Immune checkpoint inhibitors have greatly improved clinical outcomes in multiple cancer types and are increasingly being used in earlier disease settings and in combination with other therapies.1 ...However, high-grade immune-related adverse events can occur. Patients had a wide spectrum of age (median 69 years range 20-90), cancer types (most commonly melanoma and lung cancer), and geographical location (appendix). Supplementary Material 1 JD Wolchok, PD-1 blockers, Cell, Vol. 162, 2015, 937 2 DB Johnson, JM Balko, ML Compton, Fulminant myocarditis with combination immune checkpoint blockade, N Engl J Med, Vol. 375, 2016, 1749-1755 3 L Heinzerling, PA Ott, FS Hodi, Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy, J Immunother Cancer, Vol. 4, 2016, 50 4 M Escudier, J Cautela, N Malissen, Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity, Circulation, Vol. 136, 2017, 2085-2087 5 M Lindquist, VigiBase, the WHO global ICSR database system: basic facts, Drug Inf J, Vol. 42, 2008, 409-419
Background
Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but may also trigger autoimmune adverse drug reactions (ADRs) referred to as immune‐related adverse events (irAEs). ...Although endocrinopathies are among the most common form of irAEs, primary adrenal insufficiency (PAI) is infrequent and has only been published in case reports. The aim of this study was to identify and characterize the main features of PAI‐irAE.
Materials and Methods
Suspected PAI‐irAE cases were identified using VigiBase, the World Health Organization's pharmacovigilance database of individual case safety reports.
Results
From September 2, 2008, through October 5, 2018, a total of 50,108 ICI‐associated ADRs were reported. Since 2008, there were 451 cases of PAI‐irAE identified of which 45 were “definite PAI” and 406 “possible PAI.” Patients were mainly male (58.1%) with a median age of 66 years (range, 30–95). Indications of ICI were predominantly for melanoma (41.2%) and lung cancer (28.6%). The majority of patients were treated with ICI monotherapy (nivolumab: 44.3%, pembrolizumab: 11.7%, ipilimumab: 23.6%), and 17.9% were treated with ICI combination therapy. These events occurred with a median time to onset of 120 days (range, 6–576). ICI‐associated PAI was associated with significant morbidity (≥90% severe) and mortality (7.3%). Fatality rates were similar in the subgroups of combination therapy versus monotherapy. There were no relevant differences in clinical or demographical characteristics and outcomes between “definite” versus “possible” PAI group.
Conclusion
Our study represents the largest clinical description and characterization of PAI‐irAE. Although ICI‐associated PAI is a rare adverse event, early recognition is important to implement corticosteroid treatment. Further studies are required to elucidate risk factors and reversibility of this rare but severe irAE. Clinical trial identification number. NCT03492242
Implications for Practice
Immune checkpoint inhibitor (ICI)‐associated primary adrenal insufficiency (PAI) is a rare adverse event that is important to recognize because it may be severe and life‐threatening, requiring emergent and often lifelong hormonal replacement therapy. Awareness regarding this ICI‐related endocrinopathy is strongly encouraged among clinicians in addition to patient education about common PAI symptoms that should prompt urgent medical evaluation. In clinical practice, close monitoring and investigation for PAI is crucial to allow for early management and to further define the pathophysiology and prognosis of ICI‐PAI. Corticotrophin (adrenocorticotrophic hormone) circulating level evaluation may be often lacking but should be considered as part of the diagnostic workup to differentiate PAI from secondary (central) adrenal insufficiency.
Limited data are available for immune‐related adverse events related to primary adrenal insufficiency. This article characterizes such events using Vigibase, the WHO's global database of individual case safety reports.
