Objective The efficacy of tofacitinib in early diagnosis of MDA5-ILD has been described. But whether tofacitinib exposure is associated with a reduced one-year mortality remains undetermined. Methods Patients diagnosed as MDA5-ILD receiving tofacitinib or tacrolimus treatment were included. Cox proportional hazards model adjusted for age, sex, smoking history, anti-MDA5 antibody titers, concurrent use of other steroids sparing agents was performed to compare all-cause mortality and to investigate the risk factors predicting 1-year mortality in the two treatment groups. Results During the study period, twenty-six patients were treated with tofacitinib and thirty-five with tacrolimus. The 6-month and 1-year mortality in tofacitinib group were significantly lower than those in tacrolimus group (38.5% vs. 62.9%, p=0.028; 44.0% vs. 65.7%, p=0.031, respectively). There were thirteen patients diagnosed as rapidly progressive-ILD (RPILD) in tofacitinib group and twenty-two in tacrolimus group. The majority of death occurred in patients with RPILD. The 6-month and 1-year mortality of patients with RPILD in tofacitinib group were also lower than those in tacrolimus group (76.9% and 95.5%, p=0.021; 84.6% and 100.0%, p=0.017). The adjusted model showed tofacitinib exposure was associated with a lower risk for 1-year mortality (HR0.438, 95% CI 0.200-0.960, p=0.039). While the incidence of adverse events and medication discontinuation rates between the two groups were similar (73.1% and 74.3%, p=1.000; 23.1% and 14.3%, p=0.504). Conclusion Our observational study showed tofacitinib use might have a potential impact on improving the outcomes of MDA5-ILD. Future clinical trials are needed to assess the long-term efficacy and tolerability of tofacitinib.

Idiopathic pulmonary fibrosis (IPF) was considered as a telomere-mediated disease. TERT and TERC correlated with telomere length. Although telomerase gene mutations were associated with IPF, majority patients did not carry mutations. The mechanism by which telomerase expression was regulated in IPF are still unclear. In this study, we aimed to delineate the mechanisms that how TERT protein expression were regulated in alveolar epithelial cells (AECs) in pulmonary fibrosis. Here, we found that P16, P21 and fibrosis markers (αSMA and Collagen-I) were prominently increased in lung tissues of IPF patients and bleomycin-induced mouse models, while the expression of KLF4 and TERT were decreased in AECs. In vivo experiments, AAV-6 vectors mediated KLF4 over-expression with specific SP-C promoter was constructed. Over-expression of KLF4 in AECs could protect TERT expression and suppress the development of pulmonary fibrosis in bleomycin-induced mouse models. In the mechanism exploration of TERT regulation, KLF4 and TERT were both down-regulated in bleomycin-induced senescent MLE-12 and BEAS-2B cells. Compared with control group, small-interfering RNA targeting KLF4 significantly reduced the TERT expression and telomerase activity, while overexpression of KLF4 can increased the expression of TERT and telomerase activity in senescent AECs. Furthermore, ChIP showed that KLF4 protein could bind to the TERT promoter region in MLE-12 cells, suggesting that KLF4 could implicate in pathogenesis of lung fibrosis through regulating TERT transcription in AECs. Taken together, this study identified that KLF4 might be a promising potential target for further understanding the mechanism and developing novel strategy for the treatment of lung fibrosis in IPF.

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ObjectiveWhether coagulopathy exists in development of idiopathic inflammatory myopathies associated rapidly progressive interstitial lung disease (IIMs-RPILD) is unclear. In this study, we aimed to investigate soluble CD40 ligand and D-dimer levels in RPILD patients. Methods Patients with IIMs-ILD were enrolled and classified as RPILD and stable-ILD group. Clinical data, laboratory examinations including coagulation-associated parameters and the myositis antibodies status, chest high-resolutioncomputed tomography (HRCT) findings and treatment regimens were collected and serum levels of sCD40L were detected by ELISA. Univariable and adjusted multivariable cox regression were performed to identify risk factors for 6-month mortality, and further to select predictors for establishing predictive model for RPILD. ResultsEighty patients with IIMs-ILD were enrolled and 34 of them were diagnosed as RPILD while 46 as stable-ILD. Multivariable cox regression showed that albumin<32.4 g/L and sCD40L<1658.55 pg/ml were independent risk factors of short-term mortality in RPILD. A SMAD model consisting of serum sCD40L>1054 pg/ml, anti-MDA5 positivity, albumin<32.4 g/L and D-dimer>0.865 mg/L were generated. The odds for RPILD with SMAD score of 0, 1, 2, 3 and 4 were 0, 26.9%, 66.7%, 91.7% and 100%. The 6-month survival stratified by mild (SMAD score 0), moderate (SMAD score 1 and 2) and severe group (SMAD score 3 and 4) were 100%, 79.5% and 20%, respectively. Conclusion We established a predictive model for IIMs-RPILD, which provided a clue that coagulopathy might exist inIIMs-RPILD and could help to better treat patients with RPILD. This model awaits further validations.

Background Diabetes mellitus (DM) has been found to be related to lung fibrosis. However, the relationship between DM and idiopathic pulmonary fibrosis (IPF) remains uncertain. In this study, we aimed to determine the prevalence of DM in IPF and whether DM is associated with survival in IPF. Methods 415 IPF patients were classified as two groups based on whether they were combined with or without DM. The medical records were reviewed and the baseline characteristics and survival times were compared. The adjusted Cox proportional hazards model was used to investigate the risk factors predicting survival in IPF patients and patients combined with IPF and DM, respectively. Then we selected predictors to establish predictive model for mortality. Results The prevalence of DM in IPF patients was 25.54%. DM was associated with reduced survival time(P = 0.002). DM (hazard ratio [HR], 1.421; 95% CI, 1.010–1.980; P = 0.039), acute exacerbation (AE)(HR, 2.419; 95% CI, 1.704–3.434; P < 0.001) and antifibrotic drugs (HR, 0.297; 95% CI, 0.199–0.422; P < 0.001) were independent significant factors of mortality in IPF patients. We proposed a prediction model based on DM, AE, antifibrotic drugs to stratify the risk of 1-year mortality of IPF patients. A small internal validation cohort showed the odds of with DAA scores of 0, 1 and 2 were 6.25%, 12.50%, 85.71%, respectively (no patient scored 3). Further, in patients combined with IPF and DM, metformin treatment was associated with prolonged survival time (P = 0.040), and the sequence of diagnoses of IPF and DM (HR, 0.671; 95% CI, 0.363–1.240; P = 0.203) did not affect the mortality of patients combined with IPF and DM. Conlusions Our retrospective study showed that DM was prevalent and were an independent risk factor for predicting mortality in IPF patients. And we established a predictive model for the risk of 1-year mortality of IPF patients which need further validations.