Expression and diagnostic value of interleukin-22 in rheumatoid arthritis-associated interstitial lung disease.

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is characterized by a high incidence and mortality rate, highlighting the need for biomarkers to detect ILD early in RA patients. Previous studies have shown the protective effects of Interleukin-22 (IL-22) in pulmonary fibrosis using mouse models. This study aims to assess IL-22 expression in RA-ILD to validate foundational experiments and explore its diagnostic value. The study included 66 newly diagnosed RA patients (33 with ILD, 33 without ILD) and 14 healthy controls (HC). ELISA was utilized to measure IL-22 levels and perform intergroup comparisons. The correlation between IL-22 levels and the severity of RA-ILD was examined. Logistic regression analysis was employed to screen potential predictive factors for RA-ILD risk and establish a predictive nomogram. The diagnostic value of IL-22 in RA-ILD was assessed using ROC. Subsequently, the data were subjected to 30-fold cross-validation. IL-22 levels in the RA-ILD group were lower than in the RA-No-ILD group and were inversely correlated with the severity of RA-ILD. Logistic regression analysis identified IL-22, age, smoking history, anti-mutated citrullinated vimentin antibody (MCV-Ab), and mean corpuscular hemoglobin concentration (MCHC) as independent factors for distinguishing between the groups. The diagnostic value of IL-22 in RA-ILD was moderate (AUC = 0.75) and improved when combined with age, smoking history, MCV-Ab and MCHC (AUC = 0.97). After 30-fold cross-validation, the average AUC was 0.886. IL-22 expression is dysregulated in the pathogenesis of RA-ILD. This study highlights the potential of IL-22, along with other factors, as a valuable biomarker for assessing RA-ILD occurrence and progression.

Rapidly progressive interstitial lung disease risk prediction in anti-MDA5 positive dermatomyositis: the CROSS model.

Background: The prognosis of anti-melanoma differentiation-associated gene 5 positive dermatomyositis (anti-MDA5+DM) is poor and heterogeneous. Rapidly progressive interstitial lung disease (RP-ILD) is these patients' leading cause of death. We sought to develop prediction models for RP-ILD risk in anti-MDA5+DM patients. Methods: Patients with anti-MDA5+DM were enrolled in two cohorts: 170 patients from the southern region of Jiangsu province (discovery cohort) and 85 patients from the northern region of Jiangsu province (validation cohort). Cox proportional hazards models were used to identify risk factors of RP-ILD. RP-ILD risk prediction models were developed and validated by testing every independent prognostic risk factor derived from the Cox model. Results: There are no significant differences in baseline clinical parameters and prognosis between discovery and validation cohorts. Among all 255 anti-MDA5+DM patients, with a median follow-up of 12 months, the incidence of RP-ILD was 36.86%. Using the discovery cohort, four variables were included in the final risk prediction model for RP-ILD: C-reactive protein (CRP) levels, anti-Ro52 antibody positivity, short disease duration, and male sex. A point scoring system was used to classify anti-MDA5+DM patients into moderate, high, and very high risk of RP-ILD. After one-year follow-up, the incidence of RP-ILD in the very high risk group was 71.3% and 85.71%, significantly higher than those in the high-risk group (35.19%, 41.69%) and moderate-risk group (9.54%, 6.67%) in both cohorts. Conclusions: The CROSS model is an easy-to-use prediction classification system for RP-ILD risk in anti-MDA5+DM patients. It has great application prospect in disease management.

Gender differences in patients with anti-MDA5-positive dermatomyositis: a cohort study of 251 cases.

OBJECTIVE: To investigate the impact of sex differences on the clinical characteristics and prognosis of patients with anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+ DM). METHODS: We retrospectively analyzed a cohort of 251 patients with MDA5+ DM, including 71 in the male group and 180 in the female group. A multivariate logistic regression model was built to analyze independent risk factors for RPILD in each group. An ROC curve was drawn to evaluate the predictive value of independent risk factors. Kaplan‒Meier analysis was used to compare the cumulative survival rates, while the log-rank test was used to test for significant differences between the two groups. RESULTS: Patients in the male group had a significantly higher prevalence of heliotrope rash, V sign, severe interstitial lung disease (ILD), and rapidly progressive interstitial lung disease (RPILD) than those in the female group. Anti-Ro52 positivity, high CRP level and short disease were identified as independent risk factors for RPILD in both male and female groups by multivariate logistic regression analysis. The mortality rates of males and females were 33.8% and 22.0%, respectively, and the survival time of patients in the male group was shorter than that in the female group. CONCLUSION: Male patients with MDA5+ DM exhibit an increased risk of RPILD, elevated mortality rates and reduced overall survival time compared to their female counterparts, and anti-Ro52 positivity may be an unfavorable prognostic factor for these patients. Key Points • The prevalence of solar rash, V sign, severe interstitial lung disease (ILD) and rapidly progressive interstitial lung disease (RPILD) in anti-MDA5-positive female patients was significantly lower than that in male patients. • Positive Anti-Ro52, high CRP level, and short course of disease were independent risk factors for RPILD in both men and women. • Female patients exhibited a lower mortality rate than male patients (22.0% vs 33.8%) and demonstrated longer survival time.

