The clinical characteristics of patients
Table 1 showed the clinical differences among the PM/DM-ILD patients based on the autoantibodies status. We identified 30 patients (22.0%) with positive anti-MDA5, 42 patients (31.0%) with positive anti-Jo-1 and 64 patients (47.0%) with other anti-ARS. There were no significant differences in age, sex ratio, smoking status among the three groups. Skin lesion, fever and arthralgia were seen more frequently in anti MDA-5 group (P = 0.002, 0.003 and 0.02, respectively). However, other respiratory symptoms (cough, sputum and dyspnea) and other muscle symptoms did not differ significantly among the three groups. The crackle was present in almost all patients, but the clubbing did not. In addition, acute disease onset was more frequently observed in the anti-MDA5-positive group (P = 0.005). MDA5 antibodies are only found in patients with DM and CADM and do not be present in patients with PM (P = 0.01), which is consistent with previous report. In contrast, anti-Jo-1 antibodies and other ARS antibodies can exist in PM, DM and CADM. In the anti-Jo-1 group, 4 (9.5%) of 42 patients died and 3 (4.7%) of 64 patients died in the other anti-ARS group. The highest mortality rate was in the anti-MDA5 group (66.7%, 20 of 30, P < 0.001).
Table 1
Characteristics of 136 PM/DM-ILD patients
| Anti-MDA5 N = 30(22.0%) | Anti-Jo-1 N = 42(31.0%) | Other anti-ARS N = 64(47.0%) | P value |
Age, yrs, median (range) | 53.5(35–77) | 57.5(33–76) | 55.0(31–84) | 0.16 |
Gender | | | | 0.50 |
Female | 17 (56.7) | 26 (61.9) | 44 (68.8) | |
Male | 13 (43.3) | 16 (38.1) | 20 (31.3) | |
Smoking status | | | | 0.60 |
Never smokers | 21 (70.0) | 34 (81.0) | 52 (81.3) | |
Former smokers | 4 (13.3) | 5 (11.9) | 5 (7.8) | |
Current smokers | 5 (16.7) | 3 (7.1) | 7 (10.9) | |
Skin lesion | 25 (83.3) | 20 (47.6) | 30 (46.9) | 0.002 |
Muscle symptoms | 9 (30.0) | 11 (26.2) | 8 (12.5) | 0.08 |
Arthralgia | 12 (40.0) | 16 (38.1) | 11 (17.2) | 0.02 |
Dysphagia | 1 (3.3) | 0 (0) | 1 (1.6) | 0.49 |
Raynaud | 1 (3.3) | 2 (4.8) | 6 (9.4) | 0.49 |
Fever | 17 (56.7) | 12 (28.6) | 14 (21.9) | 0.003 |
Cough | 26 (86.7) | 39 (92.9) | 61 (95.3) | 0.33 |
Sputum | 18 (60.0) | 25 (59.5) | 43 (67.2) | 0.67 |
Dyspnea | 26 (86.7) | 39 (92.9) | 62 (96.9) | 0.15 |
Crackle | 28 (93.3) | 39 (92.9) | 57 (89.1) | 0.79 |
Clubbing | 0 (0) | 1 (2.4) | 2 (3.1) | 1.00 |
Disease onset | | | | 0.005 |
Acute | 23(76.7) | 23(54.8) | 26(40.6) | |
Chronic | 7(23.3) | 19(45.2) | 38(59.4) | |
Myositis diagnosis | | | | 0.01 |
PM | 0 (0) | 10 (23.8) | 10 (15.6) | |
DM | 14 (46.7) | 20 (47.6) | 22 (34.4) | |
CADM | 16 (53.3) | 12 (28.6) | 32 (50.0) | |
Mortality | 20 (66.7) | 4 (9.5) | 3 (4.7) | < 0.001 |
Data are presented as the medians (ranges) or as n (%). |
* P value calculated by using the Kruskal-Wallis test. |
The laboratory data, pulmonary function tests and HRCT findings.
