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Associations between cardiac and pulmonary involvement in patients with juvenile dermatomyositis—a cross-sectional study

Associations between cardiac and pulmonary involvement in patients with juvenile... This study aimed at exploring the association between detectable cardiac and pulmonary involvement in long-term juvenile dermatomyositis (JDM) and to assess if patients with cardiac and pulmonary involvement differ with regard to clinical char - acteristics. 57 JDM patients were examined mean 17.3 (10.5) years after disease onset; this included clinical examination, myositis specific/associated autoantibodies (immunoblot), echocardiography, pulmonary function tests and high-resolution computed tomography. Cardiac involvement was defined as diastolic and/or systolic left ventricular dysfunction and pulmo- nary involvement as low diffusing capacity for carbon monoxide, low total lung capacity and/or high-resolution computed tomography abnormalities. Patients were stratified into the following four groups: (i) no organ involvement, (ii) pulmonary only, (iii) cardiac only, and (iv) co-existing pulmonary and cardiac involvement. Mean age was 25.7 (12.4) years and 37% were males. One patient had coronary artery disease, seven had a history of pericarditis, seven had hypertension and three had known interstitial lung disease prior to follow-up. There was no association between cardiac (10/57;18%) and pulmonary (41/57;72%) involvement (p = 0.83). After stratifying by organ involvement, 21% of patients had no organ involvement; 61% had pulmonary involvement only; 7% had cardiac involvement only and 11% had co-existing pulmonary or cardiac involve- ment. Patients with co-existing pulmonary or cardiac involvement had higher disease burden than the remaining patients. Patients with either cardiac or pulmonary involvement only, differed in clinical and autoantibody characteristics. We found no increased risk of developing concomitant cardiac/pulmonary involvement in JDM. Our results shed light upon possible different underlying mechanisms behind pulmonary and cardiac involvement in JDM. Keywords Juvenile dermatomyositis/polymyositis · Cardiovascular disease · Lung disease · Echocardiography · Pulmonary fibrosis Introduction Although very rare, serious cardiac involvement (CI) has been reported in JDM [4]. However, in our cohort, subclini- Juvenile dermatomyositis (JDM) is a rheumatic disease of cal CI is relatively frequent in patients with medium- to childhood that mainly targets skin and muscles, but may long-term JDM [5, 6], also found in patients after median also affect internal organs, such as the heart and lungs [1 ]. 4.6y disease duration [7]. It is not known if patients with Clinical manifest lung disease, including interstitial lung JDM later will develop manifest cardiac disease. disease (ILD), is rare in JDM, but associates with high mor- The coexistence of CI and PI has become more acknowl- bidity and mortality [2]. Our group previously reported a edged during recent years; in the general population, sub- high frequency of mostly subclinical pulmonary involve- clinical impairment of lung function is related to mild ment (PI) in JDM patients comprehensively examined after cardiac dysfunction [8]. This relationship is also found in median 16.8  years disease duration [3]. It is not known adults with connective tissue diseases, where ILD is associ- if these patients later will develop manifest lung disease. ated with cardiovascular complications [9]. However, it is unknown whether JDM patients with PI are at higher risk of developing cardiac dysfunction and vice versa. Thus, the aim * Helga Sanner of our study was to explore the association between CI and helga.sanner@medisin.uio.no Extended author information available on the last page of the article Vol.:(0123456789) 1 3 1214 Rheumatology International (2022) 42:1213–1220 PI in JDM patients; also, to assess if patients with CI and/or Total cholesterol (TC) and high-density lipoprotein (HDL) PI differ with regard to clinical characteristics. were analyzed according to hospital routine; TC:HDL ratio was calculated (superior to other lipid parameters in predict- ing ischemic heart disease [18]. Methods Pulmonary measures Patients Pulmonary function tests (PFTs) were performed at the Inclusion criteria were a probable/definitive diagnosis of follow-up visit as previously described in detail [3]. For DM [10], disease onset before 18y, minimum 24  m dis- the present study, diffusing capacity for carbon monoxide ease duration and age ≥ 6y. There were no exclusion cri- (DLCO) (adjusted for Hgb) and total lung capacity (TLC) teria. A retrospective inception cohort of Norwegian JDM (both expressed as percentage of predicted) were included. patients (diagnosed between 1970 and 2006, n = 59) was Low TLC and DLCO were defined as less than the fifth identified [11]. Patients with complete cardiac and pulmo- percentile of the predicted values [19]. High-resolution com- nary data (for details see below) were included in the pre- puter tomography (HRCT) was carried out in all patients; sent study. Informed consents were obtained from patients HRCT-detected abnormalities includes ILD (reticular pat- (if > 16 years) or their parents (if ≤ 16 years) at the time tern, ground glass opacity) and airways disease (bronchiecta- of follow-up examination. The study was approved by the sis, air trapping, micronodules) [3]. Pulmonary involvement regional committee of health and medical research ethics was defined as low TLC, low DLCO, or HRCT- detected in South-East Norway (S-05144) (Aug 2005—June 2023). abnormalities. Data collection Stratification of patients Clinical examination was performed at a comprehensive We stratified our patients into four groups based on the pres- follow-up visit of the identified patients at Oslo University ence of detectable CI and PI at follow-up as follows: group Hospital from September 2005 to May 2009. In addition 1: neither PI nor CI; group 2: PI only; group 3: CI only; and, to lung and cardiac measures (see