Incidence and risk of autoimmune disease in patients with a previous diagnosis of myocarditis - a nationwide Danish register-based cohort study
Authors: Lundgren N L O , Holmark Andersen N , Lukacs Krogager M , Juul Riddersholm S , Porsborg Andersen M , Torp-Pedersen C , Hagendorff A , Wohlfahrt Dreyer L , Mogensen J , Hay Kragholm K 
Published: October 2024

Abstract

Introduction
Myocarditis is a severe condition with an acute onset characterized by myocardial inflammation. The aetiology is heterogenous ranging from viral infections to autoimmune diseases (AD). However, it is currently unknown if patients with a first-time diagnosis of myocarditis are at higher risk of developing an autoimmune disease (AD) at a later stage.

Purpose
To estimate the risk of developing AD in patients with a first-time diagnosis of myocarditis during 20 years of follow-up.

Methods
Data source and study design: Nationwide register-based cohort study using data from Danish national administrative registers containing data on ICD-10 codes of diagnoses, prescription of pharmaceuticals, as well as date of birth and death on all Danish citizens.
Study population: All Danish patients with a diagnosis of myocarditis from 2002-2020. Patients with previous diagnosis of AD were excluded. A control population without a diagnosis of myocarditis nor AD was sex and aged matched 1:5.
Endpoints: Receiving a diagnosis of AD out of 35 recognized AD, and all-cause mortality.
Statistics: Cumulative incidence of AD diagnosis was calculated by use of Aalen-Johansen estimation and all-cause mortality rate by Kaplan-Meier estimation. Hazard ratio (HR) by multivariate Cox regression modelling, standardized to sex, age, and comorbidities. Standardized relative (RR) and absolute (AR) risk derived from Cox regression by estimated Average Treatment Effect. Continuous variables are presented as median [1st quartile, 3rd quartile].

Results
Study population: Myocarditis cohort: n=2,684. Control cohort: n=13,420. Median follow-up time: 9.5 years [5.4, 14.6]. Median age: 46 years [28, 67]. 69.5 % were of male sex. Comorbidities including hypertension, heart failure, and ischemic heart disease were significantly more common in patients with myocarditis.
Autoimmune disease: At 20 years of follow-up, the cumulative incidence of AD diagnosis was 14.1% in the myocarditis cohort, and 5.8% in the control cohort. Adjusted HR for AD diagnosis in myocarditis vs. control cohorts was 2.65 (95% CI 2.19-3.17). Adjusted RR at 1 and 20 years of follow-up was 2.26 (95% CI 2.13-3.11) and 2.47 (95% CI 2.03-2.90), respectively. Figure 1 (left) shows AR of developing an AD at 20 years of follow-up, stratified by sex and age group.
Mortality: Kaplan-Meier all-cause mortality was 40.5% in the myocarditis cohort, and 28.5% in the control cohort. Adjusted HR: 1.84 (95% CI 1.67-2.03). Adjusted RR at 1 and 20 years of follow-up: 1.77 (95% CI 1.60-1.93) and 1.31 (95% CI 1.25-1.36), respectively. Figure 1 (right) shows stratified AR of all-cause mortality at 20 years of follow-up.

Conclusions
Patients with a diagnosis of myocarditis had a significantly higher risk of developing AD in addition to significantly higher all-cause mortality compared to patients without previous myocarditis diagnosis. These findings suggest underlying and subsequent AD should be considered in patients with myocarditis.20-year AR of AD and all-cause mortalityICD-10 codes of AD investigated