Baseline demographic
The baseline characteristics of the patients are presented in Table 1. As observed, the general baseline characteristics, including age, sex, BMI, and duration of IIMs, were comparable between both groups (Table 1). The proportion of patients with a first diagnosis of IIMs was 33 (63.46%) and 42 (67.74%) in the NPC and PC groups, respectively, showing no significant difference (p > 0.05). In the PC group, the time elapsed from prior COVID-19 infection ranged from 3 weeks to 5 months (data not shown), with an average duration of 2.48 ± 1.19 months. There were no statistically significant differences in comorbidity prevalence between the two groups (P > 0.05). Both groups included patients with various subtypes of IIMs; however, a trend toward a higher proportion of ASS subtypes was noted in the PS group (p = 0.068), while a lower proportion of DM subtypes was observed (p = 0.053).
Table 1
Baseline characteristics of IIMs patients
Characteristic
|
No prior COVID-19 (NPC, n = 52)
|
Prior COVID-19
(PC, n = 62)
|
P
|
Female sex, n(%)
|
43(82.69)
|
45(72.58)
|
0.290
|
BMI (kg/m2)§
|
22.86(19.78,25.86)
|
22.22(20.32,24.46)
|
0.576
|
Age (years)
|
50.65(44.88,57.10)
|
51.85(45.05,57.03)
|
0.567
|
Newly diagnose, n(%)
|
33(63.46)
|
42(67.74)
|
0.667
|
Disease duration (months)
|
6.0(3.0,24.0)
|
9.5(2.0,24.0)
|
0.936
|
Time since prior COVID-19 (months)#
|
-
|
2.48 ± 1.19
|
-
|
Comorbidities
|
|
|
|
Hypertension, n(%)
|
4(7.69)
|
10(16.13)
|
0.280
|
Diabetes, n(%)
|
10(19.23)
|
10(16.13)
|
0.852
|
Coronary artery disease, n(%)
|
3(5.77)
|
2(3.23)
|
0.840
|
Hyperlipidaemia, n(%)
|
14(26.92)
|
15(24.19)
|
0.907
|
COPD, n(%)
|
0
|
2(3.23)
|
-
|
Interstitial lung disease, n(%)
|
28(53.84)
|
40(64.52)
|
0.280
|
Chronic kidney disease, n(%)
|
0
|
2(3.23)
|
-
|
Chronic liver disease, n(%)
|
0
|
4(6.45)
|
-
|
Anemia, n(%)
|
7(13.46)
|
6(9.68)
|
0.736
|
Arrhythmia, n/total(%)
|
8/23(34.78)
|
14/26(53.85)
|
0.293
|
Malignant arrhythmia, n/total(%)
|
0/23(0)
|
1/26(3.85)
|
-
|
Sinus tachycardia, n/total(%)
|
5/23(21.7)
|
10/26(38.46)
|
-
|
Other types, n/total(%)
|
4/23(17.4)
|
4/26(15.38)
|
-
|
Subtypes of IIMs, n(%)
|
|
|
|
ASS
|
2 (3.85)
|
10 (16.13)
|
0.068
|
DM
|
37(71.15)
|
32 (50.00)
|
0.053
|
IMNM
|
9 (17.31)
|
10 (16.13)
|
0.933
|
PM
|
0 (0)
|
2 (3.23)
|
-
|
Unclassified IIM
|
4 (7.69)
|
8(12.90)
|
0.551
|
Disease activity evaluation
|
|
|
|
MTOACT constitutional (score)
|
6(6, 7)
|
7(6, 8)
|
0.093
|
MYOACT cutaneous (score)
|
6(0, 7)
|
5(0, 7)
|
0.101
|
MYOACT skeletal (score)
|
0(0, 0)
|
0(0, 2.8)
|
0.666
|
MYOACT gastrointestinal (score)
|
0(0, 0)
|
0(0, 5)
|
0.231
|
MYOACT pulmonary (score)
|
5(0, 6)
|
7(5.8, 7.3)
|
0.001**
|
MYOACT cardiovascular (score)
|
2(0, 6)
|
6(0, 7)
|
0.002**
|
MYOACT muscle (score)
|
4(0, 7)
|
6(0, 7.3)
|
0.200
|
MITAX constitutional (score)
|
3(3, 3)
|
3(3, 3)
|
0.967
|
MITAX cutaneous (score)
|
3(0, 3)
|
3(0, 3)
|
0.271
|
MITAX skeletal (score)
|
0(0, 0)
|
0(0, 1)
|
0.832
|
MITAX gastrointestinal (score)
|
0(0, 0)
|
0(0, 3)
|
0.249
|
MITAX pulmonary (score)