below), the examination group 4: co-existing PI and CI. included muscle strength/endurance measured by manual muscle test (MMT-8)/child myositis assessment scale Immunological analyses (CMAS) and health-related quality of life (HRQOL) by the Short Form-36 physical and mental component sum- Sera were thawed at the follow-up visit and later (2014) sub- mary scores (SF-36 PCS and MCS) in patients > 13y [12]. jected to the following tests: (a) ANA screening by indirect Cumulative prednisolone dose was calculated [11]. Inactive immunofluorescence (IIF) on HEp-2 cells at serum dilution disease was defined according to the revised PRINTO cri- 1:160. Only nuclear fluorescence patterns were considered teria [13]. Nailfold capillary density was assessed as previ- positive. Detection of myositis specific autoantibodies ously described [14]. Disease activity and cumulative organ (MSA) and myositis associated autoantibodies (MAA) [20] damage were assessed at the follow-up visit and also scored using (b) the myositis line immunoassay A1 which included: retrospectively (by chart review) at 1 year post diagnosis MDA5, TIF1-γ, NXP-2, SAE1, SAE2, HMGCR-S (Sigma), using the Disease Activity Score for JDM (DAS) and the HMGCR-E (EUROIMMUN AG), Mup44 and (c) the myosi- Myositis Damage Index (MDI), respectively, as previously tis line immunoassay A2 (Myositis Profile 3 Euroline) which described [11, 15]. included: Jo1, PL-7, PL-12, EJ, OJ, SRP, Mi-2, PM-Scl75, PM-Scl-100 Ku and Ro52; both from Euroimmun AG Cardiac measures Lübeck, Germany. The immunoblot strips were scanned and evaluated digitally, using the Euroline scan. Signal intensi- Two-dimensional, M-mode, and Doppler echocardiography ties below 11 were regarded as negative. was performed at the follow-up visit as previously described [5, 6]. Low early diastolic tissue velocity (e’) reflects left Statistical analysis ventricular (LV) diastolic dysfunction [16] and low long axis strain (LAS) reflects LV systolic dysfunction [6 ]. Cardiac Data were expressed as mean (SD), median (IQR) or num- involvement was defined as LV diastolic or systolic dys- bers (%) as appropriate. Differences between patient groups function; both defined as mean of control subjects – 2SD were tested by one-way ANOVA with Tukey post-hoc test, from one of our previous studies [6]. Heart rate variability Kruskal–Wallis test with Dunn post-hoc test or Chi-square (expressed as cSDNN) was measured by Holter ECG [17]. (no post-hoc test applied due to small numbers). Due to the 1 3 Rheumatology International (2022) 42:1213–1220 1215 hypothesis generating nature of our study, we did not correct variables defining PI (TLC, DLCO as continuous vari- for multiple comparisons. Correlations were determined by ables and HRCT abnormalities) and variables defining CI the Spearman correlation coefficient (r ). Chi-square good- (e´ and LAS as continuous variables) with each other; no sp ness of fit test was used to explore whether the number of significant correlations were found (data not shown). patients in the clinical groups were as predicted based on the fraction with CI and PI in our cohort. Due to small numbers, Variables defining CI and PI across the four clinical no statistics was performed for MSA/MAA between groups. groups IBM SPSS Statistics v. 25.0 (IBM, Armonk, NY, USA) was used for statistical analyses. Naturally, DLCO was lower in group 2 and 4 (which include patients with PI) compared with the other two groups (p’s  <  0.007) except for group 1 vs 4, NS) Results (Fig. 2A). For TLC, there were similar, albeit non-signifi- cant trends (Fig. 2B). Naturally, e´ and LAS were lower in Clinical characteristics group 3 and 4 (which include patients with CI) compared with the other two groups (p’s < 0.002) (Fig. 2C and D). The JDM cohort included 57 patients, representing 97% of the eligible patients. One patient had coronary artery dis- ease, seven had pericarditis during disease course, seven had Clinical variables across the four clinical groups hypertension and three had known ILD prior to follow-up. There were no cases of diabetes, heart failure or cardiac Group 4 (co-existing CI and PI) differed the most from the arrhythmia. In total, 10/57 (18%) of patients had CI and other groups; they were older at follow-up (only statistically 41/57 (72%) had PI; the organ involvement was mostly significant compared to group 2), had numerically more subclinical. males (5/6, NS), and 4/6 were daily smokers (Table 1). Also, group 4 had higher DAS at follow-up compared with the Associations between CI and PI remaining sub-groups, as well as higher MDI than group 1 and 2. Group 4 had numerically more calcinosis, lipodystro- After stratification into groups, group 1 (neither PI nor CI) phy as well as higher TC:HDL ratio compared with groups consisted of 12(21%) patients; group 2 (PI only) 35(61%); 1 and 2. They also had lower heart rate variability (cSDNN) group 3: (CI only) 4(7%) and, group 4: co-existing PI and than group 1. Group 4 also had more impaired SF-36 PCS CI 6(11%) (Fig. 1A) (Table 1). No associations between than both groups 2 and 3. Group 3 (CI only) had higher CI and PI were found when comparing with the expected early DAS, longer disease duration and higher cumulative distribution (Fig.  1B, p = 0.83). We then correlated the prednisolone dose compared with group 2; also, they had A B Organ involvement PULMONARY INVOLVEMENT YES NO 6 (10.5%) 4 (7.0%) YES CARDIAC Exp: 13.0% Exp: 5.0% INVOLVEMENT No organ involvement; 21% 35 (61.4%) 12 (21.1%) NO Pulmonary involvement only; 61% Exp: 59.0% Exp: 23.0% Cardiac involvement only; 7% Combined cardiopulmonary involvement; 11% Fig. 1 A Distribution of patients in the four clinical groups; B Distribution of patients in the four clinical groups compared to expected frequen- cies based the fraction with lung and cardiac involvement in our cohort; Exp expected distribution; p = 0.83 (Chi-square goodness of fit test) 1 3 1216 Rheumatology International (2022) 42:1213–1220 Table 1 Patient and disease characteristics and clinical variables stratified across the four groups Patients total Group 