Increasing number of Janus kinase (JAK) inhibitors have been approved for chronic haematopoietic neoplasms and inflammatory/autoimmune diseases. We aimed to assess safety of the first three approved ...JAK inhibitors: ruxolitinib, tofacitinib and baricitinib. In this retrospective observational study, pharmacovigilance data were extracted from the World Health Organization database. Adverse events are classified according to Medical Dictionary for Regulatory Activities hierarchy. Until February 28, 2021, all Individual Case Safety Reports ICSRs with the suspected drug ruxolitinib, tofacitinib or baricitinib were included. Disproportionality analysis was performed and the information component (IC) was estimated. Adverse events were considered a significant signal if the lower end of the 95% credibility interval of the IC (IC025) was positive. We identified 126,815 ICSRs involving JAK inhibitors. Ruxolitinib, tofacitinib and baricitinib were associated with infectious adverse events (IC025 1.7, especially with viral herpes and influenza, fungal, and mycobacterial infectious disorders); musculoskeletal and connective tissue disorders (IC025 1.1); embolism and thrombosis (IC025 0.4); and neoplasms (IC025 0.8, especially malignant skin neoplasms). Tofacitinib was associated with gastrointestinal perforation events (IC025 1.5). We did not find a significant increase in the reporting of major cardiovascular events. We identified significant association between adverse events and ruxolitinib, tofacinitib and baricitinib in international pharmacovigilance database.
While multiple pharmacological drugs have been associated with myocarditis, temporal trends and overall mortality have not been reported. Here we report the spectrum and main features of 5108 reports ...of drug-induced myocarditis, in a worldwide pharmacovigilance analysis, comprising more than 21 million individual-case-safety reports from 1967 to 2020. Significant association between myocarditis and a suspected drug is assessed using disproportionality analyses, which use Bayesian information component estimates. Overall, we identify 62 drugs associated with myocarditis, 41 of which are categorized into 5 main pharmacological classes: antipsychotics (n = 3108 reports), salicylates (n = 340), antineoplastic-cytotoxics (n = 190), antineoplastic-immunotherapies (n = 538), and vaccines (n = 790). Thirty-eight (61.3%) drugs were not previously reported associated with myocarditis. Antipsychotic was the first (1979) and most reported class (n = 3018). In 2019, the two most reported classes were antipsychotics (54.7%) and immunotherapies (29.5%). Time-to-onset between treatment start and myocarditis is 15 interquartile range: 10; 23 days. Subsequent mortality is 10.3% and differs between drug classes with immunotherapies the highest, 32.5% and salicylates the lowest, 2.6%. These elements highlight the diversity of presentations of myocarditis depending on drug class, and show the emerging role of antineoplastic drugs in the field of drug-induced myocarditis.
Immune checkpoint inhibitors (ICIs) have substantially improved clinical outcomes in multiple cancer types and are increasingly being used in early disease settings and in combinations of different ...immunotherapies. However, ICIs can also cause severe or fatal immune-related adverse-events (irAEs). We aimed to identify and characterise cardiovascular irAEs that are significantly associated with ICIs.
In this observational, retrospective, pharmacovigilance study, we used VigiBase, WHO's global database of individual case safety reports, to compare cardiovascular adverse event reporting in patients who received ICIs (ICI subgroup) with this reporting in the full database. This study included all cardiovascular irAEs classified by group queries according to the Medical Dictionary for Regulatory Activities, between inception on Nov 14, 1967, and Jan 2, 2018. We evaluated the association between ICIs and cardiovascular adverse events using the reporting odds ratio (ROR) and the information component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find associations between drugs and adverse events. IC025 is the lower end of the IC 95% credibility interval, and an IC025 value of more than zero is deemed significant. This study is registered with ClinicalTrials.gov, number NCT03387540.
