Pulmonary involvement

idiopathic inflammatory myopathy (IIM, “myositis”) is commonly associated with Interstital Lung Disease (IIM-ILD), which varies in radiological pattern, lung involvement and disease behavior. ILD is one of the main factors contributing to poor prognosis in IIM and those patients at risk for progressive IIM-ILD should be promptly identified and treated. In 20% of cases, the ILD can precede the onset of muscle involvement. The prevalence of ILD varies depending on subtype of IIM and risk factors and a clear screening strategy is currently lacking.

Symptoms are non-specific, as patients with ILD can present with dyspnea on exertion, cough, and decreased tolerance to exercise, but ILD can also be asymptomatic in an early stage. It is important to mention dyspnea could also be due to IIM itself due to (respiratory) muscle weakness in IIM patients.

Interstitial lung involvement in IIM can present with several different radiological patterns, including organizing pneumonia (OP), non-specific interstitial pneumonia (NSIP) or a combination of both and usual interstitial pneumonia (UIP). Additionally, different patterns of ILD and severity in lung involvement leads to heterogeneity in disease behaviour. The clinical course and outcomes are therefore highly variable, from rapid progressive and treatment resistant progression leading to high mortality, to chronic slowly progressive disease course. Around 30-40% of patients with IIM-ILD have anti-aminoacyl-tRNA synthetase (ARS) antibodies and anti MDA5 is found in 25-40% IIM-ILD patients, specifically in patients with clinically amyopathic dermatomyositis (CADM). While IIM-ILD patients with anti Jo-1 antibodies have better prognosis compared to other ARS, ILD associated with anti-MDA5 antibodies can have a rapid progressive phenotype, including mortality, in up to 50-80% of patients. While several IIM-ILD patterns can be responsive to anti-inflammatory treatment, progressive pulmonary fibrosis (PPF) can occur despite therapy, which may require a different treatment strategy with antifibrotic therapy. IIM-ILD diagnosis and treatment should be discussed in a multi-disciplinary team with a pulmonary physician experienced in ILD. Interstitial lung disease is infrequent in inclusion body myositis (IBM), but impairment of respiratory function due to (diaphragmatic) muscle involvement warrants additional pulmonary function testing and monitoring in symptomatic patients (e.g fatigue, dyspnea).

Cardiac Involvement

Cardiac involvement has been associated with an increased risk of mortality and morbidity in patients with IIM. However, little is known about the prevalence of cardiac involvement in IIM partially because of the lack of a consensus definition and the use of different cardiac investigation methods to detect cardiac involvement. In addition, the data that are available have been obtained from case reports and small cross-sectional or retrospective studies with heterogeneous patient cohorts, in which the presence of concomitant cardiovascular risk factors have been variably reported.

A review of the published literature was constructed to address the two questions. The 11 publications on pulmonary involvement in IIM were initially selected for full-text analysis as well as the 6 publications on cardiac involvement. All referenced publications were pooled and prevalence data and screening strategies recommendations were compared between publications.

Pulmonary involvement

Eleven publications were included for full-text review on IIM-ILD. Importantly, most of the included publications were reviews, of which 4 concerned treatment of IIM-ILD that did not address the questions and were excluded after full text analyses: Ge 2015a; Ge, 2015b; Chen, 2019; Barba, 2019.

Of the seven publications, three general reviews were included that addressed IIM-ILD: Gono (2020b) reviewed on IIM specific and associated antibodies in relation to DM. A literature review by Cavazzana (2017) described the clinical and histological spectrum of IIM, Gono (2020a) described the evolving spectrum of IIM-ILD.

Furthermore, Kamiya (2018) described 32 publications on prognostic factors for IIM-ILD in a systematic review and meta-analysis. Zhang (2016) described 2079 patients in a meta-analysis of 23 selected studies to describe factors associated with ILD in PM and DM. Lega (2014) described 3487 patients in a meta-analysis of 27 selected studies on clinical phenotype associated with myositis specific and associated antibodies. Sun (2021) described 34 studies with 10.130 included patients between 2000-2020 to describe global prevalence of ILD in PM/DM.

In addition to the literature search, a recent publication on chest CT in IIM-ILD (Laporte, 2022) and the recent German guideline (Wiendl, 2022) on IIM were included.

