Publications

Biological therapy has revolutionised the treatment of moderate to severe
inflammatory bowel disease (IBD), namely Crohn’s disease (CD) and ulcerative colitis
(UC). However, up to one-third of patients with IBD are primary non-responders, and
up to half can lose response over time.1 These unwanted outcomes can be explained
by either pharmacodynamic (mechanistic failure) or pharmacokinetic (PK) issues with
or without the development of anti-drug antibodies (ADA), so-called immunogenicity.1
Reactive therapeutic drug monitoring (TDM), defined as the measurement of drug
concentrations and anti-drug antibody (ADA) levels in the setting of primary
non-response (PNR) or secondary loss of response (SLR), can help to explain better
and manage these unwanted outcomes. However, it would make sense to try to
prevent PNR and SLR by routinely measuring drug concentrations and ADA to achieve
and maintain a targeted therapeutic drug concentration, the so-called
proactive TDM.
Here we discuss some common mistakes and significant errors to avoid when
utilising TDM of biologics in patients with IBD. The discussion is based on evidence,
whenever possible, and our clinical experience and perception of the field.

BACKGROUND: The natural history of branch-duct intraductal papillary neoplasm (BD-IPMN) in BRCA1/2 patients is unknown. Our goal was to estimate the incidence and prevalence of BD-IPMN and other pancreatic lesions in BRCA1/2 patients and compare it to that for average-risk individuals.

METHODS: We identified a cohort of BRCA1/2 patients followed at our institution between 1995 and 2020. Medical records and imaging results were reviewed to determine prevalence of pancreatic lesions. We then identified those who had undergone follow-up imaging and determined the incidence of new pancreatic lesions. We categorized pancreatic lesions as low, intermediate, or high-risk based on their malignant potential.

RESULTS: During the study period, 359 eligible BRCA1/2 patients were identified. Average patient age was 56.8 years, 88.3% were women, and 51.5% had BRCA1 . The prevalence of low-risk pancreatic lesions was 14.4%, intermediate-risk 13.9%, and high-risk 3.3%. The prevalence of BD-IPMN was 13.6% with mean cyst size 7.7 mm (range: 2 to 34 mm). The prevalence of pancreatic cancer was 3.1%. Subsequent imaging was performed in 169 patents with mean follow-up interval of 5.3 years (range: 0 to 19.7 y). The incidence of BD-IPMN was 20.1%, with median cyst size 5.5 mm (range: 2 to 30 mm). The incidence of pancreatic cancer was 2.9%. BRCA2 patients were almost 4-times more likely to develop pancreatic cancer than BRCA1 patients, however, there was no difference in incidence or prevalence of BD-IPMN.

CONCLUSIONS: Incidence and prevalence of BD-IPMNs in BRCA1/2 patients was similar to that reported for average-risk individuals. BRCA2 patients were more likely than BRCA1 patients to develop pancreatic cancer but had similar rates of BD-IPMN.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at an increased risk of malnutrition. The goal of this study was to define the prevalence of malnutrition and micronutrient deficiencies in recently diagnosed IBD patients and to compare the performance of existing malnutrition screening tools in identifying IBD patients at increased risk for malnutrition.

METHODS: This was a retrospective cohort study of adult patients with recently diagnosed IBD (≤18 months disease duration). A diagnosis of malnutrition was made utilizing the European Society for Clinical Nutrition and Metabolism malnutrition criteria. Serum micronutrient levels were included. The sensitivity of 5 malnutrition screening tools in identifying patients at moderate-high risk of malnutrition was determined based on the European Society for Clinical Nutrition and Metabolism malnutrition definition. Descriptive statistics summarized the data and univariate analyses tested associations.

RESULTS: A total of 182 patients were included for analysis; 65 (36%) met criteria for malnutrition. A total of 135 (74%) patients had ≥1 micronutrient level checked and 105 (78%) had ≥1 deficiency. Patients with prior surgery (odds ratio [OR], 4.5; P = .004), active Crohn's disease (OR, 2.8; P = .03), and diarrhea (OR, 2.1; P = .02) were more likely to be malnourished. The Malnutrition Universal Screening Tool and Saskatchewan IBD Nutrition Risk Tool had the highest sensitivity (100%) in predicting those at moderate-high risk of malnutrition at the time of screening.

CONCLUSIONS: Patients with recently diagnosed IBD have a high prevalence of malnutrition and micronutrient deficiencies. Both the Malnutrition Universal Screening Tool and Saskatchewan IBD Nutrition Risk Tool can be used to identify those at increased risk of malnutrition. Future studies and screening tool development are necessary to identify those at risk of developing malnutrition to facilitate timely referral for nutritional evaluation and prevent disease related complications.

GOALS: We sought to evaluate the association of steroids with nonalcoholic fatty liver disease (NAFLD) among patients with inflammatory bowel disease (IBD).