Coexistence of Anti-Ro52 Antibodies in Anti-MDA5 Antibody-Positive Dermatomyositis Is Highly Associated With Rapidly Progressive Interstitial Lung Disease and Mortality Risk.

OBJECTIVE: Interstitial lung disease (ILD) is a common extramuscular complication contributing to significant morbidity and mortality in patients with dermatomyositis (DM) who are positive for antimelanoma differentiation-associated gene 5 antibody (anti-MDA5+). We conducted this study to investigate the association of anti-Ro52 antibodies with clinical characteristics and prognosis in patients with anti-MDA5+ DM. METHODS: We assessed a cohort of 246 patients with anti-MDA5+ DM. To calculate hazard ratios and 95% CIs for rapidly progressive ILD (RP-ILD) and death while controlling for potential confounders, variables selected by univariate Cox regression analysis were included in a multivariate Cox regression model with the stepwise forward-selection method. A 2-tailed analysis with P < 0.05 was considered to be statistically significant. RESULTS: A total of 246 patients with anti-MDA5+ DM were enrolled; 70 patients were male, and the patient group had an average age of 53.1 (12.4) years. Anti-Ro52 was present in 64.2% (158/246) patients. Patients with anti-MDA5+ DM who were positive for anti-Ro52 had a higher rate of RP-ILD (log-rank P < 0.001) and a higher mortality rate (log-rank P = 0.01). For patients with anti-MDA5+ DM who were positive for anti-Ro52, those with a short disease course and high inflammation were at increased risk of RP-ILD and death. The appearance of active rash was an independent protective factor of death. CONCLUSION: Anti-Ro52 antibodies were highly prevalent in patients with anti-MDA5+ DM, and their coexistence correlated with a higher rate of RP-ILD and mortality. Patients with a short disease course, with increased inflammation, and without rash were more likely to have a poor prognosis.

Time-dependent changes in RPILD and mortality risk in anti-MDA5+ DM patients: a cohort study of 272 cases in China.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 positive (anti-MDA5+) DM has a close relationship with rapidly progressive interstitial lung disease (RPILD) and is associated with high mortality. However, data regarding the time-dependent risk of RPILD and deaths during disease progression are limited. We conducted this study to investigate whether the risk of RPILD and death were time-dependent or not in anti-MDA5+ DM. METHODS: We assessed a cohort of 272 patients with anti-MDA5+ DM. The clinical characteristics of patients with anti-MDA5+ were collected, and COX regression was used to analyse independent risk factors for RPILD and death. We also described changes in risk of RPILD and death over time and their potential clinical implications. RESULTS: There were 272 anti-MDA5+ DM patients enrolled in this study. According to the multivariate cox regression analysis, short disease course, high CRP level, anti-Ro52 positive and anti-MDA5 titre (++∼+++) were independent risk factors of RPILD. High creatine kinase level, high CRP level and RPILD were independent risk factors for death, and >90% RPILD and 84% mortality occurred in the first 6 months after disease onset. Notably, the first 3 months is a particularly high-risk period, with 50% of RPILD and 46% of deaths occurring. Hazards regarding RPILD and mortality diminished over time during a median follow-up of 12 months. CONCLUSION: These results suggest significant, time-dependent changes in RPILD and mortality risk in anti-MDA5+ DM patients, providing a cut-off time window to estimate disease progression and poor prognosis.

Identification of Three Different Phenotypes in Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis Patients: Implications for Prediction of Rapidly Progressive Interstitial Lung Disease.

