Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target and inhibit negative immune regulators and thereby activate immune responses against tumor cells. The approved indications for ICIs are increasing rapidly, with ICIs currently indicated for the treatment of at least 16 cancer types with over 100 ongoing trials.1 2 The use of ICIs may lead to toxicities involving a range of organ systems collectively described as immune-related adverse events (irAEs).3 The best described cardiovascular irAE is myocarditis, which may be fulminant and is frequently fatal.4–6 However, evolving data suggest that cardiac toxicities occur beyond myocarditis.7 These expanded toxicities include arrhythmias, heart failure, and atherosclerosis-related cardiovascular events.8–10 Among patients with cancer, pericardial effusions often occur due to the cancer itself, but may also develop secondary to treatment with traditional cytotoxic chemotherapy, radiation therapy, or targeted therapies.11–14 There are limited data on the occurrence of pericarditis or pericardial effusions among patients on an ICI. There have been case reports describing pericardial disease in patients treated with ICI.15 16 Additionally, in a study leveraging irAEs reported to the WHO VigiBase, pericardial disease, defined as pericarditis and pericardial effusions, represented 0.36% of all reported toxicities; this risk of pericardial disease was more than threefold higher with an ICI and was more common among patients with lung cancer.17 While this methodologic approach benefits from the large sample size, interpretation is limited by the lack of a control group or descriptive demographics to allow for adjustment due to confounders. In this work, we aimed to add to the limited evidence base linking ICI therapy to pericardial disease. We were specifically interested in whether pericarditis or pericardial diseases were increased among those on an ICI compared with controls and aimed to identify the risk factors for pericardial disease or pericarditis among those on an ICI.

In this large cohort study, the adjusted risk of pericardial disease was more than fourfold higher in patients treated with ICI compared with a control group not treated with ICI. The median time of onset of pericardial disease was approximately 6 months and those who developed pericardial disease on an ICI experienced a 1.5-fold increased risk of mortality. Finally, in patients treated with ICI, baseline high-dose corticosteroid use was associated with the occurrence of future pericardial disease.

Myocarditis is the most commonly described cardiac toxicity with ICI use.4–6 9 20 In contrast, despite a high reported mortality, data on the association between ICI use and pericardial disease are limited.17 Multiple case reports have highlighted the occurrence of pericardial effusion or tamponade in patients treated with an ICI.15 16 For example, three patients with non-small cell lung cancer treated with anti-PD-L1 therapy or combination therapy of anti-cytotoxic-T lymphocyte-associated protein 4 and anti-PD-1 monoclonal antibodies developed cardiac tamponade at 78, 98 and 131 days after ICI initiation.15 In a study leveraging the WHO VigiBase Database, a global database of individual case safety reports, pericardial disease comprised 0.36% of all ICI-related adverse events, representing a 3.8-fold higher risk of reporting pericardial disease with ICI use compared with the rest of the database. Notably, the majority (56%) of pericardial disease developed in those with lung cancer.17 Further, in a single-institution retrospective study of 3966 patients treated with ICI, compared with 82,157 patients who received a cancer treatment other than ICI, the rate of pericardiocentesis was 0.38% in the ICI patients and 0.11% in the non-ICI group (p<0.001).21 In our study, we identified a rate of 0.53% for pericardiocentesis and a rate of 1.5% for all pericardial events. Under-recognition and subsequent under-reporting of ICI cardiac toxicities has been noted in the past. For example, in a pharmacovigilance study, ICI myocarditis occurred in 0.41%.17 In contrast, in a multicenter cohort, the rate of myocarditis was reported to be closer to 1% and in a recent prospective study a rate of 1.4% was noted.9 22 We also considered whether the definitions of the endpoints were different. In the pharmacovigilance study, any pericardial effusion or pericarditis was applied as the endpoint. We restricted our analysis to only moderate or larger pericardial effusion or pericarditis; thus, if we had used the same definition, we would likely have had even more pericardial disease events, emphasizing overestimation in prior studies compared with that currently highlighted.

In our study, we observed that pericardial disease occurred 153 days (IQR: 42–288) after ICI initiation. However, the prior study using the WHO VigiBase noted a median onset of 30 days (IQR: 9–90).17 Prior case reports including a total of 12 patients reported the median time to onset, in terms of ICI cycles, as five cycles of treatment with an IQR of 1–35 cycles; with most ICI cycles 2–3 weeks in length, this corresponds to a median onset time of 14–105 days.16 The shorter time to onset observed in these studies might highlight the under-recognition and thus the under-reporting of pericardial disease associated with ICI use. As there is no definitive test for whether pericardial effusion or pericarditis is directly related to ICI use, pericardial disease that occurred later in the treatment course might be attributed to advanced malignancy rather than ICI use. This is likely for some but not all patients. In our study, cancer progression likely contributed to increased risk of pericardial disease in 22% of our cohort as these patients had malignant cells on pericardial fluid pathology. Our results are consistent with prior reports indicating that irAEs most commonly develop during the first few weeks to months after ICI therapy initiation, but can occur at later time points, and even after cessation of therapy.23 24

Although the exact mechanisms of cardiac irAEs remain incompletely understood, several theories exist. These include a loss of peripheral tolerance of self-reactive T cells due to ICI-mediated disruption of negative regulators of immune activation.23 Corticosteroids suppress immune activation via transcriptional and non-transcriptional pathways. Treatment with corticosteroids is recommended principally for grade 3 and 4, and occasionally grade 2 irAEs.3 25 They are also indicated in ICI-related cardiovascular toxicities.7 For example, for patients with cardiovascular toxicities, including myocarditis and vasculitis, high-dose corticosteroids are recommended.3 Unexpectedly, we observed that the use of corticosteroids prior to the initiation of ICIs increased the risk of subsequent pericardial disease. This may be mechanistically linked to the well-established increased risk of recurrence of non-ICI pericarditis after treatment with corticosteroids.11 26 27

This study has several limitations. First, this was a retrospective study which limited our ability to control for confounding. However, our cohort of patients treated with ICI is significantly larger than any prior publications on the same subject and the association of ICI use with pericardial disease persisted after adjusting for confounders. Second, our study did not investigate whether the increase in pericardial disease after ICI therapy reflected immune-mediated mechanisms or was due to progression of cancer. To try to control for cancer-specific factors, we matched controls for age, cancer type and only included those with metastatic disease; our control group was derived from years preceding the emergence of ICI therapy since patients not on an ICI once ICIs were available would likely have different baseline comorbidities and different severity of cancer. Patients who were on an ICI were followed up for a shorter period of time compared with those who did not receive ICI. There are several possible explanations for the difference: (1) patients who were on an ICI had treatment refractory disease, while those not on an ICI had less aggressive disease and the difference in follow-up time is a reflection of survival; (2) patients who were on an ICI were more likely to have been lost to follow-up due to the fact that some patients received cancer care elsewhere and were only referred for ICI treatment at a tertiary care center; (3) those on an ICI experienced pericardial events occurred much earlier at a higher rate, which again was reflected as shorter follow-up time; (4) patients who were not on ICI were captured between 2008 and 2012 per study design and thus were followed up for longer time. To account for (1) and (2), we performed competing risk analysis and patients who were lost to follow-up were right-censored. We also performed sensitivity analysis by including follow-up time only up to 2 years and showed similar findings.

In conclusion, ICI use among patients with cancer was associated with increased risk of pericardial disease and this increase in pericardial disease translated into a trend towards higher mortality. Our findings further highlight that pericardial disease is an under-recognized toxicity with ICI use. Increased awareness and close surveillance for pericardial disease are warranted for those treated with ICI, especially among those with lung cancer.