|
3(0, 9)
|
6(3, 9)
|
0.006*
|
MITAX cardiovascular (score)
|
1(0, 9)
|
9(0, 9)
|
0.013*
|
MITAX muscle (score)
|
1(0, 3)
|
1(0, 9)
|
0.458
|
MYOACT global (score)
|
0.3(0.2, 0.4)
|
0.4(0.3, 0.5)
|
0.001**
|
MITAX global (score)
|
0.25 ± 0.1
|
0.33 ± 0.1
|
0.005*
|
Clinical manifestation, n/total (%)
|
|
|
|
Fever
|
12(23.08)
|
20(20.97)
|
0.380
|
Loss of weight
|
17(32.69)
|
22(35.48)
|
0.909
|
Fatigue
|
40(76.92)
|
54 (87.10)
|
0.435
|
Thoracalgia
|
0 (0)
|
8(12.90)
|
-
|
Palpitation
|
3(5.77)
|
13(20.97)
|
0.040*
|
Shortness of breath/ dyspnea
|
26(50.00)
|
45(72.58)
|
0.022*
|
Rash
|
37(71.15)
|
30(48.39)
|
0.023*
|
Myasthenia
|
22(42.31)
|
29(46.77)
|
0.773
|
Myodynia
|
17(32.69)
|
15(30.65)
|
0.426
|
Arthritis / arthralgia
|
18(34.6)
|
20(24.19)
|
0.320
|
Dysphagia
|
9(17.31)
|
16(25.81)
|
0.387
|
Cough
|
24(46.15)
|
40(64.52)
|
0.075
|
Expectoration
|
24(46.15)
|
36(58.06)
|
0.280
|
Heart rate, beats per minute
|
88.50(80.00, 105.30)
|
89.00(80.00, 101.00)
|
0.693
|
Respiratory rate, breathes per minute
|
20(20, 20)
|
20(20, 21)
|
0.055
|
Data are presented as the mean±SD, median, and range, n (%) or n/N (%)
*Indicates statistical difference between two groups, *P<0.05, **P<0.005.
§ The bode-mass index(BMI) is the weight in kilograms divided by the square of the height in meters.
# The time of COVID-19-related symptoms improving and throat swab results turning negative to the time of admission.
Abbreviations:
COPD, chronic obstructive pulmonary disease; ASS, anti-synthase antibody syndrome; DM, dermatomyositis; IMNM, immune-mediated necrotizing myopathy; PM, polymyositis; immune-mediated necrotizing myopathy; MYOACT, myositis disease activity assessment visual analog scales; MITAX, myositis intention to treat activity index.
Effects of COVID-19 on the clinical characteristics of IIMs
We analyzed the clinical symptoms of patients with IIMs and observed that the PC group exhibited a higher prevalence of cardiopulmonary symptoms than the NPC group (Table 1). These symptoms included palpitation (20.97% vs. 5.77%, p = 0.04), shortness of breath/dyspnea (12.9% vs. 5.77%, p = 0.022), cough (64.52% vs. 46.15%, p = 0.075), and respiratory rate (20 (20, 21) vs. 20 (20, 20), p = 0.055). The incidence of rash in the PC group was lower than that in the NPC group (48.39% vs. 71.15%, p = 0.023). No significant difference was found in heart rate between the two groups. Furthermore, disease activity was assessed in both groups as well (Table 1). Compared to the NPC group, patients in the PC group demonstrated higher MYOACT/MITAX global scores (0.3 (0.2, 0.4) vs. 0.4 (0.3, 0.5), p = 0.001; 0.25 ± 0.1 vs. 0.33 ± 0.1, p = 0.005), pulmonary involvement scores (5 (0, 6) vs. 7 (5.8, 7.3), p = 0.001; 3 (0, 9) vs. 6 (3, 9), p = 0.006), and cardiovascular involvement scores (5 (0, 6) vs. 7 (5.8, 7.3), p = 0.001; 1 (0, 9) vs. 9 (0, 9), p = 0.013). These findings suggest a greater presence of cardiopulmonary symptoms and increased cardiopulmonary disease activity among IIMs patients with a history of COVID-19.