1 No Group 2 Pulmonary Group 3 cardiac only Group 4 coexist- Significant organ involve- only ing pulmonary and p-values (between ment cardiac groups) Number of pts, n (%) 57 (100) 12 (21) 35 (61) 4 (7) 6 (11) NA Age at follow-up, y 25.7 (12.4) 26.2 (11.9) 22.5 (11.3) 35.2 (7.6) 37.7 (13.5) 2 vs 4: p = 0.021 Disease duration, y 17.3 (10.5) 16.9 (11.5) 14.7 (9.1) 28.5 (5.2) 25.5 (11.7) 2 vs 3: p = 0.047 Male sex, n (%) 21 (37) 2(17) 11 (31) 3 (75) 5 (83) P = 0.014 Smokers daily dis- 14 (30) 2 (18) 7 (27) 1 (25) 4 (67) NS ease course; n (%) DAS 1 y 5.9 (3.9) 5.9 (4.2) 4.8 (3.5) 10.1 (4.1) 9.0 (3.0) 2 vs 3: p = 0.039 MDI 1 y 1.0 (0.0–2.0) 1.0 (0.0–2.5) 0.0 (0.0–2.0) 2.5 (1.5–3.5) 2.0 (1.0–5.0) NS Inactive Disease, 28 (49) 6 (50) 18 (51) 3 (75) 1 (17) NS n (%) Calcinosis, n (%) 21 (37) 5 (42) 10 (29) 2 (50) 4 (67) NS Lipodystrophy, n (%) 10 (18) 1 (8) 2 (6) 2 (50) 5 (83) P < 0.001 Hypertension, dis- 7 (12) 1(8) 2 (6) 2 (50) 2 (33) P = 0.025 ease course, n (%) TC:HDL ratio N = 50 3.9 (2.0) 3.1 (0.4) 3.5 (1.3) 7.4 (3.2) 5.5 (2.8) 1 vs 3: p < 0.001 1 vs 4: p = 0.044 2 vs 3: p < 0.001 2 vs 4: p = 0.049 HRV, cSDNN, 39.7 (16.7) 50.5 (21.8) 36.8 (13.6) 42.7 (2.3) 29.5 (17.6) 1 vs 4: p = 0.050 N = 55 NCD, cap/mm 6.4 (2.1) 7.1 (1.8) 6.1 (2.3) 7.5 (0.6) 6.4 (2.1) NS Pred/DMARD, n (%) 17 (30) 4 (33) 10 (29) 1 (25) 2 (33) NS Cum Prednisolone 7.9 (3.6–12.6) 8.9 (7.6–11.3) 4.8 (2.5–10.6) 17.9 (12.6–26.6) 14.4 (7.9–27.3) 2 vs 3; p = 0.008 during disease 2 vs 4; p = 0.005 course, g DAS 4.7 (3.0) 4.0 (2.4) 4.5 (2.8) 3.4 (2.5) 8.5 (2.8) 1 vs 4: p = 0.008 2 vs 4: p = 0.008 3 vs 4: p = 0.025 MDI 4.3 (3.1) 4.3 (2.2) 3.5 (2.8) 5.2 (3.3) 8.2 (3.8) 1 vs 4: p = 0.036 2 vs 4: p = 0.003 MMT-8 76.5 (4.7) 77.2 (3.1) 76.7 (4.1) 80.0 (0.0) 71.3 (8.5) 1 vs 4: p = 0.048 2 vs 4: p = 0.040 3 vs 4: p = 0.019 CMAS 48.3 (5.4) 48.8 (3.2) 48.8 (4.7) 51.0 (1.4) 42.8 (10.5) NS SF-36, PCS 50.8 (9.0) 51.0 (9.7) 52.3 (7.3) 56.0 (3.4) 40.2 (10.9) 2 vs 4: p = 0.011 3 vs 4: p = 0.023 SF-36, MCS 53.4 (7.7) 51.8 (6.4) 53.6 (8.1) 52.7 (5.7) 55.4 (10.1) NS Variables are assessed at follow-up if not otherwise stated; values are mean (SD) or median (25th—75th percentile) if not otherwise stated; NA not assessed, NS non-significant, DAS Disease activity score, MDI myositis damage index, FU follow-up, TC Total cholesterol, HDL high- density lipoprotein, NCD nailfold capillary density, HRV heart rate variability, NCD Nail fold capillary density, DMARD disease modifying anti- rheumatic drugs, CMAS child myositis assessment scale, SF-36 Short Form-36, PCS physical assessment scale, MCS mental component scale, a b Post-hoc tests not run for categorical variables due to low n in several groups. assessed in patients ≥ 14y at follow-up, n = 47; post hoc tests not assessed higher TC:HDL ratio compared to both group 1 and 2. On MSA known to be associated with lung involvement (PL-7, the other hand, group 3 had less impaired SF-36 PCS than Jo-1 and MDA5) were only found in group 2 (PI only). group 2 (Table 1). MSA and MAA are shown in Table 2 as background data. 31(54%) had no detectable ANA. 19(33%) of patients had at least one detectable MSA/MAA; of those 13(68%) had one autoantibody and 6(32%) had > 1 autoantibody (Table 2). 1 3 Rheumatology International (2022) 42:1213–1220 1217 Fig. 2 Variables defining cardiac and pulmonary involvement across ide, % of predicted; B TLC: Total lung capacity; % of predicted; C e´: the four clinical groups; p-values based on one-way ANOVA with early diastolic tissue velocity, cm/s; D LAS: long-axis strain, % Tukey post-hoc tests; A DLCO: Diffusing capacity for carbonmonox- Table 2 Myositis specific- Patients total Group 1 no Group 2 pul- Group 3 Group 4 coexisit- and myositis associated organ involve- monary only cardiac only ing pulmonary and autoantibodies stratified across ment cardiac the four JDM groups n 57 12 35 4 6 ANA IIF 26 (46) 6 (50) 16 (46) 1 (25) 3 (50) No MSA/ MAA 38 (67) 7 (58) 23 (66) 3 (75) 5 (83) Myositis specific autoantibodies Jo-1 1 (2) 0 1 (3) 0 0 PL-7 1 (2) 0 1 (3) 0 0 SRP 1 (2) 1 (8) 0 0 0 Mi-2 3 (5) 1 (8) 2 (6) 0 0 3 4 NXP-2 5 (9) 1 (8) 3 (9) 0 1 (25) TIF1- γ 1 (2) 0 0 1 (25) 0 MDA5 2 (4) 0 2 (6) 0 0 SAE-1 1 (2) 1 (8) 0 0 0 HMGCR 1 (2) 1 (8) 0 0 0 Myositis associated autoantibodies PMScl75 3 (5) 0 3 (9) 0 0 PMScl100 2 (4) 0 2 (6) 0 0 Ku 2 (4) 1 (8) 1 (3) 0 0 2,3 6 Ro52 3 (5) 2 (17) 1 (3) 0 0 MSA Myositis specific autoantibodies, MAA Myositis associated autoantibodies, Numbers are n (%); No 1,2,3,4,and 5 patients had detectable EJ, PL-12, OJ, SAE-2 or Mup44; denotes that more than one MSA and/or MAA are present in the same patient. IIF indirect immunofluorescence 1 3 1218 Rheumatology International (2022) 42:1213–1220 suggest different mechanisms underlying pulmonary and Discussion cardiac involvement in JDM; this requires further study. Based on our results, clinicians should be especially aware Based on previous studies in the general population [8] and of the risk detectable organ involvement in patients with connective tissue disease [9], we hypothesized that there high disease activity and damage after medium- to long-term was an increased risk of concomitant detectable cardiac and disease. Follow-studies are needed to see if patients with pulmonary involvement in JDM. No evidence for a higher subclinical PI and CI later develop clinical manifest lung risk of CI given PI and vice versa was detected in our study. and/or cardiac disease. However, due to small sample size our results should be interpreted with caution. Special attention should be drawn to group 4 (combined CI Statement on open data sharing and PI). Despite being small (n = 6/11% of the total cohort), several trends and statistically significant differences were The data will not be deposited, due to guidelines from the found when compared with the other groups. This group regional committee of health and medical research ethics in displayed a higher disease burden (including higher disease South-East Norway. activity and damage and also unfavorable lipid profile and heart rate variability) and experienced a reduced quality of Acknowledgements We thank professor