Abstract
Objective To determine the clinical phenotype and outcomes of patients with idiopathic inflammatory myopathies (IIMs) and myocarditis.
Methods Using the Johns Hopkins Myositis Center Research Registry, we identified 31 adult patients with IIM—out of a total of 3082 with confirmed or suspected muscle disease—with an encounter code of myocarditis from 2004 to 2021. Of these, 14 adult patients with IIM were adjudicated to have clinical myocarditis. Information about demographics, autoantibodies, and clinical outcomes was retrospectively collected and analyzed.
Results Of 14 patients with IIM with clinical myocarditis, the median age at IIM diagnosis was 49 (IQR 35-56) years, and the median age at myocarditis diagnosis was 54 (IQR 36-61) years. The median duration between IIM diagnosis and myocarditis was 3 (IQR 2-9) years. The majority of patients were female (8/14, 57%) and Black (10/14, 71%). Antisynthetase syndrome was the most common IIM subtype (9/14, 64%). Anti-Jo1 (n = 4) and anti-PL12 (n = 3) were the most frequent autoantibodies. At myocarditis diagnosis, most patients (11/14, 79%) had active myositis, defined as elevated creatine kinase and/or muscle weakness; required hospitalization (13/14, 93%); and had reduced left ventricular ejection fraction (LVEF < 50%; 10/14, 71%). Despite intensification of immunosuppression, the 5-year overall survival rate from IIM diagnosis was 84%, and the 5-year overall survival rate from myocarditis diagnosis was 53%. Systolic dysfunction (LVEF < 40%) at final evaluation was observed in all expired patients (n = 6).
Conclusion Clinical presentations of myocarditis in this select cohort of patients with IIM were severe and heterogeneous with poor outcomes despite intensification of immunosuppression, potentially reflecting late detection of myocarditis.
Idiopathic inflammatory myopathies (IIMs) are a rare and heterogeneous group of systemic autoimmune rheumatic diseases characterized by predominantly proximal muscle weakness and chronic muscle inflammation. IIMs include the main subgroups: dermatomyositis, polymyositis, immune-mediated necrotizing myopathy, antisynthetase syndrome (AS), inclusion body myositis, and overlap myositis.1 Patients with IIM may have a wide spectrum of disease manifestations, including constitutional symptoms and skin, joint, lung, heart, and/or gastrointestinal involvement. The multiorgan involvement of IIMs can result in significant morbidity and mortality.2
Clinically evident cardiac disease has been reported in up to 9% of patients with IIM in the large EuroMyositis Registry.3 However, abnormal cardiac investigations, particularly on cardiac magnetic resonance imaging (cMRI), can occur in patients with asymptomatic IIM, with subclinical disease in up to 50% of patients.4 Although clinically overt cardiac involvement is uncommon, cardiovascular disease was the dominant cause of death in some IIM cohorts, ranging from 31% to 55%.5,6 Pathophysiological mechanisms that contribute to cardiac manifestations involve coronary artery disease and myocarditis. Myocarditis can vary from asymptomatic cases to fulminant myocarditis leading to rapid deterioration, including heart failure, ventricular tachycardia, ventricular dysfunction, cardiogenic shock, and death.
Diagnosing myocarditis requires a high index of suspicion and remains a challenge in patients with IIM. The clinical manifestations can be nonspecific, subclinical, or masked by concomitant features of IIM, such as pericarditis or interstitial lung disease (ILD).7 The gold standard for myocarditis diagnosis is based on defined histopathologic changes on endomyocardial biopsy, but the histological definition is not always feasible because of the invasiveness; procedural risks; low sensitivity, as a result of the localized and patchy feature of myocarditis; and lack of expert availability.8 cMRI is the primary noninvasive method used to confirm a diagnosis of myocarditis in patients with high pretest likelihood. The Lake Louise Criteria, which are used to diagnose myocarditis by cMRI, require 2 out of 3 positive criteria for signs of hyperemia, edema, and myocardial necrosis/fibrosis.9 Other IIM studies have also described myocarditis detected by echocardiography manifesting as systolic and diastolic dysfunction or impaired longitudinal strain on speckle-tracking echocardiography and electrocardiogram (ECG) abnormalities (ie, ST/T wave abnormalities, atrioventricular block, and arrhythmias).10,11 Thus, the diagnosis of myocarditis can also be made noninvasively, dependent on a combination of clinical presentation and cardiac tests, such as troponin level, ECG, echocardiogram, and cMRI.12 It is crucial to accurately and promptly diagnose myocarditis in order to tailor therapies and avoid a potentially fatal early progression or the subsequent development of chronic heart failure.
