Burden of non-serious infections during biological use for rheumatoid arthritis.

INTRODUCTION: Biologicals have become a cornerstone in rheumatoid arthritis (RA) treatment. The increased risk of serious infections associated with their use is well-established. Non-serious infections, however, occur more frequently and are associated with a high socioeconomic burden and impact on quality of life but have not received the same attention in the literature to date. The aim of this study was to gain insight into the various non-serious infections reported in RA patients using biologicals and their experienced burden. MATERIALS AND METHODS: The Dutch Biologic Monitor was a prospective observational study that included adults with rheumatoid arthritis and biological use who answered bimonthly questionnaires on the adverse drug reactions (ADRs) they experienced from their biological and reported the associated impact score (ranging from 1, no impact, to 5, very high impact). ADRs were assigned a MedDRA code by pharmacovigilance experts and labeled as definite, probable, possible or no infection by infectious disease professionals. Descriptive statistics were performed using medians and interquartile ranges. RESULTS: A total of 586 patients were included in the final analysis. Eighty-five patients (14.5%) reported a total of 421 ADRs labeled as probable or definite infections by the experts. Patient-assigned burden was ADR-specific. Upper respiratory tract infections were most frequently reported and had a high rate of recurrence or persistence, with a median impact score of 3.0 (IQR 2.0-3.0) which remained stable over time. DISCUSSION: Non-serious infections significantly outnumbered serious infections in this real-life cohort of RA patients using biologicals (77.1 non-serious infections and 1.3 serious infections per 100 patient years, respectively). Infections in the upper respiratory tract were rated as having an average burden, which remained constant over a long period of time. Awareness of the impact of recurrent and chronic non-serious infections may enable healthcare professionals to timely treat and maybe even prevent them, which would lessen the associated personal and socioeconomic burden.

Hospital registration of adverse drug reactions in electronic health records: importance and contribution to pharmacovigilance.

BACKGROUND: Information on registered adverse drug reactions (ADRs) in hospitals may provide a large real-world data source that can be used to ensure patients' safety. This study aimed to assess the potential contribution of hospital registration of ADRs in electronic health records (EHR) to pharmacovigilance. RESEARCH DESIGN AND METHODS: An observational retrospective descriptive study using data from the Jeroen Bosch Hospital in the Netherlands in 2019. 'Serious and/or severe' and 'previously unknown' ADRs registered systematically in the corresponding field of EHRs were assessed. RESULTS: ADR data concerning 1010 patients were included. In total, 1630 ADRs were registered in EHRs. Fifty-eight serious and/or severe ADRs (5.2%) were registered. Tubulointerstitial nephritis was the most frequently registered severe ADR and was mainly associated with antibacterials for systemic use. A total of 82 previously unknown ADRs (5%) were registered. 'Migraine' and 'chest pain' were the most frequently registered unknown ADRs. Additionally, 25 ADRs (1.5%) were registered that may be attributable to 10 drugs 'under additional monitoring.' CONCLUSIONS: Hospital registrations of ADRs in EHRs provide information on ADRs, which are challenging to assess during clinical trials. However, improvements are required to optimize this registration before it can serve as a valuable data source for pharmacovigilance purposes.

Development of a Framework Structuring Themes in the Course of Adverse Drug Reactions from a Patient's Perspective.

INTRODUCTION: There is a need for more extensive information about adverse drug reactions (ADRs) for patients than currently available, including information on the course of ADRs. Aspects characterising the course of ADRs from the patient perspective have not been identified before. OBJECTIVE: We aimed to develop a framework based on common themes in the course of ADRs identified from patient descriptions in patient-reported ADRs. METHODS: In this qualitative study, patient descriptions of the course of patient-reported ADRs were analysed by a thematic analysis with an inductive approach using three different existing datasets containing patient-reported ADRs. Two datasets included patient-reported ADRs from cohort event monitoring of biologics and direct oral anticoagulants and one dataset included spontaneous reports from patients concerning medication for lower urinary tract symptoms. A conceptual framework was developed from the identified main themes and subthemes. RESULTS: Patient-reported data concerning 3888 ADRs were analysed. Six main themes with multiple subthemes were identified from patient descriptions of the course of ADRs. Four themes were descriptive: frequency of an ADR episode, duration of an ADR episode, moment or period of ADR occurrence, and development in the intensity of the ADR. Two themes concerned factors influencing the course of ADRs: triggering factors and improving factors. CONCLUSIONS: The presented framework illustrates that patients describe extensive details on the course and timeframe of ADRs. The identified themes provide a basis for improving the systematic data collection of more extensive details about ADRs from patients as a first step towards the provision of more comprehensive ADR information to patients.