BACKGROUND: Patients with IBD are at increased risk of NAFLD. Steroids may have a role in the pathogenesis of NAFLD.

STUDY: We searched MEDLINE (through PubMed) and Embase for studies from inception to July 2021. We included published interventional and observational studies of adults 18 years or older with ulcerative colitis or Crohn's disease. We reported odds ratios, 95% confidence intervals, and generated forest plots. A random effects model generated a summary effect estimate. Publication bias was assessed by funnel plot and Egger's test. Study quality was examined using modified Newcastle-Ottawa scale (NOS) and Agency for Healthcare Research and Quality (AHRQ).

RESULTS: A total of 12 observational studies with 3497 participants were included. NAFLD was identified in 1017 (29.1%) patients. The pooled odds ratio for the development of NAFLD in steroid users versus non-users was 0.87 (95% confidence interval: 0.72-1.04). There was no significant heterogeneity between studies ( I ²=0.00%, P =0.13). No publication bias was detected by funnel plot or Egger's test ( P =0.24). Findings were consistent among subgroup analyses stratified by study quality.

CONCLUSION: In this meta-analysis, steroids were not associated with NAFLD in patients with IBD. Steroids may not need to be withheld from patients with IBD for the purposes of preventing NAFLD. Additional prospective studies that systematically document steroid exposure and important confounders among patients with IBD are warranted.

RATIONALE: The increased mortality and morbidity seen in critically injured patients appears associated with systemic inflammatory response syndrome (SIRS) and immune dysfunction, which ultimately predisposes to infection. Mitochondria released by injury could generate danger molecules, for example, ATP, which in turn would be rapidly scavenged by ectonucleotidases, expressed on regulatory immune cells.

OBJECTIVE: To determine the association between circulating mitochondria, purinergic signalling and immune dysfunction after trauma.

METHODS: We tested the impact of hepatocyte-derived free mitochondria on blood-derived and lung-derived CD8 T cells in vitro and in experimental mouse models in vivo. In parallel, immune phenotypic analyses were conducted on blood-derived CD8 T cells obtained from trauma patients.

RESULTS: Isolated intact mitochondria are functional and generate ATP ex vivo. Extracellular mitochondria perturb CD8+ T cells in co-culture, inducing select features of immune exhaustion in vitro. These effects are modulated by scavenging ATP, modelled by addition of apyrase in vitro. Injection of intact mitochondria into recipient mice markedly upregulates the ectonucleotidase CD39, and other immune checkpoint markers in circulating CD8+ T cells. We note that mice injected with mitochondria, prior to instilling bacteria into the lung, exhibit more severe lung injury, characterised by elevated neutrophil influx and by changes in CD8+ T cell cytotoxic capacity. Importantly, the development of SIRS in injured humans, is likewise associated with disordered purinergic signalling and CD8 T cell dysfunction.

CONCLUSION: These studies in experimental models and in a cohort of trauma patients reveal important associations between extracellular mitochondria, aberrant purinergic signalling and immune dysfunction. These pathogenic factors with immune exhaustion are linked to SIRS and could be targeted therapeutically.

BACKGROUND: With an increasing number of therapeutic options available for the management of ulcerative colitis (UC), the variability in treatment and prescribing patterns is not well known. While recent guidelines have provided updates on how these therapeutic options should be used, patterns of long-term use of these drugs over the past 2 decades remain unclear.

METHODS: We analyzed a retrospective, nationwide cohort of more than 1.7 million prescriptions for trends in prescribing behaviors and to evaluate practices suggested in guidelines relating to ordering biologics, step-up therapy, and combination therapy. The primary outcome was 30-day steroid-free remission and secondary outcomes included hospitalization, cost, and additional steroid usage. A pipeline was created to identify cohorts of patients under active UC medical management grouped by prescribing strategies to evaluate comparative outcomes between strategies. Cox proportional hazards and multivariate regression models were utilized to assess postexposure outcomes and adjust for confounders.

RESULTS: Among 6 major drug categories, we noted major baseline differences in patient characteristics at first exposure corresponding to disease activity. We noted earlier use of biologics in patient trajectories (762 days earlier relative to UC diagnosis, 2018 vs 2008; P < .001) and greater overall use of biologics over time (2.53× more in 2018 vs 2008; P < .00001) . Among biologic-naive patients, adalimumab was associated with slightly lower rates of remission compared with infliximab or vedolizumab (odds ratio, 0.92; P < .005). Comparisons of patients with early biologic initiation to patients who transitioned to biologics from 5-aminosalicylic acid suggest lower steroid consumption for early biologic initiation (-761 mg prednisone; P < .001). Combination thiopurine-biologic therapy was associated with higher odds of remission compared with biologic monotherapy (odds ratio, 1.36; P = .01).