We identified 31 321 adverse events reported in patients who received ICIs and 16 343 451 adverse events reported in patients treated with any drugs (full database) in VigiBase. Compared with the full database, ICI treatment was associated with higher reporting of myocarditis (5515 reports for the full database vs 122 for ICIs, ROR 11·21 95% CI 9·36–13·43; IC025 3·20), pericardial diseases (12 800 vs 95, 3·80 3·08–4·62; IC025 1·63), and vasculitis (33 289 vs 82, 1·56 1·25–1·94; IC025 0·03), including temporal arteritis (696 vs 18, 12·99 8·12–20·77; IC025 2·59) and polymyalgia rheumatica (1709 vs 16, 5·13 3·13–8·40; IC025 1·33). Pericardial diseases were reported more often in patients with lung cancer (49 56% of 87 patients), whereas myocarditis (42 41% of 103 patients) and vasculitis (42 60% of 70 patients) were more commonly reported in patients with melanoma (χ2 test for overall subgroup comparison, p<0·0001). Vision was impaired in five (28%) of 18 patients with temporal arteritis. Cardiovascular irAEs were severe in the majority of cases (>80%), with death occurring in 61 (50%) of 122 myocarditis cases, 20 (21%) of 95 pericardial disease cases, and five (6%) of 82 vasculitis cases (χ2 test for overall comparison between pericardial diseases, myocarditis, and vasculitis, p<0·0001).
Treatment with ICIs can lead to severe and disabling inflammatory cardiovascular irAEs soon after commencement of therapy. In addition to life-threatening myocarditis, these toxicities include pericardial diseases and temporal arteritis with a risk of blindness. These events should be considered in patient care and in combination clinical trial designs (ie, combinations of different immunotherapies as well as immunotherapies and chemotherapy).
The Cancer Institut Thématique Multi-Organisme of the French National Alliance for Life and Health Sciences (AVIESAN) Plan Cancer 2014–2019; US National Cancer Institute, National Institutes of Health; the James C. Bradford Jr. Melanoma Fund; and the Melanoma Research Foundation.
Over the past decades, assessment of drug safety and of their benefits harms balance has been profoundly modified by the availability of large databases and computerized automated statistical ...approaches. Improvement of digital data storage capacity has been applied to pharmacovigilance reports. VigiBase, the international pharmacovigilance database, is now aggregating over 21 million individual case safety reports in 2020. Identification and investigation of drug safety signals - concerning notably rare and unknown adverse drug reactions - is one of the major tasks in pharmacovigilance that can be amplified by automated signal detection. Several quantitative statistical methods exist, each with its own strengths and limits. Integrating signal detection, pharmacovigilance databases can be used for a wide variety of retrospective observational studies illustrated here by concrete examples. Confirming these signals by orthogonal validation using pre-clinical platforms and prospective trials is helpful. Pharmacovigilance databases represent a considerable source of information. However, the quality of signal detection and of pharmacoepidemiology studies in the field of adverse drug reaction closely depends on the quality of the individual data recorded.
Background
Possible biases in pharmacovigilance reporting may impact epidermal necrolysis (EN) and drugs associations.
Objectives
To assess biases associated with EN‐reporting.
Methods
Using ...VigiBase, the World Health Organization‐pharmacovigilance database, among drugs associated with EN between 2016 and 2020, we used an unsupervised clustering including reports characteristics, that is, reporter quality, time from drug intake to EN onset, and only one suspected drug in the report.
Results
Among 152 drugs, three clusters were identified. Cluster 1 (n = 41) exhibited drugs frequently reported within a time from intake to onset longer than 4 days, in 57 ± 13% of reports. It corresponded to well‐reported drugs and was composed mainly of antivirals and antiepileptics. Cluster 2 (n = 42) exhibited drugs frequently reported within a time from drug intake to onset shorter than 4 days, in 31 ± 12% of reports. It corresponded to drugs with a high risk of protopathic bias and was composed of nonsteroidal anti‐inflammatory drugs (NSAIDs), analgesics, and antibiotics. Cluster 3 (n = 69) exhibited drugs frequently reported with an unavailable time from drug intake to reaction, in 66 ± 11% of reports, and reported by a high frequency of consumers (9 ± 9%). It corresponded to drugs reported with a high risk of classification bias, and was composed of anticancer therapies and cardiovascular drugs.
Conclusion
Protopathic and classification biases impact EN‐reporting and should be considered regarding associations with antibiotics, NSAIDs, analgesics, anticancer therapies, and cardiovascular drugs.