Subsequently, we conducted an analysis of the laboratory characteristics of the two patient groups, as presented in Table 2. Notably, there were no significant disparities observed in the positive rates of myositis-specific antibody, ANA, and anti-Ro52 antibody between the two groups. However, it is worth mentioning that troponin T and HBDH levels were significantly elevated in the PC group compared to the NPC group (51.45 (16.28, 209.18) vs. 17.50 (9.40, 70.68), p = 0.019; 278.50 (186.75, 487.50) vs. 224.0 (172.50, 290.25), p = 0.036). Additionally, ALP and GGT levels were significantly higher in the PC group than in the NPC group. Although platelet counts fell within normal ranges for both groups, patients with a history of COVID-19 exhibited lower platelet levels than those without such a history (192.59 ± 63.69 vs. 222.23 ± 76.07, p = 0.026). Conversely, CK levels, LDH levels, blood creatinine levels, triglyceride levels, cholesterol levels, CRP levels, ESR levels, hemoglobin levels, white blood cell counts, lymphocyte counts, and neutrophil counts showed no statistically significant differences between these two groups (Table 2). These findings suggest that patients with idiopathic inflammatory myopathies who have previously contracted COVID-19 display altered clinical symptoms and laboratory test results, particularly pertaining to cardiac and pulmonary characteristics.
Table 2
Laboratory findings of IIMs patients on admission to the hospital
Characteristic
|
No prior COVID-19
(NPC, n = 52)
|
Prior COVID-19
(PC, n = 62)
|
p
|
Myositis specific antibodies
|
|
|
|
MSA, negative, n (%)
|
8(15.38)
|
14(22.58)
|
0.465
|
MDA5, positive, n (%)
|
22(42.31)
|
20(32.26)
|
0.361
|
ARS, positive, n (%)
|
5(9.62)
|
12(19.35)
|
0.234
|
Mi2/SAE, positive, n (%)
|
2(3.85)
|
2(3.23)
|
0.740
|
NXP2, positive, n (%)
|
3(5.77)
|
3(4.84)
|
0.842
|
TIF1γ, positive, n (%)
|
5(9.62)
|
2(3.23)
|
0.306
|
SRP/HMGCR, positive, n (%)
|
8(15.38)
|
7(11.29)
|
0.714
|
ANA, positive, n/total (%)
|
21/50(42.00)
|
31/60(51.67)
|
0.413
|
+~++, n/total (%)
|
14/50 (28.00)
|
22/60 (36.67)
|
-
|
≥ 3+, n/total (%)
|
7/50 (14.00)
|
9/60 (15.00)
|
-
|
Anti-Ro52, positive, n/total (%)
|
15/49(30.61)
|
29/59(49.15)
|
0.079
|
MYO(ng/ml)
|
40.15(21.11, 226.28)
|
113.99(23.45, 912.93)
|
0.114
|
CK-MB, (ng/ml)
|
2.10(1.17, 9.00)
|
7.12(1.23, 126.95)
|
0.090
|
cTnT (ng/L)
|
17.50(9.40, 70.68)
|
51.45(16.28, 209.18)
|
0.019*
|
NT-proBNP(ng/L)
|
83.00(43.50, 141.75)
|
148.00(58.00,304.00)
|
0.110
|
CK(IU/L)
|
81.50(35.00, 521.25)
|
225.50(41.50, 2240.00)
|
0.174
|
LDH, (IU/L)
|
313.50(231.75, 397.50)
|
392.00(242.00, 635.50)
|
0.072
|
HBDH, (IU/L)
|
224.0(172.50, 290.25)
|
278.50(186.75, 487.50)
|
0.036*
|
ALT (U/L)
|
34.50(21.25, 97.75)
|
56.50(24.50, 129.75)
|
0.171
|
AST (U/L)
|
37.00(20.00, 93.25)
|
49.00(23.75, 118.25)
|
0.261
|
ALP (U/L)
|
64.00(51.00, 82.75)
|
77.50(58.75, 97.25)
|
0.012*
|
GGT (U/L)
|
27.00(17.00, 70.25)
|
61.50(23.00, 144.75)
|
0.028*
|
Creatinine (umol/L)
|
54.00(42.00, 59.75)
|
54.00(45.75, 64.50)
|
0.635
|
Triglyceride (mmol/L)
|
1.95(1.32, 2.73)
|
1.961.56, 2.67)
|
0.528
|
Cholesterol (mmol/L)
|
4.91(4.07, 5.81)
|
4.93(4.08, 5.78)
|
0.811
|
D dimer
|
0.91(0.27, 1.62)
|
0.61(0.36, 1.39)
|
0.772
|
White blood cell count (×109/L)
|
6.61(4.41, 8.90)
|
7.42(5.14, 10.27)
|
0.071
|
Neutrophils count (×109/L)
|
4.86(2.89, 6.48)
|
5.29(3.61, 7.68)
|
0.118
|
Lymphocyte count (×109/L)
|
1.01(0.74, 1.70)
|
1.25(0.84, 1.68)
|
0.406
|
Platelet count (×109 /L)
|
222.23 ± 76.07
|
192.59 ± 63.69
|
0.026*
|
Hemoglobin (mg/L)
|
123.14 ± 16.52
|
126.13 ± 20.36
|
0.396
|
CRP (mg/L)
|
4.60(2.03, 12.65)
|
5.53(3.13, 13.9)
|
0.279
|
ESR (mm/h)
|
43.00(20.00, 61.00)
|
31.00(9.75, 52.52)
|
0.212
|
Data are presented as the mean±SD, median, and range, n (%) or n/N (%).
