Comparisons of clinical characteristics between the survival and death group
According to the survival conditions at 6 months after onset, the patients were divided into the death group (n = 75) and the survival group (n = 224). The comparisons of baseline clinical characteristics between the two groups were shown in Table 1. Patients in the death group were significantly older and had shorter disease duration than the survival group. In the death group, skin ulcer, ILD, RP-ILD and fever occurred more commonly, but myalgia, myasthenia and arthralgia occurred less frequently compared with the survival group. Furthermore, patients in the death group exhibited obviously higher levels of NLR, ALT, AST, ALP, GGT, LDH, KL-6, ferritin, ESR and CRR, while lower levels of ALB and lymphocyte counts than those in the survival group. In addition, it was noteworthy that serum GGT levels were significantly elevated in the death group compared to the survival group [95(56–165) vs 45(26–90) U/L, p<0.001]. Similarly, patients with RP-ILD had evidently higher serum GGT levels than patients without RP-ILD [75(46–140) vs 36(23–79) U/L, p<0.001].
Table 1
Baseline characteristics of MDA5 + DM patients and comparisons between the survival and death group.
Variables | Total (n = 299) | Survival group (n = 224) | Death group (n = 75) | P-value |
Demographic characteristics | | | | |
Age at onset, years | 52(45–59) | 51(43–58) | 56(51–66) | <0.001 |
Female, n (%) | 192(64.2) | 148(66.1) | 44(58.7) | 0.247 |
Smoking history, n (%) | 33(11.0) | 19(8.5) | 14(18.7) | 0.015 |
Disease duration, months | 2.1(1.1–3.3) | 2.1(1.2–4.1) | 1.3(0.9–2.2) | <0.001 |
Clinical manifestations | | | | |
Skin ulcer, n (%) | 54(18.1) | 33(14.7) | 21(28.0) | 0.010 |
Heliotrope rash, n (%) | 189(63.2) | 147(65.6) | 42(56.0) | 0.135 |
Gottron sign, n (%) | 161(53.8) | 124(55.4) | 37(49.3) | 0.365 |
Mechanic’s hands, n (%) | 68(22.7) | 53(23.7) | 15(20.0) | 0.513 |
Myalgia, n (%) | 101(33.8) | 83(37.1) | 18(24.0) | 0.039 |
Myasthenia, n (%) | 109(36.5) | 92(41.1) | 17(22.7) | 0.004 |
ILD, n (%) | 284(95.0) | 210(93.8) | 74(98.7) | 0.167 |
RP-ILD, n (%) | 153(51.2) | 82(36.6) | 71(94.7) | <0.001 |
Fever, n (%) | 156(52.2) | 102(45.5) | 54(72.0) | <0.001 |
Arthralgia, n (%) | 140(46.8) | 117(52.2) | 23(30.7) | 0.001 |
Weight loss, n (%) | 111(37.1) | 78(34.8) | 33(44.0) | 0.154 |
Laboratory parameters | | | | |
Lymphocytes, ×109/L | 0.75(0.48–1.11) | 0.81(0.54–1.11) | 0.53(0.35–0.81) | <0.001 |
NLR | 5.1(3.1–8.9) | 4.3(2.9–6.8) | 8.9(4.8–16.0) | <0.001 |
ALT, U/L | 42(24–75) | 40(21–67) | 56(30–99) | 0.002 |
AST, U/L | 50(32–86) | 45(28–82) | 68(47–104) | <0.001 |
GGT, U/L | 52(28–121) | 45(26–90) | 95(56–165) | <0.001 |
ALP, U/L | 76(61–97) | 73(60–92) | 88(67–108) | 0.001 |
Total bilirubin, µmol/L | 7.2(5.4–9.6) | 7.1(5.3-9.0) | 7.9(5.8–11.1) | 0.022 |
ALB, g/L | 33.6 ± 5.2 | 34.8 ± 5.0 | 30.2 ± 3.9 | <0.001 |
CK, U/L | 71(37–130) | 69(37–122) | 74(39–157) | 0.348 |
LDH, U/L | 345(291–433) | 327(274–400) | 421(342–606) | <0.001 |
KL-6, U/mL | 966(663–1539) | 842(615–1304) | 1287(857–2052) | <0.001 |
