The burden of adverse drug reactions reported by patients in the Dutch ADR monitor: a proof of concept.

BACKGROUND: We aimed to describe the burden of adverse drug reactions (ADRs) reported by patients participating in the Dutch ADR Monitor using a multifactorial burden measurement instrument. METHODS: The Dutch ADR Monitor is a cohort event monitoring system that collects information on ADR experiences, including burden. This study includes the initial data (November 2022 until May 2023). Patients were asked if experienced ADRs impacted 7 domains of burden: appearance, medical treatment, daily life, fatigue, physical consequences, mental consequences and the course of ADRs. Burden was scored from 0 to 10 on impacted domains. The distributions of these burden scores were demonstrated in Likert plots. The burden between persistent and recurrent ADRs was compared. RESULTS: 92 patients reported 199 ADRs. Impact on the domains fatigue and daily life were experienced most frequently, except for skin and subcutaneous tissue ADRs, where impact on appearance and mental consequences were experienced most frequently. Fatigue was considered the most burdensome domain. No difference in burden was found between persistent (median = 7, IQR = 4) and recurrent ADRs (median = 6, IQR = 4, p = 0.59). CONCLUSIONS: This is the first study investigating burden of ADRs on 7 domains in patients with chronic diseases. Impact on the domain fatigue was considered most burdensome.

Patients with skin and subcutaneous ADRs experienced impact on appearance and mental consequences most often, but found impact on fatigue most burdensome.For most reported ADRs, patients scored the highest burden on the domain fatigue and thus found impact on this domain to be the most burdensome.Patients with skin and subcutaneous ADRs experienced impact on appearance and mental consequences most often, but found impact on fatigue most burdensome.

Quantification of Longitudinal Patient-Reported Burden of Adverse Drug Reactions Attributed to the Use of TNF-α Inhibitors in inflammatory rheumatic diseases: an observational prospective cohort study.

BACKGROUND: There is a lack of knowledge on patient perspectives on adverse drug reactions (ADRs) attributed to the use of biologics. The aim of this study is to quantify the burden over time of ADRs attributed to TNF-α inhibitors in patients with inflammatory rheumatic diseases (IRDs) and investigate whether the burden over time differs between different types of ADRs. RESEARCH DESIGN AND METHODS: Data were used from the Dutch Biologic Monitor (DBM), an observational prospective cohort study for patient-reported ADRs attributed to biologics. Patients with an IRD using a TNF-α inhibitor reporting an ADR, lasting for three consecutive questionnaires, were included. Questionnaires were sent every two months and burden was scored on a 5-point Likert-type scale. Burden scores were analyzed using linear mixed models. RESULTS: Data from 166 unique patients reporting 274 ADRs were included. The burden score decreased every month by 0.29 points (95% CI -0.34 - -0.24) on average on a 5-point Likert-type scale. The burden score for infections and infestations decreased significantly faster than the burden score for injection site reactions. CONCLUSIONS: Patient-reported burden of ADRs attributed to the use of a TNF-α inhibitor in patients with IRDs decreased significantly over time, especially for infections and infestations.

The Dutch Pregnancy Drug Register: Suitable to Study Paternal Drug Exposures?

Paternal medication use around the time of conception is common, but information about its effects on pregnancy outcome and the health of the child is generally limited. The aim of this study is to examine the feasibility of studying paternal exposure in the Dutch Pregnancy Drug Register by using immunosuppressants as a proof of concept. In 113 of 15,959 pregnancies, long-term paternal immunosuppressant use was reported 3 months before conception. In total, 134 immunosuppressants were used. Pregnancy outcome was known for 54 cases and was in accordance with previous findings. Two spontaneous abortions, two premature births, six small for gestational age babies, and two major congenital malformations were reported. Time to pregnancy (TTP) was known for 9548 pregnancies, including 89 with paternal immunosuppressant use. TTP analysis did not show a difference in pregnancies with paternal immunosuppressant use compared to the control group. Moreover, the number of fertility treatments in the paternal immunosuppressant group was similar to the control group. In our opinion, it is feasible to use the Dutch Pregnancy Drug Register to study the effects of paternal exposure on pregnancy outcome. However, to study the potential effects on fertility, more information is needed, particularly since the beginning of pregnancy attempts.

Sex differences in adverse drug reactions from Adalimumab and etanercept in patients with inflammatory rheumatic diseases.

