Reporting of immune checkpoint inhibitor-associated myocarditis – Authors' reply

We thank Sadeer G Al-Kindi and Guilherme H Oliveira for their Correspondence, and we completely agree with the use of multiple databases to verify and validate our findings on fatalities linked with immune checkpoint inhibitor-associated myocarditis. Their use of the large US Food and Drug Administration database and incorporation of demographic features is commendable and provides additional evidence showing the fulminant and unpredictable nature of immune checkpoint inhibitor-associated myocarditis. We appreciate and agree with the rigorous analyses by Emanuel Raschi and colleagues in their Correspondence and their calculation of reporting odds ratios, thus statistically linking cardiotoxicities to immune checkpoint inhibitors. The association between these drugs and pericardial disorders is very intriguing, and we have made a similar observation using Vigibase1Lindquist M VigiBase, the WHO Global ICSR database system: basic facts.Drug Inf J. 2008; 42: 409-419Crossref Scopus (276) Google Scholar (unpublished). We also thank Roberta Noseda and colleagues for their Correspondence and agree that determining the exact cause of death in many fatal cases associated with immune checkpoint inhibitors is challenging, particularly when using incomplete reporting databases. However, among 40 cases in which fatalities were linked with a specific event, 26 (65%) had myocarditis listed as the only or contributing cause of death.2Moslehi JJ Salem J-E Sosman JA Lebrun-Vignes B Johnson DB Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis.Lancet. 2018; 391: 933Summary Full Text Full Text PDF PubMed Scopus (335) Google Scholar For another five (13%) fatal cases, other cardiac events were noted as the cause of death (eg, cardiac failure, arrhythmia, cardiac arrest), which are known as direct manifestations of myocarditis.2Moslehi JJ Salem J-E Sosman JA Lebrun-Vignes B Johnson DB Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis.Lancet. 2018; 391: 933Summary Full Text Full Text PDF PubMed Scopus (335) Google Scholar Furthermore, for a further six (15%) cases, an outcome of death was listed, with myocarditis having not recovered.2Moslehi JJ Salem J-E Sosman JA Lebrun-Vignes B Johnson DB Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis.Lancet. 2018; 391: 933Summary Full Text Full Text PDF PubMed Scopus (335) Google Scholar Other studies 3Johnson DB Balko JM Compton ML et al.Fulminant myocarditis with combination immune checkpoint blockade.N Engl J Med. 2016; 375: 1749-1755Crossref PubMed Scopus (910) Google Scholar, 4Escudier M Cautela J Malissen N et al.Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity.Circulation. 2017; 136: 2085-2087Crossref PubMed Scopus (181) Google Scholar, 5Mahmood SS Fradley MG Cohen JV et al.Myocarditis in patients treated with immune checkpoint inhibitors.J Am Coll Cardiol. 2018; 71: 1755-1764Crossref PubMed Scopus (426) Google Scholar have confirmed a high mortality with myocarditis (including the analysis in the Correspondence by Al-Kindi and colleagues). By contrast, we have also assessed the 3905 cases of immune checkpoint inhibitor-associated colitis in Vigibase (excluding those with known cancer progression; search done Jan 28, 2018), only 225 (6%) cases had fatal outcomes, highlighting the comparatively serious nature of myocarditis. In our experience, given its fulminant nature, myocarditis is frequently associated with complications associated with a critical illness that could be listed as the proximate cause of death. Thus, we maintain that the fatality rate from myocarditis is quite high, particularly in severe cases, warranting pharmacovigilance reporting. We also agree that determining comorbidities rather than concurrent medications would be an improved approach. However, other medical conditions are reported extremely sparsely in Vigibase, thus restricting the ability to reliably obtain and analyse such data. Immune checkpoint inhibitor-associated myocarditis is frequently fatal and diagnostically challenging. Characterising the pathophysiology and optimal diagnostic, prevention, and management strategies are still crucial for these rapidly expanding therapeutics. Ultimately, Vigibase1Lindquist M VigiBase, the WHO Global ICSR database system: basic facts.Drug Inf J. 2008; 42: 409-419Crossref Scopus (276) Google Scholar only allows us to identify patterns of timing, demographics, concurrent medications, and fatality rates that will need thorough clinical validation. The supplied data come from a variety of sources. The likelihood of a causal relationship is not the same in all reports. The information does not represent the opinion of WHO. This work was supported by The Cancer ITMO of the French National Alliance for Life and Health Sciences (AVIESAN): Plan Cancer 2014–2019, by NIH/NCI K23 CA204726, and by the James C Bradford Jr Melanoma Fund. JJM has served as a consultant to Novartis, Pfizer, Bristol-Myers Squibb, Pharmacyclics, Regeneron, Daiichi Sankyo, and Heat Biologics. DBJ serves on advisory boards for Bristol-Myers Squibb, Genoptix, Incyte, Merck, and Novartis. JAS reports grants and personal fees from Bristol-Meyers Squibb, Genentech, and Curis outside the submitted work. All other authors declare no competing interests. Reporting of immune checkpoint inhibitor-associated myocarditisWe read with great interest the Correspondence by Javid J Moslehi and colleagues,1 on immune checkpoint inhibitor-associated myocarditis. Full-Text PDF Reporting of immune checkpoint inhibitor-associated myocarditisWe read with interest the Correspondence by Javid J Moslehi and colleagues,1 who used the WHO Vigibase reporting system, to describe the first case series of severe myocarditis after treatment with immune checkpoint inhibitors—an emerging clinical entity.2 They noted that fatality was increased with combination therapy and saw substantial increases in reporting over time (especially in 2017). Full-Text PDF Reporting of immune checkpoint inhibitor-associated myocarditisWe read with interest the Correspondence by Javid J Moslehi and colleagues (March 10, p 933),1 in which they reported an increase in reporting incidence of myocarditis associated with immune checkpoint inhibitors in WHO's VigiBase database and shed insight on patient outcomes. Full-Text PDF Increased reporting of fatal immune checkpoint inhibitor-associated myocarditisImmune 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. Fulminant cases of immune checkpoint inhibitor-related myocarditis have been reported,2–4 but the characteristics, timing, and outcomes of this new clinical entity are unknown. We used VigiBase ,5 WHO's database of individual case safety reports, to identify 101 cases of severe myocarditis following treatment with immune checkpoint inhibitors, and observed early onset of symptoms, frequent deaths, and substantially increased reporting in 2017. Full-Text PDF