Øyvind Molberg, MD, PhD life (SF-36 PCS) compared with the other groups. They were at department of Rheumatology, Oslo University hospital, for critical characterized by older age, more likely to be males and daily review of the manuscript and Randi Karlsen, Senior Biomedical Labo- smokers. Importantly, the high MDI observed in this group is ratory Scientist at the Department of Immunology, Oslo University Hospital, Ullevål for help with the immunological analyses. not explained by subclinical PI and CI. Second, group 3 (CI only) had higher disease activity at Author contributions BNW, IS and HS: Conception of the study, data 1 year post-diagnosis, unfavorable lipid profile, and higher collection, analysis and interpretation, drafting of manuscript. TS: cumulative prednisolone dose than group 2 (PI only). The Data collection and interpretation, critical review of the manuscript. higher age found in patients with cardiac involvement might ZB: Data analysis and interpretation, critical review of the manuscript. MBL, TMA, ET and BF: Data interpretation, critical review of the reflect that they were diagnosed in a time with less aggres- manuscript. All co-authors have read and approved the final manuscript sive treatment; also, it is known that cardiac involvement and take full responsibility for the correctness and integrity of the work. increases with age. Interestingly, the patients with CI, either isolated (group Funding Open access funding provided by University of Oslo (incl 3) or combined (group 4) bear little resemblance with the Oslo University Hospital). We thank the following foundations for financial support: Anders Jahre’s Foundation for the promotion of patients with PI. Possibly, abnormalities in the heart and science, Simon Fougner Hartmann’s Family Found, Rakel and Otto lung may represent two different mechanisms/phenotypes. Bruun’s Foundation. This may explain the lack of correlation between subclini- cal heart and lung involvement in JDM patients. Although Declarations no statistical difference in NCD across clinical groups was found in the present study, we have previously reported an Conflict of interest None of the authors have any conflicts of interests. association between microvascular findings and PI, but no association between microvascular findings and CI [14]. Open Access This article is licensed under a Creative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- Data on MSA and MAA was used as background infor- tion, distribution and reproduction in any medium or format, as long mation. 67% has no detectable MSA or MAA which is lower as you give appropriate credit to the original author(s) and the source, than reported in the literature [20]. This might be explained provide a link to the Creative Commons licence, and indicate if changes by methodological differences between assay methods [21]. were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated Interestingly, MSA known to be associated with pulmonary otherwise in a credit line to the material. If material is not included in involvement in JDM (MDA5, PL-7 and Jo-1)[20], were only the article's Creative Commons licence and your intended use is not found in patients with PI. permitted by statutory regulation or exceeds the permitted use, you will Strengths of our study include that our patients come need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://cr eativ ecommons. or g/licen ses/ b y/4.0/ . from a restrospective inception cohort and they were com- prehensively examined after medium- to long term follow- up. Limitations include that we did not calculate sample size (due to the hypothesis-generating nature of our study) and References the cross-sectional design. 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Tansley SL, Li D, Betteridge ZE, McHugh NJ (2020) The reli- Activity, Manual Muscle Testing (MMT), Health Assessment ability of immunoassays to detect autoantibodies in patients with Questionnaire (HAQ)/Childhood Health Assessment Question- myositis is dependent on autoantibody specificity. Rheumatology naire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), (Oxford) 59:2109–2114. https:// doi. org/ 10. 1093/ rheum atolo gy/ Myositis Disease Activity Assessment Tool (MDAAT), Disease keaa0 21 Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Dam- Publisher's Note Springer Nature remains neutral with regard to age Index (MDI), Quantitative Muscle Testing (QMT), Myositis jurisdictional claims in published maps and institutional affiliations. Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis 1 3 1220 Rheumatology International (2022) 42:1213–1220 Authors and Affiliations 1 1 1 2 3,5 Birgit Nomeland Witczak  · Thomas Schwartz  · Zoltan Barth  · Eli Taraldsrud  · May Brit Lund  · 3,6 3,7 1,8 4,7 Trond Mogens Aaløkken  · Berit Flatø  · Ivar Sjaastad  · Helga Sanner Birgit Nomeland Witczak Institute for Experimental Medical Research and KG Jebsen birgit.witczak@gmail.com Center for Cardiac Research, Oslo University Hospital and University of Oslo, Oslo, Norway Thomas Schwartz thomasschwartz1410@gmail.com Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway Zoltan Barth zoltan.barth@gmail.com Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway Eli Taraldsrud etaralds@ous-hf.no Oslo New University College, Oslo, Norway May Brit Lund Department of Respiratory Medicine, Oslo University m.b.samersaw-lund@medisin.uio.no Hospital, Rikshospitalet, Oslo, Norway Trond Mogens Aaløkken Department of Radiology, Oslo University Hospital, trond.mogens.aalokken@ous-hf.no Rikshospitalet, Oslo, Norway Berit Flatø Department of Rheumatology, Oslo University Hospital, berit.flato@medisin.uio.no Rikshospitalet, Oslo, Norway Ivar Sjaastad Department of Cardiology, Oslo University Hospital, Ullevål, ivar.sjaastad@medisin.uio.no Oslo, Norway 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology International Springer Journals

Associations between cardiac and pulmonary involvement in patients with juvenile dermatomyositis—a cross-sectional study

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Springer Journals
