Ground-glass opacity score predicts the prognosis of anti-MDA5 positive dermatomyositis: a single-centre cohort study
Orphanet Journal of Rare Diseases volume 18, Article number: 208 (2023)
Dermatomyositis (DM) positive with anti-melanoma differentiation-associated gene 5 (anti-MDA5-DM) is a systemic autoimmune disease with high mortality. This study aimed to explore the risk factors of death in anti-MDA5-DM and validate a prediction model for all-cause mortality in anti-MDA5-DM.
We conducted a retrospective study using a single-centre cohort of patients with newly onset anti-MDA5-DM from June 1, 2018 to August 31, 2021. Patients were divided into four groups according to baseline ground-glass opacity (GGO) score: Group A, GGO ≤ 1; Group B, 1 < GGO ≤ 2; Group C, 2 < GGO ≤ 3; Group D, GGO > 3. The primary outcome was death during the follow-up. Secondary outcomes included death within 3, 6, 12 months, severe infection, and remission during the first 12 months.
A total of 200 patients were included in the study. Based on multivariable Cox regression, the prognostic factors at baseline were identified as CRP > 5 mg/L, serum ferritin (SF) > 600ng/ml, positive anti-Ro52 antibody, prophylactic use of compound sulfamethoxazole (SMZ Co), four-category GGO score: GGO ≤ 1, 1 < GGO ≤ 2, 2 < GGO ≤ 3, GGO > 3. The final mortality of four groups was 16.4, 22.2, 48.5, 92.0%, respectively. Compared with Group A, the Hazards Ratio (HR) of Group B was 1.408, (p = 0.408), HR of Group C was 3.433 (p = 0.005), HR of Group D was 4.376 (p = 0.001).
GGO score is a reliable predictor for risk stratification in anti-MDA5-DM and may provide guidance for individualized managements of patients.
Rheumatology key messages
• GGO score is a simple and reliable predictor for risk stratification in anti-MDA5-DM.
• Baseline CRP > 5 mg/L, serum ferritin > 600 ng/ml and positive anti-Ro52 antibody are risk factors for death in anti-MDA5-DM patients, and prophylactic use of compound sulfamethoxazole is protective.
Anti-MDA5-DM is a systemic autoimmune disease with high mortality. Interstitial lung disease (ILD) is a common complication and a leading cause of death . Anti-MDA5 antibody was a risk factor for rapidly progressive ILD (RPILD) [2, 3]. The mortality of anti-MDA5-DM is significantly increased when RPILD occurs [4,5,6,7,8].
Great endeavors have been made in recent years to stratify the prognosis of anti-MDA5 patients. Although no consensus has been reached, we recognize that some clinical, laboratory and imaging features are associated with prognosis. First, advanced age, ulcerative rash, and RPILD may be risk factors for mortality [9, 10]. Second, in terms of pulmonary function test, the FVC value is helpful for ILD assessment and risk stratification . Among the serological indicators, higher titers of anti-MDA5 antibody, anti-Ro52 antibody positivity, and higher levels of CRP, lactate dehydrogenase (LDH), serum ferritin (SF) and KL-6 have been reported to be associated with mortality [7, 10, 12,13,14,15]. With regards to image-based parameters, high-resolution computed tomography (HRCT) scores have been implicated to be associated with the prognosis [7, 15, 16]. No consensus is currently available for the optimal treatment of anti-MDA5-DM. The most frequently used drugs included glucocorticoids (GC), calcineurin inhibitors and cyclophosphamide (CYC) [17, 18]. Studies have shown that initial intensive combination of immunosuppressants can improve prognosis [7, 12, 19]. In fact, the triple combination of sufficient doses of GC, CYC and high-dose tacrolimus are widely used in clinical practice . Other studies indicate that the combination of tofacitinib may significantly benefit the patients [20,21,22].
The newly onset anti-MDA5-DM patients admitted to our center from June 1, 2018 to August 31, 2021 were followed-up for a median of 15 months in order to further explore the prognosis-related risk factors of anti-MDA5-DM and to provide a basis for risk stratification of such patients.
