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Immune-mediated inflammatory diseases (IMID), such as inflammatory bowel disease (IBD), multiple sclerosis (MS), and rheumatoid arthritis (RA), are highly prevalent in Canada and the United States and result in substantial personal and societal burden. The prevalence of psychiatric comorbidities, primarily depression and anxiety, in IMID exceeds those in the general population by two- to threefold, but remains underdiagnosed and undertreated. Furthermore, the effects of psychiatric comorbidity on IMID are not well understood.
The objectives of this study were (1) to compare health-related quality of life and work ability in persons with IMID and psychiatric comorbidity with those of persons with IMID without psychiatric comorbidity and with those of persons with depression and anxiety disorders alone, and (2) to validate existing case identification tools for depression and anxiety in persons with IMID to facilitate improved identification of depression and anxiety by clinicians. To achieve these objectives, we designed a prospective 3-year longitudinal study. In this paper, we aim to describe the study rationale and design and the characteristics of study participants.
Between November 2014 and July 2016, we recruited 982 individuals from multiple clinic and community sources; 18 were withdrawn due to protocol violations.
The final study sample included 247 participants with IBD, 255 with MS, 154 with RA, and 308 with depression or anxiety. The majority were white, with the proportion ranging from 85.4% (IBD [210/246]; MS [217/254]) to 74.5% (114/153, RA;
This paper presents the rationale for this study, describes study procedures, and characterizes the cohort enrolled. Ultimately, the aim is improved care for individuals affected by IMID.
Immune-mediated inflammatory diseases (IMID), such as inflammatory bowel disease (IBD), multiple sclerosis (MS), and rheumatoid arthritis (RA), are highly prevalent in Canada and the United States, and substantially burden affected individuals and society [
Increasingly, psychiatric comorbidity, including depression and anxiety disorders, is recognized as common among individuals with IMID, with a prevalence exceeding that in the general population by two- to threefold. Psychiatric disorders are commonly associated with adverse health outcomes, including impaired HRQOL and missed work [
Several potential mechanisms may underlie the association between psychiatric morbidity and adverse outcomes. Psychiatric comorbidity may lead to changes in health behaviors such as poorer diet or sleep hygiene, lower adherence to treatment, and increased smoking [
Despite the adverse effects of depression and anxiety disorders on chronic disease outcomes, these psychiatric disorders are undertreated when they co-occur in IMID [
We designed a prospective 3-year longitudinal study of persons with IMID with 2 principal aims. The first aim was to compare HRQOL and work ability in persons with IMID and psychiatric comorbidity with those of persons with IMID without psychiatric comorbidity and with those of persons with depression and anxiety disorders alone. The second aim was to validate existing screening tools for depression and anxiety in persons with IMID to facilitate improved identification of depression and anxiety by clinicians. We expect that improved identification and management of these disorders would positively affect patient-centered outcomes such as HRQOL.
This paper describes the study design, recruitment of participants, and the characteristics of the established cohort.
We enrolled participants with any of the following 5 diagnoses: (1) IBD—Crohn disease or ulcerative colitis [
All participants were required to be aged 18 years or older (without an upper age limit), able to provide informed consent, willing to participate in the study for 3 years, and to have an adequate knowledge of the English language to complete questionnaires (this latter criterion did not exclude anyone). Diagnoses of IBD, MS, and RA were confirmed by medical records review and by querying treating physicians directly if needed. Diagnoses of depression or anxiety were confirmed by structured clinical interview as delineated below. The presence of comorbid psychiatric disorders was not an exclusion criterion.
We obtained ethics approvals from the University of Manitoba Health Research Ethics Board and research committee approval from the Winnipeg Regional Health Authority, Winnipeg Health Sciences Centre, St. Boniface Hospital, Seven Oaks Hospital, and Victoria General Hospital. All participants provided written informed consent. In addition to consenting to core study activities, participants were also asked to agree to blood sample collection at each visit and to linkage of the collected data to health administrative data records.
We used general and targeted strategies to recruit participants from the community and tertiary care settings. General strategies included the placement of posters in local hospitals, private medical and psychology clinics, and academic institutions within the Winnipeg region; use of social media outlets (tweets and Facebook posts) through the largest tertiary center (Winnipeg Health Sciences Centre); and self-help groups for mental health concerns. The targeted strategies used for each group are described below.