BACKGROUND: We examine sex differences in relation to the nature, frequency, and burden of patient-reported adverse drug reactions (ADRs) in patients with inflammatory rheumatic diseases. RESEARCH DESIGN AND METHODS: Rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis patients using etanercept or adalimumab from the Dutch Biologic Monitor were sent bimonthly questionnaires concerning experienced ADRs. Sex differences in the proportion and nature of reported ADRs were assessed. Additionally, 5-point Likert-type scales reported for the burden of ADRs, were compared between sexes. RESULTS: In total 748 consecutive patients were included (59% female). From the women 55% reported ≥1 ADR, which was significantly higher than 38% of the men that reported ≥1 ADR (p < 0.001). A total of 882 ADRs were reported comprising 264 distinct ADRs. The nature of the reported ADRs differed significantly between both sexes (p = 0.02). Women in particular reported more injection site reactions than men. The burden of ADRs was similar between sexes. CONCLUSIONS: Sex differences in the frequency and nature of ADRs, but not in ADR burden, exist during treatment with adalimumab and etanercept in patients with inflammatory rheumatic diseases. This should be taken into consideration when investigating and reporting results on ADRs and when counseling patients in daily clinical practice.

First-time adverse drug reactions, survival analysis, and the share of adverse drug reactions in treatment discontinuation in real-world rheumatoid arthritis patients: a comparison of first-time treatment with adalimumab and etanercept.

BACKGROUND: This study aims to compare nature and frequency of adverse drug reactions (ADRs), time to first ADR, drug survival, and the share of ADRs in treatment discontinuation of first-time treatment with adalimumab (ADA) and etanercept (ETN) in real-world RA patients. RESEARCH DESIGN AND METHODS: Retrospective, single-center cohort study including naïve patients treated between January 2003-April 2020. Time to first ADR and drug survival of first-time treatment were studied using Kaplan-Meier and Cox-regression models up to 10 years, with 2- and 5-year post-hoc sensitivity analysis. Nature and frequencies of first-time ADRs and causes of treatment discontinuation were assessed. RESULTS: In total, 416 patients (ADA: 255, ETN: 161, 4865 patient years) were included, of which 92 (22.1%) experienced ADR(s) (ADA: 59, 23.1%; ETN: 33, 20.4%). Adjusted for age, gender and concomitant conventional DMARD use, ADA was more likely to be discontinued than ETN up to 2-, 5- and 10-year follow-up (adjusted HRs 1.63; 1.62; 1.59 (all p<0.001)). ADRs were the second reason of treatment discontinuation (ADA 20.7%, ETN 21.4%). CONCLUSIONS: Despite seemingly different nature and frequencies, ADRs are the second reason of treatment discontinuation for both bDMARDs. Furthermore, 2-, 5-, and 10-year drug survival is longer for ETN compared to ADA.

Disease-specific ADRs of TNF-α inhibitors as reported by patients with inflammatory rheumatic diseases: a registry-based prospective multicenter cohort study.

BACKGROUND: The extent to which adverse drug reactions (ADRs) of biologics differ per immune-mediated inflammatory disease (IMID), and the relevance of tailoring ADR information per IMID is not fully investigated. We aimed to compare patient-reported ADRs attributed to adalimumab and etanercept between different inflammatory rheumatic diseases (IRDs). RESEARCH DESIGN AND METHODS: ADR reports from IRD patients were extracted from the Dutch Biologic Monitor. ADR frequencies were compared using Fischer-Freeman-Halton exact test and the influence of covariates was assessed using binomial logistic regression.A total, of 729 participants were included, of which 354 participants reported 887 unique ADRs. ADR frequencies were not significantly different between the IRDs. Rheumatoid arthritis and ankylosing spondylitis including axial spondyloarthritis patients had an increased risk of ADRs related to 'Respiratory, thoracic and mediastinal disorders' and as compared to psoriatic arthritis patients. Etanercept use, combination therapy with methotrexate and/or corticosteroids, and age also influenced the risk of reporting specific ADRs. CONCLUSIONS: There were no differences in frequencies and nature of patient-reported ADRs attributed to adalimumab and etanercept between different IRDs. However, more research is needed to align patients' and health-care professionals' perspectives to improve knowledge on disease-specific ADRs.

