Cardiovascular toxicity of immune therapies for cancer.

In addition to conventional chemoradiation and targeted cancer therapy, the use of immune based therapies, specifically immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T cell therapy (CAR-T), has increased exponentially across a wide spectrum of cancers. This has been paralleled by recognition of off-target immune related adverse events that can affect almost any organ system including the cardiovascular system. The use of ICIs has been associated with myocarditis, a less common but highly fatal adverse effect, pericarditis and pericardial effusions, vasculitis, thromboembolism, and potentially accelerated atherosclerosis. CAR-T resulting in a systemic cytokine release syndrome has been associated with myriad cardiovascular consequences including arrhythmias, myocardial infarction, and heart failure. This review summarizes the current state of knowledge regarding adverse cardiovascular effects associated with ICIs and CAR-T.

Immune checkpoint inhibitor-induced myopericarditis.

A woman in her 30s with a medical history of metastatic rectal adenocarcinoma, currently on pembrolizumab, which started a few weeks ago, was admitted for abdominal pain. During the hospital stay, she experienced sharp chest pain. Troponin was 1885 ng/mL which peaked at 7338 ng/mL. ECG was unremarkable. The echocardiogram showed an Ejection fraction (EF) of 55%-60% and basal-inferior wall hypokinesis. Left heart catheterisation showed no coronary abnormalities. Cardiac MRI showed a non-coronary area of focal T1 and T2 hyperintense signal and transmural delayed gadolinium enhancement in the mid-basal inferior/inferoseptal wall consistent with myocardial damage. Pericardium showed increased thickness and adhesions at the right ventricular outflow tract consistent with pericarditis. Steroid therapy was initiated, and a marked clinical response was achieved. Immune checkpoint inhibitor-induced myocarditis and pericarditis is a rare complication associated with a high mortality rate, if untreated. Diagnosis requires a multidisciplinary approach, and early detection is critical to preventing a fatal outcome.

Vaccine-carditis study: Spanish multicenter registry of inflammatory heart disease after COVID-19 vaccination.

INTRODUCTION AND OBJECTIVES: Vaccines against SARS-CoV-2 have been a major scientific and medical achievement in the control of the COVID-19 pandemic. However, very infrequent cases of inflammatory heart disease have been described as adverse events, leading to uncertainty in the scientific community and in the general population. METHODS: The Vaccine-Carditis Registry has included all cases of myocarditis and pericarditis diagnosed within 30 days after COVID-19 vaccination since August 1, 2021 in 29 centers throughout the Spanish territory. The definitions of myocarditis (probable or confirmed) and pericarditis followed the consensus of the Centers for Disease Control and the Clinical Practice Guidelines of the European Society of Cardiology. A comprehensive analysis of clinical characteristics and 3-month evolution is presented. RESULTS: From August 1, 2021, to March 10, 2022, 139 cases of myocarditis or pericarditis were recorded (81.3% male, median age 28 years). Most cases were detected in the 1st week after administration of an mRNA vaccine, the majority after the second dose. The most common presentation was mixed inflammatory disease (myocarditis and pericarditis). 11% had left ventricular systolic dysfunction, 4% had right ventricular systolic dysfunction, and 21% had pericardial effusion. In cardiac magnetic resonance studies, left ventricular inferolateral involvement was the most frequent pattern (58%). More than 90% of cases had a benign clinical course. After a 3-month follow-up, the incidence of adverse events was 12.78% (1.44% mortality). CONCLUSIONS: In our setting, inflammatory heart disease after vaccination against SARS-CoV-2 predominantly affects young men in the 1st week after the second dose of RNA-m vaccine and presents a favorable clinical course in most cases.

Cardiovascular Toxicities Associated with Anaplastic Lymphoma Kinase Inhibitors: A Disproportionality Analysis of the WHO Pharmacovigilance Database (VigiBase).

