Association between anti-PL7 antibodies and increased fibrotic component in patients with antisynthetase syndrome and interstitial lung disease: a cross-sectional study.

OBJECTIVE: To evaluate whether anti-PL7 and anti-PL12 autoantibodies are associated with a greater extent of the fibrotic component of ILD in ASSD patients. METHODS: Patients with ILD-ASSD who were positive for one of the following autoantibodies: anti-Jo1, anti-PL7, anti-PL12, and anti-EJ were included. Clinical manifestations, CPK levels, pulmonary function tests, and HCRT assessments were prospectively collected according to the Goh index. The fibrotic, inflammatory, and overall extension of the Goh index and DLCO were assessed by multiple linear analyses and compared between ASSD antibody subgroups. RESULTS: Sixty-six patients were included; 17 were positive for anti-Jo1 (26%), 17 for anti-PL7 (26%), 20 for anti-PL12 (30%), and 9 (14%) for anti-EJ. Patients with anti-PL7 and anti-PL12 had a more extensive fibrotic component than anti-Jo1. Anti-PL7 patients had a 7.9% increase in the fibrotic extension (cß = 7.9; 95% CI 1.863, 13.918), and the strength of the association was not modified after controlling for sex, age, and time of disease evolution (aß = 7.9; 95% CI 0.677, 15.076) and also was associated with an increase in ILD severity after adjusting for the same variables, denoted by a lower DLCO (aß = - 4.47; 95% CI - 8.919 to - 0.015). CONCLUSIONS: Anti-PL7-positive ASSD patients had more extensive fibrosis and severe ILD than the anti-Jo1 subgroup. This information is clinically useful and has significant implications for managing these patients, suggesting the need for early consideration of concurrent immunosuppressive and antifibrotic therapy.

Pulmonary manifestations and prognosis of a cohort of patients with interstitial lung disease and positive to anti-Th/To autoantibodies / Manifestaciones pulmonares y pronóstico de una cohorte de pacientes con enfermedad pulmonar intersticial y autoanticuerpos anti-Th/To positivos

Introduction: Th/To autoantibody may be relevant in evaluating patients with interstitial lung disease (ILD) because the clinical diagnosis of systemic sclerosis (SSc) may not be evident. The study's objective was to describe manifestations and evolution of pulmonary function in a cohort of ILD patients positive for Th/To autoantibodies. Methods: ILD patients positive for anti-Th/To autoantibody were enrolled in this protocol. Baseline clinical features were registered, and survival analysis was performed to identify risk factors associated with worse survival. Results: Fifty-two patients positive for anti-Th/To autoantibodies with ILD were included. Only 21% of the patients fulfilled the ACR/EULAR 2013 systemic sclerosis classification criteria, and 63.4% fulfilled the IPAF ATS/ERS 2015 criteria. Twenty-five percent of the patients died during follow-up. Respiratory failure was the principal cause of death. Twenty-nine patients (56%) were positive for other hallmark SSc autoantibodies. The most frequent HRCT pattern was nonspecific interstitial pneumonia (NISP). Survival was strongly associated to the systolic pulmonary arterial pressure (sPAP), male sex and the extent of fibrosis in HRCT; besides, patients positive for other hallmark SSc autoantibodies had worse survival compared to those positive only to anti-Th/To. Seventy-six percent of them behaved as fibrotic progressive pulmonary disease, with an absolute decline of the FVC of at least 5%. Conclusions: Only a small proportion of ILD patients positive for Th/To meet the criteria to be classified as SSc; however, most met criteria for IPAF. A high proportion of patients behave as progressive fibrotic pulmonary disease. Survival is associated with sPAP, the extent of lung disease, and the presence of other hallmark SSc autoantibodies. (AU)