CONCLUSIONS: As biologic drugs have become increasingly available for UC management, they have increasingly been used at earlier stages of disease management. Large-scale analyses of prescribing behaviors provide evidence supporting early use of biologics compared with step-up therapy and use of thiopurine and biologic combination therapy.

Tricyclic antidepressants (TCAs) are frequently prescribed for chronic functional pain disorders. Although the mechanism of action targets pain perception, treating patients with TCAs for disorders conceptualized as "functional" can promote stigmatization in these patients because it hints at psychological dimensions of the disorder. The goal of this study was to understand how physicians prescribe TCAs in the face of this challenge. We interviewed eleven gastroenterologists in tertiary care clinics specializing in functional gastrointestinal disorders, such as irritable bowel syndrome. We found that the physicians interviewed (1) were aware of the stigma attached to taking antidepressants for a medical condition, (2) emphasized biological, as opposed to psychological, mechanisms of action, (3) while focusing on biological mechanisms, they nevertheless prescribed TCAs in a way that is highly attentive to the psychology of expectations, making specific efforts to adjust patients' expectations to be realistic and to reframe information that would be discouraging and (4) asked patients to persist in taking TCAs despite common and, at times, uncomfortable side effects. In this context of shared decision making, physicians described nuanced understanding and behaviours necessary for treating the complexity of functional disorders and emphasized the importance of a strong patient-provider relationship.

BACKGROUND: To demonstrate treatment efficacy in Crohn's disease (CD), regulatory authorities require that trials include an endoscopic remission/response end point; however, standardized endoscopic assessment of disease activity, such as the Simple Endoscopic Score for Crohn's Disease (SES-CD), is not typically recorded by clinicians in practice or outside of clinical trials. The novel Simplified Endoscopic Mucosal Assessment for Crohn's Disease (SEMA-CD) was developed to be easy to use in routine clinical practice and as a trial end point. We conducted a study to assess and validate the reliability and feasibility of SEMA-CD as a measure of endoscopic disease activity.

METHODS: Pre- and post-treatment ileocolonoscopy videos of pediatric (n = 36) and adult (n = 74) CD patients from 2 ustekinumab clinical trials were each scored with SEMA-CD by 2 to 3 professional central readers, blinded to clinical history and other video scorings; the correlation between SEMA-CD and SES-CD previously completed during the trials was assessed. Sensitivity to change, inter- and intrarater reliability, and comparative ease of scoring were also assessed.

RESULTS: The SEMA-CD strongly correlated with SES-CD (Spearman ρ = 0.89; 95% confidence interval, 0.86-0.92). Pre- to post-treatment changes in SEMA-CD vs in SES-CD were strongly correlated, and the correlation remained strong between the scores when compared by study population (pediatric, adult), disease severity, and video quality. Intra- and inter-rater reliability were good, and SEMA-CD was rated easier than SES-CD to score 63.0% of the time, although slightly more difficult than SES-CD to score <1.0% of the time.

CONCLUSIONS: The SEMA-CD is reliable, reproducible, sensitive to change, and easy to use in both pediatric and adult patients with CD.

BACKGROUND AND AIMS: Overuse of screening colonoscopy increases cost and procedural adverse events, but inadequate surveillance can miss the development of colorectal cancer. We measured compliance with the 2020 U.S. Multi-Society Task Force on Colorectal Cancer (USMSTF) polypectomy surveillance guidelines in clinical records and a survey.

METHODS: We performed a retrospective study comparing surveillance intervals for first-time average-risk colonoscopies with the 2020 USMSTF guidelines. Cases were analyzed from 3 intervals (March 2021 to May 2021, November 2021 to January 2022, and April 2022 to May 2022), collectively termed the postguideline period, and a baseline period from November 2019 to January 2020. Real-world compliance rates were compared with results of a survey conducted between November 2020 and February 2021.

RESULTS: Overall compliance was 48.9% among 532 colonoscopies, ranging from 8.3% for low-risk adenomas (LRAs), 88.3% for high-risk adenomas, 63.1% for sessile serrated polyps (SSPs), and 88.6% for hyperplastic polyps. Compliance for LRA increased from the baseline period (.8% vs 8.3%, P = .003), and 95.3% of nonadherent LRA cases followed the 2012 USMSTF guidelines. Compliance for LRAs was 18.6% among respondents who provided a compliant surveillance interval for LRAs in the survey. Noncompliance was associated with finishing training >10 years ago (odds ratio, 1.9; 95% confidence interval, 1.4-2.7) and performing over 800 colonoscopies annually (odds ratio, 2.0; 95% confidence interval, 1.5-2.6).

CONCLUSIONS: Adoption of the 2020 USMSTF surveillance guidelines remains low at 2 years. Further research into outcomes for patients with LRAs and SSPs may increase guideline adoption.