INTRODUCTION: Recently, cases of cardiovascular toxicities, such as pericarditis, caused by anaplastic lymphoma kinase (ALK) inhibitors have been reported; however, whether these adverse events are common among all ALK inhibitors remains unclear. AIMS: This study aimed to clarify the cardiovascular toxicity profile of ALK inhibitors using an adverse event spontaneous report database. METHODS: We analyzed data from VigiBase, the WHO global database of individual safety reports, from its inception in 1968 to December 2021. We calculated the reporting odds ratio to evaluate the association between ALK inhibitors (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib) and 21 cardiovascular adverse events. Time to onset of pericarditis from ALK inhibitor administration was analyzed. RESULTS: Of the 27,994,584 reports, 19,911 involved treatment with ALK inhibitors. Among the 21 cardiovascular toxicities, only pericarditis signals were detected with all five ALK inhibitors (crizotinib [reporting odds ratios (ROR), 4.7; 95% CI 3.63-6.15], ceritinib [ROR, 12.9; 95% CI 9.37-17.79], alectinib [ROR, 4.8; 95% CI 3.15-7.42], brigatinib [ROR, 3.5; 95% CI 1.33-9.46], and lorlatinib [ROR, 6.4; 95% CI 3.60-11.22]). For torsade de pointes/QT prolongation, signals were detected with crizotinib (ROR, 5.0; 95% CI 3.72-6.77) and ceritinib (ROR, 4.2; 95% CI 2.17-8.05), whereas for hypertension, they were identified only with brigatinib (ROR, 3.9; 95% CI 2.88-5.20), and for heart failure, they were detected with alectinib (ROR, 2.2; 95% CI 1.60-2.90), crizotinib (ROR, 2.1; 95% CI 1.72-2.48), and lorlatinib (ROR, 2.0; 95% CI 1.27-3.23). Regarding time-to-onset analysis from drug administration to adverse event reporting, for pericarditis, it ranged from 52.5 days for alectinib to 166.5 days for crizotinib. CONCLUSIONS: Systematic evaluation of ALK inhibitor-associated adverse events revealed differences in the cardiotoxicity profiles among ALK inhibitors. Understanding the differences in the cardiovascular toxicity profile of each ALK inhibitor will contribute to safe drug therapy when switching between ALK inhibitors.

Safety Signal between Azacitidine and Pericarditis.

BACKGROUND: Drug-induced pericarditis is an important cause of pericarditis and if unnoticed and unmanaged can lead to constrictive pericarditis, pericardial effusion, and cardiac tamponade. OBJECTIVE: The objective of this analysis was to determine if a significant signal exists between azacitidine use and pericarditis. METHODS: A pharmacovigilance analysis was performed using the FDA Adverse Event Database. RESULTS: 48 reports of azacitidine-induced pericarditis with azacitidine as the suspect drug were identified. The most common indications for azacitidine use in the adverse event reports were myelodysplastic syndrome (48%) and acute myelogenous leukemia (27%). Physicians reported 44% of the azacitidine-induced pericarditis reports, while other health professional reported 52% of the reports. The disproportionality analysis showed a proportional reporting ratio of 5.0, χ2 of 149.8, reporting odds ratio of 5.0, and IC025 of 1.8. Literature review found 3 case reports of azacitidine-induced pericarditis. CONCLUSION: The signal between azacitidine and pericarditis was found to be statistically significant. Clinicians should be aware of the possible risk of pericarditis when prescribing azacitidine. If there is suspicion for azacitidine-induced pericarditis, clinicians should consider discontinuation of azacitidine to improve patient's symptoms and reduce the likelihood of the development of constrictive pericarditis, pericardial effusion, and cardiac tamponade.

Background incidence rates of adverse events of special interest related to COVID-19 vaccines in Ontario, Canada, 2015 to 2020, to inform COVID-19 vaccine safety surveillance.

BACKGROUND: Background incidence rates are critical in pharmacovigilance to facilitate identification of vaccine safety signals. We estimated background incidence rates of 11 adverse events of special interest related to COVID-19 vaccines in Ontario, Canada. METHODS: We conducted a population-based retrospective observational study using linked health administrative databases for hospitalizations and emergency department visits among Ontario residents. We estimated incidence rates of Bell's palsy, idiopathic thrombocytopenia, febrile convulsions, acute disseminated encephalomyelitis, myocarditis, pericarditis, Kawasaki disease, Guillain-Barré syndrome, transverse myelitis, acute myocardial infarction, and anaphylaxis during five pre-pandemic years (2015-2019) and 2020. RESULTS: The average annual population was 14 million across all age groups with 51% female. The pre-pandemic mean annual rates per 100,000 population during 2015-2019 were 191 for acute myocardial infarction, 43.9 for idiopathic thrombocytopenia, 28.8 for anaphylaxis, 27.8 for Bell's palsy, 25.0 for febrile convulsions, 22.8 for acute disseminated encephalomyelitis, 11.3 for myocarditis/pericarditis, 8.7 for pericarditis, 2.9 for myocarditis, 2.0 for Kawasaki disease, 1.9 for Guillain-Barré syndrome, and 1.7 for transverse myelitis. Females had higher rates of acute disseminated encephalomyelitis, transverse myelitis and anaphylaxis while males had higher rates of myocarditis, pericarditis, and Guillain-Barré syndrome. Bell's palsy, acute disseminated encephalomyelitis, and Guillain-Barré syndrome increased with age. The mean rates of myocarditis and/or pericarditis increased with age up to 79 years; males had higher rates than females: from 12 to 59 years for myocarditis and ≥12 years for pericarditis. Febrile convulsions and Kawasaki disease were predominantly childhood diseases and generally decreased with age. CONCLUSIONS: Our estimated background rates will permit estimating numbers of expected events for these conditions and facilitate detection of potential safety signals following COVID-19 vaccination.