Recurring Fatigue After Biologic Administration: Patient-Reported Data from the Dutch Biologic Monitor.

BACKGROUND: Fatigue is a common problem in immune-mediated inflammatory disease (IMID) patients, significantly impacting their quality of life. OBJECTIVES: In this study, we describe the pattern and characteristics of fatigue as a patient-reported adverse drug reaction (ADR) of biologics, and compared patient and treatment characteristics with patients reporting other ADRs or no ADRs. METHODS: In this cohort event monitoring study, the description and characteristics of fatigue reported as a possible ADR in the Dutch Biologic Monitor were assessed and analysed for commonly recurring themes or patterns. Baseline and treatment characteristics of patients with fatigue and patients reporting other ADRs or no ADRs were compared. RESULTS: Of 1382 participating patients, 108 patients (8%) reported fatigue as an ADR of a biologic. Almost half of these patients (50 patients, 46%) described episodes of fatigue during or shortly after biologic injection, which often recurred following subsequent injections. Patients with fatigue were significantly younger than patients with other ADRs or patients without ADRs (median age for patients with fatigue, 52 years; median age for patients with other ADRs, 56 years; and median age for patients without ADRs, 58 years); significantly more often smoked (25% vs. 16% and 15%); used infliximab (22% vs. 9% and 13%), rituximab (9% vs. 3% and 1%) or vedolizumab (6% vs. 2% and 1%); and significantly more often had Crohn's disease (28% vs. 13% and 13%) and other comorbidities (31% vs. 20% and 15%). Patients with fatigue significantly less frequently used etanercept (12% vs. 29% and 34%) or had rheumatoid arthritis (30% vs. 45% and 43%). CONCLUSIONS: IMID patients may experience fatigue as a postdosing effect of biologics.

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.

Neuropsychiatric adverse drug reactions associated with low dose methotrexate in rheumatoid arthritis patients.

BACKGROUND: Neuropsychiatric adverse drug reactions (NPADRs) are not commonly associated with low dose methotrexate (LDMTX) in patients with rheumatoid arthritis (RA). RESEARCH DESIGN AND METHODS: In this case series assessment, we described the nature and frequency of NPADRs with LDMTX in the Dutch DREAM-RA registry, including causality of NPADRs, the impact on further LDMTX treatment and the impact on patient reported Health Related Quality of Life (HRQoL). RESULTS: A total of 71 NPADRs (frequency 6.8%) associated with LDMTX were captured in the DREAM-RA registry. NPADRs were registered for 62 (5.9%) out of 1048 patients with 10.9 NPADRs per 1000 patient years. Headache, dizziness and depression were most frequently reported. The causality was considered probable for 67 NPADRs (94.4%) and definite for 1 NPADR (1.4%). NPADRs led to LDMTX withdrawal in 34 cases (47.9%) and was not restarted in 16 cases (47.1%). Median mental HRQoL was significantly decreased around the occurrence of the NPADR and remained significantly lower after the event. Median physical HRQoL was not significantly affected. CONCLUSIONS: Knowledge on the nature, frequency and impact of the demonstrated NPADRs during LDMTX therapy will enhance attention toward these potential ADRs allowing better risk assessment and communication to patients.

Discrepancy between patient- and healthcare provider-reported adverse drug reactions in inflammatory bowel disease patients on biological therapy.

BACKGROUND: Only limited data is available on the extent and burden of adverse drug reactions (ADRs) to biological therapy in inflammatory bowel disease (IBD) patients in daily practice, especially from a patient's perspective. OBJECTIVE: The aim of this study was to systematically assess patient-reported ADRs during biological therapy in IBD patients and compare these with healthcare provider (HCP)-reported ADRs. METHODS: This multicentre, prospective, event monitoring study enrolled IBD patients on biological therapy. Patients completed bimonthly comprehensive web-based questionnaires regarding description of biological induced ADRs, follow-up of previous ADRs and experienced burden of the ADR using a five-point Likert scale. The relationship between patient-reported ADRs and biological therapy was assessed. HCP-reported ADRs were extracted from the electronic healthcare records. RESULTS: In total, 182 patients (female 51%, mean age 42.2 [standard deviation 14.2] years, Crohn's disease 77%) were included and completed 728 questionnaires. At baseline, 60% of patients used infliximab, 30% adalimumab, 9% vedolizumab and 1% ustekinumab. Fifty percent of participants reported at least one ADR with a total of 239 unique ADRs. Fatigue (n = 26) and headache (n = 20) resulted in the highest burden and a correlation in time with the administration of the biological was described in 56% and 85% respectively. Out of 239 ADRs, 115 were considered biological-related. HCPs reported 119 ADRs. Agreement between patient-reported ADRs and HCP-reported ADRs was only 13%. CONCLUSION: IBD patients often report ADRs during biological therapy. We observed an important significant difference between the type and frequency of patient-reported ADRs versus HCP-reported ADRs, leading to an underestimation of more subjective ADRs and patients' ADR-related burden.