The study included patients with newly onset anti-MDA5-DM admitted to the First Affiliated Hospital of Zhengzhou University from June 1, 2018 to August 31, 2021. Patients with juvenile onset (n = 1), overlapping diseases (n = 6), poor compliance (n = 2) and coexisting malignancies (n = 5) were excluded. Treatment with low-dose glucocorticoids for less than one month was allowed. The clinical data were obtained from the medical system and followed up by phone. The diagnosis of DM was established based on Bohan and Peter criteria . This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (2022-KY-0427).
Data collection included demographic and clinical features at baseline, as well as treatment, survival and infections. Anti-MDA5 antibody was determined by the same laboratory and team using ELISA kits (MBL, Japan). Anti-Ro52 antibody was determined using lining immunofluorescence (Euroimmun, Germany). Baseline HRCT assessment was based on GGO score using the method proposed by Kazerooni, et al. . The GGO score represented as the average extent of GGO (0: none, 1: < 5%, 2: 5 to < 25%, 3: 25 to < 50%, 4: 50 to < 75%, 5 :75% <) of five lobes. Patients were divided into four groups according to baseline GGO: Group A, GGO ≤ 1; Group B, 1 < GGO ≤ 2; Group C, 2 < GGO ≤ 3; Group D, GGO > 3. RPILD was defined as acute progressive dyspnea and hypoxemia within 4 weeks from the onset of respiratory symptoms, accompanied by the aggravation of ILD on HRCT .
Pulse GC was defined as initial prednisone 1–2 mg/kg/day. Pulse intravenous immunoglobulin (IVIG) was defined as a total of 2 g/kg given in 3–5 days. The doses of calcineurin inhibitors (CNIs) were tacrolimus 3–4 mg/d or cyclosporine A 3-5 mg/kg/d. The doses of CYC were intravenous CYC: 0.4 g weekly or 0.6 g every other week, and oral CYC: 0.1 g/day. Tofacitinib was given as 10 mg/day. Prophylactic use of SMZ Co (each tablet contains 400 mg of sulfamethoxazole and 80 mg of trimethoprim) was defined as 2 tablets daily, 1 tablet daily, 1 tablet every other day, or 2 tablets twice a week. Pulse GC was administered to all patients immediately after diagnosis. Other agents include mycophenolate mofetil, rituximab and tocilizumab. According to the application of immunosuppressants, the treatment regimens were divided into 5 categories: GC + CNIs + CYC; GC + CNIs + tofacitinib; GC + CYC; GC + CNIs; other regimens.
The primary outcome was designated as the death during the follow-up. Other outcomes were as follows: death within 3, 6, and 12 months, remission and serious infections within 12 months. Remission was defined as relief of clinical symptoms (not limited to respiratory symptoms), reduction or stabilization of GGO score on HRCT, and glucocorticoid dose of no more than prednisone 7.5 mg/day or its equivalents.
Categorical variables were described as percentages. Continuous variables were tested for K-S normality. Variables with normal distribution were presented by mean ± standard deviation, and those with skewed distribution were described by median and quartiles. For continuous variables with missing values less than 20%, missing values were filled up with the expectation maximization method. Except for the GGO scores, other continuous variables were converted to dichotomous variables, and cutoff values were set according to the ROC analysis or medians, as appropriate. Patients’ baseline features, treatment and prognosis were compared among the four-category-GGO groups. Categorical variables were assessed by the Chi-squared test or Fisher’s exact test. Variables with normal distribution were assessed by univariate ANOVA, and variables with skewed distribution was assessed by non-parametric tests. All baseline parameters and treatment data were compared by the univariable Cox proportional hazards model between survivors and deceased. Candidate predictors with P < 0.1 were included in the multivariable Cox regression. The four-category-GGO score was introduced as a fixed variable, and other variables were selected by a forward stepwise (likelihood ratio) procedure based on the P-value. Cumulative survival for different groups was described by Cox regression.
Data analysis was performed with SPSS (version 26.0, USA). P-value < 0.05 was considered significant. GraphPad Prism (Version 6.0, USA) was used for graphing.