The laboratory data, pulmonary function tests and HRCT findings in three groups are presented in Table 2. Among the laboratory data, serum LDH, CEA and NSE were significantly higher in the anti-MDA5 group compared to the other two groups(P < 0.001), while CD4 + T cells, NK cells and lymphocyte counts were markedly lower than the anti-Jo-1 group and the other ARS group(P = 0.01, P < 0.001 and P < 0.001, respectively). In addition, the median PaO2 level and oxygenation index were relatively low in anti-MDA5 group and significantly differed among the three groups (both P < 0.001). Likewise, patients in the anti-MDA5 group were more likely to have lower PaCO2 level (P = 0.01).
The pulmonary function tests including %FVC, %FEV1 and %DLCO were tend to elevate in anti-MDA5 group although no significant difference was observed. Chest HRCT images were available for all 136 patients. NSIP pattern was more likely to be observed in 25(59.5%) patients of the anti-Jo-1 group and 40(62.5%) patients of the other anti-ARS group (P < 0.001). Conversely, OP + NSIP and DAD patterns were more commonly found in patients with anti-MDA5, especially DAD pattern. 7 (23.3%) cases of the anti-MDA5 group were interpreted as exhibiting DAD pattern compared with 2(4.8%) patients in the anti-Jo-1 group and there was no DAD pattern found in the other anti-ARS group(P < 0.001)).
Table 2
The differences of laboratory data, pulmonary function tests and HRCT findings in three groups
| Anti-MDA5 N = 30(22.0%) | Anti-Jo-1 N = 42(31.0%) | Other anti-ARS N = 64(47.0%) | P value |
PaO2, torr,mmHg (n = 115) | 60.0 (50.0–85.0) (n = 29) | 72.0 (51.1–117.0) (n = 36) | 81.5 (52.0-164.0) (n = 50) | < 0.001 |
PaCO2, torr,mmHg (n = 115) | 33.7 (24.7–43.7) (n = 29) | 36.9 (24.9–48.9) (n = 36) | 38.2 (23.0-45.7) (n = 50) | 0.001 |
OI (n = 115) | 201.0 (56–404) (n = 29) | 333.0 (98–557) (n = 36) | 371.0 (80–565) (n = 50) | < 0.001 |
CK, U/L (n = 130) | 37.0 (11–377) (n = 29) | 58.0 (15-4796) (n = 40) | 50.0 (16-1442) (n = 61) | 0.41 |
LDH, U/L (n = 135) | 408.0(214-15743) (n = 29) | 295.5 (162–2150) (n = 42) | 263.5 (166–596) (n = 64) | < 0.001 |
CRP, mg/dL (n = 135) | 16.9 (2.2–79.1) (n = 29) | 4.9 (1.4–91.2) (n = 42) | 6.4 (1.2-151.6) (n = 64) | 0.17 |
ESR, mm/h(n = 130) | 33.0 (7–81) (n = 27) | 25.0 (2–94) (n = 41) | 27.5 (4-139) (n = 62) | 0.08 |
CD4 + T cells, ×109/L(n = 115) | 0.235 (0.037–1.166) (n = 27) | 0.372 (0.140–1.462) (n = 36) | 0.414(0.087–1.009) (n = 52) | 0.01 |
NK cells, ×109/L (n = 115) | 0.067 (0.013–0.401) (n = 27) | 0.267(0.029–1.087) (n = 36) | 0.170(0.035–0.533) (n = 52) | < 0.001 |
IgG, g/L (n = 130) | 12.5 (7.4–25.7) (n = 28) | 11.1 (7.2–25.2) (n = 41) | 13.7 (8.2–21.9) (n = 61) | 0.07 |
CEA,ng/ml (n = 131) | 5.32 (0.34-47.0) (n = 30) | 1.72 (0.50–18.40) (n = 40) | 1.29 (0.50-11.73) (n = 61) | < 0.001 |
NSE, ng/ml(n = 131) | 20.61 (12.64–67.93) (n = 30) | 16.865 (7.84–64.41) (n = 40) | 14.77 (8.74–31.24) (n = 61) | < 0.001 |
CyFRA21-1, ng/ml(n = 131) | 6.525 (1.74–48.59) (n = 30) | 4.525 (1.36–18.72) (n = 40) | 4.06 (1.13–36.05) (n = 61) | 0.09 |
Lymphocyte, ×109/L (n = 136) | 0.7 (0.2–3.4) (n = 30) | 1.4 (0.2–13.4) (n = 42) | 15. (0.6–4.9) (n = 64) | < 0.001 |