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Copyright © The Author(s) 2022
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0172-8172
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10.1007/s00296-021-05071-3
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Abstract

This study aimed at exploring the association between detectable cardiac and pulmonary involvement in long-term juvenile dermatomyositis (JDM) and to assess if patients with cardiac and pulmonary involvement differ with regard to clinical char - acteristics. 57 JDM patients were examined mean 17.3 (10.5) years after disease onset; this included clinical examination, myositis specific/associated autoantibodies (immunoblot), echocardiography, pulmonary function tests and high-resolution computed tomography. Cardiac involvement was defined as diastolic and/or systolic left ventricular dysfunction and pulmo- nary involvement as low diffusing capacity for carbon monoxide, low total lung capacity and/or high-resolution computed tomography abnormalities. Patients were stratified into the following four groups: (i) no organ involvement, (ii) pulmonary only, (iii) cardiac only, and (iv) co-existing pulmonary and cardiac involvement. Mean age was 25.7 (12.4) years and 37% were males. One patient had coronary artery disease, seven had a history of pericarditis, seven had hypertension and three had known interstitial lung disease prior to follow-up. There was no association between cardiac (10/57;18%) and pulmonary (41/57;72%) involvement (p = 0.83). After stratifying by organ involvement, 21% of patients had no organ involvement; 61% had pulmonary involvement only; 7% had cardiac involvement only and 11% had co-existing pulmonary or cardiac involve- ment. Patients with co-existing pulmonary or cardiac involvement had higher disease burden than the remaining patients. Patients with either cardiac or pulmonary involvement only, differed in clinical and autoantibody characteristics. We found no increased risk of developing concomitant cardiac/pulmonary involvement in JDM. Our results shed light upon possible different underlying mechanisms behind pulmonary and cardiac involvement in JDM. Keywords Juvenile dermatomyositis/polymyositis · Cardiovascular disease · Lung disease · Echocardiography · Pulmonary fibrosis Introduction Although very rare, serious cardiac involvement (CI) has been reported in JDM [4]. However, in our cohort, subclini- Juvenile dermatomyositis (JDM) is a rheumatic disease of cal CI is relatively frequent in patients with medium- to childhood that mainly targets skin and muscles, but may long-term JDM [5, 6], also found in patients after median also affect internal organs, such as the heart and lungs [1 ]. 4.6y disease duration [7]. It is not known if patients with Clinical manifest lung disease, including interstitial lung JDM later will develop manifest cardiac disease. disease (ILD), is rare in JDM, but associates with high mor- The coexistence of CI and PI has become more acknowl- bidity and mortality [2]. Our group previously reported a edged during recent years; in the general population, sub- high frequency of mostly subclinical pulmonary involve- clinical impairment of lung function is related to mild ment (PI) in JDM patients comprehensively examined after cardiac dysfunction [8]. This relationship is also found in median 16.8  years disease duration [3]. It is not known adults with connective tissue diseases, where ILD is associ- if these patients later will develop manifest lung disease. ated with cardiovascular complications [9]. However, it is unknown whether JDM patients with PI are at higher risk of developing cardiac dysfunction and vice versa. Thus, the aim * Helga Sanner of our study was to explore the association between CI and helga.sanner@medisin.uio.no Extended author information available on the last page of the article Vol.:(0123456789) 1 3 1214 Rheumatology International (2022) 42:1213–1220 PI in JDM patients; also, to assess if patients with CI and/or Total cholesterol (TC) and high-density lipoprotein (HDL) PI differ with regard to clinical characteristics. were analyzed according to hospital routine; TC:HDL ratio was calculated (superior to other lipid parameters in predict- ing ischemic heart disease [18]. Methods Pulmonary measures Patients Pulmonary function tests (PFTs) were performed at the Inclusion criteria were a probable/definitive diagnosis of follow-up visit as previously described in detail [3]. For DM [10], disease onset before 18y, minimum 24  m dis- the present study, diffusing capacity for carbon monoxide ease duration and age ≥ 6y. There were no exclusion cri- (DLCO) (adjusted for Hgb) and total lung capacity (TLC) teria. A retrospective inception cohort of Norwegian JDM (both expressed as percentage of predicted) were included. patients (diagnosed between 1970 and 2006, n = 59) was Low TLC and DLCO were defined as less than the fifth identified [11]. Patients with complete cardiac and pulmo- percentile of the predicted values [19]. High-resolution com- nary data (for details see below) were included in the pre- puter tomography (HRCT) was carried out in all patients; sent study. Informed consents were obtained from patients HRCT-detected abnormalities includes ILD (reticular pat- (if > 16 years) or their parents (if ≤ 16 years) at the time tern, ground glass opacity) and airways disease (bronchiecta- of follow-up examination. The study was approved by the sis, air trapping, micronodules) [3]. Pulmonary involvement regional committee of health and medical research ethics was defined as low TLC, low DLCO, or HRCT- detected in South-East Norway (S-05144) (Aug 2005—June 2023). abnormalities. Data collection Stratification of patients Clinical examination was performed at a comprehensive We stratified our patients into four groups based on the pres- follow-up visit of the identified patients at Oslo University ence of detectable CI and PI at follow-up as follows: group Hospital from September 2005 to May 2009. In addition 1: neither PI nor CI; group 2: PI only; group 3: CI only; and, to lung