A total of 200 eligible patients were included for the analysis. Of those, 33.5% of patients died cumulatively within a median follow-up of 15 months from baseline. This retrospective cohort was female predominant (68.5%), with a median age of 52 years (46, 59) and a median disease course of 2 months on admission. The comparison of demographic and clinical features, laboratory results, treatment and outcomes among the four-category-GGO groups were recorded in Table 1. There were no significant differences in gender, disease course, positive anti-Ro52, creatine kinase (CK) and serum ferritin (SF) level among four groups, but age, KL-6 level, and RPILD proportion were increased in groups with higher GGO scores. Mortality in 3, 6, 12 months and all follow-up was increased significantly with GGO scale increased. The mortality during the median follow-up of 15 months were 16.4, 22.2, 48.5, 92.0%, respectively, with an overall mortality of 33.5%. Remission of all patients at 12th month was 35.2%, which was significantly higher in Group A and B.
ILD classifications based on baseline HRCT were shown as Table 2. Nonspecific interstitial pneumonia (NSIP) is the dominant pattern, followed by organizing pneumonia (OP) and NSIP + OP mixture.
Causes of death
The causes of death were summarized in Table 3. Progression of ILD was the leading cause of death, accounting for 64.2%, followed by infection (25.4%), and mediastinal emphysema (6%). Two patients (3.0%) died of macrophage activation syndrome (MAS) and one patient (1.5%) committed suicide.
Univariable analysis and determination of cut-off values
Univariate Cox regression showed that age (16–55, > 55y), disease course (1–2, > 2 months), RPILD, KL-6 (0-1000, > 1000 U/ml), LMYP (0-0.6, > 0.6 × 109/L), LDH (0-460, > 460 U/L), SF (0-600, > 600 ng/ml), ESR (0–45, > 45 mm/h), CRP (0–5, > 5 mg/L), positive anti-Ro52, four-category-GGO score, prophylactic use of SMZ Co and five-category-treatment regimens were associated with death (Table 4). Creatine kinase (0–70, > 79U/L) and anti-MDA5 (0-180, > 180U/ml) were not associated with death.
Finally, 13 candidate predictors were chosen: age > 55y, disease course > 2 months, RPILD, KL-6 > 1000 U/ml, LMYP > 0.6 × 109/L, LDH > 460 U/L, SF > 600 ng/ml, ESR > 45 mm/h, CRP > 5 mg/L, anti-Ro52, four-category-GGO score, prophylactic use of SMZ Co and five-category-treatment regimens, and they were included in multivariate Cox regression (Table 4).
Multivariable analysis and determination of final prognostic predictor
The 13 variables screened out with P < 0.1 in univariate analysis were included in multivariate analysis, among which, the four-category GGO was introduced as a fixed variable, and other variables were selected by a forward stepwise (likelihood ratio) procedure based on the P-value. In the final multivariable Cox regression models, high level GGO score, CRP > 5 mg/L, positive anti-Ro52 and SF > 600 ng/ml were determined as independent risk factors for mortality of anti-MDA5-DM, and prophylactic use of SMZ Co were determined as an independent protective factor (Table 4). Compared with Group A, the mortality of Group B was not significantly increased. In contrast, the mortality of Group C increased 2.433 times (exp(B) = 3.433, p = 0.005, [1.464, 8.047]), and the mortality of Group D increased 3.376 times (exp(B) = 4.376, p = 0.001, [1.897, 10.097]) (Fig. 1). The mortality of patients with CRP > 5 mg/L increased 1.377 times (exp(B) = 2.377, p = 0.018, [1.160, 4.870]). The mortality of patients with SF > 600 ng/ml increased 1.240 times (exp(B) = 2.240, p = 0.023, [1.117, 4.494]). The mortality of patients with positive anti-Ro52 increased 1.295 times (exp(B) = 2.295, p = 0.009, [1.228, 4.289]). The mortality of patients who took prophylactic use of SMZ Co were significantly decreased (exp(B) = 0.315, p < 0.001, [0.178, 0.556]).