PLT, ×109/L (n = 136) | 196.5 (97–347) (n = 30) | 241.0 (125–422) (n = 42) | 223.5 (5-346) (n = 64) | 0.10 |
WBC, ×109/L (n = 136) | 7.1 (1.9–16.9) (n = 30) | 7.5 (4.4–23.3) (n = 42) | 7.2 (3.4–16.1) (n = 64) | 0.42 |
HRCT findings | | | | < 0.001 |
OP | 4(13.3) | 3(7.1) | 7(10.9) | |
NSIP | 7(23.3) | 25(59.5) | 40(62.5) | |
OP + NSIP | 12(40.0) | 12(28.6) | 17(26.6) | |
DAD | 7(23.3) | 2(4.8) | 0(0) | |
FVC, % predicted median (range) (n = 96) | 67.1 (36.1–86.2) (n = 10) | 57.8 (18.7-101.6) (n = 32) | 59.0 (28.5–97.9) (n = 54) | 0.79 |
FEV1, % predicted median (range) (n = 96) | 70.8 (44.1–95.2) (n = 10) | 62.6 (20.3-103.3) (n = 32) | 63.15 (32.2-100.6) (n = 54) | 0.83 |
DLCO, % predicted median (range) (n = 85) | 68.6 (43.2–81.7) (n = 8) | 50.4 (10.1-136.2) (n = 25) | 47.0 (5.4–86.4) (n = 52) | 0.04 |
Data are presented as the medians (ranges) or as n (%).* P value calculated by using the Kruskal-Wallis test. |
OI: Oxygenation Index, CK: Creatine kinase, LDH: Lactate dehydrogenase, CRP: C-reactive protein, ESR: Erythrocyte sedimentation rate, CEA: Carcinoembryonic antigen, NSE: Neuron-specific enolase, CyFRA21-1: Cytokeratin 19 fragment, PLT: Platelet, WBC: White blood cell. |
The survival analysis for the patients with PM/DM-ILD.
Figure 1 shows the Kaplan-Meier survival curves for the entire cohort. The overall survival of patients with anti-Jo-1-ILD was significantly better than that of patients with anti-MDA5-ILD (log-rank, P<0.001) and similar to that of patients with other anti-ARS-ILD.
Univariate Cox hazard analysis showed that acute disease onset [hazard ratio (HR) 4.51; 95%CI: 1.70–11.90, P = 0.002), DAD pattern for HRCT imaging (HR 24.25; 95%CI: 8.76–67.14, P < 0.001), current smokers (HR 3.00; 95%CI: 1.19–7.57, P = 0.02), presence of Anti-MDA5(HR 23.01; 95%CI: 6.79–78.02, P < 0.001), fever(HR5.21; 95%CI: 6.79–78.02, P < 0.001) were significantly associated with the CTD-ILD death of the study population (Table 3). Among laboratory data,lower PaO2(HR 0.92; 95%CI: 0.89–0.96, P < 0.001), decreased PaCO2(HR 0.89; 95%CI: 0.83–0.96, P = 0.001), LDH level ≥ 300U/L(HR 15.39; 95%CI: 3.64–65.17, P < 0.001), elevated ESR, CEA, NSE and CyFRA21-1(HR 1.03, 1.140, 1.064, 1.098, respectively, all P < 0.001) were found to be positively correlated with mortality. The patients with higher CD4 + T cells counts (HR 0.996; 95%CI: 0.994–0.999, P = 0.002) and NK cells counts (HR 0.993; 95%CI: 0.989–0.997, P = 0.002) associated with lower mortality. Interestingly, increasing in platelet count was found associated with lower mortality risk (HR 0.992; 95%CI: 0.987–0.998, P = 0.004). (HR 2.47; 95%CI: 1.13–5.42, P = 0.02).
It is worth mentioning that the administration of high-dose prednisolone (PSL) pulse and intravenous immunoglobulin (IVIG) were positively correlated with mortality (HR 23.04; 95%CI: 10.30-51.53; HR 12.35; 95%CI: 5.60-27.24, respectively, both P < 0.001). Corticosteroids and immunosuppressive agents combination therapy can reduce the risk of death than using corticosteroid alone during hospitalization (HR 0.36, 95%CI: 0.14–0.95, P = 0.04).
