Assessing adherence to objective disease monitoring and outcomes with adalimumab in a real-world IBD cohort.

BACKGROUND: Data suggests that tight objective monitoring may improve clinical outcomes in IBD. AIM: To assess the adherence to serial tight objective monitoring(clinical and biomarkers) and its effect on clinical outcomes. METHODS: We retrospectively reviewed the chart of 428 consecutive IBD patients started on adalimumab between January 1,2015-January 1,2019 [338 Crohn's disease(CD), 90 ulcerative colitis(UC)]. Clinical symptoms(assessed by Harvey-Bradshaw-Index,partial Mayo),C-Reactive Protein(CRP), and fecal calprotectin(FCAL) assessments were captured at treatment initiation and at 3,6,9, and12 months. Dose optimization and drug sustainability curves were plotted by Kaplan-Meier method. RESULTS: Clinical evaluation was available in nearly all patients at 3(CD-UC:95-94%), 6(90-83%), 9(86-85%) and 12(96-89%) months. CRP testing frequency decreased in CD patients over time. Compliance to serial FCAL testing was low. Clinical remission at one-year was higher in patients adherent to early assessment visit at 3 months(p = 0.001 for CD and UC). Adherence to early follow-up resulted in earlier dose optimization in CD and UC patients(pLogrank=0.026 for UC & p = 0.09 for CD). Overall drug sustainability did not differ. CONCLUSION: Clinical & CRP, but not FCAL, were frequently assessed in patients starting adalimumab. Adherence to early objective combined follow-up visits resulted in earlier dose optimization, improved one-year clinical outcomes but did not change drug sustainability.

Undiagnosed depression, persistent depressive symptoms and seeking mental health care: analysis of immigrant and non-immigrant participants of the Canadian Longitudinal Study of Aging.

AIMS: Early diagnosis and treatment of depression are associated with better prognosis. We used baseline data of the Canadian Longitudinal Study on Aging (2012-2015; ages 45-85 years) to examine differences in prevalence and predictors of undiagnosed depression (UD) between immigrants and non-immigrants at baseline and persistent and/or emerging depressive symptoms (DS) 18 months later. At this second time point, we also examined if a mental health care professional (MHCP) had been consulted. METHODS: We excluded individuals with any prior mood disorder and/or current anti-depressive medication use at baseline. UD was defined as the Center for Epidemiological Studies Depression 10 score ⩾10. DS at 18 months were defined as Kessler 10 score ⩾19. The associations of interest were examined in multivariate logistic regression models. RESULTS: Our study included 4382 immigrants and 18 620 non-immigrants. The mean age (standard deviation) in immigrants was 63 (10.3) years v. 65 (10.7) years in non-immigrants and 52.1% v. 57.1% were male. Among immigrants, 12.2% had UD at baseline of whom 34.2% had persistent DS 18 months later v. 10.6% and 31.4%, respectively, among non-immigrants. Female immigrants were more likely to have UD than female non-immigrants (odds ratio 1.50, 95% confidence interval 1.25-1.80) but no difference observed for men. The risk of persistent DS and consulting an MHCP at 18 months did not differ between immigrants and non-immigrants. CONCLUSIONS: Female immigrants may particularly benefit from depression screening. Seeking mental health care in the context of DS should be encouraged.

Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn's disease--the McGill experience.

BACKGROUND: Ustekinumab is a fully human IgG1κ monoclonal antibody that blocks the biologic activity of interleukin-12/23. Ustekinumab is approved for treatment of plaque psoriasis and has been shown to be effective for induction and maintenance of clinical response in anti-TNF resistant Crohn's disease (CD). The aim of the study was to describe the real-life experience with open-label use of ustekinumab in anti-TNF resistant CD patients. METHODS: A retrospective observational open-label study. Clinical response was defined by physician's global assessment combined with decision to continue therapy. The clinical response was evaluated at 3, 6, 12months and last follow-up. RESULTS: Thirty-eight patients were included in the study. Initial clinical response was achieved in 28/38 (73.7%) of the patients. Among the initial responders, 80% with follow-up data maintained their response for 6months. At 12months of follow-up, 88.9% of patients responding at 6months maintained their response. At the last follow-up (7.9±5.2 mo) 27/38 (71%) of the patients were responding, and 73.3% were able to discontinue corticosteroids. Dose escalation was required in 47.7% of the patients and was successful in 61.1% of them. SUMMARY: In this real-life cohort of severe anti-TNF resistant CD, an initial clinical response to subcutaneous ustekinumab was observed in 73.7% of the patients. The initial response was successfully maintained in the majority of patients for up to 12months. Subcutaneous ustekinumab is an effective therapeutic option in this challenging patient cohort. The optimal dosing and injection schedule remain to be established in future studies.