Gastrointestinal Adverse Drug Reaction Profile of Etanercept: Real-world Data From Patients and Healthcare Professionals.

OBJECTIVE: We aimed to describe the nature and frequency of gastrointestinal adverse drug reactions (GI-ADRs) of etanercept (ETN) using patient-reported and healthcare professional (HCP)-registered data and compared this frequency with the GI-ADR frequency of the widely used tumor necrosis factor-α inhibitor adalimumab (ADA). METHODS: Reported GI-ADRs of ETN for rheumatic diseases were collected from the Dutch Biologic Monitor and DREAM registries. We described the clinical course of GI-ADRs and compared the frequency with ADA in both data sources using Fisher exact test. RESULTS: Out of 416 patients using ETN for inflammatory rheumatic diseases in the Dutch Biologic Monitor, 25 (6%) patients reported 36 GI-ADRs. In the DREAM registries 11 GI-ADRs were registered for 9 patients (2.3%), out of 399 patients using ETN, with an incidence of 7.1 per 1000 patient-years. Most GI-ADRs consisted of diarrhea, nausea, and abdominal pain. GI-ADRs led to ETN discontinuation in 1 patient (4%) and dose adjustment in 4 (16%) in the Dutch Biologic Monitor. Eight GI-ADRs (73%) led to ETN discontinuation in the DREAM registries. The frequency of GI-ADRs of ETN did not significantly differ from GI-ADRs of ADA in both data sources (Dutch Biologic Monitor: ETN 8.7% vs ADA 5.3%, P = 0.07; DREAM: ETN 2.8% vs ADA 4.7%, P = 0.16). CONCLUSION: Most GI-ADRs associated with ETN concerned gastrointestinal symptoms. These ADRs may lead to dose adjustment or ETN discontinuation. The frequency of ETN-associated GI-ADRs was comparable to the frequency of ADA-associated GI-ADRs. Knowledge about these previously unknown ADRs can facilitate early recognition and improve patient communication.

Adverse Drug Reactions from Real-World Data in Inflammatory Bowel Disease Patients in the IBDREAM Registry.

INTRODUCTION: Inflammatory bowel disease (IBD) frequently requires chronic immunosuppressive treatment and active involvement from patients during treatment decision making. Information about the risk of developing adverse drug reactions (ADRs) to IBD therapies is required in this process. OBJECTIVE: The aim of this study was to describe the ADRs reported in IBD patients from real-world data, using the Dutch nationwide IBDREAM registry, and compare the occurrence and cumulative incidences with the Summary of Product Characteristics (SmPC) of the associated drugs. METHODS: In this retrospective multicentre study, ADRs related to IBD medication were assessed. Only reports associated with the use of drugs used for the maintenance treatment of IBD were included. All ADRs were verified by healthcare professionals and coded by trained pharmacovigilance assessors. RESULTS: In total, 3080 ADRs were reported in 1179 patients. Twenty-three new drug-ADR associations related to the use of azathioprine, mercaptopurine, infliximab, oral mesalamine and thioguanine were reported in the IBDREAM registry that were not mentioned in the corresponding SmPCs. The most frequently reported new association was pyrexia for azathioprine (3.1%) and mercaptopurine (4.9%). In addition, there were seven ADRs with a higher cumulative incidence in IBDREAM compared with the SmPC, and included, among others, arthralgia during mercaptopurine use (2.5%), and diarrhoea (1.4%), alopecia (1.2%) and infections (1.6%) during azathioprine use. CONCLUSIONS: Based on real-world data, ADR reporting demonstrated new ADRs and higher incidences of ADRs to IBD therapies. This information will contribute to drug safety by updating the SmPCs, allowing better risk assessment and communication towards patients.

Patient-Reported Burden of Adverse Drug Reactions Attributed to Biologics Used for Immune-Mediated Inflammatory Diseases.