Table 3
Univariate Cox hazards analysis for mortality of PM/DM-ILD patients
| HR | 95% CI | P value |
Age, yrs | 1.02 | 0.99–1.06 | 0.23 |
≤55 | Ref | | |
>55 | 1.79 | 0.83–3.86 | 0.14 |
Gender | | | |
Male | Ref | | |
Female | 0.63 | 0.29–1.34 | 0.22 |
Disease onset | | | |
Chronic | Ref | | |
Acute | 4.51 | 1.70–11.90 | 0.002 |
HRCT findings | | | |
NSIP | Ref | | |
OP | 1.34 | 0.28–6.31 | 0.71 |
OP + NSIP | 2.11 | 0.81–5.46 | 0.12 |
DAD | 24.25 | 8.76–67.14 | < 0.001 |
Smoking status | | | |
Never smokers | Ref | | |
Former smokers | 1.33 | 0.39–4.50 | 0.65 |
Current smokers | 3.00 | 1.19–7.57 | 0.02 |
Myositis diagnosis | | | |
PM | Ref | | |
DM | 2.22 | 0.50–9.91 | 0.30 |
CADM | 2.23 | 0.50–9.88 | 0.29 |
Myositis-specific Abs | | | |
Other anti-ARS | Ref | | |
Anti-Jo-1 | 2.00 | 0.45–8.95 | 0.36 |
Anti-MDA5 | 23.01 | 6.79–78.02 | < 0.001 |
Skin lesion | | | |
No | Ref | | |
Yes | 2.00 | 0.88–4.58 | 0.10 |
Muscle symptoms | | | |
No | Ref | | |
Yes | 1.58 | 0.69–3.62 | 0.28 |
Arthralgia | | | |
No | Ref | | |
Yes | 1.24 | 0.56–2.76 | 0.60 |
Dysphagia | | | |
No | Ref | | |
Yes | 2.93 | 0.40-21.67 | 0.29 |
Fever | | | |
No | Ref | | |
Yes | 5.21 | 2.34–11.61 | < 0.001 |
Cough | | | |
No | Ref | | |
Yes | 2.26 | 0.31–16.63 | 0.42 |
Sputum | | | |
No | Ref | | |
Yes | 1.87 | 0.79–4.44 | 0.15 |
Dyspnea | | | |
No | Ref | | |
Yes | 2.01 | 0.27–14.79 | 0.49 |
Crackle | | | |
No | Ref | | |
Yes | 0.85 | 0.26–2.82 | 0.79 |
PaO2, torr,mmHg (n = 115) | 0.92 | 0.89–0.96 | < 0.001 |
PaCO2, torr,mmHg (n = 115) | 0.89 | 0.83–0.96 | 0.001 |
OI (n = 115) | 0.98 | 0.98–0.99 | < 0.001 |
CK,U/L (n = 130) | 0.999 | 0.996–1.001 | 0.263 |
LDH, U/L (n = 135) | 1.0003 | 1.0001–1.0004 | < 0.001 |
<300 | Ref | | |
≥300 | 15.39 | 3.64–65.17 | < 0.001 |
CRP, mg/dL (n = 135) | 1.03 | 1.01–1.04 | < 0.001 |
ESR, mm/h(n = 130) | 1.01 | 1.00-1.03 | 0.14 |
CD4 + T cells, ×109/L (n = 115) | 0.996 | 0.994–0.999 | 0.002 |
NKcells, ×109/L,(n = 115) | 0.993 | 0.989–0.997 | 0.002 |
IgG,g/L (n = 130) | 0.929 | 0.833–1.036 | 0.186 |
CEA, ng/ml (n = 131) | 1.140 | 1.095–1.186 | < 0.001 |
NSE, ng/ml (n = 131) | 1.064 | 1.041–1.087 | < 0.001 |
CyFRA21-1, ng/ml (n = 131) | 1.098 | 1.064–1.133 | < 0.001 |
Lymphocyte, ×109/L (n = 136) | | | |
≥1.5% | Ref | | |
<1.5% | 5.64 | 1.34–23.83 | 0.02 |
PLT, ×109/L (n = 136) | 0.992 | 0.987–0.998 | 0.004 |
WBC, ×109/L (n = 136) | 1.000 | 0.889–1.126 | 0.994 |
Treatment during Hospitalization (n = 134) | | | |
CS alone | Ref | | |
CS + IM | 0.36 | 0.14–0.95 | 0.04 |
PSL pulse | | | |
No | Ref | | |
Yes | 23.04 | 10.30-51.53 | < 0.001 |