Serum ferritin, ng/mL | 876(415–1877) | 756(352–1312) | 1651(734-29111) | <0.001 |
ESR, mm/H | 30(18–49) | 27(16–45) | 44(28–60) | <0.001 |
CRP, mg/L | 4.3(1.5–18.7) | 3.1(1.5–10.5) | 14.3(5.2–43.3) | <0.001 |
ANA positive, n (%) | 129(43.1) | 95(42.4) | 34(45.3) | 0.658 |
Anti-Ro52 antibody positive, n (%) | 174(58.2) | 117(52.2) | 57(76.0) | <0.001 |
Anti-MDA5 antibody levels, U/mL | 179(151–202) | 175(145–201) | 181(162–205) | 0.079 |
ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate aminotransferase; CK, creatine kinase; CRP, C-reactive protein; DM, dermatomyositis; ESR, erythrocyte sedimentation rate; GGT, gamma-glutamyl transpeptidase; ILD, interstitial lung disease; LDH, lactate dehydrogenase; MDA5, melanoma differentiation-associated gene 5; NLR, Neutrophil-to‐lymphocyte ratio; KL-6, Krebs Von den Lungen-6; RPILD, rapidly progressive interstitial lung disease.
Statistically significant results (p < 0.05) are highlighted in bold.
Comparisons of clinical characteristics and survival outcomes between the normal GGT group and elevated GGT group
Given that serum GGT levels were obviously higher in the death group than in the survival group. Next, based on the serum GGT levels at the time of diagnosis, we divided all the patients into two groups: normal GGT group (GGT ≤ 58U/L, n = 155) and elevated GGT group (GGT>58U/L, n = 144). Considering the convenience of clinical practice, the final cut-off value of GGT was determined by the upper limit of the normal reference range rather than the ROC curve. We further compared the clinical characteristics and outcomes between the two groups (Table 2).
Table 2
Comparisons of clinical features and survival outcomes between normal GGT group and elevated GGT group.
Variables | Normal GGT group (n = 155) | Elevated GGT group (n = 144) | P-value |
Demographic characteristics | | | |
Age at onset, years | 51(43–59) | 53(48–59) | 0.178 |
Female, n (%) | 107(69.0) | 85(59.0) | 0.071 |
Smoking history, n (%) | 13(8.4) | 23(13.9) | 0.129 |
Disease duration, months | 2.3(1.2–4.3) | 1.5(1.0-2.3) | <0.001 |
Clinical manifestations | | | |
Skin ulcer, n (%) | 21(14.2) | 33(22.2) | 0.035 |
Heliotrope rash, n (%) | 98(63.2) | 91(63.2) | 0.996 |
Gottron sign, n (%) | 84(54.2) | 77(53.5) | 0.901 |
Mechanic’s hands, n (%) | 33(21.3) | 35(24.3) | 0.534 |
Myalgia, n (%) | 57(36.8) | 44(30.6) | 0.256 |
Myasthenia, n (%) | 60(38.7) | 49(34.0) | 0.401 |
ILD, n (%) | 142(91.6) | 142(98.6) | 0.006 |
RP-ILD, n (%) | 57(36.8) | 96(66.7) | <0.001 |
Fever, n (%) | 69(44.5) | 87(60.4) | 0.006 |
Arthralgia, n (%) | 81(52.3) | 59(41.0) | 0.051 |
Weight loss, n (%) | 59(38.1) | 52(36.1) | 0.727 |
Laboratory parameters | | | |
Lymphocytes, ×109/L | 0.81(0.53–1.11) | 0.72(0.45–0.96) | 0.047 |
NLR | 4.00(2.92–6.55) | 6.57(3.72–11.49) | <0.001 |
ALT, U/L | 30(18–44) | 68(37–111) | <0.001 |
AST, U/L | 40(24–63) | 68(45–110) | <0.001 |
GGT, U/L | 28(21–43) | 124(79–187) | <0.001 |
ALP, U/L | 68(57–80) | 92(67–113) | <0.001 |
Total bilirubin, µmol/L | 6.9(5.3–8.7) | 7.9(5.5–10.8) | 0.003 |
ALB, g/L | 35.0 ± 4.9 | 32.2 ± 5.1 | <0.001 |