For IBD, research assistants directly approached individuals attending gastroenterology clinic visits using a standardized script and contacted participants in a population-based IBD research registry via email. The registry was established in 1995 by one of the investigators (CB) and includes nearly half the provincial IBD population [
For MS, research assistants contacted participants in the Winnipeg MS Clinic registry by phone and mail. This clinic was established in 1998 and is the sole source of care for Manitobans with MS being treated with disease-specific therapies, although the clinic population is not limited to those receiving such therapies. A research registry was established in 2011, and most of the individuals with MS attending the clinic have agreed to participate.
For RA, research assistants directly approached individuals attending scheduled clinic visits at the University of Manitoba Arthritis Centre, the tertiary care clinic for rheumatologic disease in Manitoba, using a standardized script. The University of Manitoba Arthritis Centre also contacted individuals with RA in their clinic database by mail, as did one other local community rheumatology clinic.
For depression and anxiety disorders, information about the study was included in appointment letters sent to individuals referred for psychology or psychiatry consultation at tertiary care centers within the Winnipeg region. Information letters were also mailed by primary care clinics operated in partnership by the Winnipeg Regional Health Authority and the University of Manitoba and at a local primary care practice to patients with diagnoses of depression or an anxiety disorder identified using their electronic medical records. Research coordinators also presented information about the study to individuals attending psychoeducational classes for cognitive behavioral therapy held by the Psychiatry Program at the Health Sciences Centre.
We collected information regarding sociodemographic characteristics, height, weight, blood pressure, physical function, cognitive function, psychiatric morbidity, and self-reported smoking status, stress, pain, fatigue, HRQOL, and work disability from all participants. Disease-specific measures tailored to each disease group were also collected. Unless otherwise specified, each of these measures was collected at study enrollment and will be collected at 3 annual study-specific assessments thereafter for a total of 4 assessments. Annual assessments will be booked within ±1 month of the enrollment date.
Using questionnaires, participants reported sex, date of birth, ethnicity, total number of years of formal education, highest level of education attained, annual household income, marital status, whether they had any children (yes vs no), and current or most recent occupation. Ethnicity was captured using the categories specified by Statistics Canada in regular surveys. Highest level of education completed was reported using the following categories: elementary school, junior high school, high school diploma or General Education Diploma (GED), college, technical/trade, university bachelor’s degree, university master’s degree, university doctorate, and other. Annual household income was reported as less than Can $15,000, Can $15,000-29,999, Can $30,000-49,999, Can $50,000-100,000, more than Can $100,000 or “I do not wish to answer.” Responses for marital status included single/never married, married, common law, divorced, widowed, and separated. Occupation was categorized using Statistics Canada’s categories as management; business, finance, and administration occupations; health occupations; occupations in education, law, and social, community, and government services; occupations in art, culture, recreation, and sport; sales and service occupations; trades, transport and equipment operators, and related occupations; natural resources, agriculture, and related production occupations; and occupations in manufacturing and utilities [
Research assistants measured height and weight to derive body mass index (kg/m2).
Blood pressure and heart rate were measured in the seated position using an automatic blood pressure machine.
We assessed lower limb function and ambulation using the timed 25-foot walk test [
We selected validated neuropsychological measures to assess cognitive domains of processing speed, working memory, and verbal learning, which are often found to be affected in MS [
We assessed smoking status because smoking may confound associations between psychiatric status and study outcomes, such as HRQOL [
To assess self-reported physical and psychiatric comorbidities, we used questions derived from a survey validated for the general population [
We assessed psychiatric morbidity at enrollment using the structured clinical interview for DSM-IV-TR Axis I Disorders—Research version (SCID), a semistructured interview to identify anxiety, mood, and substance use disorder DSM-IV diagnoses [
Participants also completed several case identification (screening) instruments for depression and anxiety (
The Perceived Stress Scale (PSS) is widely used to measure the degree to which individuals are experiencing stress, the underlying concept being that stress is the extent to which perceived demands exceed the perceived personal resources to cope [
The Pain Effects Scale assesses pain, and it was originally developed and validated for the Medical Outcomes Study [
Fatigue was evaluated using the Fatigue Impact Scale for Daily Use (D-FIS), a brief validated instrument adapted from the Fatigue Impact Scale that includes 8 items that reflect daily fatigue [
We measured HRQOL using the Short Form-36, a generic measure of HRQOL validated in the general population as well as in multiple IMID populations [
We used the Work Productivity and Activity Impairment Questionnaire (WPAI), a 6-item questionnaire to measure work and activity impairment. Impairment due to a specified health problem during the past 7 days is reported, where higher scores indicate greater impact of health. Outcomes include percentage of work time missed (absenteeism), percentage of impairment while working (presenteeism), percentage of overall work impairment, and percentage of activity impairment due to health problems. The first 3 outcomes are calculated for persons who are working for pay, and the last outcome is calculated for all persons. In a clinical trial for IBD, the WPAI had adequate discriminative validity, reliability, and responsiveness [
The disease-specific measures were chosen to describe disease activity and disease progression or functional status.