Review article: a clinician's guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease.

BACKGROUND: Tumour necrosis factor (TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies (ADAs) may decrease their efficacy. AIM: The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed. METHODS: The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab. RESULTS: Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy. CONCLUSIONS: Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials.

Predictors of inappropriate utilization of intravenous proton pump inhibitors.

BACKGROUND: Inappropriate use of intravenous proton pump inhibitors is prevalent. AIM: To assess appropriateness of intravenous proton pump inhibitor prescribing. METHODS: Retrospective review of in-patient prescribing of intravenous pantoprazole over a 2-month period in 2004, in an academic centre. Prescribing was deemed appropriate before and after endoscopic haemostasis, and in fasting individuals requiring a proton pump inhibitor. RESULTS: Amongst 107 patients, 49 (46%) had upper gastrointestinal bleeding. Overall, 33 (31%, 95% CI: 22-41%) received appropriate therapy (indication, dose and duration), 61 (57%, 95% CI: 47-67%) had an inappropriate indication, and 13 (12%, 95% CI: 7-20%) had an incorrect treatment dose or duration. Therapy was appropriate in 20 (41%, 95% CI: 27-55%) with upper gastrointestinal bleeding, and 13 (22%, 95% CI: 12-33%) in the non-upper gastrointestinal bleeding group. Appropriate prescribing rates decreased (from 41% to 16%, 95% on difference CI: 14-38%) when considering intravenous proton pump inhibitor use while awaiting endoscopy as inappropriate. Significant predictors of inappropriate use were increasing age and decreasing mean daily dose, with a trend for prescriptions written during evening shifts. CONCLUSION: Inappropriate intravenous proton pump inhibitor utilization was most frequent in the non-upper gastrointestinal bleeding group, mostly for unrecognized indications. Educational interventions to optimize utilization should target prescribing in older patients, those receiving lower mean daily doses, and, perhaps, prescribing outside regular hours.

Dichotomy between neurokinin receptor actions in modulating allergic airway responses in an animal model of helper T cell type 2 cytokine-associated inflammation.

Neurokinins (NKs), which include substance P (SP) and neurokinin A (NKA), act through NK-1 and NK-2 receptors. There is considerable evidence of interaction between the neurogenic and the immune systems, and NKs are candidates for mediating such interactions. We hypothesized that selective inhibition of pulmonary NK-1 or NK-2 receptors may modulate immune responses so as to prevent the development of allergic airway responses in the atopic BN rat sensitized to ovalbumin (OA). To address this hypothesis, we have validated our animal model by showing that NK-1 and NK-2 receptors are expressed in the lungs, and that SP is released in the airways after allergen challenge. The selective NK-1 (CP-99,994) or NK-2 (SR-48968) antagonists before allergen challenge failed to reduce the allergic early airway responses. In contrast, both neurokinin antagonists decreased allergen-induced late airway responses in OA-challenged animals. However, only the NK-2 antagonist decreased the eosinophil numbers in the bronchoalveolar lavage (BAL). Likewise, the NK-2, but not NK-1, antagonist decreased both Th1 (INF-gamma) and Th2 (IL-4 and -5) cytokine expression in BAL cells by in situ hybridization. These results provide initial in vivo evidence linking neurokinins to the regulation of cytokine expression in cells without discrimination as to their phenotype. We conclude that there is a dichotomy between NK receptors in the modulation of the allergic airway inflammation, which has important implications for future therapeutic strategies for asthma using the NK antagonists.