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Anti-synthetase syndrome (ASSD) is an autoimmune disorder characterized by inflammatory interstitial lung disease (ILD). The main objective of this work was to quantify the concentrations of cytokines and molecules associated with inflammasome activation in bronchoalveolar lavage (BAL) of patients with ASSD and a comparison group of systemic sclerosis (SSc) patients. Cytokines and lactate dehydrogenase (LDH) were determined using the concentrated BAL protein. The activity of caspase-1 and concentration of NLRP3 with the protein purified from the cell pellet in each group of patients. We found higher caspase-1 levels in ASSD vs. SSc, 1.25 RFU vs. 0.75 RFU p = 0.003, and LDH levels at 0.15 OD vs. 0.09 OD p < 0.001. A significant difference was observed in molecules associated with inflammasome activation, IL-18: 1.42 pg/mL vs. 0.87 pg/mL p = 0.02 and IFN-γ: 0.9 pg/mL vs. 0.86 pg/mL, p = 0.01. A positive correlation was found between caspase-1 and LDH in the patients with ASSD Rho 0.58 (p = 0.008) but not in the SSc group. In patients with ASSD, greater caspase-1 and higher LDH activity were observed in BAL, suggesting cell death due to pyroptosis and activation of the inflammasome pathway. [ABSTRACT FROM AUTHOR]

The major risk factor for idiopathic pulmonary fibrosis (IPF), MUC5B rs35705950, was found to be associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Whilst the MUC5B rs35705950 T risk allele has been associated with better survival in IPF, its impact on RA-ILD prognosis remains to be determined. Our objective was to explore the influence of MUC5B rs35705950 on survival and progression in RA-ILD. Through an international retrospective observational study, patients with RA-ILD were genotyped for the MUC5B rs35705950 variant and consecutive pulmonary function tests (PFTs) findings were collected. Longitudinal data up to a 10-year follow-up were considered and analyzed using mixed regression models. Proportional hazards and joint proportional hazards models were used to analyze the association of baseline and longitudinal variables with lung transplant-free survival. Significant progression of RA-ILD was defined as at least an absolute or relative 10% decline of forced vital capacity at 2 years from baseline. Out of 321 registered patients, 261 were included in the study: 139 women (53.3%), median age at RA-ILD diagnosis 65 years (interquartile range [IQR] 57 to 71), 151 ever smokers (59.2%). Median follow-up was 3.5 years (IQR 1.3 to 6.6). Mortality rate was 32% (95%CI 19 to 42) at 10 years. The MUC5B rs35705950 variant did not impact lung transplant-free survival (HR for the T risk allele carriers=1.26; 95%CI 0.61 to 2.62; P=0.53). Decline in pulmonary function at 2 years was not influenced by MUC5B rs35705950 (OR=0.95; 95%CI 0.44 to 2.05; P=0.89), irrespective of the HRCT pattern. In this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD. [ABSTRACT FROM AUTHOR]