CK, U/L | 64(35–113) | 79(38–152) | 0.132 |
LDH, U/L | 320(265–411) | 374(306–466) | <0.001 |
KL-6, U/mL | 823(575–1237) | 1159(730–1773) | <0.001 |
Serum ferritin, ng/mL | 580(225–1179) | 1203(736–2281) | <0.001 |
ESR, mm/H | 27(16–44) | 34(21–57) | 0.021 |
CRP, mg/L | 3.4(1.5–11.6) | 6.1(1.5–28.0) | 0.026 |
Anti-Ro52 antibody positive, n (%) | 76(49.0) | 98(68.1) | 0.001 |
Survival outcomes | | | |
3-month mortality, n/N (%) | 16(10.3) | 35(24.3) | 0.001 |
6-month mortality, n/N (%) | 19(12.3) | 56(38.9) | <0.001 |
ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; CRP, C-reactive protein; DM, dermatomyositis; ESR, erythrocyte sedimentation rate; GGT, gamma-glutamyl transpeptidase; ILD, interstitial lung disease; LDH, lactate dehydrogenase; MDA5, melanoma differentiation-associated gene 5; NLR, Neutrophil-to‐lymphocyte ratio; KL-6, Krebs Von den Lungen-6; RPILD, rapidly progressive interstitial lung disease.
Statistically significant results (p < 0.05) are highlighted in bold.
Compared with the normal GGT group, the incidence rate of skin ulcer, RP-ILD and fever was higher in the elevated GGT group. Moreover, patients with elevated GGT levels had significantly increased levels of ALT, AST, ALP, LDH, ferritin, KL-6, ESR and CRP, but obviously decreased levels of ALB and lymphocyte counts than the normal GGT group (Fig. 1A-E). In terms of survival outcomes, the 3-month and 6-month mortality were both evidently higher in the elevated GGT group than that in the normal GGT group (24.3% vs 10.3%, p = 0.001; 38.9% vs 12.3, p<0.001) (Fig. 1F). Likewise, the Kaplan–Meier survival analysis demonstrated that the cumulative survival rate was significantly lower in the elevated GGT group than that in the normal GGT group (log-rank p < 0.001, Fig. 2).
Factors associated with mortality in MDA5 + DM patients
Cox regression analysis was conducted to explore the factors associated with death in MDA5 + DM patients. The optimal cut-off values of age, disease duration, lymphocyte count, ALT, AST, ALP, ALB, LDH, CRP, KL-6 and ferritin were determined based on the maximum Youden index. Univariable Cox regression analysis showed that age at onset > 51 years, disease duration ≤ 3 months, smoking history, skin ulcer, fever, RP-ILD, lymphocyte count ≤ 0.6×109/L, ALT > 45U/L, AST > 47U/L, GGT > 58U/L, ALP > 75U/L, Total bilirubin > 10µmol/L, ALB ≤ 33g/L, LDH > 345U/L, CRP > 5mg/L, KL-6 > 808U/mL, ferritin > 1484ng/mL and anti-Ro52 antibody positivity were risk factors associated with death for MDA5 + DM patients, while myalgia, myasthenia and arthralgia were protective factors of death.
Further multivariate Cox regression analysis revealed that RP-ILD (HR 9.260, 95%CI 3.287–26.092), GGT>58U/L (HR 1.885, 95%CI 1.047–3.394), LDH>345U/L (HR 2.252, 95%CI 1.221–4.154), CRP>5mg/L (HR 2.985, 95%CI 1.582–5.632) and anti-Ro52 antibody positivity (HR 1.983, 95%CI 1.018–3.863) were independent risk factors of mortality (Table 3). Therefore, elevated serum GGT level, defined as serum GGT level>58U/L, was an independent risk factor for mortality in MDA5 + DM patients.