*Indicates statistical difference between two groups, *P<0.05.
Abbreviations:
MAS, myositis specific antibody; MDA5, antimelanoma differentiation associated gene 5 antibody; ARS, anti-aminoacyl transfer RNA synthetase antibody; NXP2, antinuclear matrix protein 2 antibody; Mi2, anti-helicase protein antibody; SAE, anti-small ubiquitin-like modifier activating enzyme; TIF1γ, anti-transcription intermediary factor 1 γ; HMGCR, anti-3-hydroxy-3-methyglutaryl coenzyme A reductase; SRP, anti-signal recognition particle; ANA, antinuclear antibody; Ro52, anti-cytoplasmic ribonucleoprotein of 52 kDa; MYO, myoglobin; CK-MB, creatinine kinase MB; cTnT, cardiac troponin T; NT-proBNP, N-terminal pro-B-type natriuretic peptide; CK, creatine kinase; LDH, lactate dehydrogenase; HBDH, hydroxybutyrate dehydrogenase; ALT, alanine transaminase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma glutamyltransferase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate;
Echocardiographic parameters exhibited alterations in IIMs patients with a history of COVID-19
To further investigate the impact of COVID-19 on cardiac function in patients with idiopathic inflammatory myopathies (IIMs), we analyzed echocardiography parameters, including measures of cardiac structure and function (Table 3). Due to missing echocardiography data, there were 48 and 54 patients in the no prior COVID-19 (NPC) and prior COVID-19 (PC) groups, respectively. Cardiac structural parameters revealed that the left atrium (LA) was larger in the PC group than in the NPC group (33.00 (29.00, 36.00) vs. 30 (28.00, 33.00), p = 0.021), as was the interventricular septum ((10.00 (9.00, 12.00) vs. 9.00 (8.00, 10.00), p = 0.019, IVS). The velocity of early diastolic myocardial movement at the mitral ring (e’) was lower in the PC group than in the NPC group (6.00 (5.00, 8.00) vs. 7.80 (6.00, 10.00), p = 0.012), while the peak velocity ratio of left ventricular early-diastolic fast filling (E)/e’ was higher in the PC group than in the NPC group (10.00 (8.50, 13.50) vs. 10.00 (8.00, 12.00), p = 0.028). No significant differences were observed for other echocardiographic parameters examined. The characteristics associated with cardiac damage in all patients with IIMs are summarized in Fig. 2.