Results

Results on pulmonary involvement

A considerable variation in prevalence of IIM-ILD was reported in literature, probably due to different IIM populations and screening strategies used. High quality prospective studies are lacking. A systemic literature review of pooled data from selected studies published between 2000 and 2020 on prevalence of ILD in PM/DM was found most appropriate to answer the main question (Sun, 2021). A total of 34 studies on 10130 patients were included in this meta-analysis. Importantly, nearly half of the selected studies were conducted in Asia. Global overall prevalence was found to be 41% of patients with PM and/or DM (95% CI 35-48) but varied significantly in different geographical regions. In Europe, overall prevalence of IIM-ILD was 26% (95% CI 18-34) while the prevalence in Asia was 50% (95% CI 0.42-0.57). Importantly, recent studies reported a higher prevalence compared to studies between 2000 and 2010, which may reflect improved awareness and screening modalities such as high-resolution CT according to the authors. The overall prevalence of ILD in patients with DM, PM and CADM was 42% (95% CI 35-49), 35% (95% CI 27-42) and 53% (95% CI 32-74) respectively. When stratified by MSA, pooled ILD prevalence was found 88% (95% CI 81-95) in anti-MDA5, 77% (95% CI 60-93) in anti Jo-1, 62% (95% CI 31-93) in anti PL-7. Almost all included studies used high-resolution CT, the gold standard, to screen for ILD. Although publication bias, inclusion of small and retrospective studies and heterogeneity in screening methods should be taken into account, overall prevalence of IIM-ILD was high in this meta-analysis, specifically in patients with antiMDA5 and ASS antibodies.

A recent radiological study including all IIM patients (n= 257) in one center, found 36.6% of IIM patients had ILD, most in patients with antisynthetasis syndrome (57%) and least in IBM patients (3%) (Laporte 2022).

Another meta-analysis specifically looking at myositis specific and myositis associated antibodies found patients with anti-synthetase-antibodies presented significantly more ILD compared to anti-SRP (RR 2.44; 95% CI 1.52-3.91) or anti-Mi2 (RR 6.05; 95% CI 2.02-18.12) (Lega, 2014). Chen (2019) also found anti-melanoma differentiation associated gene-5 (anti-MDA5) and anti-aminoacyl-tRNA synthetase (ARS) antibodies most strongly associated with ILD. Zhang (2016) investigated risk factors associated with an increased ILD prevalence in PM/DM in a systematic review and meta-analysis and found older age at diagnosis, arthritis/arthralgia, fever, Jo-1 or MDA5 antibodies and elevated ESR or CRP associated with ILD. The authors concluded these variables may be used to guide screening strategies for ILD in patients with PM/DM.

Regarding evaluation and screening, Gono (2020) suggest all patients should undergo detailed history taking regarding dyspnea and cough, auscultation and chest X-ray. Furthermore, these authors suggest that if there are signs suggestive of pulmonary involvement, high-resolution CT is necessary in conjunction with functional assessment (pulmonary function testing, saturation, arterial blood gas analysis and 6-minute walking test) according to severity of symptoms and imaging findings. None of the other publications made suggestions on ILD screening strategies.

A meta-analysis of 32 articles on prognosis found older age, acute or subacute onset of ILD, decreased pulmonary function as measured by forced vital capacity (FVC), ground glass opacity and extent of radiographic abnormality as poor prognostic indicators. The recent German guideline (Wiendl, 2022) on diagnosis and therapy of IIM evaluated evidence on treatment of IIM-ILD.

Results on cardiac involvement

In general, the prevalence of cardiac involvement may range from 9% to 72%, depending on the definition and method used for assessment (Cheng, 2022; Fairley, 2021). In the Euromyositis registry, clinically apparent cardiac involvement is present in up to 9% of IIM patients (Lilleker, 2018). In post-mortem studies, inflammation of the cardiac muscle was detected in almost 25% of IIM patients (Bulkley, 1975). However, numerous studies suggest that subclinical cardiac involvement in IIM patients may be far more frequent than its symptomatic manifestation, with a prevalence even up to 72% of patients (Opinc, 2021).

Unselected IIM patients: cardiac events in IIM patients include arrhythmias (~2-14%; often premature ventricular contractions, premature atrial contractions, and paroxysmal supraventricular tachycardia), congestive heart failure (~6-12%), and myocarditis (~3%); clinically relevant conduction defects and pericarditis have been reported in only a small number of patients (~1%) (Zhang, 2012). However, the risk of conduction defects may be higher in those with exacerbation of IIM and prior conduction abnormalities on baseline ECG (e.g., atrioventricular block or bundle branch block). Symptoms may include dyspnoea (~11%), angina (~8%), palpitations (~5%), and peripheral oedema (~1,5%) (Opinc, 2021). However, it must be noted that muscle weakness and interstitial lung disease may contribute or cause dyspnoea, while chest wall muscle pain may underlie or be a contributing factor to angina complaints. Syncope is rare but may be due to severe conduction defects.

IIM patients with clinical myocarditis: in patients with IIM and clinically manifest myocarditis, cardiac troponin I, troponin T, and NT-proBNP levels are virtually always elevated. ECG abnormalities are common and include atrial arrhythmias (17-53%), ventricular arrhythmias (77%) and conduction block (42–63%). In patients with IIM and myocarditis, transthoracic echocardiography (TTE) generally shows a reduced left ventricular ejection fraction (in 58–74% of patients), while cardiovascular magnetic resonance (CMR) displays late gadolinium enhancement in a majority (50–64%) of cases (Opinc, 2021).