Anakinra effectiveness in refractory polyserositis: An Italian multicenter study.

OBJECTIVES: Polyserositis is an inflammatory condition involving different serosal membranes at the same time, specifically the pericardium, pleura, and peritoneum with exudates in the respective cavities. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and glucocorticoids may be effective in patients with polyserositis, but relapses often occur when these drugs are tapered or discontinued. The interleukin (IL)-1 receptor antagonist anakinra has shown a beneficial effect in idiopathic recurrent pericarditis, mostly in unresponsive patients who develop steroid dependence and/or colchicine resistance. To date, there are no data suggesting the best therapy for managing acute episodes and/or relapses of polyserositis. On this basis, we performed a retrospective study aimed at evaluating the effectiveness and safety profile of anakinra in treating patients with refractory polyserositis. METHODS: Patients with idiopathic polyserositis or rheumatic diseases presenting inflammation of 2 or more serous membranes were included. Serositis had to be confirmed by imaging tests comprising either echocardiography, abdominal ultrasound, chest or abdomen computed tomography and/or chest x-ray scan. We included patients with polyserositis who started anakinra from January 2011 to January 2019 due to a poorly controlled disease despite treatment with NSAIDs, conventional immunosuppressant drugs, or the need to minimize oral corticosteroids intake. Erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and imaging tests, were recorded to monitor serositis at baseline and either at 3, 6 and 12-month follow-up. Patients with malignancies and infectious diseases were excluded from the analysis. RESULTS: Forty-five patients with recurrent polyserositis (23 women) (mean age 43.2±15.8 years and mean disease duration 23.1±28 years) were analysed. Polyserositis was idiopathic in 26 (57.8%) patients. Thirteen patients suffered from autoinflammatory diseases, whereas 6 were affected by autoimmune diseases. Combination treatment with colchicine and NSAIDs at anakinra baseline was administered in 38/45 (84.4%) and 37/45 (82.2%) patients, respectively. After starting anakinra, 84.5% of patients experienced a resolution of serositis with a dramatic decrease in ESR and CRP (P<0.001, for both) already at 3 months, furthermore the same beneficial effect was observed up to 12 months. No relapse was seen at 3 months, whereas the median number of relapses at 6 and 12 months was 0 (interquartile range 0-1). Glucocorticoids were discontinued in 22/45 (48.9%) patients already after 3 months (P<0.001). After 12 months 32/37 (86.5%) patients were steroid-free. Similarly, NSAIDs use significantly was decreased at 3 months (7/45 [15.6%] patients, P<0.001), whereas at 12-month follow-up no patient was on NSAIDs. Urticarial rashes at anakinra injection site occurring in 3 patients were the most common adverse events. CONCLUSIONS: Anakinra appeared to be a safe and useful therapeutic choice for patients refractory to optimal anti-inflammatory therapy (NSAIDs, colchicine and corticosteroids), allowing not only a dramatic reduction of recurrences but also of corticosteroids use. Anakinra was effective both in the idiopathic forms of polyserositis and in those with an underlying rheumatic disease, suggesting a common pathogenic pathway leading to serositis onset.

Immune checkpoint inhibitor cardiotoxicity: Breaking barriers in the cardiovascular immune landscape.

Immune checkpoint inhibitors (ICI) have changed the landscape of cancer therapy, but their use carries a high risk of cardiac immune related adverse events (iRAEs). With the expanding utilization of ICI therapy, there is a growing need to understand the underlying mechanisms behind their anti-tumor activity as well as their immune-mediated toxicities. In this review, we will focus on clinical characteristics and immune pathways of ICI cardiotoxicity, with an emphasis on single-cell technologies used to gain insights in this field. We will focus on three key areas of ICI-mediated immune pathways, including the anti-tumor immune response, the augmentation of the immune response by ICIs, and the pathologic "autoimmune" response in some individuals leading to immune-mediated toxicity, as well as local factors in the myocardial immune environment predisposing to autoimmunity. Discerning the underlying mechanisms of these immune pathways is necessary to inform the development of targeted therapies for ICI cardiotoxicities and reduce treatment related morbidity and mortality.