Introducción: El autoanticuerpo Th/To puede ser relevante en la evaluación de pacientes con enfermedad pulmonar intersticial (EPI) debido a que el diagnóstico clínico de esclerosis sistémica (ES) puede no ser evidente. El objetivo del estudio fue describir las manifestaciones clínicas y la evolución de la función pulmonar en una cohorte de pacientes con EPI positivos para autoanticuerpos Th/To. Métodos: En este protocolo se inscribieron pacientes con EPI positivos para autoanticuerpos anti-Th/To. Se registraron las características clínicas iniciales y se realizó un análisis de supervivencia para identificar los factores de riesgo asociados con una peor supervivencia. Resultados: Se incluyeron 52 pacientes positivos para autoanticuerpos anti-Th/To con EPI. Solo el 21% de los pacientes cumplió los criterios de clasificación para esclerosis sistémica ACR/EULAR 2013 y el 63,4% cumplió los criterios de neumonía con características autoinmunes ATS/ERS 2015. El 25% de los pacientes falleció durante el seguimiento. La insuficiencia respiratoria fue la principal causa de muerte. Veintinueve pacientes (56%) dieron positivo para otros autoanticuerpos distintivos de ES. El patrón más frecuente en la tomografía computarizada de alta resolución (TCAR) fue la neumonía intersticial inespecífica. La supervivencia estuvo estrechamente asociada con la presión arterial pulmonar sistólica (PAPs), el sexo masculino y la extensión de fibrosis en la TCAR. Además, los pacientes positivos para otros autoanticuerpos distintivos de ES tuvieron una peor supervivencia en comparación con aquellos positivos solo para anti-Th/To. El 66% de ellos se comportaron como enfermedad pulmonar fibrótica progresiva, con una disminución absoluta de la capacidad vital forzada de al menos el 5%. Conclusiones: Solo una pequeña proporción de pacientes con EPI positivos para Th/To cumplieron con los criterios para ser clasificados como ES... (AU)

Pulmonary manifestations and prognosis of a cohort of patients with interstitial lung disease and positive to anti-Th/To autoantibodies.

INTRODUCTION: Th/To autoantibody may be relevant in evaluating patients with interstitial lung disease (ILD) because the clinical diagnosis of systemic sclerosis (SSc) may not be evident. The study's objective was to describe manifestations and evolution of pulmonary function in a cohort of ILD patients positive for Th/To autoantibodies. METHODS: ILD patients positive for anti-Th/To autoantibody were enrolled in this protocol. Baseline clinical features were registered, and survival analysis was performed to identify risk factors associated with worse survival. RESULTS: Fifty-two patients positive for anti-Th/To autoantibodies with ILD were included. Only 21% of the patients fulfilled the ACR/EULAR 2013 systemic sclerosis classification criteria, and 63.4% fulfilled the IPAF ATS/ERS 2015 criteria. Twenty-five percent of the patients died during follow-up. Respiratory failure was the principal cause of death. Twenty-nine patients (56%) were positive for other hallmark SSc autoantibodies. The most frequent HRCT pattern was nonspecific interstitial pneumonia (NISP). Survival was strongly associated to the systolic pulmonary arterial pressure (sPAP), male sex and the extent of fibrosis in HRCT; besides, patients positive for other hallmark SSc autoantibodies had worse survival compared to those positive only to anti-Th/To. Seventy-six percent of them behaved as fibrotic progressive pulmonary disease, with an absolute decline of the FVC of at least 5%. CONCLUSIONS: Only a small proportion of ILD patients positive for Th/To meet the criteria to be classified as SSc; however, most met criteria for IPAF. A high proportion of patients behave as progressive fibrotic pulmonary disease. Survival is associated with sPAP, the extent of lung disease, and the presence of other hallmark SSc autoantibodies.