Agenesis of the septum pellucidum is a rare congenital defect that has been associated with psychiatric disorders, cognitive deficits, learning disabilities, seizures, and neuropsychiatric disturbances. We present the case of a patient with partial agenesis of the septum pellucidum who exhibits disorganized behavior and paranoid and persecutory delusions. We add to the literature of incidental neuropsychiatric symptoms in patients with partial agenesis of the septum pellucidum which is an area that requires further exploration and study. We discuss the implications of these findings in light of previous literature findings. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung disease (ILD) is a frequent manifestation of Sjögren's syndrome (SS), an autoimmune disease of salivary and lacrimal glands, and affects approximately 20% of patients. No clinical or serological features appear to be useful to predict its presence, severity or progression, and chest high-resolution computed tomography (CT) remains the gold standard for diagnosis. Semiquantitative CT (SQCT) based on visual assessment (Goh and Taouli scoring) can estimate ILD extent, although it is burdened by relevant intra- and interobserver variability. Quantitative chest CT (QCT) is a promising alternative modality to assess ILD severity. Aim: To determine whether QCT assessment can identify extensive or limited lung disease in patients with SS and ILD. Methods: This multi-center, cross-sectional and retrospective study enrolled patients with SS and a chest CT scan. SQCT assessment was carried out in a blinded and centralized manner to calculate both Goh and Taouli scores. An operator-independent analysis of all CT scans with the open-source software platform Horos was used to evaluate the QCT indices. Patients were classified according to the extent of ILD and differences in QCT index distribution were investigated with non-parametric tests. Results: From a total of 102 consecutive patients with SS, the prevalence of ILD was 35.3% (36/102). There was a statistically significant difference in QCT index distribution between the SS with ILD and SS without ILD groups (p<0.001). Moreover, SS-ILD patients with ILD >20% (by Goh score) had a QCT index statistically different from those with limited ILD extent (p<0.001). Finally, QCT indices showed a moderate-to-good correlation with the Goh and Taouli scores (from 0.44 to 0.65; p<0.001). Conclusions: QCT indices can identify patients with SS and ILD and discriminate those with lesser or greater lung disease. [ABSTRACT FROM AUTHOR]

KEY WORDS: gastroesophageal reflux, asthma, prevalence, diagnosis, esophagitis [ABSTRACT FROM AUTHOR]

Anti-tRNA autoantibodies are associated with interstitial lung disease (ILD), in at least two clinical scenarios: the anti-synthetase syndrome (ASSD) and interstitial pneumonia with autoimmune features (IPAF). Under pathological conditions, cytokines indicate the participating elements and the course of inflammatory phenomena. We aimed to quantify serum concentrations of different inflammatory cytokines profiles in patients with anti-tRNA associated ILD (anti-tRNA-ILD) and estimate the association between these and ILD improvement and progression. Serum levels of 18 cytokines from baseline and after six months of treatment of ILD patients' positives to anti-tRNA were included in the current study. At six months, patients were classified as with or without ILD progression. A total of 39 patients were included (10 anti-Jo1, eight anti-PL7, 11 anti-PL12, and 10 anti-Ej). Three patients (7.6%) had ILD progression (progressors patients, PP) and showed statistically higher levels in IL-4, IL-10, IL-17A, IL-22, GM-CSF, IL-1β, IL-6, IL-12, IL-18, and TNF-α, compared to patients without disease progression (no progressors patients, NPP). IL-17A, IL-1β, and IL-6 (T-helper-lymphocyte (Th)17 inflammatory cytokine profile) were elevated and had a high discriminatory capacity in distinguishing ILD PP of those NPP at follow-up. Overall, there is an association between the cytokines of the Th17 inflammatory profile and the ASSD progression. [ABSTRACT FROM AUTHOR]

Anti-synthetase syndrome (ASSD) is an autoimmune disorder characterized by inflammatory interstitial lung disease (ILD). The main objective of this work was to quantify the concentrations of cytokines and molecules associated with inflammasome activation in bronchoalveolar lavage (BAL) of patients with ASSD and a comparison group of systemic sclerosis (SSc) patients. Cytokines and lactate dehydrogenase (LDH) were determined using the concentrated BAL protein. The activity of caspase-1 and concentration of NLRP3 with the protein purified from the cell pellet in each group of patients. We found higher caspase-1 levels in ASSD vs. SSc, 1.25 RFU vs. 0.75 RFU p = 0.003, and LDH levels at 0.15 OD vs. 0.09 OD p < 0.001. A significant difference was observed in molecules associated with inflammasome activation, IL-18: 1.42 pg/mL vs. 0.87 pg/mL p = 0.02 and IFN-γ: 0.9 pg/mL vs. 0.86 pg/mL, p = 0.01. A positive correlation was found between caspase-1 and LDH in the patients with ASSD Rho 0.58 ( p = 0.008) but not in the SSc group. In patients with ASSD, greater caspase-1 and higher LDH activity were observed in BAL, suggesting cell death due to pyroptosis and activation of the inflammasome pathway.