IVIG | | | |
No | Ref | | |
Yes | 12.35 | 5.60-27.24 | < 0.001 |
Table 4 showed the results of multivariate Cox proportional hazard analyses for myositis-specific Abs including anti-MDA5, anti-Jo-1 and other anti-ARS. After adjusting for disease onset, HRCT findings, smoking status, treatment before admission, treatment after admission,fever༌PaO2༌PaCO2༌LDH༌CRP༌CD4+T cells༌NK cells༌CEA༌NSE༌CyFRA21-1༌lymphocyte and PLT, the patients with anti-MDA5 antibody had a 17.61-fold (95%CI: 2.28-135.95, P = 0.006) higher risk for the mortality than those in other anti-ARS groups (model 1, Table 4). As shown in model 2, anti-MDA5 still predicted a worse outcome (HR, 8.44; 95% CI, 1.09–65.03; P = 0.04) after adjusting for all the risk factors showed significance in univariate Cox regression analysis including PSL pulse and IVIG.
Table 4
Multivariate Cox hazards analysis for myositis-specific Abs
| Model 1 | Model 2 |
HR | 95% CI | P value | HR | 95% CI | P value |
Other anti-ARS | Ref | | | Ref | | |
Anti-Jo-1 | 2.45 | 0.30–19.70 | 0.40 | 1.46 | 0.16–12.95 | 0.73 |
Anti-MDA5 | 17.61 | 2.28-135.95 | 0.006 | 8.44 | 1.09–65.03 | 0.04 |
The Cox hazard analysis for mortality in anti-MDA5 subgroup.
Univariate Cox hazard analysis for mortality in anti-MDA5 subgroup showed that DAD pattern for HRCT imagings (HR 5.36; 95%CI: 1.44–20.01, P = 0.01), current smokers (HR 5.83; 95%CI: 1.90-17.87, P = 0.002), elevated CEA, NSE and CyFRA21-1(HR 1.088, 1.106, 1.163, respectively, all P < 0.001) were still significantly associated with the death of the patients with anti-MDA5 (Table 5). (HR 1.03, 1.140, 1.064 and 1.098, respectively, all P < 0.001). Increased CD4 + T cells (HR 0.996; 95%CI: 0.993–0.999, P = 0.011) and lymphocyte counts (HR 0.71; 95%CI: 0.59–0.86, P < 0.001) can reduce mortality. Higher PaO2 (HR 0.95; 95%CI: 0.91–0.99, P = 0.02) and PaCO2(HR 0.89; 95%CI: 0.81–0.98, P = 0.01), were also found to be found to be beneficial to survival. Age was a risk factor for death of patients with anti-MDA5 (HR 1.05; 95%CI: 1.01–1.09, P = 0.02). Those older than 55 years old showed higher mortality risk compared to those younger than 55 years old (HR 2.61; 95%CI: 1.06–6.39, P = 0.04). In addition, the presence of sputum (HR 3.18; 95%CI: 1.14–8.84, P = 0.03) and high level of CRP (HR 1.026; 95%CI: 1.004–1.048, P = 0.019) showed associated with higher mortality. Interestingly, in the subgroup analysis for anti-MDA5 group, the treatment with PSL pulse and IVIG were still markedly correlated with high mortality (HR 21.78, 95%CI: 4.71-100.73, P < 0.001; HR 5.65; 95%CI: 2.06–15.48, P = 0.001, respectively)