Patients' and health-care professionals' perspectives on adverse drug reaction burden attributed to the use of biological DMARDs: a qualitative study.

BACKGROUND: Previous studies showed a discrepancy between health-care professionals' (HCPs') and patients' perspective on adverse drug reaction (ADR) burden. However, it is unclear which factors make an ADR burdensome. We aimed to give insight into why ADRs are perceived as burdensome by inflammatory rheumatic disease (IRD) patients, and whether this differs from the HCPs' perspective. RESEARCH DESIGN AND METHODS: A qualitative study was conducted using Dutch Biologic Monitor data. Participants received bimonthly questionnaires on experienced ADRs attributed to biological DMARDs and were asked to elaborate on ADR burden using a Likert-type scale and an open-ended question for clarification. Data of 440 IRD patients were analyzed following thematic analysis. A similar analysis was done with semi-structured interviews with 13 HCPs. RESULTS: We identified seven themes associated with ADR burden: 'effect on medication prescription,' 'impact on appearance,' 'impact on autonomy,' 'impact on daily life,' 'psychological consequences,' 'distressing aspects of ADR,' and 'physical consequences.' Identical themes were identified by HCPs, although they identified most subthemes in 'psychological consequences,' and less subthemes in 'impact on daily life' and 'impact on autonomy.' CONCLUSION: Patients describe perceived ADR burden in both physical and psychological themes. The HCPs' perspective is comparable, but mostly focuses on psychological impact.

Patients' perspectives on a drug safety monitoring system for immune-mediated inflammatory diseases based on patient-reported outcomes.

BACKGROUND: Patient-reported outcomes (PROs) on adverse drug reactions (ADRs) are increasingly used in cohort event monitoring (CEM) to obtain a better understanding of patients' real-world experience with drugs. Despite the leading role for patients, little is known about their perspectives on CEM systems. RESEARCH DESIGN AND METHODS: In a cross-sectional open survey following the rationale of the Technology Acceptance Model, we aimed to obtain insight in patients' perspectives on the perceived usefulness, ease of use and attitude toward using a PRO-based drug safety monitoring system for ADRs attributed to biologics. RESULTS: Patients considered structural reporting of ADRs in web-based questionnaires as useful and not burdensome. It was preferred to link the questionnaire frequency to regular hospital consultations or the biologic administration schedule. Various respondents were interested in sharing questionnaires with their medical specialist (49.0%) or pharmacist (34.2%), and suggested to minimize the questionnaire frequency in case of an unaltered situation or absence of ADRs. CONCLUSIONS: Patients' perspectives should be considered in the setup of PRO-based CEM studies, as this contributes to data quality and patient centeredness. Since incorporation of patients' perspectives in CEM studies is indispensable, a delicate balance should be found between user-friendliness and study aims.

Inflammatory bowel disease patients provide reliable self-reported medical information: A multicentre prospective pharmacovigilance monitoring system.

PURPOSE: To assess the agreement between patient-reported and health care provider-reported medical information in inflammatory bowel disease (IBD). METHODS: This multicentre, prospective, event monitoring study enrolled adult Crohn's disease (CD) and ulcerative colitis (UC) patients treated with a biological in four medical centers in the Netherlands. At two-monthly intervals, patients completed questionnaires on biological use, combination therapy and indication. The patient-reported information was compared with their electronic health records (EHRs) and analysed for percentage agreement and Cohen's kappa. A reference population from a prospective IBD registry was used to assess the representativeness of the study population. RESULTS: In total, 182 patients (female 50.5%, mean age 42.2 years, CD 76.9%) were included in the analysis. At baseline, 51.0% of the patients were prescribed an immunomodulator (43.9% thiopurines, 7.1% methotrexate), and patients were prescribed biologicals as follows: 59.3% infliximab, 30.2% adalimumab, 9.3% vedolizumab, and 1.1% ustekinumab. Agreement on patient-reported indication and biological use was almost perfect (κ = 0.878 and κ = 1.000, respectively); substantial for combination therapy (κ = 0.672). Gender, age, type of IBD, biological use and combination therapy were comparable with the reference population. CONCLUSION: Systematic patient-reporting by questionnaires was reliable in retrieving indication and treatment specific information from IBD patients. These results indicate that the use of patient-reporting outcomes in daily IBD practice can ensure reliable information collection.