Objectives: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies., Methods: We conducted a multicentre, international, retrospective cohort study., Results: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD., Conclusions: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

Question Addressed by the Study: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD., Methods: Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques., Results: Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted OR 0.46, 95% CI 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR 0.39, 95% CI 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI 0.26-0.69; p=0.0006). MTX ever-users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high-resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever-users compared to never-users (11.4±10.4 years and 4.0±7.4 years, respectively; p<0.001)., Answer to the Question: Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX-treated patients., Competing Interests: Conflict of interest: P-A. Juge has nothing to disclose. Conflict of interest: J.S. Lee reports grants from NIH, personal fees for advisory board work from Genentech and Celgene, outside the submitted work. Conflict of interest: J. Lau has nothing to disclose. Conflict of interest: L. Kawano-Dourado has nothing to disclose. Conflict of interest: J. Rojas-Serrano has nothing to disclose. Conflict of interest: M. Sebastiani has nothing to disclose. Conflict of interest: G. Koduri has nothing to disclose. Conflict of interest: E. Matteson has nothing to disclose. Conflict of interest: K. Bonfiglioli has nothing to disclose. Conflict of interest: M. Sawamura has nothing to disclose. Conflict of interest: R. Kairalla has nothing to disclose. Conflict of interest: L. Cavagna has nothing to disclose. Conflict of interest: E. Bozzalla Cassione has nothing to disclose. Conflict of interest: A. Manfredi has nothing to disclose. Conflict of interest: M. Mejia has nothing to disclose. Conflict of interest: P. Rodríguez-Henriquez has nothing to disclose. Conflict of interest: M.I. González Pérez has nothing to disclose. Conflict of interest: R. Falfán-Valencia has nothing to disclose. Conflict of interest: I. Buendia-Roldán has nothing to disclose. Conflict of interest: G. Pérez-Rubio has nothing to disclose. Conflict of interest: E. Ebstein reports personal fees from Sanofi, outside the submitted work. Conflict of interest: S. Gazal has nothing to disclose. Conflict of interest: R. Borie reports grants and personal fees for lectures from Roche and Boehringer Ingelheim, outside the submitted work. Conflict of interest: S. Ottaviani has nothing to disclose. Conflict of interest: C. Kannengiesser has nothing to disclose. Conflict of interest: B. Wallaert reports grants and personal fees for advisory board work and meeting attendance from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: Y. Uzunhan reports personal fees from Roche and Boehringer Ingelheim, non-financial support from Oxyvie, outside the submitted work. Conflict of interest: H. Nunes has nothing to disclose. Conflict of interest: D. Valeyre reports personal fees for advisory board work from Roche and Boehringer Ingelheim, personal fees for lectures from AstraZeneca, outside the submitted work. Conflict of interest: N. Saidenberg-Kermanac'h has nothing to disclose. Conflict of interest: M-C. Boissier has nothing to disclose. Conflict of interest: L. Wemeau-Stervinou reports personal fees for lectures and travel support from Roche, personal fees for lectures and advisory board work, and travel support from Boehringer-Ingelheim, personal fees for lectures from Janssen-Cilag and Bristol-Myers-Squibb, outside the submitted work. Conflict of interest: R.M. Flipo reports grants and personal fees from Roche Chugai, Abbvie and Pfizer, personal fees from Bristol-Meyers Squibb, outside the submitted work. Conflict of interest: S. Marchand-Adam reports fees for research, lectures, meeting attendance, consultancy and advisory board work from Roche, Boehringer Ingelheim and Novartis, outside the submitted work. Conflict of interest: P. Richette reports personal fees from Ipsen/Menarini, AstraZeneca, Savient and Grünenthal, outside the submitted work. Conflict of interest: Y. Allanore reports personal fees from Actelion, Bayer, Bristol-Myers Squibb, Boehringer and Inventiva, grants from Sanofi and Roche, outside the submitted work. Conflict of interest: C. Dromer has nothing to disclose. Conflict of interest: M-E. Truchetet has nothing to disclose. Conflict of interest: C. Richez has nothing to disclose. Conflict of interest: T. Schaeverbeke has nothing to disclose. Conflict of interest: H. Lioté has nothing to disclose. Conflict of interest: G. Thabut reports personal fees from AstraZeneca, outside the submitted work. Conflict of interest: K.D. Deane has nothing to disclose. Conflict of interest: J. Solomon has nothing to disclose. Conflict of interest: T. Doyle has nothing to disclose. Conflict of interest: J.H. Ryu has nothing to disclose. Conflict of interest: I. Rosas reports personal fees for advisory board work from Genentech, Boehringer and Three Lakes Partners, outside the submitted work. Conflict of interest: V.M. Holers reports grants from NIH/NIAID (U01 Grant), during the conduct of the study. Conflict of interest: C. Boileau has nothing to disclose. Conflict of interest: M-P. Debray reports personal fees and non-financial support for travel to meetings from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: R. Porcher has nothing to disclose. Conflict of interest: D.A. Schwartz reports grants from NIH-NHLBI (P01 HL092870, R01 HL097163, R33 HL120770 and UH2 HL123442) and DOD Focused Program (W81XWH-17-1-0597), during the conduct of the study; personal fees for consultancy and advisory board work from NuMedii, Inc., and is an employee of Eleven P15, Inc., outside the submitted work; and has a patent Compositions and Methods of Treating or Preventing Fibrotic Diseases pending, a patent Biomarkers for the Diagnosis and Treatment of Fibrotic Lung Disease pending, and a patent Methods and Compositions for Risk Prediction, Diagnosis, Prognosis, and Treatment of Pulmonary Disorders issued. Conflict of interest: R. Vassallo reports grants from Pfizer, Bristol-Myers-Squibb and SunPharma, outside the submitted work. Conflict of interest: B. Crestani reports grants from Apellis and MedImmune, grants and personal fees for lectures from Boehringer Ingelheim and Roche, personal fees for lectures from AstraZeneca and Sanofi, outside the submitted work. Conflict of interest: P. Dieudé reports fees for consultancy from Pfizer, Abbvie and MSD, grants and personal fees for consultancy and lectures from Roche, Chugai and BMS, outside the submitted work., (Copyright ©ERS 2021.)