Ibrutinib has revolutionized treatment for several B-cell malignancies. However, a recent clinical trial where ibrutinib was used in a front-line setting showed increased mortality during treatment ...compared with conventional chemotherapy. Cardiovascular toxicities were suspected as the culprit but not directly assessed in the study.
The purpose of this study was to identify and characterize cardiovascular adverse drug reactions (CV-ADR) associated with ibrutinib.
This study utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds ratios (ROR) and information component (IC) to determine whether CV-ADR and CV-ADR deaths were associated with ibrutinib. IC compares observed and expected values to find associations between drugs and adverse drug reactions using disproportionate Bayesian-reporting; IC025 (lower end of the IC 95% credibility interval) >0 is significant.
This study identified 303 ibrutinib-associated cardiovascular deaths. Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVAs) (ROR: 23.1; 95% confidence interval: 21.6 to 24.7; p < 0.0001; IC025: 3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7; 95% confidence interval: 3.4 to 4.1; p < 0.0001; IC025: 1.63), heart failure (ROR: 3.5; 95% confidence interval: 3.1 to 3.8; p < 0.0001; IC025: 1.46), ventricular arrhythmias (ROR: 4.7; 95% confidence interval: 3.7 to 5.9; p < 0.0001; IC025: 0.96), conduction disorders (ROR: 3.5; 95% confidence interval: 2.7 to 4.6; p < 0.0001; IC025: 0.76), CNS ischemic events (ROR: 2.2; 95% confidence interval: 2.0 to 2.5; p < 0.0001; IC025: 0.73), and hypertension (ROR: 1.7; 95% confidence interval: 1.5 to 1.9; p < 0.0001; IC025: 0.4). CV-ADR often occurred early after ibrutinib administration. Importantly, CV-ADR were associated with fatalities that ranged from ∼10% (SVAs and ventricular arrhythmias) to ∼20% (CNS events, heart failure, and conduction disorders). Ibrutinib-associated SVA portends poor prognosis when CNS events occur concomitantly, with 28.8% deaths (15 of 52 cases).
Severe and occasionally fatal cardiac events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs. (Evaluation of Reporting of Cardio-vascular Adverse Events With Antineoplastic and Immunomodulating Agents EROCA; NCT03530215)
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Aims
Drug‐induced aseptic meningitis (DIAM) is an adverse drug reaction of exclusion; only few studies have addressed this iatrogenic disease. The aim was to characterize DIAM and to identify ...suspected drugs.
Methods
Data were collected from the analysis of the French Pharmacovigilance Database from inception (1 January 1985) to 8 March 2017. All cases were initially analysed according to the French imputability method by institutional pharmacologists (clinicians or pharmacists). Further analyses of well documented cases were then performed.
Results
In this study, 329 cases of aseptic meningitis were retrieved from the French Pharmacovigilance Database for a total of 429 suspected drugs. Analysis of 203 well documented cases, including 282 drugs, showed that the main reported classes were intravenous polyvalent immunoglobulin, nonsteroidal anti‐inflammatory drugs (NSAIDs), vaccines, antimicrobials, intrathecal antimetabolites, corticosteroids and antalgics/anaesthetics (except NSAIDs). Lymphocytic (33.0%) and purulent (44.8%) meningitis represented the majority of cases of aseptic meningitis. In other cases, the cerebrospinal fluid was mixed (45–55% of neutrophils +45–55% of lymphocytes) or data about cerebrospinal fluid composition were lacking. Most DIAM cases (96%) had a favourable reported outcome with full recovery or minimal residual symptoms.
Conclusion
The most frequently involved drugs in DIAM were intravenous polyvalent immunoglobulin, NSAIDs, vaccines, and antimicrobials and this without being able to differentiate them in terms of biological characteristics. Although further studies are needed to better understand the pathophysiological mechanisms of DIAM, a continuous enrichment of pharmacovigilance databases is essential to identify new signals and to help clinicians in the understanding of DIAM.
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