Nomograms based on ratio indexes to predict severity and prognosis in immune checkpoint inhibitors-related myocarditis: a retrospective analysis

Abstract

Purpose: Immune checkpoint inhibitors-related myocarditis (ICI-M) is one of the immune-related adverse events (irAEs), which is rare and highly lethal. This study aimed to establish nomograms based on ratio biomarkers to predict the severity and prognosis of ICI-M.

Methods: We retrospectively examined patients with advanced cancers who were also diagnosed with ICI-M at the Fourth Hospital of Hebei Medical University. The patients of ICI-M were divided into mild and severe groups and a 40-day following up was carried out. The major adverse cardiovascular events(MACEs) were regarded as the endpoint. Nomogram-based models were established and validated.

Results: Seventy-seven patients were involved, including 31 severe cases(40.3%). Lactate dehydrogenase-to-albumin ratio(LAR) combined with the change rate from baseline to onset of LAR( $▵$ LAR) which performed best to diagnose the severe ICI-M was identified to establish the nomogram-based model. The bootstrap-corrected concordance index [0.752 95% confidence interval (CI): 0.635 $-$ 0.866] and calibration plot with good degree of fitting confirmed this diagnostic model. Neutrophil-to-high-density lipoprotein cholesterol ratio(NHR) and LAR were also screened into the nomogram-based model for 40-day MACEs after ICI-M, which performed well by validating for concordance index(0.779 95% CI: 0.677 $-$ 0.865)and calibration plots after being bootstrap-corrected. Moreover, a $\ge$ 101% increase in LAR significantly separated patients in MACE-free survival.

Conclusion: Ratio indexes at onset and their change rates from baseline showed good diagnostic value for the severity of ICI-M and prognostic value for subsequent MACEs, particularly LAR, NHR and their change rates. The nomogram-based models of ratio indexes could provide a potential choice for early detection and monitor of the severe ICI-M and subsequent MACEs.

Keywords: Diagnostic analysis; ICI-associated myocarditis; MACE; Nomogram; Predictive model; Prognostic analysis.

Fig. 1

The diagnostic value of (the change rates of) ratio indexes for the severity of ICI-M. Comparison of ratio indexes at onset and their change rates by division of mild and severe groups (A), univariate logistic regression of (the change rates of)ratio indexes and their difference comparison between mild and severe groups after being standardized scaled (B), the AUC of the risk scores of different combination models and the ROC curves of the best performance models (C and D). MACEs Major adverse cardiovascular events; ICI-M Immune checkpoint inhibitors-related myocarditis; AUC Area under the curve; ROC Receiver operating characteristic; NS No significance; *P<0.01; **P<0.001; ***P<0.0001. ${\phantom{0}}^T$Logarithmic form of the ratio indexes to display

Fig. 2

The dynamic nomogram based on ${\text{LAR}}^T$ and $\mathrm{\Delta }$LAR for the prediction of severe ICI-M (A), decision curve analysis of the nomogram (B) and calibration curve for nomogram predictions of severe ICI-M survival by bootstrap with 1000 repetitions (C). MACEs Major adverse cardiovascular events; ICI-M Immune checkpoint inhibitors-related myocarditis. ${\phantom{0}}^T$Logarithmic form of the ratio indexes

Fig. 3

The proccesion of selecting the risk factors for MACEs after ICI-M. The composition of subsequent MACEs (A), Best subset regression (BSR) (B), least absolute shrinkage and selection operator (LASSO) regression analysis and tenfold cross-validation (C and D). Combination of two methods to select factors (E). Kaplan Meier curves of ${\text{NHR}}^T$ and ${\text{LAR}}^T$ seprated by the median (F and G). MACEs Major adverse cardiovascular events; ICI-M Immune checkpoint inhibitors-related myocarditis; Adj2 Adjusted R-squared. ${\phantom{0}}^T$Logarithmic form of the ratio indexes

Fig. 4

The nomogram based on ${\text{NHR}}^T$ and ${\text{LAR}}^T$ for the prediction of 40-day MACEs after ICI-M (A), decision curve analysis of the nomogram (B), the risk score $\ge$ 9.43 selected by “survminer” package performed best for risk stratification of 40-day MACEs survival (C) and calibration curve for nomogram predictions of 40-day MACEs survival by bootstrap with 1000 repetitions (D). MACEs Major adverse cardiovascular events; ICI-M Immune checkpoint inhibitors-related myocarditis. ${\phantom{0}}^T$Logarithmic form of the ratio indexes

Fig. 5

Unicox regression of the change rates of ratio indexes and multicox regression with further adjustment of basic information, tumor-related information, the immunotherapy-related factors and cardiac-related parameters (A), the Spearman correlation test of LAR (NHR) and $▵$LAR ($▵$NHR) (B) and Kaplan Meier curves of $▵$NHR and $▵$LAR seprated by the median (C and D).MACEs Major adverse cardiovascular events