Stakeholders' perspectives on a patient-reported outcome measure-based drug safety monitoring system for immune-mediated inflammatory diseases.

BACKGROUND: Biologics are used as effective therapeutics to treat a variety of diseases. Even though biologics are widely used, knowledge on the post-marketing experience of patients is limited. Therefore, a framework was established for a patient-reported outcome measure (PROM)-based drug safety monitoring system for ADRs attributed to biologics, known as the 'Dutch Biologic Monitor'. OBJECTIVE: Generation of a multi-stakeholder perspective on the preferred setup, potential and added value of a PROM-based national drug safety monitoring system. METHODS: Nineteen stakeholders were interviewed following a structured interview guide. Transcribed data were coded and analyzed to count frequencies and to generate recurring themes. RESULTS: Stakeholders (84.2%) support the establishment of a national drug safety monitoring system, but the feasibility depends on the implementation process. The need for integration and assessment of PROMs on ADRs in clinical practice and the preference to monitor small molecules and new drugs were emphasized. Preferably, all pharmacological options per indication should be monitored. CONCLUSIONS: Stakeholders recommend to establish a PROM-based national drug safety monitoring system focused on ADRs attributed to biologics, small molecules, and new drugs. Moreover, PROMs on ADRs ideally need to become integrated in clinical practice to provide health-care providers more insight in patients' perspectives.

Immune-mediated inflammatory disease patients' preferences in adverse drug reaction information regarding biologics.

OBJECTIVES: Patient-reported outcomes (PROs) are increasingly used in studies and medical practice to obtain information on patients' perspectives toward their treatment or disease. However, most study outcomes are primarily directed at healthcare professionals. It was aimed to obtain insight in which type of information immune-mediated inflammatory disease (IMID) patients prefer to receive after participating in the Dutch Biologic Monitor (DBM), a PRO-based prospective cohort event monitoring system focused on adverse drug reactions (ADRs). METHODS: A survey was conducted among DBM participants that wanted information about the results. Patients' preferences were identified using twelve statements and rated with five-point Likert-type scales. Subgroup analyses and differences between statements were performed using Mann-Whitney U Tests. RESULTS: The survey was completed by 591 patients (response rate 67.6%). Most respondents had inflammatory rheumatic diseases (76.8%) and used adalimumab (37.2%) or etanercept (33.2%). Respondents preferred results per IMID over aggregated results (p = <0.001). Information on whether patients with similar IMIDs experience ADRs (average 4.5), which biologics are most likely to cause ADRs (4.4) and whether ADRs disappear (4.4) were most interesting. CONCLUSION: DBM participants prefer to receive disease-specific information on ADRs that is tailored to their own biologic and IMID, including the outcome of ADRs.

Patients with inflammatory rheumatic diseases: quality of self-reported medical information in a prospective cohort event monitoring system.

OBJECTIVES: Assessment of the quality of patient-reported medical information in the Dutch Biologic Monitor and evaluation of the representativeness of the sampled participants. METHODS: Consecutive adult patients using a biologic DMARD (bDMARD) for an immune-mediated inflammatory disease were included in eight Dutch centres. For this substudy, data of 550 patients with inflammatory rheumatic diseases were used. Patient-reported bDMARD prescription, indication and combination therapy were verified for patients that permitted access to their electronic health record using percentage agreement and/or Cohen's kappa (n = 483). Conservative post hoc sensitivity analysis was performed to account for missing data. Population representativeness was tested for the entire substudy population by comparing age, gender and prescribed bDMARD to the centres' reference populations using Mann-Whitney U-test, χ2 goodness-of-fit or Fisher's exact test with Monte Carlo simulation (n = 550). RESULTS: The correct bDMARD was reported by 95.8% of the participants. Agreement between patients and electronic health record was almost perfect for indications (κ = 0.832) and substantial for combination therapies (κ = 0.725). Agreement on combination therapies remained substantial after post hoc sensitivity analysis (κ = 0.640). Gender distribution (P > 0.05) and bDMARD use (P > 0.05) were similar to the reference populations. Median age was different (58.0 vs 56.0 years, P = 0.04), but considered clinically irrelevant. CONCLUSION: The Dutch Biologic Monitor seems to be a valid tool to obtain patient-reported medical information. Reported medical information generally corresponded to the electronic health records and the participants represented their reference populations regarding age, gender and prescribed bDMARD.