Kaiwen Wang

BACKGROUD: There is an unmet need for the development of new biomarkers for idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD). METHODS: Peripheral CD4+CXCR4+ T cells, stromal cell-derived factor-1 and Krebs von den Lungen-6 were measured in patients with IIM-ILD (n = 85) and controls. The relation to pulmonary functions, high-resolution CT scores, specific clinical phenotypes and survival was analysed. Cytokine-expression profiling of these CD4+CXCR4+ T cells and their co-culture with pulmonary fibroblasts were conducted. RESULTS: The peripheral percentages of CD4+CXCR4+ T cells were significantly elevated in IIM-ILD patients, and correlated with high-resolution CT score (r = 0.7136, P < 0.0001) and pulmonary function impairments, such as percentage of forced volume vital capacity (r = -0.4734, P = 0.0005). They were associated with anti-melanoma differentiation-associated gene 5 autoantibodies and the amyopathic DM phenotype. In IIM-ILD, peripheral percentages of CD4+CXCR4+ T cells ⩾30% revealed a 6-month mortality as high as 47%. These CD4+CXCR4+ T cells express high levels of IL-21 and IL-6. In vitro blockade of IL-21 signalling by neutralization of IL-21 or Janus kinase inhibitor could abolished the fibroblast proliferation. CONCLUSION: Overall, peripheral CD4+CXCR4+ T cells appear to be a potentially valuable novel biomarker associated with the severity and prognosis of IIM-ILD. They promote pulmonary fibroblast proliferation via IL-21, which may herald future targeted treatments for this severe disease.

Objective To compare the effectiveness and safety of tofacitinib versus calcineurin inhibitor (CNI) as initial immunosuppressive regimen for anti-melanoma differentiation-associated gene 5-positive dermatomyositis with interstitial lung disease (MDA5 + DM-ILD). Methods Adult Chinese patients with newly diagnosed MDA5 + DM-ILD (ILD course &lt;3 months) from five tertiary referral centres between April 2014 and January 2023 were included in this retrospective cohort study. The primary effectiveness end-point was lung transplantation-free survival within 1 year. Propensity score-based inverse probability of treatment weighting (IPTW) was applied for adjustment in this real-world study. Results In the eligible cohort, a total of 94 (32.4%) and 105 (46.7%) patients died or underwent lung transplantation within 1 year in the tofacitinib group (n=290) and the CNI group (n=225), respectively. After adjustment by IPTW, patients’ lung transplantation-free survival rate within 1 year was significantly higher in the tofacitinib group compared to the CNI group (log-rank p=0.013). Multivariable Cox analysis performed in the IPTW dataset revealed that the hazard ratio of tofacitinib versus CNI for 1-year survival was 0.72 (95% CI 0.56–0.94; p=0.013). The adjusted difference of survival rate was 9.3% (95% CI 2.8–15.8%). Alternative analytic strategies yielded consistent results in sensitivity analyses. Patients aged &lt;60 years, without rapidly progressive ILD, or with baseline arterial oxygen tension/inspiratory oxygen fraction ≥300 mmHg might benefit more from tofacitinib. Opportunistic infection was the major treatment-related serious adverse event, with generally comparable incidence (42.4% versus 45.3%). Conclusion In this large multicentre cohort study, tofacitinib showed significantly more benefits for 1-year lung transplantation-free survival than calcineurin inhibitors in MDA5 + DM-ILD.

Abstract Anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated interstitial lung disease (MDA5 + DM-ILD) is a life-threatening disease. This study aimed to develop a novel pulmonary CT visual scoring method for assessing the prognosis of the disease, and an artificial intelligence (AI) algorithm-based analysis and an idiopathic pulmonary fibrosis (IPF)-based scoring were conducted as comparators. A retrospective cohort of hospitalized patients with MDA5 + DM-ILD was analyzed. Since most fatalities occur within the first half year of the disease course, the primary outcome was the six-month all-cause mortality since the time of admission. A ground glass opacity (GGO) and consolidation-weighted CT visual scoring model for MDA5 + DM-ILD, namely ‘MDA5 score’, was then developed with C-index values of 0.80 (95%CI 0.75–0.86) in the derivation dataset (n = 116) and 0.84 (95%CI 0.71–0.97) in the validation dataset (n = 57), respectively. While, the AI algorithm-based analysis, namely ‘AI score’, yielded C-index 0.78 (95%CI 0.72–0.84) for the derivation dataset and 0.77 (95%CI 0.64–0.90) for the validation dataset. These findings suggest that the newly derived ‘MDA5 score’ may serve as an applicable prognostic predictor for MDA5 + DM-ILD and facilitate further clinical trial design. The AI based CT quantitative analysis provided a promising solution for ILD evaluation.

Objectives: Anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated interstitial lung disease (MDA5 + DM-ILD) is a life-threatening disease. The current study aimed to quantitatively assess the pulmonary high-resolution computed tomography (HRCT) images of MDA5 + DM-ILD by applying the radiomics approach and establish a multidimensional risk prediction model for the 6-month mortality. Methods: This retrospective study was conducted in 228 patients from two centers, namely, a derivation cohort and a longitudinal internal validation cohort in Renji Hospital, as well as an external validation cohort in Guangzhou. The derivation cohort was randomly divided into training and testing sets. The primary outcome was 6-month all-cause mortality since the time of admission. Baseline pulmonary HRCT images were quantitatively analyzed by radiomics approach, and a radiomic score (Rad-score) was generated. Clinical predictors selected by univariable Cox regression were further incorporated with the Rad-score, to enhance the prediction performance of the final model (Rad-score plus model). In parallel, an idiopathic pulmonary fibrosis (IPF)-based visual CT score and ILD-GAP score were calculated as comparators. Results: The Rad-score was significantly associated with the 6-month mortality, outperformed the traditional visual score and ILD-GAP score. The Rad-score plus model was successfully developed to predict the 6-month mortality, with C-index values of 0.88 [95% confidence interval (CI), 0.79–0.96] in the training set ( n = 121), 0.88 (95%CI, 0.71–1.0) in the testing set ( n = 31), 0.83 (95%CI, 0.68–0.98) in the internal validation cohort ( n = 44), and 0.84 (95%CI, 0.64–1.0) in the external validation cohort ( n = 32). Conclusions: The radiomic feature was an independent and reliable prognostic predictor for MDA5 + DM-ILD.