Case identification (screening) instruments for depression and anxiety.
Screening instruments for depression and anxiety | Construct | Number of items | Scoring | Published cut points | Possible range of values |
Patient Health Questionnaire—brief (PHQ-2) [ |
Depression (presence of) | 2 | Items scored 0-3, summed |
3 | 0-6 |
Patient Health Questionnaire (PHQ-9) [ |
Depression (presence of) | 9 | Items scored 0-3, summed | 10 | 0-27 |
Generalized Anxiety Disorder 7-Item Scale [ |
Anxiety, generalized (severity of) | 7 | Items scored 0-5, summed | 10 | 0-21 |
Overall Anxiety and Severity Impairment Scale [ |
Anxiety (severity of) | 5 | Items scored 0-4, summed | 8 | 0-20 |
Hospital Anxiety and Depression Scale [ |
Depression (severity of), anxiety (severity of) | 14 (7 for anxiety, 7 for depression) | Items scored 0-3, summed | 8, 11 | 0-21 |
Kessler-6 Distress Scale [ |
Nonspecific distress | 6 | Items scored 1-5, summed | 19 | 6-30 (alternative scoring) |
National Institutes of Health Patient-Reported Outcomes Measurement Information System—emotional distress depression—Short Form 8a [ |
Depression (severity of) | 8 | Items scored, summed, and then converted to T score | T-score 60 | 8-40, T score 38.2-81.3 |
National Institutes of Health Patient-Reported Outcomes Measurement Information System—emotional distress anxiety—Short Form 8a [ |
Anxiety (severity of) | 8 | Items scored, summed, and then converted to T score | T score 60 | 8-40, T score 37.1-83.1 |
We characterized disease activity using the Powell Tuck Index (PTI) for ulcerative colitis [
Participants reported the year of symptom onset and the month and year of diagnosis of their IMID. Dates of symptom onset and diagnosis were verified using medical records. Current disease-modifying therapies were also captured from medical records. We characterized disease phenotype and progression in IBD using the Montreal Classification [
At the end of each assessment, consenting participants provided a blood sample collected by venipuncture using a straight needle into an EDTA tube and into a Paxgene (Qiagen) deoxyribonucleic acid (DNA) tube. Samples collected in EDTA tubes were centrifuged at 1500-2500 × g for 15 min at room temperature. The resulting plasma layer and buffy coat layers were aliquoted separately into 2 mL cyro vial tubes for storage at −80°C. DNA was extracted using a Paxgene DNA kit using a single tube procedure according to the manufacturer’s (Qiagen) instructions and stored at −80°C.
Study data were managed using REDCap electronic data capture tools hosted at the University of Manitoba [
The required sample size for the 2 principal aims was determined as follows. For the first aim, to test the baseline association between psychiatric comorbidity and either HRQOL or work disability in each IMID group, we assumed that at least 30% of the sample will experience any psychiatric comorbidity [
For the second aim, which sought to test the performance of the case identification (screening) tools for depression and anxiety as compared with the SCID in the IMID groups, we assumed a lower bounds sensitivity=0.75 and specificity≥0.85 [
Therefore, we sought to recruit 250 participants for each IMID group, and 150 each for the depression and anxiety disorder groups.
We summarized the characteristics of the sample at enrollment for the purpose of assessing the potential generalizability of the findings. We summarized categorical variables using frequency (percentage) and continuous variables using mean (standard deviation) or median (25th-75th percentiles). Each of the disease groups was also reviewed relative to samples in other studies of those disease groups, to consider representativeness and generalizability of the samples. Statistical analyses were conducted using SAS V9.4 (SAS Institute Inc., Cary, NC).