and cardiac measures (see below), the examination group 4: co-existing PI and CI. included muscle strength/endurance measured by manual muscle test (MMT-8)/child myositis assessment scale Immunological analyses (CMAS) and health-related quality of life (HRQOL) by the Short Form-36 physical and mental component sum- Sera were thawed at the follow-up visit and later (2014) sub- mary scores (SF-36 PCS and MCS) in patients > 13y [12]. jected to the following tests: (a) ANA screening by indirect Cumulative prednisolone dose was calculated [11]. Inactive immunofluorescence (IIF) on HEp-2 cells at serum dilution disease was defined according to the revised PRINTO cri- 1:160. Only nuclear fluorescence patterns were considered teria [13]. Nailfold capillary density was assessed as previ- positive. Detection of myositis specific autoantibodies ously described [14]. Disease activity and cumulative organ (MSA) and myositis associated autoantibodies (MAA) [20] damage were assessed at the follow-up visit and also scored using (b) the myositis line immunoassay A1 which included: retrospectively (by chart review) at 1 year post diagnosis MDA5, TIF1-γ, NXP-2, SAE1, SAE2, HMGCR-S (Sigma), using the Disease Activity Score for JDM (DAS) and the HMGCR-E (EUROIMMUN AG), Mup44 and (c) the myosi- Myositis Damage Index (MDI), respectively, as previously tis line immunoassay A2 (Myositis Profile 3 Euroline) which described [11, 15]. included: Jo1, PL-7, PL-12, EJ, OJ, SRP, Mi-2, PM-Scl75, PM-Scl-100 Ku and Ro52; both from Euroimmun AG Cardiac measures Lübeck, Germany. The immunoblot strips were scanned and evaluated digitally, using the Euroline scan. Signal intensi- Two-dimensional, M-mode, and Doppler echocardiography ties below 11 were regarded as negative. was performed at the follow-up visit as previously described [5, 6]. Low early diastolic tissue velocity (e’) reflects left Statistical analysis ventricular (LV) diastolic dysfunction [16] and low long axis strain (LAS) reflects LV systolic dysfunction [6 ]. Cardiac Data were expressed as mean (SD), median (IQR) or num- involvement was defined as LV diastolic or systolic dys- bers (%) as appropriate. Differences between patient groups function; both defined as mean of control subjects – 2SD were tested by one-way ANOVA with Tukey post-hoc test, from one of our previous studies [6]. Heart rate variability Kruskal–Wallis test with Dunn post-hoc test or Chi-square (expressed as cSDNN) was measured by Holter ECG [17]. (no post-hoc test applied due to small numbers). Due to the 1 3 Rheumatology International (2022) 42:1213–1220 1215 hypothesis generating nature of our study, we did not correct variables defining PI (TLC, DLCO as continuous vari- for multiple comparisons. Correlations were determined by ables and HRCT abnormalities) and variables defining CI the Spearman correlation coefficient (r ). Chi-square good- (e´ and LAS as continuous variables) with each other; no sp ness of fit test was used to explore whether the number of significant correlations were found (data not shown). patients in the clinical groups were as predicted based on the fraction with CI and PI in our cohort. Due to small numbers, Variables defining CI and PI across the four clinical no statistics was performed for MSA/MAA between groups. groups IBM SPSS Statistics v. 25.0 (IBM, Armonk, NY, USA) was used for statistical analyses. Naturally, DLCO was lower in group 2 and 4 (which include patients with PI) compared with the other two groups (p’s  <  0.007) except for group 1 vs 4, NS) Results (Fig. 2A). For TLC, there were similar, albeit non-signifi- cant trends (Fig. 2B). Naturally, e´ and LAS were lower in Clinical characteristics group 3 and 4 (which include patients with CI) compared with the other two groups (p’s < 0.002) (Fig. 2C and D). The JDM cohort included 57 patients, representing 97% of the eligible patients. One patient had coronary artery dis- ease, seven had pericarditis during disease course, seven had Clinical variables across the four clinical groups hypertension and three had known ILD prior to follow-up. There were no cases of diabetes, heart failure or cardiac Group 4 (co-existing CI and PI) differed the most from the arrhythmia. In total, 10/57 (18%) of patients had CI and other groups; they were older at follow-up (only statistically 41/57 (72%) had PI; the organ involvement was mostly significant compared to group 2), had numerically more subclinical. males (5/6, NS), and 4/6 were daily smokers (Table 1). Also, group 4 had higher DAS at follow-up compared with the Associations between CI and PI remaining sub-groups, as well as higher MDI than group 1 and 2. Group 4 had numerically more calcinosis, lipodystro- After stratification into groups, group 1 (neither PI nor CI) phy as well as higher TC:HDL ratio compared with groups consisted of 12(21%) patients; group 2 (PI only) 35(61%); 1 and 2. They also had lower heart rate variability (cSDNN) group 3: (CI only) 4(7%) and, group 4: co-existing PI and than group 1. Group 4 also had more impaired SF-36 PCS CI 6(11%) (Fig. 1A) (Table 1). No associations between than both groups 2 and 3. Group 3 (CI only) had higher CI and PI were found when comparing with the expected early DAS, longer disease duration and higher cumulative distribution (Fig.  1B, p = 0.83). We then correlated the prednisolone dose compared with group 2; also, they had A B Organ involvement PULMONARY INVOLVEMENT YES NO 6 (10.5%) 4 (7.0%) YES CARDIAC Exp: 13.0% Exp: 5.0% INVOLVEMENT No organ involvement; 21% 35 (61.4%) 12 (21.1%) NO Pulmonary involvement only; 61% Exp: 59.0% Exp: 23.0% Cardiac involvement only; 7% Combined cardiopulmonary involvement; 11% Fig. 1 A Distribution of patients in the four clinical groups; B Distribution of patients in the four clinical groups compared to expected frequen- cies based the fraction with lung and cardiac involvement in our cohort; Exp expected distribution; p = 0.83 (Chi-square goodness of fit test) 1 3 1216 Rheumatology International (2022) 42:1213–1220 Table 1 Patient and disease characteristics and clinical variables stratified across the four