Explore the vast range of titles available.

Background Biomarkers have been actively investigated to supplement functional and imaging modalities to predict the severity, therapeutic responsiveness, and progression of connective tissue disease-associated interstitial lung disease (CTD-ILD). This study aimed to evaluate Krebs von den Lungen 6 (KL-6) as a potential biomarker reflecting the severity of CTD-ILD as assessed through computed tomography (CT) and pulmonary function test (PFT) parameters. Methods This retrospective study included 549 Korean patients with rheumatoid arthritis, systemic sclerosis, inflammatory myositis, and other CTDs with or without concurrent ILD. Serum KL-6 concentration (U/mL) was measured using the latex-enhanced immunoturbidimetric assay method. CT and PFT results were collected within 1 year of serum collection. A semiquantitative grade of ILD extent was evaluated through CT scan (grade 1, 0–25%; grade 2, 26–50%; grade 3, 51–75%; grade 4, 76–100%). Results CTD-ILD patients ( n  = 165) had elevated serum KL-6 levels compared to CTD patients without ILD ( n  = 384) ( p  < 0.001), and those findings were preserved after adjusting for age, sex, and CTD type. The semiquantitative grade of ILD on CT scan was significantly proportional to the KL-6 level, and the optimal cut-off KL-6 value effectively differentiated each ILD grade. The percent diffusing capacity of the lung for carbon monoxide (DLCO) ( p  < 0.001) and forced vital capacity (FVC) ( p  < 0.001) parameters had a moderate, negative correlation with the KL-6 level. Conclusion Serum KL-6 levels were increased in CTD-ILD patients and had a positive correlation with CT grade and a negative correlation with FVC and DLCO. Serum KL-6 levels may reflect CTD-ILD severity.

Our previous study demonstrated increased expression of Heat shock protein (Hsp) 90 in the skin of patients with systemic sclerosis (SSc). We aimed to evaluate plasma Hsp90 in SSc and characterize its association with SSc-related features. Ninety-two SSc patients and 92 age-/sex-matched healthy controls were recruited for the cross-sectional analysis. The longitudinal analysis comprised 30 patients with SSc associated interstitial lung disease (ILD) routinely treated with cyclophosphamide. Hsp90 was increased in SSc compared to healthy controls. Hsp90 correlated positively with C-reactive protein and negatively with pulmonary function tests: forced vital capacity and diffusing capacity for carbon monoxide (DLCO). In patients with diffuse cutaneous (dc) SSc, Hsp90 positively correlated with the modified Rodnan skin score. In SSc-ILD patients treated with cyclophosphamide, no differences in Hsp90 were found between baseline and after 1, 6, or 12 months of therapy. However, baseline Hsp90 predicts the 12-month change in DLCO. This study shows that Hsp90 plasma levels are increased in SSc patients compared to age-/sex-matched healthy controls. Elevated Hsp90 in SSc is associated with increased inflammatory activity, worse lung functions, and in dcSSc, with the extent of skin involvement. Baseline plasma Hsp90 predicts the 12-month change in DLCO in SSc-ILD patients treated with cyclophosphamide.

Background Systemic sclerosis (SSc) is a disorder characterized by immune system alterations, vasculopathy and fibrosis. SSc-related interstitial lung disease (ILD) represents a common and early complication, being the leading cause of mortality. Monocytes/macrophages seem to have a key role in SSc-related ILD. Interestingly, the classically (M1) and alternatively (M2) activated monocyte/macrophage phenotype categorization is currently under revision. Our aim was to evaluate if circulating monocyte/macrophage phenotype could be used as biomarker for lung involvement in SSc. To this purpose we developed a wide phenotype characterization of circulating monocyte/macrophage subsets in SSc patients and we evaluated possible relations with lung involvement parameter values. Methods A single centre cross-sectional study was performed in fifty-five consecutive SSc patients, during the year 2017. All clinical and instrumental tests requested for SSc follow up and in particular, lung computed tomography (CT) scan, pulmonary function tests (PFTs), Doppler echocardiography with systolic pulmonary artery pressure (sPAP) measurement, blood pro-hormone of brain natriuretic peptide (pro-BNP) evaluation, were performed in each patient in a maximum one-month period. Flow cytometry characterization of circulating cells belonging to the monocyte/macrophage lineage was performed using specific M1 (CD80, CD86, TLR2 and TLR4) and M2 surface markers (CD204, CD163 and CD206). Non-parametric tests were used for statistical analysis. Results A higher percentage of circulating CD204 + CD163 + CD206 + TLR4 + CD80 + CD86 + and CD14 + CD206 + CD163 + CD204 + TLR4 + CD80 + CD86 + mixed M1/M2 monocyte/macrophage subsets, was identified to characterize patients affected by SSc-related ILD and higher systolic pulmonary artery pressure. Mixed M1/M2 monocyte/macrophage subset showed higher percentages in patients positive for anti-topoisomerase antibody, a known lung involvement predictor. Conclusions The present study shows for the first time, through a wide flow cytometry surface marker analysis, that higher circulating mixed M1/M2 monocyte/macrophage cell percentages are associated with ILD, sPAP and anti-topoisomerase antibody positivity in SSc, opening the path for research on their possible role as pathogenic or biomarker elements for SSc lung involvement.