INTRODUCTION: Although the burden of adverse drug reactions (ADRs) has a significant impact on patients' quality of life, thorough knowledge about patients' perspectives on the burden of ADRs attributed to biologics is lacking. OBJECTIVES: This study was conducted to gain insight into the patient burden of ADRs experienced with biologic use. METHODS: The Dutch Biologic Monitor is a prospective, multicentre, event monitoring cohort system including information collected by web-based questionnaires from patients using biologics, mainly for immune-mediated inflammatory diseases (IMIDs). Patients were asked to complete bimonthly questionnaires on biologics used, indication for the biologic, experienced ADRs, consequences of ADRs and burden on a five-point Likert-type scale, ranging from 1 (no burden) to 5 (very high burden). We assessed potential factors associated with patient-reported burden of ADRs. RESULTS: A total of 1355 patients completed 6293 questionnaires between 1 January 2017 and 1 May 2019. Almost half of the patients (665 patients, 49%), 69% with rheumatic diseases and 31% with other diseases, collectively reported 1720 unique ADRs. Infections and musculoskeletal complaints were the most burdensome ADRs and injection-site reactions were the least burdensome. ADRs leading to healthcare professional contact were more burdensome than ADRs without healthcare professional contact. Smoking, respiratory and psychiatric comorbidities were associated with higher burden of ADRs. Crohn's disease, use of adalimumab and use of sulfasalazine as combination therapy were associated with lower burden of ADRs. CONCLUSIONS: The patient perspective gives important insights into the burden of ADRs experienced with biologics. This information could be used by healthcare professionals to optimise treatment with biologics.

Access to patients' health records for drug therapy problem determination by pharmacists.

OBJECTIVES: To evaluate differences in the number and type of drug therapy problems (DTPs) identified by pharmacists with and without access to patients' primary care health records; determine the confidence level of pharmacists in their assessment of DTPs with and without access to health records; and determine the type of information pharmacists need to confirm their assessment. METHODS: The study design was an exploratory and comparative evaluation of comprehensive medication management assessments. Pharmacists initially completed patient assessments without access to the patient's primary care health record. Pharmacists documented the visit according to the standard of care and documented the assessment in a standardized study form. Pharmacists then reviewed the patient's primary care health record and documented a revised assessment in the standardized study form. The standardized form included sections about the number of DTPs, the classification of DTPs, the pharmacist's confidence level in identifying DTPs, and the information needed to increase the pharmacist's confidence level in identifying DTPs. RESULTS: Pharmacists evaluated 24 patients and identified 132 DTPs. After reviewing patients' primary care health records, 31 DTPs were deemed "false DTPs," 3 DTPs were recategorized, and 9 new DTPs were identified. Practitioner confidence levels in DTP determination improved after reviewing patients' primary care health records. The health information most frequently identified as desirable after the initial review was laboratory tests. CONCLUSION: Pharmacists identified more DTPs with lower confidence levels without access to patients' primary care health records. Fewer DTPs were deemed "confirmed DTPs" and confidence in the practitioners' assessments improved after review of the primary care health records. Access to primary care health records can help community pharmacists build an efficient and comprehensive medication management practice.

Access to patients' health records for drug therapy problem determination by pharmacists.

OBJECTIVES: To evaluate differences in the number and type of drug therapy problems (DTPs) identified by pharmacists with and without access to patients' primary care health records; determine the confidence level of pharmacists in their assessment of DTPs with and without access to health records; and determine the type of information pharmacists need to confirm their assessment. METHODS: The study design was an exploratory and comparative evaluation of comprehensive medication management assessments. Pharmacists initially completed patient assessments without access to the patient's primary care health record. Pharmacists documented the visit according to the standard of care and documented the assessment in a standardized study form. Pharmacists then reviewed the patient's primary care health record and documented a revised assessment in the standardized study form. The standardized form included sections about the number of DTPs, the classification of DTPs, the pharmacist's confidence level in identifying DTPs, and the information needed to increase the pharmacist's confidence level in identifying DTPs. RESULTS: Pharmacists evaluated 24 patients and identified 132 DTPs. After reviewing patients' primary care health records, 31 DTPs were deemed "false DTPs," 3 DTPs were recategorized, and 9 new DTPs were identified. Practitioner confidence levels in DTP determination improved after reviewing patients' primary care health records. The health information most frequently identified as desirable after the initial review was laboratory tests. CONCLUSION: Pharmacists identified more DTPs with lower confidence levels without access to patients' primary care health records. Fewer DTPs were deemed "confirmed DTPs" and confidence in the practitioners' assessments improved after review of the primary care health records. Access to primary care health records can help community pharmacists build an efficient and comprehensive medication management practice.