Introduction: Phenotypic age better represents age-related biological dysregulation than chronological age. Recently, a multisystem-based ageing measure, which integrates chronological age and nine biomarkers, was proposed., Methods: Phenotypic age was determined in 774 residents of Mexico City over 60 years old and without respiratory problems. We arbitrarily classified as "accelerated" ageing, those showing >4 years compared with their chronological age, and "slowed" ageing, those with <4 years compared with chronological age. Demographic risk factors were analysed with structured questionnaires. Lung structure was evaluated by high-resolution computed tomography and functional competence was analysed by forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 ), diffusion capacity of carbon monoxide ( D LCO ), and the 6-minute walk test (6MWT)., Results: Overall, 13% of this cohort showed accelerated ageing, which was corroborated with four independent biomarkers of ageing, 42% had normal ageing and 46% had slowed ageing. Risk factors associated with accelerated ageing were male sex (OR 4.4, 95% CI 2.4-7.9; p<0.01), diabetes mellitus (OR 9.7, 95% CI 5.5-17.2; p<0.01), and long-term sleep duration (OR 2.9 95% CI 1.34-6.35, p<0.01). Among smokers, there was a slight but significant association with the number of pack-years. Subjects with accelerated ageing showed decreased FVC (p<0.0001), FEV 1 (p<0.0001), D LCO (p<0.02) and walking distance in the 6MWT (p=0.0001). Slowed-ageing subjects presented less frequently with emphysematous lesions compared with those with accelerated ageing., Conclusions: A small but significant proportion of residents of Mexico City age rapidly, which is associated with male sex, diabetes, and long-term sleep duration. They exhibit lower levels of lung function and develop emphysema more frequently., Competing Interests: Conflict of interest: I. Buendia-Roldan has nothing to disclose. Conflict of interest: R. Fernández-Plata has nothing to disclose. Conflict of interest: A. Valdes-Bartolo has nothing to disclose. Conflict of interest: M. Mejia has nothing to disclose. Conflict of interest: L.E. Jaramillo has nothing to disclose. Conflict of interest: D. Martinez-Briseño has nothing to disclose. Conflict of interest: A. Santiago-Ruiz has nothing to disclose. Conflict of interest: H. Tapia-Aguilar has nothing to disclose. Conflict of interest: B. Gómez-Zamora has nothing to disclose. Conflict of interest: A. Pardo has nothing to disclose. Conflict of interest: M. Selman has nothing to disclose., (Copyright ©ERS 2020.)

Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group's cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The "ex-novo" occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies' positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition.

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by the insidious onset of dyspnea or cough. However, a subset of patients has a short duration of symptoms with rapid progression to end-stage disease. In this study, we evaluated clinical and molecular features of "rapid" and "slow" progressors with IPF., Methods and Findings: 26 patients with <6 months of symptoms before first presentation [rapid progressors] and 88 patients with >24 months of symptoms [slow progressors] were studied. Survival was analyzed by the Kaplan-Meyer method and proportional hazard's model. Lung microarrays and tissue proteins were measured in a subset of patients. No differences were found in age, physiologic impairment and bronchoalveolar lavage (BAL) cellular profile. There were more males (OR = 6.5; CI:1.4-29.5; p = 0.006) and smokers (OR = 3.04; CI:1.1-8.3; p = 0.04) in the rapid progressors group. Survival from the beginning of symptoms was significantly reduced in rapid progressors (HR = 9.0; CI:4.48-18.3; p<0.0001) and there was a tendency for decreased survival from the time of diagnosis (HR = 1.5; CI:0.81-2.87; p = 0.18). We identified 437 differentially expressed genes. Lungs of rapid progressors overexpressed genes involved in morphogenesis, oxidative stress, migration/proliferation, and genes from fibroblasts/smooth muscle cells. Upregulation of two of these genes, adenosine-2B receptor and prominin-1/CD133, was validated by immunohistochemistry and were expressed by alveolar epithelial cells. BAL from rapid progressors showed a >2-fold increase of active matrix metalloproteinase-9, and induced a higher fibroblast migration compared with slow progressors and controls [238+/-98% versus 123+/-29% (p<0.05) and 30+/-17% (p<0.01)]., Conclusions/significance: A subgroup of IPF patients, predominantly smoking males, display an accelerated clinical course and have a gene expression pattern that is different from those with slower progression and longer survival. These findings highlight the variability in the progression of IPF, and may explain, in part, the difficulty in obtaining significant and reproducible results in studies of therapeutic interventions in patients with IPF.

We describe 12 patients with a form of interstitial lung disease characterized pathologically by small airway-centered interstitial fibrosis and metaplastic bronchiolar epithelium extending around and often linking fibrotic and sometimes heavily muscularized bronchioles. Clinically, patients presented with chronic cough and progressive dyspnea. One was a current light smoker and two were ex-smokers. In 8 patients, a history of possible inhalational exposures, including wood smoke, birds, cotton, pasture, chalk dust, agrochemical compounds, and cocaine use, was elicited. Pulmonary function tests showed moderate to severe physiologic abnormalities, in most instances indicating a restrictive lung disease with decreased peripheral flow rates. Chest radiographs revealed predominantly diffuse reticulonodular infiltrates in the central lung fields, with thickening of the bronchial walls and decreased lung volumes. Chest computed tomography demonstrated peribronchovascular fibrosis and interstitial thickening. Bronchoalveolar lavage showed a mild increase in lymphocytes in 4 subjects. Patients were treated with corticosteroids and bronchodilators. Follow-up data were available in 10 patients. In 5 patients, the disease progressed and 4 of them died. Two patients remained stable and 3 improved or healed. We propose that these findings represent a distinct airway-centered disease that mostly behaves as an interstitial lung disease and may exhibit a poor outcome.