At our institution, Sharma et al13 previously reported AS with histologically proven myocarditis resulting in congestive heart failure in 2 patients; of these, 1 patient recovered and the other patient died. To better understand the clinical phenotype and trajectory of all patients with IIM with myocarditis, we leveraged the large myositis registry at Johns Hopkins University to identify associated clinical features, autoantibodies, and outcomes of patients with IIM that develop myocarditis.
METHODS
Study design and setting. This was a single-center retrospective cohort including patients with IIM with myocarditis diagnosed any time after IIM onset. All patients were evaluated as part of routine clinical care at the outpatient Myositis Clinic at the Johns Hopkins Bayview Medical Center in Baltimore, Maryland. The Johns Hopkins Myositis Center began in 2005 as a unique multidisciplinary clinic with representation from the Divisions of Rheumatology and Pulmonary and Critical Care Medicine, and the Departments of Neurology and Physical Medicine and Rehabilitation. All patients participating in this study consented to enrollment into the Johns Hopkins Myositis Center Research Registry (Institutional Review Board [IRB] 00235256). This retrospective study was approved with a waiver of signed consent by the Johns Hopkins University’s IRB (IRB 00296679).
Patient selection and data collection. The Myositis Center Research Registry was screened for participants with an occurrence of “myocarditis” and “myositis” entered as an outpatient encounter diagnosis or admission diagnosis in the electronic medical record (EMR). A manual chart review of the EMR was performed on the resulting list to validate that participants (1) met the IIM criteria, according to the 2017 European Alliance of Associations for Rheumatology/American College of Rheumatology classification criteria,1 and/or the Bohan and Peter criteria14,15 (both criteria were used to allow greater inclusivity of patients); and (2) had clinically suspected myocarditis, according to the 2013 European Society of Cardiology (ESC) Working Group on Myocardial and Pericardial Diseases diagnostic criteria.16 The ESC Working Group criteria requires > 1 clinical presentation and > 1 diagnostic criterion from different categories (ie, ECG/Holter/stress test features, elevated troponin, functional and structural abnormalities on cardiac imaging, or tissue characterization by cMRI) or > 2 diagnostic criteria if the patient is asymptomatic. Given the retrospective nature of this study, there were no standardized prospective procedures performed to detect myocarditis; thus, cardiac evaluation was only implemented if clinically indicated at the discretion of the treatment team. Myocarditis cases were reviewed and adjudicated by a rheumatologist (MPC) and a cardiologist (JL), with a heart failure cardiologist (NAG) serving as a final adjudicator. Clinical variables, demographics, autoantibodies, and outcomes were obtained through retrospective chart review and database queries. When ranges of left ventricular ejection fraction (LVEF) were reported, the lower value was used.
Available myositis-specific autoantibody results were assayed on banked sera using the line immunoblot platform (EUROLINE Autoimmune Inflammatory Myopathies Profile, Euroimmun). Only those with moderate or high positive titer were considered positive. Additional serologies were also sent as clinically indicated, including for antimitochondrial, anti-Scl-70, anti-RNA polymerase III, and anti-dsDNA antibodies using commercial assays.
Statistical analysis. Descriptive statistics (ie, frequencies, proportions, medians, and ranges) were used to describe baseline demographic and clinical characteristics. The Kaplan-Meier method was used to assess 5-year overall survival rates from IIM diagnosis and myocarditis diagnosis. Participants were censored at the earliest of the following: lost to follow-up, defined as last known medical encounter; death; or end of study period (December 9, 2021). All analyses were conducted using SAS software, version 9.4 (SAS Institute Inc.).
RESULTS
Characteristics of the study cohort. Out of a total of 3082 patients with confirmed or suspected muscle disease enrolled in the myositis registry from 2004 to 2021, a total of 31 patients were identified to have had an encounter diagnosis of myocarditis, 14 of whom were retrospectively adjudicated to have myocarditis. Reasons for exclusion included the following: myocarditis criteria not met (n = 12), sarcoidosis (n = 2), IIM criteria not met (n = 2), and insufficient records (n = 1).