LXR-Mediated Regulation of Marine-Derived Piericidins Aggravates High-Cholesterol Diet-Induced Cholesterol Metabolism Disorder in Mice.

Reported as two antirenal cell carcinoma (RCC) drug candidates, marine-derived compounds piericidin A (PA) and glucopiericidin A (GPA) exhibit hepatotoxicity in renal carcinoma xenograft mice. Proteomics and transcriptomics reveal the hepatotoxicity related with cholesterol disposition since RCC is characterized by cholesterol accumulation. PA/GPA aggravate hepatotoxicity in high-cholesterol diet (HCD)-fed mice while exhibiting no toxicity in chow diet-fed mice. High cholesterol accumulation in liver is liver X receptor (LXR)-mediated cytochrome P450 family 7 subfamily a member 1 (CYP7A1) depression and low-density lipoprotein receptor (LDLR) activation. The farnesoid X nuclear receptor (FXR) is also depressed with a downregulated target gene OSTα. Different from PA directly combined with LXRα as an inhibitor, GPA exists as a prodrug in the liver and exerts toxic effects due to transformation into PA. Surface plasmon resonance (SPR) and docking results of 17 piericidins illustrate that glycosides exert no LXRα binding activity. A longer survival time of GPA-treated mice indicates that further exploration in anti-RCC drug research should focus on reducing glycosides transformed into PA and concentrating in the kidney tumor rather than the liver for lowering the risk of hepatotoxicity.

Case Report: Cytomegalovirus Reactivation and Pericarditis Following ChAdOx1 nCoV-19 Vaccination Against SARS-CoV-2.

As the coronavirus disease 2019 (COVID-19) pandemic is ongoing and new variants of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are emerging, there is an urgent need for vaccines to protect individuals at high risk for complications and to potentially control disease outbreaks by herd immunity. Surveillance of rare safety issues related to these vaccines is progressing, since more granular data emerge about adverse events of SARS-CoV-2 vaccines during post-marketing surveillance. Varicella zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation has already been reported in COVID-19 patients. In addition, adverse events after SARS-CoV-2 mRNA vaccination have also been in the context of varicella zoster virus (VZV) reactivation and directly associated with the mRNA vaccine. We present the first case of CMV reactivation and pericarditis in temporal association with SARS-CoV-2 vaccination, particularly adenovirus-based DNA vector vaccine ChAdOx1 nCoV-19 against SARS-CoV-2. After initiation of antiviral therapy with oral valganciclovir, CMV viremia disappeared and clinical symptoms rapidly improved. Since huge vaccination programs are ongoing worldwide, post-marketing surveillance systems must be in place to assess vaccine safety that is important for the detection of any events. In the context of the hundreds of millions of individuals to be vaccinated against SARS-CoV-2, a potential causal association with CMV reactivation may result in a considerable number of cases with potentially severe complications.

Tumor necrosis factor inhibitor-induced pleuropericarditis: A retrospective evaluation using data from VigiBase.

OBJECTIVE: The aim of this study was to assess the causality of anti-TNFα agents-associated pleuropericarditis in VigiBase with a focus on its diverse types. METHODS: All variables contained in the pleuropericarditis reports were reviewed. Well-documented reports, vigiGrade completeness score ≥ 0.80 or with an informative narrative, were analyzed and with a focus on the clinical features of the cases. Bradford-Hill criteria were used in the case series assessment of causality. RESULTS: From 1968 up to 18 December 2019, there were 94 unique cases from 18 countries reporting pleuropericarditis with anti-TNFα agents as a suspected or interacting medicine. Among the 94 reports, 42 were identified as well-documented and further assessed for clinical features. Of the 42 cases, 39 were serious, including three fatal and seven life-threatening. In 35 cases, an anti-TNFα agent was the only suspected drug. Positive de- and re-challenge were reported in 95% and 17% of the 42 cases, respectively. The times to onset (TTO) varied greatly among individual cases, ranging from one month to 75 months (mean = 24 months). The most commonly involved anti-TNFα agents were adalimumab, infliximab and etanercept; and the mostly reported pleuropericarditis types were classified as autoimmune-related with (n = 17) or without (n = 15) co-reported drug-induced lupus (DIL), or infection-related (n = 8). While adalimumab was the most reported in the infection-related cases (7/8), infliximab was the most frequent in the autoimmune-related cases, in particular co-reported with DIL (9/17). There were four cases where the reaction occurred one to two months after the anti-TNFα agents (infliximab and adalimumab) were stopped. Based on the review of the case series using Bradford-Hill criteria the anti-TNFα agents associated pleuropericarditis are considered as a class effect. CONCLUSIONS: To clinically recognize and manage these potentially life-threatening serious cardiopulmonary complications, health care professionals should be aware of this possible risk. Meanwhile, attention should be paid to the clinical features of pleuropericarditis cases, since they may cause diagnostic and therapeutic difficulties. Considering the long elimination time, clinicians need to be reminded to remain vigilant for the adverse reactions even after discontinuing anti-TNFα therapy.