Clinical risk factors in patients with interstitial lung disease associated with anti-MDA5 autoantibodies / Factores de riesgo clínicos en pacientes con enfermedad pulmonar intersticial con anticuerpos anti-MDA5

Introduction The anti-MDA5-associated autoimmune disease represents a poorly understood entity. The study's objectives were to describe a cohort of interstitial lung disease (ILD) patients who were positive for anti-MDA5 autoantibody and identify clinical risk factors associated with survival. Methods This single-center cohort study included ILD patients positive for anti-MDA5 autoantibody. Baseline clinical features were registered, and survival analysis was performed to identify risk factors associated with worse survival. Results Fifty-three ILD-MDA5 positive patients were included; twelve died during follow-up due to rapidly progressive interstitial lung disease (RP-ILD). Dermatological signs of anti-MDA5 (Gottron papules, Gottron sign, palmar papules, V-neck sign, facial dermatomyositis rashes, and skin ulcers) were strongly associated with death secondary to RP-ILD (HR: 3.7, 95% CI: 1.02–13.35). Patients with dermatological signs were younger, had higher anti-MDA5 autoantibodies titers, more frequent inflammatory patterns in HRCT evaluation, and less fibrosis extent in HRCT. Conclusion Dermatological manifestation in ILD patients to anti-MDA5 autoantibodies are associated with RP-ILD and short-term fatal outcomes. Dermatological signs may identify a subgroup of ILD-positive to anti-MDA5 patients with a high risk of RP-ILD (AU)

Introducción La enfermedad autoinmune asociada a los anticuerpos anti-MDA5 es una entidad poco estudiada. Los objetivos de este estudio son describir una cohorte de sujetos con enfermedad pulmonar intersticial (EPI) positivos al anticuerpo anti-MDA5 e identificar los factores clínicos de riesgo asociados con la supervivencia. Métodos Estudio de cohorte de un solo centro de pacientes con EPI y positivos al anticuerpo anti-MDA5. Se registraron las características clínicas basales y se realizó un análisis de supervivencia para identificar los factores de riesgo asociados con la supervivencia. Resultados Se incluyeron 53 pacientes con EPI y positivos a anti-MDA5; 12 pacientes fallecieron por una enfermedad intersticial rápidamente progresiva (EPI-RP). Los signos dermatológicos asociados a anti-MDA5 (pápulas de Gottron, signo de Gottron, pápulas palmares, signo de la V del escote, eritema facial de dermatomiositis y úlceras cutáneas) se asociaron fuertemente con la EPI-RP (HR: 3,7, IC 95%: 1,02-13,35). Los pacientes con manifestaciones dermatológicas eran más jóvenes, tenían mayores títulos de anticuerpos anti-MDA5, tenían mayor frecuencia de patrones inflamatorios en la tomografía de tórax de alta resolución y menor extensión de la fibrosis en la TCAR. Conclusión Las manifestaciones dermatológicas en los pacientes con EPI positivos a anticuerpos anti-MDA5 están asociados a EPI-RP y a desenlaces fatales al corto plazo. Los signos dermatológicos pueden identificar un subgrupo de pacientes positivos a anti-MDA5 con mayor riesgo de EPI-RP (AU)

Lung microbiome alterations in patients with anti-Jo1 antisynthetase syndrome and interstitial lung disease.

Aim: To characterize the lung microbiome in the bronchoalveolar lavage fluid (BALF) of patients with Antisynthetase Syndrome (ASSD) according to anti-Jo1 autoantibody positivity and evaluate the correlation with differential cell count and other bacterial genera in BALF. Methods: We sequenced the 16S ribosomal RNA gene in the BALF of anti-Jo1-positive (JoP, n=6) and non-Jo1-positive (NJo, n=17) patients, and the differential cell count in BALF was evaluated. The Spearman's correlation was calculated for the quantitative variables and abundance of bacterial species. Results: The Veillonella genus showed a significant decrease (p<0.01) in JoP (2.2%) in comparison to NJo (4.1%) patients. The correlation analysis showed several high (rho ≥ ± 0.7) and significant (p < 0.05) correlations. We analyzed the results obtained for the Veillonella genera and other study variables. The JoP group showed that the abundance of Veillonella had a high negative correlation with macrophages (rho = - 0.77) and a positive correlation with eosinophils (rho = 0.77), lymphocytes (rho = 0.77), and Prevotella (rho = 1). Conclusions: The lung microbiome in ASSD patients differs and may affect cell composition, contributing to lung damage mechanisms. The presence of anti-Jo1 autoantibodies showed a low abundance of Veillonella. This genus had a strong and positive correlation with Prevotella abundance and levels of eosinophils and lymphocytes, and it showed a strong negative correlation with the percentage of macrophages.