Clinical features of individual patients with IIM with confirmed myocarditis are shown in the Table. The median age at IIM diagnosis was 49 (IQR 35-56) years, and the median age at myocarditis diagnosis was 54 (IQR 36-61) years. The median duration between IIM diagnosis and myocarditis was 3 (IQR 2-9) years. Females (8/14, 57%) comprised slightly more than half of the cohort. Most patients were self-reported to be Black (10/14, 71%). The most common IIM subtype was AS (9/14, 64%), and the most frequent autoantibodies were anti-Jo1 (n = 4) and anti-PL12 (n = 3).
Patient characteristics.
Clinical presentation of myocarditis. Most patients (11/14, 79%) had active myositis at the time of myocarditis diagnosis, defined as elevated creatine kinase and/or muscle weakness. Of the 3 patients without active myositis, 1 had an ILD flare at the time of myocarditis diagnosis. Most patients were symptomatic at myocarditis diagnosis (n = 12), with a heterogenous initial presentation: subacute/chronic (> 3 months) worsening of dyspnea (n = 5), acute chest pain (n = 3), palpitation and/or unexplained arrhythmia and/or syncope (n = 2), cardiogenic shock (n = 2), or new-onset dyspnea (n = 1). Almost all required hospitalization (13/14, 93%) at the time of myocarditis diagnosis, with almost half (n = 6) requiring intensive care unit admission for various reasons: cardiogenic shock (n = 2), high flow oxygen (n = 2), cardiac arrest (n = 1), or hemodynamic monitoring for hypotension not requiring vasopressors or inotropes (n = 1).
Myocarditis diagnostic testing. When available, troponin I levels at the time of myocarditis (n = 12) were elevated in 10 patients. Coronary angiography (n = 13) showed no coronary artery disease and/or nonobstructive coronary artery disease in all patients for whom the procedure was performed. ECGs (n = 14) were abnormal in 79% (n = 11) of patients but had nonspecific findings. Transthoracic echocardiogram (n = 14) at the time of myocarditis diagnosis revealed that 71% (n = 10) of patients had reductions in LVEF < 50%; 6 of these patients had severely reduced LVEF < 35% at presentation. No significant valvulopathy was observed. Elevated right ventricular systolic pressure (defined as > 40 mmHg) was observed in 3 patients.
cMRI (n = 12) revealed myocardial edema in 3 cases and late gadolinium enhancement in 10 cases. Pericardial effusion was observed in 5 cases, but all were mild and not hemodynamically significant. Endomyocardial biopsy (n = 6) revealed that 50% (n = 3) of patients had focal active and chronic inflammatory lesions, with both lymphocytes and neutrophils invading the myocardium, and met histopathologic diagnostic criteria for myocarditis. In total, 3 cases were equivocal and had nonspecific findings of fibrosis. The Figure shows cMRI and histopathologic findings from select patients in this cohort.
(A) Mild T2 hyperintensity within the basal septal walls (solid red arrow) consistent with edema with (B) associated delayed enhancement in a patient with antimitochondrial necrotizing myopathy and myocarditis. (C) Midmyocardial delayed enhancement in the inferolateral wall and anteroseptal wall at the base (dashed red arrows) suggestive of myocarditis in a patient with Jo1 antisynthetase syndrome. (D) Focal mild T lymphocyte infiltrate (asterisk) in a patient with myositis/scleroderma overlap.
Treatment and outcomes. Treatments targeted both the cardiac and immune systems. Cardiac treatment was at the discretion of the treating cardiologist and comprised diuretics (n = 12), beta blockers (n = 13), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (n = 9), and intravenous inotropic drugs (n = 3). Most patients (12/14, 86%) received intensification of baseline immunosuppression after myocarditis diagnosis, typically with prednisone (n = 8) and/or addition of rituximab (n = 5). Despite intensification of pharmacologic agents, 71% (10/14) of patients had a cardiac relapse defined as cardiogenic shock, arrhythmias, congestive heart failure exacerbations, cardiac arrest, and/or any decline in LVEF (defined as a > 5% drop). Almost one-third of patients (4/14, 29%) received implantable cardioverter defibrillators. Despite intervention, 43% (6/14) of patients expired; the median survival after IIM diagnosis was 6.1 (IQR 5.7-11.2) years, and the mean survival after myocarditis diagnosis was 2.5 (IQR 2.3-3.8) years. The 5-year overall survival rate from IIM diagnosis was 84%, and the 5-year overall survival rate from myocarditis diagnosis was 53%. All expired patients had an LVEF < 40% (mean 26%, SD 10%) at final evaluation. In comparison, most survivors had a preserved LVEF > 50% (mean 54%, SD 8%), except for 1 patient who had an LVEF of 40%.