OBJECTIVE: There is substantial heterogeneity among the phenotypes of patients with anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) dermatomyositis (DM), hindering disease assessment and management. This study aimed to identify distinct phenotype groups in patients with anti-MDA5+ DM and to determine the utility of these phenotypes in predicting patient outcomes. METHODS: A total of 265 patients with anti-MDA5+ DM were retrospectively enrolled in the study. An unsupervised hierarchical cluster analysis was performed to characterize the different phenotypes. RESULTS: Patients were stratified into 3 clusters characterized by markedly different features and outcomes. Cluster 1 (n = 108 patients) was characterized by mild risk of rapidly progressive interstitial lung disease (RPILD), with the cumulative incidence of non-RPILD being 85.2%. Cluster 2 (n = 72 patients) was characterized by moderate risk of RPILD, with the cumulative incidence of non-RPILPD being 73.6%. Patients in cluster 3 (n = 85 patients), which was characterized by a high risk of RPILD and a cumulative non-RPILD incidence of 32.9%, were more likely than patients in the other 2 subgroups to have anti-Ro 52 antibodies in conjunction with high titers of anti-MDA5 antibodies. All-cause mortality rates of 60%, 9.7%, and 3.7% were determined for clusters 3, 2, and 1, respectively (P < 0.0001). Decision tree analysis led to the development of a simple algorithm for anti-MDA5+ DM patient classification that included the following 8 variables: age >50 years, disease course of <3 months, myasthenia (proximal muscle weakness), arthritis, C-reactive protein level, creatine kinase level, anti-Ro 52 antibody titer, and anti-MDA5 antibody titer. This algorithm placed patients in the appropriate cluster with 78.5% accuracy in the development cohort and 70.0% accuracy in the external validation cohort. CONCLUSION: Cluster analysis identified 3 distinct clinical patterns and outcomes in our large cohort of anti-MDA5+ DM patients. Classification of DM patients into phenotype subgroups with prognostic values may help physicians improve the efficacy of clinical decision-making.

Iguratimod decreases bleomycin-induced pulmonary fibrosis in association with inhibition of TNF-α in mice.

Severe interstitial lung disease secondary to connective tissue diseases, characterized by pulmonary inflammation and fibrosis, often have very poor prognosis due to lack of effective treatments. Iguratimod (IGU) shows encouraging efficacy in treating connective tissue diseases, however, the underlying mechanism is still to be elucidated. In this study, we investigated the impact of IGU on bleomycin-induced interstitial lung disease and the related tumor necrosis factor-α (TNF-α) signaling pathway in mice and in the alveolar epithelial cell A549. We found IGU decreased pulmonary inflammation and fibrosis and expression of fibrosis-related genes such as Collagen I, α-smooth muscle actin (α-SMA) and matrix metalloproteinase-2 (MMP-2) induced by bleomycin. IGU inhibited epithelial-mesenchymal transition as evidenced by decreased E-cadherin expression but increased vimentin expression. IGU reduced TNF-α production in the pulmonary fibrosis murine model and in the in vitro cultured A549 cells. Furthermore, IGU ameliorated TNF-α-induced severe pulmonary fibrosis and inhibited TNF-α-induced activation of NF-κB. In addition, IGU decreased IL-6 production and phosphorylation of STAT3. In conclusion, the IGU-mediated anti-fibrogenesis effect was associated with the inhibition of TNF-α and NF-κB.

IL-22 promotes tumor growth of breast cancer cells in mice.

Increased interleukin-22 (IL-22) level was reported to associate with progression of breast cancer. Regulation of IL-22 in breast cancer still needs to be elucidated. We assessed the effect of giving IL-22 in tumor growth of mice inoculated with 4T1, MCF7 and MDA-MB-231 breast cancer cells. IL-22-producing cells were analyzed in tumor tissues. We also analyzed the impact of giving IL-1ß and IL-23 on IL-22 levels in tumor tissues. Giving exogenous IL-22 increased tumor size and intra-tumor Ki-67-positive cells in vivo. IL-22 increased phosphorylated STAT3 level and proliferation of breast cancer cells in vitro, an effect blocked by a STAT3-inhibitor stattic. Endogenous IL-22 mRNA level was up-regulated in tumor tissue, compared with normal mammary tissue. Innate lymphoid cell group 3 (ILC3) is a major producer of IL-22 in 4T1 tumor. Giving IL-1ß and/or IL-23 increased cell proliferation in 4T1 tumor, which was reversed by concurrent use of an IL-22 neutralization antibody. IL-1ß and IL-23 increased levels of IL-22 mRNA and IL-22-producing ILC3 in 4T1 tumor. Our findings suggest a mechanism for how IL-22 regulates tumor growth in breast cancer, and indicate blocking IL-22 function might reduce IL-1ß- and IL-23-induced tumor progression of breast cancer.