Background Stratifin/14-3-3σ (SFN) is a new diagnostic biomarker of interstitial lung disease (ILD) with a diffuse alveolar damage (DAD) pattern as well as a predictor of resistance to anticancer therapy. Despite the potential clinical benefit of SFN, its impact on therapeutic efficacy of immune checkpoint inhibitors (ICIs) and ICI-induced interstitial lung disease (ICI-ILD) in patients with non-small cell lung cancer (NSCLC) receiving cancer immunotherapy is unknown. Methods Plasma samples were collected from patients with NSCLC at ICI initiation and 6 weeks later. The relationship between SFN levels and therapeutic efficacy of ICIs and development of ICI-ILD was analyzed. Results Pre-SFN levels were measured for 165 patients and post- and delta-SFN levels were measured for 113 patients. Of the patients with pre-SFN values, 25 developed ICI-ILD and 10 exhibited a DAD pattern. Among patients with post- and delta-SFN values, 15 developed ICI-ILD, and 6 had a DAD pattern. Pre- and post-SFN levels were not associated with ICI therapeutic efficacy or ICI-ILD. Meanwhile, delta-SFN, representing the change in SFN values between ICI initiation and at the 6-week point, was associated with progression-free survival, overall survival, disease control rate, and ICI-ILD image patterns. Conclusion SFN levels in plasma were associated with therapeutic efficacy and ICI-ILD pattern in patients with NSCLC receiving cancer immunotherapy. SFN can be a diagnostic biomarker for ICI-ILD with DAD patterns as well as a prognostic biomarker for cancer immunotherapy.

Background Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is difficult to manage due to the heterogeneous disease course. There is a high need for new biomarkers to identify patients at high risk for ILD progression. Fibroblast activation protein (FAP) has gained interest as a biomarker to reflect fibrotic activity. As circulating FAP (cFAP) can be measured in blood, we aimed to investigate the value of cFAP in SSc-ILD. Methods cFAP concentrations were determined in plasma samples of 210 patients with systemic sclerosis (SSc) using an enzyme-linked immunosorbent assay. We compared cFAP in baseline and repeated longitudinal samples between SSc patients with ( n  = 63) and without ILD ( n  = 147). Furthermore, we investigated the correlation between cFAP and ILD progression at follow-up. In an exploratory analysis, we also investigated if cFAP was associated with other disease-related clinical features and all-cause mortality. Results cFAP levels were not different between SSc patients with- and without ILD, both at baseline (median 91.5 and 97.7 ng/mL respectively; p  = 0.80) or during follow-up. Furthermore, we found no association between cFAP at baseline and ILD progression at 1, 2 and 5 years of follow-up. Notably, cFAP levels were elevated at baseline in patients with higher skin scores (mRSS ≥ 10 compared to mRSS < 10; p  = 0.01). Finally, we did not find an association between cFAP and all-cause mortality at 5 and 10 years of follow-up. Conclusion In conclusion, cFAP does not seem useful as a biomarker in SSc-ILD. However, the association between cFAP and skin score deserves further investigation.

Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized. To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD. Subjects enrolled in Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR. A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD. Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA-ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.

To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs). This was a retrospective analysis of 166 adult Japanese patients with anti-ARS Abs detected by immunoprecipitation assays. These patients had visited Kanazawa University Hospital or collaborating medical centers from 2003 to 2009. Anti-ARS Ab specificity included anti-Jo-1 (36%), anti-EJ (23%), anti-PL-7 (18%), anti-PL-12 (11%), anti-KS (8%), and anti-OJ (5%). These anti-ARS Abs were mutually exclusive, except for one serum Ab that had both anti-PL-7 and PL-12 reactivity. Myositis was closely associated with anti-Jo-1, anti-EJ, and anti-PL-7, while interstitial lung disease (ILD) was correlated with all 6 anti-ARS Abs. Dermatomyositis (DM)-specific skin manifestations (heliotrope rash and Gottron's sign) were frequently observed in patients with anti-Jo-1, anti-EJ, anti-PL-7, and anti-PL-12. Therefore, most clinical diagnoses were polymyositis or DM for anti-Jo-1, anti-EJ, and anti-PL-7; clinically amyopathic DM or ILD for anti-PL-12; and ILD for anti-KS and anti-OJ. Patients with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset, and most patients with anti-ARS Abs eventually developed ILD if they did not have ILD at disease onset. Patients with anti-ARS Abs are relatively homogeneous. However, the distribution and timing of myositis, ILD, and rashes differ among patients with individual anti-ARS Abs. Thus, identification of individual anti-ARS Abs is beneficial to define this rather homogeneous subset and to predict clinical outcomes within the \"anti-synthetase syndrome.\"