DISCUSSION
This is the first retrospective study to report baseline clinical characteristics and the overall trajectory of patients with IIM with myocarditis seen at the Johns Hopkins Myositis Center. Interestingly, less than 1% of patients in our database were identified as having overt myocarditis, suggesting that the prevalence of myocarditis is underestimated in this cohort compared to other estimates and that only the most severe cases were included. Patients with milder or subclinical manifestations were likely not included because of a lack of standardized screening algorithms for detection of myocarditis. Since patients included in this study represent the overt cases of myocarditis in our cohort, they tended to have severe clinical presentations and poor outcomes despite intensification of immunosuppression and/or cardiac medications.
Since myocarditis indicates severe organ involvement, it is an important condition to diagnose in patients with IIM and to identify which subgroups of patients are at highest risk of developing this complication. In this study, most patients were Black, had active myositis and cardiopulmonary symptoms at the time of diagnosis with worsening of subacute dyspnea as the most common symptom, and had AS or scleroderma/myositis overlap. As patients with AS or scleroderma/myositis overlap can have concomitant ILD, worsening of dyspnea should raise clinical suspicion for cardiac etiologies as well. Patients with dermatomyositis who had myocarditis were not observed, though several case reports of myocarditis have been described in this subset of patients17-19; thus, myocarditis in dermatomyositis may have either been underrecognized and/or not clinically overt in this cohort. Myocarditis in inclusion body myositis was also not observed in our cohort, consistent with a prior study that found that the prevalence of cardiac abnormalities and the prevalence of cardiovascular causes of death in patients with inclusion body myositis were similar to those found in the age-matched overall population.20,21
The diagnosis of myocarditis remains challenging in patients with IIM, given the variable clinical presentation, nonspecific findings, and need for comprehensive cardiac testing. As such, it is difficult to quantify the true incidence and prevalence of myocarditis in IIM. Prior studies have reported a high prevalence ranging from 25% to 30% in small autopsy studies to 56% to 75% using cMRI criteria.22-24 However, since there are no standardized cardiac screening guidelines for patients with IIM, there are very inconsistent and imprecise approaches practiced for evaluating cardiac manifestations in patients with IIM. Although we only identified a small number of patients with overt myocarditis in our registry, myocarditis is likely underestimated as patients with IIM in our registry were not systematically screened for cardiac manifestations, and study inclusion required coding in the EMR for myocarditis. Thus, patients in our study may represent only the most severe cases with clinically overt disease. This is supported by the observation that most patients were hospitalized at the time of myocarditis diagnosis, with half requiring intensive care, reflecting the late and severe presentation of these patients. Interestingly, myocarditis was often diagnosed a few years after IIM onset in most patients while they were already on immunosuppressive medications. It is unclear whether myocarditis was present all along and eventually worsened to the point of clinician recognition or whether this truly represents an increase in disease activity through unknown mechanisms. Prospective studies in patients with IIM are needed to determine the true incidence and prevalence of myocarditis, including those with subclinical or more mild forms of disease.
Despite intensification of immunosuppression and addition of cardiac medications in most patients, overall cardiac and survival outcomes were poor, with cardiac relapses, such as cardiogenic shock, arrhythmias, and heart failure exacerbations, occurring in 71% of patients and an overall 5-year survival rate of 53% from myocarditis diagnosis. The poor outcomes in our study may, in part, be due to the late diagnosis and treatment of these patients. Starting specific treatments early, as well as urgent referral to cardiologists, could be important in preventing the development of complications, including myocardial fibrosis, arrhythmias, heart failure, and dilated cardiomyopathy. Serial echocardiograms and/or cMRI images may be useful to monitor the cardiac trajectory and cardiac function, although the exact interval and prognostic factors of poor outcomes remain to be determined.