Table 5
Univariate Cox hazards analysis for mortality in anti-MDA5 group
| HR | 95% CI | P value |
Age, yrs | 1.05 | 1.01–1.09 | 0.02 |
≤55 | Ref | | |
>55 | 2.61 | 1.06–6.39 | 0.04 |
Gender | | | |
Male | Ref | | |
Female | 0.67 | 0.28–1.62 | 0.37 |
Disease onset | | | |
Chronic | Ref | | |
Acute | 3.61 | 0.83–15.68 | 0.09 |
HRCT findings | | | |
NSIP | Ref | | |
OP | 0.72 | 0.13–3.95 | 0.71 |
OP + NSIP | 0.74 | 0.22–2.53 | 0.63 |
DAD | 5.36 | 1.44–20.01 | 0.01 |
Smoking status | | | |
Never smokers | Ref | | |
Former smokers | 1.77 | 0.49–6.35 | 0.38 |
Current smokers | 5.83 | 1.90-17.87 | 0.002 |
Myositis diagnosis | | | |
DM | Ref | | |
CADM | 0.83 | 0.34–1.99 | 0.67 |
Skin lesion | | | |
No | Ref | | |
Yes | 0.60 | 0.20–1.81 | 0.37 |
Muscle symptoms | | | |
No | Ref | | |
Yes | 0.55 | 0.20–1.53 | 0.25 |
Arthralgia | | | |
No | Ref | | |
Yes | 0.87 | 0.35–2.12 | 0.75 |
Dysphagia | | | |
No | Ref | | |
Yes | 1.39 | 0.18–10.58 | 0.75 |
Fever | | | |
No | Ref | | |
Yes | 2.51 | 0.95–6.61 | 0.06 |
Cough | | | |
No | Ref | | |
Yes | 4.64 | 0.62–34.82 | 0.14 |
Sputum | | | |
No | Ref | | |
Yes | 3.18 | 1.14–8.84 | 0.03 |
Dyspnea | | | |
No | Ref | | |
Yes | 5.04 | 0.67–37.92 | 0.12 |
Crackle | | | |
No | Ref | | |
Yes | 1.72 | 0.23–12.85 | 0.60 |
PaO2, torr, mmHg (n = 115) | 0.95 | 0.91–0.99 | 0.02 |
PaCO2, torr, mmHg (n = 115) | 0.89 | 0.81–0.98 | 0.01 |
OI (n = 115) | 0.992 | 0.986–0.997 | 0.004 |
CK,U/L (n = 130) | 1.0004 | 0.9952–1.0056 | 0.8888 |
LDH, U/L (n = 135) | 1.0002 | 1.00004–1.0004 | 0.015 |
<300 | Ref | | |
≥300 | 6.18 | 0.82–46.56 | 0.08 |
CRP, mg/dL (n = 135) | 1.026 | 1.004–1.048 | 0.019 |
ESR, mm/h(n = 130) | 0.997 | 0.977–1.017 | 0.764 |
CD4 + T cells, ×109/L (n = 115) | 0.996 | 0.993–0.999 | 0.011 |
NKcells, ×109/L,(n = 115) | 0.994 | 0.986–1.003 | 0.184 |
IgG,g/L (n = 130) | 0.901 | 0.781–1.039 | 0.150 |
CEA, ng/ml (n = 131) | 1.088 | 1.038–1.139 | < 0.001 |
NSE, ng/ml (n = 131) | 1.106 | 1.046–1.169 | < 0.001 |
CyFRA21-1, ng/ml (n = 131) | 1.163 | 1.076–1.258 | < 0.001 |
Lymphocyte,%, 0.1 increase (n = 30) | 0.71 | 0.59–0.86 | < 0.001 |
PLT, ×109/L (n = 30) | 0.994 | 0.986–1.001 | 0.090 |
WBC, ×109/L (n = 30) | 1.048 | 0.902–1.217 | 0.539 |
Treatment before admission | | | |
None | Ref | | |
CS alone | 1.35 | 0.54–3.37 | 0.52 |
CS + IM | 0.74 | 0.09–5.93 | 0.78 |
Treatment during Hospitalization | | | |
CS alone | Ref | | |
CS + IM | 0.41 | 0.12–1.41 | 0.16 |
PSL pulse | | | |
No | Ref | | |
Yes | 21.78 | 4.71-100.73 | < 0.001 |
IVIG | | | |
No | Ref | | |
Yes | 5.65 | 2.06–15.48 | 0.001 |