IIM patients without cardiac symptoms: studies in IIM patients without cardiac symptoms or clinical evidence of cardiac disease have used 5 main investigative methods to detect myocardial involvement: cardiac biomarkers testing, ECG (and ambulatory monitoring), TTE imaging, CMR imaging and nuclear medicine testing. It should be noted that divergent  definitions for myocardial involvement have been used in these studies. Furthermore, the implications and the prognostic value of the early subclinical signs for cardiac involvement detected by these investigative methods are poorly understood and remain to be studied.

Cardiac biomarker testing: cardiac troponins can be abnormal in IIM patients even without overt features of cardiac disease. Troponin I appears most specific for cardiac involvement and increased troponin I levels have been associated with CMR confirmed myocarditis. However, troponin T elevation is more common and correlates with different markers of IIM disease severity, including increased muscle weakness and reduced patient functioning. In addition, several studies could not find an association between abnormal troponin T and cardiac involvement using ECG, TTE, or CMR (Zhang, 2012). NT-proBNP levels may correlate with CMR features of cardiac disease, although the available evidence remains ambiguous and the predictive value of abnormal cardiac biomarkers for symptomatic cardiac involvement is unclear (Opinc, 2021).

ECG: ECG abnormalities are common in IIM patients and most often involve nonspecific ST segment changes. Also ECG criteria for left ventricular hypertrophy have been reported. Ambulatory ECG recordings have revealed the occurrence of paroxysmal supraventricular tachycardia, premature atrial contractions, and premature ventricular contractions.

TTE: while left ventricular ejection fraction is usually normal in IIM patients, signs of subclinical systolic dysfunction can be found if more sensitive echocardiographic techniques are used (e.g., tissue Doppler imaging and global longitudinal strain). In addition, echocardiographic parameters indicative of left ventricular diastolic dysfunction have often been found in IIM patients (Gupta, 2011; Zhang, 2022). However, most of these studies used isolated parameters to measure diastolic dysfunction and did not adjust for age, gender or relevant comorbidities. Therefore, it is yet unknown whether diastolic dysfunction is a sign of cardiac involvement in IIM or results from factors such as disease duration, therapy effects, or comorbidities such as hypertension.

CMR: CMR in asymptomatic patients frequently shows (in up to ~62% of IIM patients) (Rosenbohm, 2015) signs of left ventricular myocarditis despite normal left ventricular systolic function, including the presence of late gadolinium contrast enhancement (LGE; suggestive of regional fibrosis) and abnormal tissue characterization (i.e. T1, T2 and ECV mapping, suggestive of myocardial inflammation and oedema). While CMR detects subclinical involvement of myocardium more accurately than cardiac muscle scintigraphy or TTE, the clinical implication of these findings remains unknown.

Nuclear medicine: limited studies have used cardiac muscle scintigraphy to detect cardiac involvement in IIM and have reported abnormal ^99mTc-PYP or ⁶⁷Ga uptake and regional wall abnormalities in some patients (Opinc, 2021).

Juvenile Dermatomyositis

There is limited evidence on screening for JDM-associated pulmonary and cardiac disease.

Both are rare but severe complications, and as such most experts agree that screening is warranted. This screening at diagnosis should exist of pulmonary function tests, including carbon monoxide (CO) diffusion capacity. When abnormal, HR-CT scan should be considered.

Cardiac involvement such as myocarditis and pericarditis should be excluded at diagnosis by electrocardiogram and ultrasonography. There is no evidence supporting a frequency or duration of cardiac and pulmonary screening (Belutti Enders, 2017).

An exploratory search of the literature was performed because the working group was interested in gaining insight in the prevalence and incidence of ILD and cardiac involvement in difference types of IIM.

How should be screened for pulmonary involvement (including ILD), cardiac involvement and the involvement of other organs?

PICO 1

P: Patients with idiopathic inflammatory myopathy (IIM)

I&C: Organ involvement, ILD

O: prevalence, incidence

PICO 2

P: Patients with IIM

I&C: cardiac involvement

O: prevalence, incidence

Search and select (methods)

The database Embase (via Embase.com) was searched with relevant search terms until 3-2-2022. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 171 hits. Studies were selected based on the following criteria:

• Article full text available in Engels or Dutch
• Primary comparative research
• Study design systematic Review
• Published between 2000 and February 2022
• Study population are patients with IIM and comorbidities

In total 17 studies were initially selected based on title and abstract screening. After reading the full text, 5 studies were excluded (see the table with reasons for exclusion under the tab Methods), and 12 studies were included (pulmonary involvement 11 selected, 7 included and 4 excluded; cardiac involvement 6 selected, 5 included and 1 excluded).