Table 3
Variables associated with death in MDA5 + DM patients from univariable and multivariate Cox regression analysis.
| Univariate | Multivariate |
HR (95%CI) | P-value | HR (95%CI) | P-value |
Age at onset > 51 years | 2.741(1.682–4.465) | < 0.001 | | |
Disease duration ≤ 3 months | 2.925(1.646–5.197) | < 0.001 | | |
Smoking history | 1.964(1.105–3.491) | 0.022 | | |
Skin ulcer | 2.282(1.426–3.651) | 0.001 | | |
Myalgia | 0.593(0.361–0.972) | 0.038 | | |
Myasthenia | 0.514(0.313–0.843) | 0.008 | | |
Arthralgia | 0.494(0.313–0.778) | 0.002 | | |
Fever | 2.153(1.359–3.409) | 0.001 | | |
RP-ILD | 20.331(8.222–50.274) | < 0.001 | 9.260(3.287–26.092) | <0.001 |
Lymphocyte ≤ 0.6×109/L | 2.928(1.890–4.538) | < 0.001 | | |
ALT > 45U/L | 2.024(1.304–3.144) | 0.002 | | |
AST > 47U/L | 3.279(1.981–5.425) | < 0.001 | | |
GGT > 58U/L | 3.334(2.060–5.397) | < 0.001 | 1.885(1.047–3.394) | 0.035 |
ALP > 75U/L | 2.510(1.561–4.037) | < 0.001 | | |
ALB ≤ 33g/L | 5.315(3.116–9.065) | < 0.001 | | |
Total bilirubin > 10µmol/L | 2.204(1.402–3.465) | 0.001 | | |
LDH > 345U/L | 3.966(2.393–6.570) | < 0.001 | 2.252(1.221–4.154) | 0.009 |
CRP > 5mg/L | 4.656(2.747–7.892) | < 0.001 | 2.985(1.582–5.632) | 0.001 |
KL-6 > 808U/mL | 2.378(1.359–4.161) | 0.002 | | |
Serum ferritin > 1484ng/mL | 3.302(2.026–5.382) | < 0.001 | | |
Anti-Ro52 antibody positivity | 2.727(1.634–4.553) | < 0.001 | 1.983(1.018–3.863) | 0.044 |
ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; CRP, C-reactive protein; DM, dermatomyositis; GGT, gamma-glutamyl transpeptidase; HR, hazard ratio; LDH, lactate dehydrogenase; MDA5, melanoma differentiation-associated gene 5; KL-6, Krebs Von den Lungen-6; RPILD, rapidly progressive interstitial lung disease.
Predictive value of serum GGT level for mortality
Previous studies suggested that some laboratory parameters including lymphocyte counts and serum LDH, CRP, and ferritin levels could predict mortality in MDA5 + DM patients. We further compared the predictive value of serum GGT level for mortality with the above prognostic biomarkers. ROC curves indicated that the AUC of CRP, LDH, GGT, lymphocyte counts and ferritin levels for predicting 6-month mortality were 0.725(95%CI 0.653–0.796), 0.719(95%CI 0.650–0.788), 0.711(95%CI 0.647–0.774), 0.680(95%CI 0.610–0.751) and 0.676(95%CI 0.594–0.757) respectively (Fig. 3). These results indicated that serum GGT level exhibited a comparable predictive value for mortality in MDA5 + DM patients.
In addition, Spearman correlation analysis was employed to determine the correlations between serum GGT levels and these prognostic biomarkers. Serum GGT levels showed positive correlations with serum ferritin, LDH and KL-6 levels (r = 0.475, p<0.001; r = 0.311, p<0.001; r = 0.295, p<0.001 respectively), while negatively associated with ALB concentrations (r=-0.368, p<0.001).