We will assess the impact of changes in psychiatric status on change in these HRQOL and work ability outcomes over the 4 measurement occasions (3-year period) using generalized linear models with generalized estimating equations to account for the dependence among the repeated measurements. We will select the distribution to model each outcome using a combination of empirical (eg, ratio of model deviation to its degrees of freedom) and theoretical considerations. We will choose a correlation structure for the repeated measurements by examining the pattern of empirical correlations. The independent variables of interest will be IMID type and psychiatric status. Psychiatric status will be determined based on the SCID-determined diagnoses (at enrollment) and symptom severity based on whichever screening instrument has the best performance characteristics (as described below). Potential confounding covariates will be age, sex, disease duration, education, smoking, body mass index, physical comorbidity, and disease activity status.
On the basis of published cut points, we will compare depression and anxiety status based on the SCID and the screening instruments using sensitivity, specificity, positive predictive value, and negative predictive value. We will also use receiver operating curve analysis to understand the relationship between sensitivity and the false positive rate, which allows an optimal cut point to be assigned depending on the requirements in a specific context. We will assess internal consistency reliability using Cronbach alpha [
Between November 2014 and July 2016, we enrolled 982 individuals. Of these, 18 were later withdrawn; 6 did not meet inclusion criteria after review of their medical records because they did not have confirmed diagnoses of IBD (3) or RA (2), or had 2 of the IMID of interest (1). A total of 11 individuals enrolled as members of the psychiatric cohort were withdrawn as they did not have a confirmed diagnosis of depression or anxiety disorder following SCID administration. Finally, 1 individual in the IBD cohort withdrew from the study and that person’s data were destroyed shortly after enrollment. Therefore, the final study population included 247 participants with IBD, 255 with MS, 154 with RA, and 308 with depression or anxiety (172 with depression, 136 with an anxiety disorder as self-identified at enrollment) for a total of 964. As expected, participants were recruited from multiple sources (
Recruitment sources for study participants.
Source | Inflammatory bowel disease (N=247), n (%) | Multiple sclerosis (N=255), n (%) | Rheumatoid arthritis (N=154), n (%) | Depression/anxiety disorder (N=308), n (%) |
Targeted email/maila | 98 (39.7) | 222 (87.0) | 52 (33.8) | 59 (19.1) |
Clinic/CBT classb | 133 (53.8) | 30 (11.8) | 80 (51.9) | 60 (19.4) |
Poster (paper/electronic) | 5 (2.0) | 3 (1.2) | 10 (6.5) | 60 (19.4) |
Tweets/Facebook/Internet | 5 (2.0) | 0 (0) | 0 (0) | 15 (4.9) |
News article | 1 (0.4) | 0 (0) | 0 (0) | 2 (0.6) |
Clinician referral | 0 (0) | 0 (0) | 0 (0) | 7 (2.3) |
Word of mouth | 1 (0.4) | 0 (0) | 12 (7.8) | 18 (5.8) |
Unknown | 4 (1.6) | 0 (0) | 0 (0) | 87 (29.2) |
aSome participants in the MS Clinic registry were contacted by telephone rather than by mail.
bCognitive behavioral therapy (CBT) classes served as a recruitment source only for those with depression/anxiety.
Sociodemographic characteristics of the participants are shown in
As has been observed in other IBD cohorts, participants were more likely to be females than males (
The proportion of women in the depressed/anxiety disorder cohort was higher than that in a previous cohort from the Canadian Community Health Survey—Mental Health (CCHS) in 2012 (
Cohort demographics stratified by disease group.
