with intralesional therapies are options for the treatment of small bowel fibrostenotic Crohn's disease (CD).

Aim: To perform a systematic review summarising evidence for efficacy of systemic and endoscopic intralesional medical therapy in established small bowel strictures in adult CD patients.

Methods: A systematic search of MEDLINE, EMBASE, CENTRAL and Scopus was conducted. Primary outcomes were rates of surgical resection and repeat endoscopic dilation. Pooled event rates from random effects models across studies with 95% confidence intervals were reported.

Results: Ten studies describing systemic medical therapy and eight studies of intralesional injection were included. One randomised controlled trial each for systemic therapy and intrastricture injection were identified. Only observational studies were found for systemic biologic therapies, which exclusively included tumour necrosis factor (TNF) antagonists, while intralesional therapies all involved corticosteroids except for one study that evaluated infliximab. Pooled event rates for surgical resection after systemic and intralesional therapy were 28.3% (95% CI: 18.2%-41.3%) and 18.5% (95% CI: 8.3%-36.2%), respectively over a median follow-up of 23 months (range 5.5-105.8), and 21.8 months (range 5-47). Risk of repeat endoscopic balloon dilation in those with intralesional therapy was 58.3% (95% CI: 36.6%-77.3%) over a median follow-up of 21.8 months (range 5-47).

Conclusions: There are no favoured therapies for patients with stricturing small bowel CD. Data are lacking for ustekinumab and vedolizumab. No endoscopic intralesional medications provided a clear benefit for prevention of repeat EBD or surgery.
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http://dx.doi.org/10.1111/apt.15750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7777136PMC
June 2020

A Diversified Dietary Pattern Is Associated With a Balanced Gut Microbial Composition of Faecalibacterium and Escherichia/Shigella in Patients With Crohn's Disease in Remission.

J Crohns Colitis 2020 Nov;14(11):1547-1557

Department of Medicine, University of Calgary, Calgary, AB, Canada.

Background And Aims: Crohn's disease [CD] is associated with alterations in gut microbial composition and function. The present controlled-intervention study investigated the relationship between patterns of dietary intake and baseline gut microbiota in CD patients in remission and examined the effects of a dietary intervention in patients consuming a non-diversified diet [NDD].

Methods: Forty outpatients with quiescent CD were recruited in Calgary, Alberta, Canada. Based on 3-day food records, patients consuming a lower plant-based and higher red and processed meat-based diet were assigned to the NDD group [n = 15] and received a 12-week structured dietary intervention; all other patients were assigned to the diversified diet [DD] control group [n = 25] and received conventional management. Faecal microbiota composition, short chain fatty acids [SCFAs] and calprotectin were measured.

Results: At baseline the NDD and DD groups had a different faecal microbial beta-diversity [p = 0.003, permutational multivariate analysis of variance]. The NDD group had lower Faecalibacterium and higher Escherichia/Shigella relative abundances compared to the DD group [3.3 ± 5.4% vs. 8.5 ± 10.6%; 6.9 ± 12.2% vs. 1.6 ± 4.4%; p ≤ 0.03, analysis of covariance]. These two genera showed a strong negative correlation [rs = -0.60, q = 0.0002]. Faecal butyrate showed a positive correlation with Faecalibacterium [rs = 0.52, q = 0.002], and an inhibitory relationship with Escherichia/Shigella abundance [four-parameter sigmoidal model, R = -0.83; rs = -0.44, q = 0.01], respectively. After the 12 weeks of dietary intervention, no difference in microbial beta-diversity between the two groups was observed [p = 0.43]. The NDD group demonstrated an increase in Faecalibacterium [p < 0.05, generalized estimated equation model], and resembled the DD group at the end of the intervention [p = 0.84, t-test with permutation]. We did not find an association of diet with faecal SCFAs or calprotectin.

Conclusions: Dietary patterns are associated with specific gut microbial compositions in CD patients in remission. A diet intervention in patients consuming a NDD modifies gut microbial composition to resemble that seen in patients consuming a DD. These results show that diet is important in shaping the microbial dysbiosis signature in CD towards a balanced community.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa084DOI Listing
November 2020
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