The Cox survival curves were shown in Fig. 2. The cumulative survival rate of Group A was higher, followed by Group B, Group C, and then Group D.
This study was based on a large single-centre cohort and several prognostic factors of anti-MDA5-DM were identified. GGO-based categorical parameter (GGO ≤ 1, 1 < GGO ≤ 2, 2 < GGO ≤ 3, GGO > 3) was a reliable predictor of all-cause mortality. Previous studies have also explored the association between HRCT scores and prognosis in anti MDA5-DM, but the number of cases was relatively small [7, 12, 16, 21].
Accumulating data suggest that higher serum ferritin levels are associated with poor prognosis in anti-MDA5-DM [5, 9, 15, 16]. Our study made similar observations although the cut-off value was different. In other studies, the cut-off values set the critical value as 450, 1000 or 1500 ng/ml [7, 16, 21], while the critical value we obtained through the ROC curve is 591.2 ng/ml.
The titer of anti-MDA5 antibody is useful for the evaluation of the treatment response in anti-MDA5-DM, and resistance to treatment, and sustained high levels of anti-MDA5 antibody were present in patients who died . It has been shown that the titer of anti-MDA5 antibody may be used to predict outcomes of RPILD as well as to monitor disease activity . Another study demonstrates that higher titer of anti-MDA5 antibody is an independent risk factor of RPILD . Inconsistent with their findings, we did not find an association of anti-MDA5 titer with either RPILD or mortality. However, we did notice that rapidly decreased level of anti-MDA5 antibody was often accompanied by remission, and re-elevation of anti-MDA5 antibody was often accompanied by relapse. Therefore, we posit that the titer of anti-MDA5 antibody may be related to disease activity.
A previous report shows that high-level KL-6 is associated with poor prognosis in anti-MDA5-DM patients . Similar results were obtained from our study after univariate analysis, although the difference was not significant in multivariate analysis. Bivariate correlation analysis revealed that KL-6 and GGO scores were significantly correlated. Therefore, KL-6 was not considered an independent risk factor of mortality.
Successful treatment of patients with anti-MDA5-DM, particularly, those with RPILD, poses a tremendous challenge to rheumatology society. A previous study shows that a combination of high-dose GC and CNIs with or without CYC is the first choice . Previous studies indicate that a triple combination of high-dose GC with CYC and CNI significantly improves the prognosis of patients . Adding tofacitinib to basic treatments may bring refractory anti-MDA5-DM under control . Accordantly, Chen, et al. also demonstrate that tofacitinib benefits patients with anti-MDA5-DM . Our study compared GC + CTX + CNI, GC + tofacitinib + CNI, GC + CTX, GC + CNI and other regimens, and did not detect statistical difference among five groups in mortality. It should be pointed out that the baseline GGO score of GC + CNI group was significantly lower than the other groups. It is reasonable to draw the conclusion that GC + CNI is less effective than other regimens in anti-MDA5-DM.
As pneumocystis jirovecii infection (PJP) is common in anti-MDA5-DM, effective prevention of PJP is crucial for reducing the mortality . This study revealed prophylactic use of SMZ Co may significantly decrease risk of mortality in anti-MDA5-DM, thus, we strongly recommend prophylactic use of SMZ Co.
Our study is a real-world study that included a large number of anti-MDA5-DM patients, which may shed light on the risk stratification anti-MDA5-DM. However, this study has its limitations. Firstly, it is a single centered retrospective study, multi-centered investigation may improve our current findings. Secondly, it was not a randomized controlled clinical study, and further studies are needed to consolidate our observations.
In conclusion, our study investigated the risk factors for all-cause death, and explored the value of four-category-GGO score as a prognostic basis in anti-MDA5-DM. GGO-based categorical parameter (GGO ≤ 1, 1 < GGO ≤ 2, 2 < GGO ≤ 3, GGO > 3) was a reliable predictor of all-cause mortality.
Data sets generated during the current study are available from the corresponding author on reasonable request, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available.