Characteristics | Total (N=964) | Inflammatory bowel disease (N=247) | Multiple sclerosis (N=255) | Rheumatoid arthritis (N=154) | Depression/anxiety disorder (N=308) | ||
Age in years, mean (SDa) | 49.2 (14.2) | 47.4 (14.8) | 51.1 (12.9) | 59.5 (11.7) | 43.9 (13.0) | ||
<.001 | |||||||
Male | 235 (24.4) | 92 (37.2) | 47 (18.4) | 24 (15.6) | 72 (23.5) | ||
Female | 729 (75.6) | 155 (62.7) | 208 (81.6) | 130 (84.4) | 235 (76.6) | ||
White | 786 (81.9) | 210 (85.4) | 217 (85.4) | 114 (74.5) | 245 (79.8) | .01 | |
Other | 174 (18.1) | 36 (14.6) | 37 (14.5) | 39 (25.5) | 62 (20.2) | ||
Missing | 4 | 1 | 1 | 1 | 1 | ||
.06 | |||||||
Elementary school | 5 (0.5) | 0 (0) | 1 (0.4) | 3 (1.9) | 1 (0.3) | ||
Middle school | 44 (4.5) | 8 (3.2) | 9 (3.5) | 11 (7.1) | 16 (5.2) | ||
High school or GEDb | 268 (27.8) | 68 (27.5) | 78 (30.6) | 37 (24.0) | 85 (27.6) | ||
College | 253 (26.2) | 51 (20.6) | 72 (28.2) | 45 (29.2) | 85 (27.6) | ||
Technical or trade | 107 (11.1) | 32 (13.0) | 29 (11.4) | 19 (12.3) | 27 (8.8) | ||
Bachelor’s degree | 215 (22.3) | 60 (24.3) | 56 (22.0) | 27 (17.5) | 72 (23.4) | ||
Master’s degree | 54 (5.6) | 21 (8.5) | 7 (2.8) | 10 (6.5) | 16 (5.2) | ||
Doctoral degree | 18 (1.9) | 7 (2.8) | 3 (1.2) | 2 (1.3) | 6 (1.9) | ||
<.001 | |||||||
Less than Can $15,000 | 100 (10.4) | 14 (5.7) | 20 (7.8) | 19 (12.3) | 47 (15.3) | ||
Can $15,000-29,999 | 88 (9.1) | 14 (5.7) | 24 (9.4) | 19 (12.3) | 31 (10.1) | ||
Can $30,000-49,999 | 162 (16.8) | 29 (11.7) | 37 (14.5) | 32 (20.8) | 64 (20.8) | ||
Can $50,000-100,000 | 341 (35.4) | 104 (42.1) | 99 (38.8) | 48 (31.2) | 90 (29.2) | ||
More than Can $100,000 | 189 (19.6) | 68 (27.5) | 47 (18.4) | 25 (16.2) | 49 (15.9) | ||
I do not wish to answer | 84 (8.7) | 18 (7.3) | 28 (11.0) | 11 (7.1) | 27 (8.8) | ||
<.001 | |||||||
Single or never married | 217 (22.5) | 56 (22.7) | 30 (11.8) | 20 (13.0) | 111 (36.0) | ||
Married or common law | 569 (59.0) | 160 (64.8) | 182 (71.4) | 93 (60.4) | 134 (43.5) | ||
Divorced or separated | 150 (15.6) | 24 (9.7) | 39 (15.3) | 31 (20.1) | 56 (18.2) | ||
Widowed | 28 (2.9) | 7 (2.8) | 4 (1.6) | 10 (6.5) | 7 (2.3) |
aSD: standard deviation.
bGED: General Education Diploma.
This paper presents the study rationale, describes study procedures, and characterizes the cohort enrolled. The ultimate goal of the study was to compare and contrast the impact of psychiatric comorbidity on outcomes in IMID that affect different organ systems but share the issues of immune dysregulation and inflammation. We hope to gain more specific insights into the role of psychiatric comorbidity in IMID, with the aim of improved care for individuals affected by IMID. These analyses will be conducted once the cohort completes follow-up.
When selecting the measures for this study, we sought standardized measures appropriate for the domains of interest. Where possible, we chose instruments with good criterion and construct validity, and high reliability, which had been demonstrated in one or more of the disease groups of interest. If this was not possible, we favored validated measures used in Canadian national data collection efforts to offer the opportunity for comparisons of this cohort with national cohorts.