To investigate the clinical features, risk factors and outcomes of patients with interstitial pneumonia with autoimmune features (IPAF). A total of 1429 patients with idiopathic interstitial pneumonia (IIP) and undifferentiated connective tissue disease-associated interstitial lung disease (UCTD-ILD) were screened to identify patients who met IPAF criteria. Clinical, serological, and morphological features of patients with IPAF were characterized. Outcomes between patients with IPAF, UCTD-ILD, and IIP who were divided into idiopathic pulmonary fibrosis (IPF) and non-IPF groups were compared using survival as an endpoint. Patients with IPAF were much common in young female and had lower percentage of ever smoking and a significantly shorter survival than those with non-IPAF (P < 0.001). Subgroup analysis revealed that IPAF cohort survival was worse than that in non-IPF (P < 0.001), but better than that in IPF (P < 0.001). In IPAF cohort, the most common systemic symptom and serological abnormality were Raynaud’s phenomenon (12.9%) and ANA ≥ 1:320 (49.2%); the most frequent high-resolution computed tomography (HRCT) pattern was nonspecific interstitial pneumonia (NSIP) (61.6%). Multivariate analysis indicated that several factors including age, smoking history, organizing pneumonia (OP) pattern in HRCT, and anti-RNP positivity were independently associated with significantly worse survival. IPAF had the distinct clinical features and outcomes compared with other groups of ILD. Additional studies should be needed to explore the underlying autoimmune mechanism and to determine risk stratification in future clinical research.

Backgroud Anti-melanoma differentiation-associated protein 5 antibody-positive dermatomyositis (anti-MDA5-positvie DM) is a subtype of dermatomyositis with a poor prognosis, characterized by rapidly progressive interstitial lung disease (RP-ILD). The study aims to investigate the significance of serum cytokines profiles and peripheral lymphocytes in predicting prognoses of anti-MDA5-positvie DM with RP-ILD. Furthermore, it seeks to analyze longitudinal data of lymphocytes during hospitalization to identify distinct trajectories and cluster patients accordingly. Methods A total of 168 patients with anti-MDA5-positive DM were enrolled in this retrospective study from two cohorts. Univariate and multivariate Cox regression analyses were conducted to determine the predictors of 6-month all-cause mortality and RP-ILD. Group-based trajectory modeling (GBTM) was employed to model the trajectories of longitudinal peripheral lymphocytes. Results In the multivariate Cox regression analysis, IL-6 ≥ 13.41pg/mL, lymphocytes < 0.5 × 10 9 /L, lymphocytes from 0.5 to 1.0 × 10 9 /L, older age, and elevated LDH were identified as independent predictors of 6-month all-cause mortality. Furthermore, IL-6 ≥ 13.41pg/mL, lymphocytes < 0.5 × 10 9 /L, and lymphocytes from 0.5 to 1.0 × 10 9 /L were found to be independent predictors of RP-ILD. Additionally, three trajectory groups of lymphocytes within the first week after admission were established based on GBTM. These groups included: Group 1, with low-level of lymphocytes that declined; Group 2, with medium-level of lymphocytes that slightly rose; and Group 3, with high-level of lymphocytes that rose. Notably, group 1 showed the highest mortality (90.7%) and all experiencing RP-ILD. Increased expression of IL-6 in lung tissues was observed in two cases with RP-ILD compared to two cases without RP-ILD. We also found the increased infiltration of CD4 + and CD8 + T cells, particularly CD8 + T cells, in lung tissues from patients with RP-ILD. Conclusions Our study demonstrated that increased level of serum IL-6 (≥ 13.41pg/mL) and severe lymphopenia were promising predictors of 6-month all-cause mortality and the occurrence of RP-ILD in anti-MDA5-positive DM patients. Furthermore, tracking distinct trajectories of lymphocytes during hospitalization can be utilized to cluster patients.

Krebs von den Lungen-6 (KL-6) levels are potentially indicative markers of prospective acute exacerbation (AE) in interstitial lung disease (ILD); however, their longitudinal trends have not been sufficiently investigated. We investigated the predictive ability of patient-specific changes in serum KL-6 levels for predicting AE in patients with fibrotic ILD. We included patients with fibrotic ILDs from the RWD database in Japan who received antifibrotic therapy and had at least two serum KL-6 values during the follow-up. The outcome was AE defined based on primary diagnoses, emergency admission, and pulse/high-dose steroids on the day of or after admission. We used the joint regression model integrating longitudinal and survival analyses to assess the predictive ability of each patient’s serial serum KL-6 measurements for AE. Among 939 patients with fibrotic ILDs, 194 (21%) patients experienced AE during follow-up (event rate, 0.13/person-year; 1-year incidence, 35%). The AE hazard ratio comparing patients with differing cumulative serum KL-6 levels was 1.54 (95% confidence interval: 1.20–1.98, p  < 0.001). In conclusion, AE in fibrotic ILD patients on antifibrotic therapy may be predicted by high baseline KL-6 levels and their increasing trend. Serial KL-6 monitoring can serve as a valuable tool in a multifaceted approach.