groups Patients total Group 1 No Group 2 Pulmonary Group 3 cardiac only Group 4 coexist- Significant organ involve- only ing pulmonary and p-values (between ment cardiac groups) Number of pts, n (%) 57 (100) 12 (21) 35 (61) 4 (7) 6 (11) NA Age at follow-up, y 25.7 (12.4) 26.2 (11.9) 22.5 (11.3) 35.2 (7.6) 37.7 (13.5) 2 vs 4: p = 0.021 Disease duration, y 17.3 (10.5) 16.9 (11.5) 14.7 (9.1) 28.5 (5.2) 25.5 (11.7) 2 vs 3: p = 0.047 Male sex, n (%) 21 (37) 2(17) 11 (31) 3 (75) 5 (83) P = 0.014 Smokers daily dis- 14 (30) 2 (18) 7 (27) 1 (25) 4 (67) NS ease course; n (%) DAS 1 y 5.9 (3.9) 5.9 (4.2) 4.8 (3.5) 10.1 (4.1) 9.0 (3.0) 2 vs 3: p = 0.039 MDI 1 y 1.0 (0.0–2.0) 1.0 (0.0–2.5) 0.0 (0.0–2.0) 2.5 (1.5–3.5) 2.0 (1.0–5.0) NS Inactive Disease, 28 (49) 6 (50) 18 (51) 3 (75) 1 (17) NS n (%) Calcinosis, n (%) 21 (37) 5 (42) 10 (29) 2 (50) 4 (67) NS Lipodystrophy, n (%) 10 (18) 1 (8) 2 (6) 2 (50) 5 (83) P < 0.001 Hypertension, dis- 7 (12) 1(8) 2 (6) 2 (50) 2 (33) P = 0.025 ease course, n (%) TC:HDL ratio N = 50 3.9 (2.0) 3.1 (0.4) 3.5 (1.3) 7.4 (3.2) 5.5 (2.8) 1 vs 3: p < 0.001 1 vs 4: p = 0.044 2 vs 3: p < 0.001 2 vs 4: p = 0.049 HRV, cSDNN, 39.7 (16.7) 50.5 (21.8) 36.8 (13.6) 42.7 (2.3) 29.5 (17.6) 1 vs 4: p = 0.050 N = 55 NCD, cap/mm 6.4 (2.1) 7.1 (1.8) 6.1 (2.3) 7.5 (0.6) 6.4 (2.1) NS Pred/DMARD, n (%) 17 (30) 4 (33) 10 (29) 1 (25) 2 (33) NS Cum Prednisolone 7.9 (3.6–12.6) 8.9 (7.6–11.3) 4.8 (2.5–10.6) 17.9 (12.6–26.6) 14.4 (7.9–27.3) 2 vs 3; p = 0.008 during disease 2 vs 4; p = 0.005 course, g DAS 4.7 (3.0) 4.0 (2.4) 4.5 (2.8) 3.4 (2.5) 8.5 (2.8) 1 vs 4: p = 0.008 2 vs 4: p = 0.008 3 vs 4: p = 0.025 MDI 4.3 (3.1) 4.3 (2.2) 3.5 (2.8) 5.2 (3.3) 8.2 (3.8) 1 vs 4: p = 0.036 2 vs 4: p = 0.003 MMT-8 76.5 (4.7) 77.2 (3.1) 76.7 (4.1) 80.0 (0.0) 71.3 (8.5) 1 vs 4: p = 0.048 2 vs 4: p = 0.040 3 vs 4: p = 0.019 CMAS 48.3 (5.4) 48.8 (3.2) 48.8 (4.7) 51.0 (1.4) 42.8 (10.5) NS SF-36, PCS 50.8 (9.0) 51.0 (9.7) 52.3 (7.3) 56.0 (3.4) 40.2 (10.9) 2 vs 4: p = 0.011 3 vs 4: p = 0.023 SF-36, MCS 53.4 (7.7) 51.8 (6.4) 53.6 (8.1) 52.7 (5.7) 55.4 (10.1) NS Variables are assessed at follow-up if not otherwise stated; values are mean (SD) or median (25th—75th percentile) if not otherwise stated; NA not assessed, NS non-significant, DAS Disease activity score, MDI myositis damage index, FU follow-up, TC Total cholesterol, HDL high- density lipoprotein, NCD nailfold capillary density, HRV heart rate variability, NCD Nail fold capillary density, DMARD disease modifying anti- rheumatic drugs, CMAS child myositis assessment scale, SF-36 Short Form-36, PCS physical assessment scale, MCS mental component scale, a b Post-hoc tests not run for categorical variables due to low n in several groups. assessed in patients ≥ 14y at follow-up, n = 47; post hoc tests not assessed higher TC:HDL ratio compared to both group 1 and 2. On MSA known to be associated with lung involvement (PL-7, the other hand, group 3 had less impaired SF-36 PCS than Jo-1 and MDA5) were only found in group 2 (PI only). group 2 (Table 1). MSA and MAA are shown in Table 2 as background data. 31(54%) had no detectable ANA. 19(33%) of patients had at least one detectable MSA/MAA; of those 13(68%) had one autoantibody and 6(32%) had > 1 autoantibody (Table 2). 1 3 Rheumatology International (2022) 42:1213–1220 1217 Fig. 2 Variables defining cardiac and pulmonary involvement across ide, % of predicted; B TLC: Total lung capacity; % of predicted; C e´: the four clinical groups; p-values based on one-way ANOVA with early diastolic tissue velocity, cm/s; D LAS: long-axis strain, % Tukey post-hoc tests; A DLCO: Diffusing capacity for carbonmonox- Table 2 Myositis specific- Patients total Group 1 no Group 2 pul- Group 3 Group 4 coexisit- and myositis associated organ involve- monary only cardiac only ing pulmonary and autoantibodies stratified across ment cardiac the four JDM groups n 57 12 35 4 6 ANA IIF 26 (46) 6 (50) 16 (46) 1 (25) 3 (50) No MSA/ MAA 38 (67) 7 (58) 23 (66) 3 (75) 5 (83) Myositis specific autoantibodies Jo-1 1 (2) 0 1 (3) 0 0 PL-7 1 (2) 0 1 (3) 0 0 SRP 1 (2) 1 (8) 0 0 0 Mi-2 3 (5) 1 (8) 2 (6) 0 0 3 4 NXP-2 5 (9) 1 (8) 3 (9) 0 1 (25) TIF1- γ 1 (2) 0 0 1 (25) 0 MDA5 2 (4) 0 2 (6) 0 0 SAE-1 1 (2) 1 (8) 0 0 0 HMGCR 1 (2) 1 (8) 0 0 0 Myositis associated autoantibodies PMScl75 3 (5) 0 3 (9) 0 0 PMScl100 2 (4) 0 2 (6) 0 0 Ku 2 (4) 1 (8) 1 (3) 0 0 2,3 6 Ro52 3 (5) 2 (17) 1 (3) 0 0 MSA Myositis specific autoantibodies, MAA Myositis associated autoantibodies, Numbers are n (%); No 1,2,3,4,and 5 patients had detectable EJ, PL-12, OJ, SAE-2 or Mup44; denotes that more than one MSA and/or MAA are present in the same patient. IIF indirect immunofluorescence 1 3 1218 Rheumatology International (2022) 42:1213–1220 suggest different mechanisms underlying pulmonary and Discussion cardiac involvement in JDM; this requires further study. Based on our results, clinicians should be especially aware Based on previous studies in the general population [8] and of the risk detectable organ involvement in patients with connective tissue disease [9], we hypothesized that there high disease activity and damage after medium- to long-term was an increased risk of concomitant detectable cardiac and disease. Follow-studies are needed to see if patients with pulmonary involvement in JDM. No evidence for a higher subclinical PI and CI later develop clinical manifest lung risk of CI given PI and vice versa was detected in our study. and/or cardiac disease. However, due to small sample size our results should be interpreted with caution. Special attention should be drawn to group 4 (combined CI Statement on open data sharing and PI). Despite being small (n = 6/11% of the total cohort), several trends and statistically significant differences were The data will not be deposited, due to guidelines from the found when compared with the other groups. This group regional committee of health and medical research ethics in displayed a higher disease burden (including higher disease South-East Norway. activity and damage and also unfavorable lipid profile and heart rate variability) and experienced a reduced quality of