Our recruitment strategy precluded the determination of a participation rate, as it was designed to reach potential participants from a broad range of settings using general and targeted strategies. For all of the groups except for the RA group, we were able to recruit the desired number of participants; the time period for recruitment was limited by the need to complete 3 years of follow-up by the end of the funding period. It has been noted that participation rates in cohort studies and surveys have declined over the last 3 decades [
Retention of study participants will be critical, and we aimed to minimize attribution by employing several strategies that have been successful in other studies [
The characteristics of participants enrolled in our study are similar to those enrolled in other studies after accounting for differences in how variables were measured, supporting the representativeness of the sample across the disease groups. However, some differences with respect to other cohorts and the general IMID populations of interest are worth noting. Participants in the MS cohort were older than those in some other cohorts, likely reflecting recruitment efforts aimed at capturing the full spectrum of individuals with MS. The proportion of participants with MS who were women was slightly higher than expected, even when considering that women are affected by MS two to three times more often than men [
Selection bias is a potential limitation of any study. As reviewed elsewhere [
In addition to potential selection biases, attrition may occur despite the use of appropriate retention strategies due to death, loss to follow-up, or other reasons. As noted, we did not achieve the desired sample size for the RA cohort, and this will reduce statistical power for RA-specific analyses. To minimize participant burden, we included only a single measure of pain and of fatigue, although these are multidimensional concepts that may be better evaluated with multiple instruments that capture different dimensions. We did not capture all potential confounders such as the life events (eg, pregnancy, menopause) that may be unique to subgroups of the study population and that may be associated with disease activity and psychiatric status in IMID [
Nonetheless, this study has several strengths including the establishment of representative cohorts of those with IMID and depression and anxiety disorders, which will support comparative work, as well as careful attention to retention and stakeholder engagement. We expect this comprehensive prospective longitudinal study to provide valuable new knowledge about the impact of psychiatric comorbidity on IMID, including on outcomes important to affected individuals and society, such as HRQOL and work disability. We also expect that this study will contribute to improved diagnosis of psychiatric comorbidity by identifying validated instruments which can be used in clinical practice. For health care providers, an understanding of the relationships between psychiatric disorders, symptoms of pain, and fatigue and outcomes should encourage more attention to the identification and treatment of psychiatric disorders and change the approach to disease management to improve outcomes in IMID. The analytical methods used will support future research regarding patient-reported outcome measures. Focusing on three IMID with similarities and differences will support the generalizability of our findings to other IMID and provide policy makers with the evidence base to make decisions regarding health services for IMID broadly.
Characteristics of participants with inflammatory bowel disease (IBD) and those of participants in other IBD cohorts.
Characteristics of participants with multiple sclerosis (MS) and those of participants in other Canadian MS studies.
Characteristics of participants with rheumatoid arthritis (RA) and those of participants in other RA cohorts.
Characteristics of participants with depression or anxiety disorder and those of participants in other depression or anxiety disorder cohorts.
American College of Rheumatology/European League Against Rheumatism
Canadian Community Health Survey
Clinical Disease Activity Index
Fatigue Impact Scale for Daily Use
deoxyribonucleic acid
Expanded Disability Status Scale
General Education Diploma
Harvey Bradshaw Disease Activity Index
health-related quality of life
inflammatory bowel disease
immune-mediated inflammatory diseases
mental component score
Modified Health Assessment Questionnaire
multiple sclerosis
physical component score
Perceived Stress Scale
Powell Tuck Index
rheumatoid arthritis
structured clinical interview for DSM-IV-TR Axis I Disorders—Research version
standard deviation
Work Productivity and Activity Impairment Questionnaire
This study was funded by the Canadian Institutes of Health Research (THC-135234), Crohn’s and Colitis Canada, and the Waugh Family Chair in Multiple Sclerosis (to RAM). Dr Bernstein is supported in part by the Bingham Chair in Gastroenterology. Dr Sareen is supported by CIHR #333252. Dr Katz is supported by Research Manitoba and the Health and Stroke Foundation through the Manitoba Chair in Primary Prevention Research. Dr Lix is supported by a Research Manitoba Chair. Dr Zarychanski is supported by a CIHR New Investigator Salary Award. The sponsors had no role in the design and conduct of the study, collection and interpretation of the data, or in the decision to submit the manuscript for publication.
Members of the CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease are as follows: RAM, JB, JS, JRW, SBP, AS, LML, CAH, RE-G, AK, JDF, CNB, LG, LIB, RZ, CAP, and JM.
RAM has conducted clinical trials for Sanofi Aventis. CAH has research funds for unrelated studies from UCB Canada. JS holds stocks in Johnson and Johnson. CNB has consulted Abbvie Canada, Ferring Canada, Janssen Canada, Pfizer Canada, Shire Canada, Takeda Canada, and Napo Pharmaceuticals and has consulted Mylan Pharmaceuticals. He has received unrestricted educational grants from Abbvie Canada, Janssen Canada, Shire Canada, and Takeda Canada. He has been on speaker’s bureau of Abbvie Canada, Ferring Canada, and Shire Canada. All other authors have no conflicts of interest to declare.