The optimal immunosuppressive or immunomodulatory regimen for treatment of myocarditis in patients with IIM requires further investigation. Escalation of therapy with corticosteroids and/or rituximab was the most common regimen in this cohort, although outcomes remained poor. Intravenous immunoglobulin (IVIG) therapy has known efficacy in treating skeletal muscle weakness in patients with IIM, but only 5 patients in this cohort had treatment with IVIGs, either at baseline or with escalation. The low number of patients treated with IVIGs may, in part, be due to concerns of exacerbating IVIG-related volume overload in patients with heart failure. Further studies should investigate the efficacy of various treatment regimens for myocarditis in patients with IIM and evaluate whether slower infusions or lower volumes of IVIGs may be beneficial.
Our results add to the existing but limited number of studies describing myocarditis in patients with IIM. In a study of 12 patients with AS retrospectively selected from the French national registry, myocarditis was not associated with a specific autoantibody but was always observed with active myositis. Similar to our cohort, half of the patients required intensive care and all patients received immunosuppression medications. After a median follow-up of 11 months, 75% of patients recovered, whereas 25% of patients developed chronic cardiac insufficiency. There were no deaths at a median follow-up of 11 months.7 Although the French cohort had more favorable outcomes than did ours, the results are difficult to directly compare given the different and heterogeneous patient populations, myositis disease subtypes, and nonstandardized diagnostic and treatment strategies for myocarditis. In a case-control study from China, patients with polymyositis and dermatomyositis who had myocarditis (n = 31) had shorter disease durations; higher frequency of cardiac symptoms, related to heart failure, arrhythmia, and ischemia; and elevated serum troponin I, creatine kinase, and N-terminal pro-brain natriuretic peptide levels compared to a nonmyocarditis control group.25 Positive antimitochondrial antibodies were more frequent in those with myocarditis, and these patients exhibited more diffuse late gadolinium enhancement on cMRI. In a prior study from our group, antimitochondrial antibodies were frequently associated with severe cardiac involvement, including myocarditis, atrial and ventricular arrhythmias, and cardiomyopathy.26 Based on our current study, patients with elevated troponin I and creatine kinase are at the highest risk for myocarditis, but definitive screening recommendations require large prospective studies to validate these results. Further work is also needed to determine whether screening based on clinical symptoms alone is sufficient or whether there are certain high-risk groups that warrant screening even if asymptomatic.
Strengths of this study include the detailed clinical phenotyping of patients with IIM, the length of clinical follow-up, adjudication of IIM and myocarditis diagnoses, and the accuracy of collected data through retrospective chart review. There were several limitations of this study, including the retrospective design, selection bias, and lack of a control group without myocarditis. Since our patients were not screened for cardiac manifestations using a standardized algorithm, the prevalence of myocarditis in IIM in our cohort cannot be calculated and mild/subclinical disease is likely underrepresented. Additionally, causes of death were not available; thus, it is unknown if patients died from cardiovascular causes. Finally, patients not enrolled in the Myositis Center Research Registry may have been missed.
In conclusion, patients with IIM with clinically overt myocarditis in this cohort presented in a severe and heterogeneous fashion, with poor cardiac outcomes and overall survival despite treatment. Larger prospective studies are needed to validate these results, determine which high-risk patients may benefit from cardiac screening for earlier diagnosis and intervention to prevent adverse myocarditis-related outcomes and death, and guide optimal screening procedures for early detection of cardiac complications in patients with IIM.
Footnotes
JJP is supported, in part, by a National Institutes of Health (NIH) grant (K23 AR073927). CAM is supported by a grant from the NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23 AR075898). The Rheumatic Diseases Research Core Center, where the autoantibodies were assayed, is supported by an NIH grant (P30-AR070254). JA is supported by the Jerome L. Greene Foundation. Support for the Johns Hopkins Myositis cohort is funded, in part, by the Huayi and Siuling Zhang Discovery Fund. This work was supported by the Peter and Carmen Lucia Buck Foundation.
M.P. Chung and J. Lovell contributed equally as co–first authors.
N.A. Gilotra and J.J. Paik contributed equally as co–senior authors.
The authors declare no conflicts of interest relevant to this article.
- Accepted for publication March 21, 2023.
- Copyright © 2023 by the Journal of Rheumatology
