In a single academic hospital network retrospective case-control study reported in JACC:CardioOncology, Charlotte Lee, MD, of Columbia University Irving Medical Center, New York, along with senior author Tomas Neilan, MD, MPH, of Massachusetts General Hospital and colleagues found that patients with compared to without preexisting autoimmune disease who received immune checkpoint inhibitor therapy for cancer had a significantly increased risk of cardiovascular events.¹ Preexisting autoimmune disease was also associated with significantly higher rates of some noncardiovascular immune-related adverse events.

Charlotte Lee, MD

Tomas Neilan, MD, MPH

Study Details

The study included 6,683 patients receiving immune checkpoint inhibitor therapy as standard treatment or in a clinical trial between May 2015 and March 2019 within the Massachusetts General Brigham network. A total of 251 patients had autoimmune disease prior to treatment, most commonly rheumatoid arthritis (23%), psoriasis (23%), and polymyalgia rheumatica (9.1%). These patients were matched 1:1 with 251 patients without prior autoimmune disease on the basis of age, sex, history of coronary artery disease, history of heart failure, and diabetes mellitus. The most common cancer types in both the autoimmune disease and non–autoimmune disease groups were thoracic (37.1% vs 34.7%) and melanoma (19.5% vs 31.5%). In the autoimmune disease and non–autoimmune disease groups, the most common immune checkpoint inhibitor therapy consisted of anti–PD-1 monotherapy, in 82.9% and 71.3% of patients; combined anti–PD-1/CTLA-4 therapy was received by 2.4% and 7.6%.

Cardiovascular events were defined as a composite of myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke, transient ischemic attack, deep venous thrombosis, pulmonary embolism, or myocarditis. Analysis of risk for noncardiovascular immune-mediated adverse events included colitis, dermatitis, hepatitis, hypopituitarism, myositis, nephritis, pancreatitis, pneumonitis, psoriasis, and thyroiditis.

Patients in the non–autoimmune disease group were significantly more likely to have a history of hypertension (47.4% vs 28.3%) and a trend toward a higher rate of history of smoking (12.8% vs 7.6%) and were significantly more likely to have a history of pulmonary embolism (8.8% vs 4.0%) and venous thromboembolism (deep venous thrombosis/pulmonary embolism; 12.4% vs 6.0%). Those in the autoimmune disease group were significantly more likely to have been prescribed cardiovascular medications prior to the start of immune checkpoint inhibitor therapy, including angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (38.3% vs 24.7%), beta-blockers (41.0% vs 21.9%), and diuretics (35.9% vs 24.3%).

Risk of Cardiovascular Events

During the median follow-up of 205 days (interquartile range = 56–471 days), there were 45 cardiovascular events among 251 patients with autoimmune disease and 22 cardiovascular events among 251 without autoimmune disease (unadjusted hazard ratio [HR] = 1.81, 95% confidence interval [CI] = 1.09–3.02, P = .023). On multivariate analysis adjusting for cardiovascular risk factors (stroke, smoking, hypertension) and cardiovascular medications, the adjusted hazard ratio was 1.77 (95% CI = 1.04–3.03, P = .0364). Event-free survival was significantly better in the non–autoimmune disease group (P = .02).

The rates of all individual cardiovascular events except coronary artery bypass graft were numerically but not statistically significantly higher in the autoimmune disease group, including myocardial infarction (2.4% vs 1.2%), percutaneous coronary intervention (1.2% vs 0.8%), coronary artery bypass graft (0.0% vs 0.4%), stroke (2.8% vs 1.2%), transient ischemic attack (2.0% vs 0.0%), deep venous thrombosis (7.2% vs 3.6%), pulmonary embolism (2.8% vs 2.4%), and myocarditis (1.6% vs 0.4%).

Noncardiovascular Immune-Related Adverse Events

A numerically greater incidence of noncardiovascular immune-related adverse events was observed in the autoimmune disease group, with such events occurring in 89 (35.5%) of the autoimmune disease group vs 72 (28.7%) of the non–autoimmune disease group (P = .13). Incidence in the autoimmune disease group was significantly higher for colitis (24.3% vs 16.7%, P = .045) and psoriasis (11.2% vs 0.4%, P <.001). No significant differences were observed for dermatitis (20.7% vs 17.9%), hepatitis (7.2% vs 4.0%), hypopituitarism (3.6% vs 5.2%), myositis (1.2% vs 1.6%), nephritis (2.8% vs 4.0%), pancreatitis (2.4% vs 1.2%), pneumonitis (8.8% vs 8.8%), or thyroiditis (4.0% vs 2.8%). Steroid therapy for any immune-related adverse event was used in 35.5% vs 28.7% of patients (P = .13).

The investigators concluded: “Patients with [autoimmune disease] have an increased risk of cardiovascular and non-cardiovascular events post-[immune checkpoint inhibitor therapy]…. [We] observed an increased rate of [cardiovascular] events in patients with preexisting autoimmune disease post-[immune checkpoint inhibitor therapy] after adjusting for age and prior history of hypertension, despite a lower cardiovascular risk profile at baseline. Our study contributes to the current literature that even in those with overall well-controlled autoimmune disease, close monitoring is necessary [for] both [cardiovascular] and non-[cardiovascular] events. Future studies on preventive measures prior to [immune checkpoint inhibitor therapy] will be needed for this patient population once risk factors are better identified and especially if patients with less well-controlled autoimmune diseases are to be enrolled in [immune checkpoint inhibitor therapy]-based trials.” 

DISCLOSURE: The study was supported by National Heart, Lung, and Blood Institute grants and others. Dr. Lee reported no conflicts of interest.

REFERENCE

1. Lee C, Drobni ZD, Zafar A, et al: Pre-existing autoimmune disease increases the risk of cardiovascular and non-cardiovascular events after immunotherapy. JACC: CardioOncol 4:660-669, 2022.