Concomitant myopericarditis and takotsubo syndrome following immune checkpoint inhibitor therapy.

A 62-year-old man with metastatic hepatocellular carcinoma presented with ST elevation myocardial infarction had received one dose of nivolumab 3 weeks prior. Cardiac catheterisation was negative for obstructive coronary artery disease. He was transferred to the cardiac intensive care unit due to ventricular arrhythmias and markedly elevated troponin T levels. Transthoracic echocardiogram showed severely depressed left ventricular ejection fraction of 18% (normal 55%-70%) with mid and apical ballooning consistent with takotsubo syndrome (TTS). Intravenous glucocorticoids were administered due to suspicion for superimposed myocarditis. Cardiac MRI 3 days later showed mid-myocardial and subepicardial delayed enhancement in the inferior and lateral walls as well as apex indicative of myopericarditis. He clinically improved on steroids and was discharged with outpatient follow-up. This case highlights major cardiac complications that may arise with immune checkpoint inhibitor therapy. In addition, it emphasises the importance of assessing for concomitant myocarditis even when initial imaging suggests TTS.

Cancer Treatment-Associated Pericardial Disease: Epidemiology, Clinical Presentation, Diagnosis, and Management.

PURPOSE OF REVIEW: Cancer therapeutics have seen tremendous growth in the last decade and have been effective in the treatment of several cancer types. However, with advanced therapies like kinase inhibitors and immunotherapies, there have been unintended consequences of cardiotoxicities. While traditional chemotherapy and radiation-induced cardiotoxicity have been well studied, further research is needed to understand the adverse effects of newer regimens. RECENT FINDINGS: Both immune-mediated and non-immune-medicated cytotoxicity have been noted with targeted therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. In this manuscript, we describe the pericardial syndromes associated with cancer therapies and propose management strategies. Pericardial effusion and pericarditis are common presentations in cancer patients and often difficult to diagnose. Concomitant myocarditis may also present with pericardial toxicity, especially with immunotherapies. In addition to proper history and physical, additional testing such as cardiovascular imaging and tissue histology need to be obtained as appropriate. Holding the offending oncology drug, and institution of anti-inflammatory medications, and immunosuppressants such as steroids are indicated. A high index of suspicion, use of standardized definitions, and comprehensive evaluation are needed for early identification, appropriate treatment, and better outcomes for patients with cancer treatment-associated pericardial disease. Further research is needed to understand the pathophysiology and to evaluate how the management of pericardial conditions in these patients differ from traditional management and also evaluate new therapies.

[Diffuse infiltrative lung disease, pericarditis, pleural effusion and ceritinib hypersensitivity]. / Pneumopathie infiltrative diffuse, péricardite et pleurésie d'hypersensibilité compliquant un traitement par ceritinib.

Tyrosine kinase inhibitors are now major actors for the treatment of non-small-cell metastatic lung cancers where ROS 1 gene rearrangement is present. Because of the rapid development of these new therapies, developing information about their monitoring and knowledge about their potential toxicities is essential. We describe the case of a patient who was treated with ceritinib as a third line approach for a metastatic lung adenocarcinoma with ROS1 rearrangement. After two months, the patient developed acute respiratory distress with pericarditis and pleurisy. A hypersensitivity reaction was suggested and supported by favorable clinical and radiological outcomes within three days following ceritinib discontinuation and systemic corticosteroid introduction. Pleural effusion, pericarditis and diffuse pulmonary infiltration associated to ceritinib have not often been described previously. Despite few data of pulmonary toxicity related to ceritinib, the current observation highlights the need for caution and regular monitoring when using these inhibitors.

Cascade of immunologic adverse events related to pembrolizumab treatment.

Immune checkpoint inhibitors, such as pembrolizumab, have significantly improved cancer patient outcome. Toxicities are usually moderate and manageable. However, some adverse events, if not early recognised, could be life-threatening. We report a patient with non-small cell lung cancer who received treatment with pembrolizumab and developed multiple immune-related adverse events both during and after completing treatment, including rash, pericarditis, colitis and myasthenia gravis.