Table 3
Echocardiographic characteristics of IIMs patients
Characteristic
|
No prior COVID-19
(NPC, n = 48)
|
Prior COVID-19
(PC, n = 54)
|
p
|
LV, mm
|
45.00(44.00, 47.50)
|
46.00(42.00, 48.00)
|
0.558
|
LA, mm
|
30(28.00, 33.00)
|
33.00(29.00, 36.00)
|
0.021*
|
RV, mm
|
21.00(19.00, 22.00)
|
20.00(19.00, 22.00)
|
0.544
|
RA, mm
|
31.36 ± 4.06
|
32.48 ± 4.42
|
0.314
|
IVS, mm
|
9.00(8.00, 10.00)
|
10.00(9.00, 12.00)
|
0.019*
|
LVPW, mm
|
8.00(8.00, 9.00)
|
9.00(8.00, 10.00)
|
0.129
|
AAO, mm
|
30.37 ± 3.74
|
31.34 ± 3.96
|
0.206
|
MPA, mm
|
21.00(20.00, 23.00)
|
22.00(20.00, 23.00)
|
0.784
|
E, m/s
|
0.70(0.60, 0.80)
|
0.70(0.60, 0.80)
|
0.374
|
A, m/s
|
0.75 ± 0.23
|
0.80 ± 0.19
|
0.232
|
AV, m/s
|
1.31 ± 0.20
|
1.37 ± 0.27
|
0.211
|
PV, m/s
|
0.90(0.80, 1.00)
|
0.90(0.80, 1.05)
|
0.502
|
e’, cm/s
|
7.80(6.00, 10.00)
|
6.00(5.00, 8.00)
|
0.012*
|
a’, cm/s
|
8.00(7.00, 9.00)
|
8.00(7.00, 10.00)
|
0.565
|
E/ e’
|
10.00(8.00, 12.00)
|
10.00(8.50, 13.50)
|
0.028*
|
EDD, mm
|
45.00(43.50, 47.00)
|
46.00(42.00, 48.00)
|
0.458
|
ESD, mm
|
29.00(26.00, 31.00)
|
29.00(26.00, 31.50)
|
0.407
|
EDV, ml
|
90.00(84.00, 102.00)
|
98.00(78.50, 111.50)
|
0.218
|
ESV, ml
|
31.00(25.50, 36.00)
|
32.00(26.00, 42.50)
|
0.155
|
SV, ml
|
62.45 ± 10.31
|
62.51 ± 12.49
|
0.979
|
EF, %
|
67.00(61.00, 72.00)
|
65.00(61.00, 69.00)
|
0.184
|
FS, %
|
37.18 ± 4.50
|
35.74 ± 4.67
|
0.140
|
Data are presented as the mean±SD, median, and range.
*Indicates statistical difference between two groups, *P<0.05.
Abbreviations:
LV, left ventricle; LA, left atrium; RV, right ventricle; RA, right atrium; IVS, interventricular septum; LVPW, left-ventricular posterior wall; AAO, ascending aorta. MPA, main pulmonary artery; E, peak velocity of left ventricular early-diastolic fast filling; A, peak velocity of left ventricular late-diastolic filling; AV, aortic valve; PV, pulmonary valve; e’, velocity of early diastolic myocardial movement at mitral ring; a’, velocity of late diastolic myocardial movement at mitral ring; EDD, end-diastolic dimension; ESD, end-systolic dimension; EDV, end-diastolic volume; ESV, end-systolic volume; SV, stroke volume per minute; EF, ejection fraction; FS, fraction shortening;
To ascertain the potential association between the extent of cardiac impairment in individuals with post-COVID-19 IIMs and the duration elapsed since their COVID-19 infection. Patients with a history of COVID-19 from IIMs were categorized based on the time elapsed since their prior infection, and no statistically significant differences in clinical features were observed among all groups (Supplementary Table 1, Table 2).
The putative mechanism underlying COVID-19-induced cardiac damage in patients with IIMs
To investigate the potential mechanism of cardiac injury in patients with IIMs and a history of COVID-19, we employed RNA-seq technology coupled with bioinformatics analysis to elucidate disparities in gene expression profiles between dermatomyositis (DM) patients and COVID-19 patients. Upon examining the number of differentially expressed genes (DEGs) between DM patients and COVID-19 patients, we identified 7189 DEGs in DM patients (Fig. 3A), comprising 5654 upregulated genes (depicted as red dots) and 1679 downregulated genes (depicted as blue dots). Conversely, COVID-19 patients exhibited 3080 DEGs (Fig. 3A), including 1278 upregulated genes (red dots) and 1802 downregulated genes (blue dots). A comparison of DEGs between DM patients and COVID-19 patients revealed an overlap of 720 genes (Fig. 3C). To explore the underlying mechanisms and pathways associated with these DEGs within our datasets, functional enrichment analyses using Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes were performed. The results demonstrated that biological processes and enriched pathways related to collagen matrix proliferation, calcium ion pathway regulation, oxidative stress response, cell proliferation, and cell inflammatory molecules were significantly enriched among these targets (Fig. 3D).