Acknowledgements We thank professor Øyvind Molberg, MD, PhD life (SF-36 PCS) compared with the other groups. They were at department of Rheumatology, Oslo University hospital, for critical characterized by older age, more likely to be males and daily review of the manuscript and Randi Karlsen, Senior Biomedical Labo- smokers. Importantly, the high MDI observed in this group is ratory Scientist at the Department of Immunology, Oslo University Hospital, Ullevål for help with the immunological analyses. not explained by subclinical PI and CI. Second, group 3 (CI only) had higher disease activity at Author contributions BNW, IS and HS: Conception of the study, data 1 year post-diagnosis, unfavorable lipid profile, and higher collection, analysis and interpretation, drafting of manuscript. TS: cumulative prednisolone dose than group 2 (PI only). The Data collection and interpretation, critical review of the manuscript. higher age found in patients with cardiac involvement might ZB: Data analysis and interpretation, critical review of the manuscript. MBL, TMA, ET and BF: Data interpretation, critical review of the reflect that they were diagnosed in a time with less aggres- manuscript. All co-authors have read and approved the final manuscript sive treatment; also, it is known that cardiac involvement and take full responsibility for the correctness and integrity of the work. increases with age. Interestingly, the patients with CI, either isolated (group Funding Open access funding provided by University of Oslo (incl 3) or combined (group 4) bear little resemblance with the Oslo University Hospital). We thank the following foundations for financial support: Anders Jahre’s Foundation for the promotion of patients with PI. Possibly, abnormalities in the heart and science, Simon Fougner Hartmann’s Family Found, Rakel and Otto lung may represent two different mechanisms/phenotypes. Bruun’s Foundation. This may explain the lack of correlation between subclini- cal heart and lung involvement in JDM patients. Although Declarations no statistical difference in NCD across clinical groups was found in the present study, we have previously reported an Conflict of interest None of the authors have any conflicts of interests. association between microvascular findings and PI, but no association between microvascular findings and CI [14]. Open Access This article is licensed under a Creative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- Data on MSA and MAA was used as background infor- tion, distribution and reproduction in any medium or format, as long mation. 67% has no detectable MSA or MAA which is lower as you give appropriate credit to the original author(s) and the source, than reported in the literature [20]. This might be explained provide a link to the Creative Commons licence, and indicate if changes by methodological differences between assay methods [21]. were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated Interestingly, MSA known to be associated with pulmonary otherwise in a credit line to the material. If material is not included in involvement in JDM (MDA5, PL-7 and Jo-1)[20], were only the article's Creative Commons licence and your intended use is not found in patients with PI. permitted by statutory regulation or exceeds the permitted use, you will Strengths of our study include that our patients come need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://cr eativ ecommons. or g/licen ses/ b y/4.0/ . from a restrospective inception cohort and they were com- prehensively examined after medium- to long term follow- up. Limitations include that we did not calculate sample size (due to the hypothesis-generating nature of our study) and References the cross-sectional design. 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Tansley SL, Li D, Betteridge ZE, McHugh NJ (2020) The reli- Activity, Manual Muscle Testing (MMT), Health Assessment ability of immunoassays to detect autoantibodies in patients with Questionnaire (HAQ)/Childhood Health Assessment Question- myositis is dependent on autoantibody specificity. Rheumatology naire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), (Oxford) 59:2109–2114. https:// doi. org/ 10. 1093/ rheum atolo gy/ Myositis Disease Activity Assessment Tool (MDAAT), Disease keaa0 21 Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Dam- Publisher's Note Springer Nature remains neutral with regard to age Index (MDI), Quantitative Muscle Testing (QMT), Myositis jurisdictional claims in published maps and institutional affiliations. Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis 1 3 1220 Rheumatology International (2022) 42:1213–1220 Authors and Affiliations 1 1 1 2 3,5 Birgit Nomeland Witczak  · Thomas Schwartz  · Zoltan Barth  · Eli Taraldsrud  · May Brit Lund  · 3,6 3,7 1,8 4,7 Trond Mogens Aaløkken  · Berit Flatø  · Ivar Sjaastad  · Helga Sanner Birgit Nomeland Witczak Institute for Experimental Medical Research and KG Jebsen birgit.witczak@gmail.com Center for Cardiac Research, Oslo University Hospital and University of Oslo, Oslo, Norway Thomas Schwartz thomasschwartz1410@gmail.com Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway Zoltan Barth zoltan.barth@gmail.com Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway Eli Taraldsrud etaralds@ous-hf.no Oslo New University College, Oslo, Norway May Brit Lund Department of Respiratory Medicine, Oslo University m.b.samersaw-lund@medisin.uio.no Hospital, Rikshospitalet, Oslo, Norway Trond Mogens Aaløkken Department of Radiology, Oslo University Hospital, trond.mogens.aalokken@ous-hf.no Rikshospitalet, Oslo, Norway Berit Flatø Department of Rheumatology, Oslo University Hospital, berit.flato@medisin.uio.no Rikshospitalet, Oslo, Norway Ivar Sjaastad Department of Cardiology, Oslo University Hospital, Ullevål, ivar.sjaastad@medisin.uio.no Oslo, Norway 1 3

Journal

Rheumatology InternationalSpringer Journals

Published: Jul 1, 2022

Keywords: Juvenile dermatomyositis/polymyositis; Cardiovascular disease; Lung disease; Echocardiography; Pulmonary fibrosis

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