Anti-melanoma differentiation-associated protein-5 antibody
Erythrocyte sedimentation rate
Interstitial lung disease
Krebs von den Lungen-6
Rapidly progressive interstitial lung disease
- SMZ Co:
Fathi M, Dastmalchi M, Rasmussen E, Lundberg IE, Tornling G. Interstitial lung disease, a common manifestation of newly diagnosed polymyositis and dermatomyositis. Ann Rheum Dis. 2004;63(3):297–301.
Li Y, Gao X, Li Y, Jia X, Zhang X, Xu Y, et al. Predictors and mortality of Rapidly Progressive interstitial lung disease in patients with idiopathic inflammatory myopathy: a Series of 474 patients. Front Med (Lausanne). 2020;7:363.
Sato S, Hoshino K, Satoh T, Fujita T, Kawakami Y, Fujita T, et al. RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: Association with rapidly progressive interstitial lung disease. Arthritis Rheum. 2009;60(7):2193–200.
Hamaguchi Y, Kuwana M, Hoshino K, Hasegawa M, Kaji K, Matsushita T, et al. Clinical correlations with dermatomyositis-specific autoantibodies in adult japanese patients with dermatomyositis: a multicenter cross-sectional study. Arch Dermatol. 2011;147(4):391–8.
Gono T, Sato S, Kawaguchi Y, Kuwana M, Hanaoka M, Katsumata Y, et al. Anti-MDA5 antibody, ferritin and IL-18 are useful for the evaluation of response to treatment in interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis. Rheumatology (Oxford). 2012;51(9):1563–70.
Li J, Liu Y, Li Y, Li F, Wang K, Pan W, et al. Associations between anti-melanoma differentiation-associated gene 5 antibody and demographics, clinical characteristics and laboratory results of patients with dermatomyositis: a systematic meta-analysis. J Dermatol. 2018;45(1):46–52.
Yang Q, Li T, Zhang X, Lyu K, Wu S, Chen Y, et al. Initial predictors for short-term prognosis in anti-melanoma differentiation-associated protein-5 positive patients. Orphanet J Rare Dis. 2021;16(1):58.
Vuillard C, Pineton de Chambrun M, de Prost N, Guerin C, Schmidt M, Dargent A, et al. Clinical features and outcome of patients with acute respiratory failure revealing anti-synthetase or anti-MDA-5 dermato-pulmonary syndrome: a french multicenter retrospective study. Ann Intensive Care. 2018;8(1):87.
Motegi SI, Sekiguchi A, Toki S, Kishi C, Endo Y, Yasuda M, et al. Clinical features and poor prognostic factors of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with rapid progressive interstitial lung disease. Eur J Dermatol. 2019;29(5):511–7.
You H, Wang L, Wang J, Lv C, Xu L, Yuan F et al. Time-dependent changes in RPILD and mortality risk in anti-MDA5 + DM patients: a cohort study of 272 cases in China. Rheumatology (Oxford). 2022.
Wu W, Xu W, Sun W, Zhang D, Zhao J, Luo Q, et al. Forced vital capacity predicts the survival of interstitial lung disease in anti-MDA5 positive dermatomyositis: a multi-centre cohort study. Rheumatology (Oxford). 2021;61(1):230–9.
Wang LM, Yang QH, Zhang L, Liu SY, Zhang PP, Zhang X et al. Intravenous immunoglobulin for interstitial lung diseases of anti-melanoma differentiation-associated gene 5-positive dermatomyositis. Rheumatology (Oxford). 2021.
Xu A, Ye Y, Fu Q, Lian X, Chen S, Guo Q, et al. Prognostic values of anti-Ro52 antibodies in anti-MDA5-positive clinically amyopathic dermatomyositis associated with interstitial lung disease. Rheumatology (Oxford). 2021;60(7):3343–51.
Xu YT, Zhang YM, Yang HX, Ye LF, Chen F, Lu X et al. Evaluation and validation of the prognostic value of anti-MDA5 IgG subclasses in dermatomyositis-associated interstitial lung disease. Rheumatology (Oxford). 2022.
Zou J, Guo Q, Chi J, Wu H, Bao C. HRCT score and serum ferritin level are factors associated to the 1-year mortality of acute interstitial lung disease in clinically amyopathic dermatomyositis patients. Clin Rheumatol. 2015;34(4):707–14.
Fujiki Y, Kotani T, Isoda K, Ishida T, Shoda T, Yoshida S, et al. Evaluation of clinical prognostic factors for interstitial pneumonia in anti-MDA5 antibody-positive dermatomyositis patients. Mod Rheumatol. 2018;28(1):133–40.
Romero-Bueno F, Diaz Del Campo P, Trallero-Araguas E, Ruiz-Rodriguez JC, Castellvi I, Rodriguez-Nieto MJ, et al. Recommendations for the treatment of anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated rapidly progressive interstitial lung disease. Semin Arthritis Rheum. 2020;50(4):776–90.
Li T, Guo L, Chen Z, Gu L, Sun F, Tan X, et al. Pirfenidone in patients with rapidly progressive interstitial lung disease associated with clinically amyopathic dermatomyositis. Sci Rep. 2016;6:33226.
Tsuji H, Nakashima R, Hosono Y, Imura Y, Yagita M, Yoshifuji H, et al. Multicenter prospective study of the efficacy and safety of combined immunosuppressive therapy with high-dose glucocorticoid, Tacrolimus, and Cyclophosphamide in interstitial lung Diseases accompanied by Anti-Melanoma Differentiation-Associated Gene 5-Positive Dermatomyositis. Arthritis Rheumatol. 2020;72(3):488–98.
Chen Z, Wang X, Ye S. Tofacitinib in Amyopathic Dermatomyositis-Associated interstitial lung disease. N Engl J Med. 2019;381(3):291–3.
Kurasawa K, Arai S, Namiki Y, Tanaka A, Takamura Y, Owada T, et al. Tofacitinib for refractory interstitial lung diseases in anti-melanoma differentiation-associated 5 gene antibody-positive dermatomyositis. Rheumatology (Oxford). 2018;57(12):2114–9.
Takanashi S, Kaneko Y, Takeuchi T. Tofacitinib in interstitial lung disease complicated with anti-MDA5 antibody-positive dermatomyositis: a literature review. Mod Rheumatol. 2022;32(1):231–7.
Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344–7.
Kazerooni EA, Martinez FJ, Flint A, Jamadar DA, Gross BH, Spizarny DL, et al. Thin-section CT obtained at 10-mm increments versus limited three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with pathologic scoring. AJR Am J Roentgenol. 1997;169(4):977–83.
Sato S, Hirakata M, Kuwana M, Suwa A, Inada S, Mimori T, et al. Autoantibodies to a 140-kd polypeptide, CADM-140, in japanese patients with clinically amyopathic dermatomyositis. Arthritis Rheum. 2005;52(5):1571–6.
Sato S, Kuwana M, Fujita T, Suzuki Y. Anti-CADM-140/MDA5 autoantibody titer correlates with disease activity and predicts disease outcome in patients with dermatomyositis and rapidly progressive interstitial lung disease. Mod Rheumatol. 2013;23(3):496–502.
Huang L, Fu Q, Ye Y, Lin Y, Yan Q, Chen S. High incidence and mortality of Pneumocystis jirovecii infection in anti-MDA5-antibody-positive dermatomyositis: experience from a single center. Arthritis Res Ther. 2021;23(1):232.
The study was supported by grants from the National Natural Science Foundation of China [grant numbers U1704177, 81871811], the Youth Fund of the First Affiliated Hospital of Zhengzhou University [grant numbers 70200, 700203] and the Youth Project of Medical Science and Technology of Henan Provincial and Ministerial Joint Projects [grant numbers 11551].
Ethics approval and consent to participate
This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (2022-KY-0427).
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Liu, L., Zhang, Y., Wang, C. et al. Ground-glass opacity score predicts the prognosis of anti-MDA5 positive dermatomyositis: a single-centre cohort study. Orphanet J Rare Dis 18, 208 (2023). https://doi.org/10.1186/s13023-023-02827-x
- Ground-glass opacity score
- Anti-melanoma differentiation-related gene 5