Molecular Factors in PAD2 (PADI2) and PAD4 (PADI4) Are Associated with Interstitial Lung Disease Susceptibility in Rheumatoid Arthritis Patients.

Around 50% of rheumatoid arthritis (RA) patients show some extra-articular manifestation, with the lung a usually affected organ; in addition, the presence of anti-citrullinated protein antibodies (ACPA) is a common feature, which is caused by protein citrullination modifications, catalyzed by the peptidyl arginine deiminases (PAD) enzymes. We aimed to identify single nucleotide variants (SNV) in PADI2 and PADI4 genes (PAD2 and PAD4 proteins, respectively) associated with susceptibility to interstitial lung disease (ILD) in RA patients and the PAD2 and PAD4 levels. Material and methods: 867 subjects were included: 118 RA-ILD patients, 133 RA patients, and 616 clinically healthy subjects (CHS). Allelic discrimination was performed in eight SNVs using qPCR, four in PADI2 and four in PADI4. The ELISA technique determined PAD2 and PAD4 levels in serum and bronchoalveolar lavage (BAL) samples, and the population structure was evaluated using 14 informative ancestry markers. Results: The rs1005753-GG (OR = 4.9) in PADI2 and rs11203366-AA (OR = 3.08), rs11203367-GG (OR = 2.4) in PADI4 are associated with genetic susceptibility to RA-ILD as well as the ACTC haplotype (OR = 2.64). In addition, the PAD4 protein is increased in RA-ILD individuals harboring the minor allele homozygous genotype in PADI4 SNVs. Moreover, rs1748033 in PADI4, rs2057094, and rs2076615 in PADI2 are associated with RA susceptibility. In conclusion, in RA patients, single nucleotide variants in PADI4 and PADI2 are associated with ILD susceptibility. The rs1748033 in PADI4 and two different SNVs in PADI2 are associated with RA development but not ILD. PAD4 serum levels are increased in RA-ILD patients.

Clinical risk factors in patients with interstitial lung disease associated with anti-MDA5 autoantibodies.

INTRODUCTION: The anti-MDA5-associated autoimmune disease represents a poorly understood entity. The study's objectives were to describe a cohort of interstitial lung disease (ILD) patients who were positive for anti-MDA5 autoantibody and identify clinical risk factors associated with survival. METHODS: This single-center cohort study included ILD patients positive for anti-MDA5 autoantibody. Baseline clinical features were registered, and survival analysis was performed to identify risk factors associated with worse survival. RESULTS: Fifty-three ILD-MDA5 positive patients were included; twelve died during follow-up due to rapidly progressive interstitial lung disease (RP-ILD). Dermatological signs of anti-MDA5 (Gottron papules, Gottron sign, palmar papules, V-neck sign, facial dermatomyositis rashes, and skin ulcers) were strongly associated with death secondary to RP-ILD (HR: 3.7, 95% CI: 1.02-13.35). Patients with dermatological signs were younger, had higher anti-MDA5 autoantibodies titers, more frequent inflammatory patterns in HRCT evaluation, and less fibrosis extent in HRCT. CONCLUSION: Dermatological manifestation in ILD patients to anti-MDA5 autoantibodies are associated with RP-ILD and short-term fatal outcomes. Dermatological signs may identify a subgroup of ILD-positive to anti-MDA5 patients with a high risk of RP-ILD.

Survey of Lichenized Fungi DNA Barcodes on King George Island (Antarctica): An Aid to Species Discovery.

DNA barcoding is a powerful method for the identification of lichenized fungi groups for which the diversity is already well-represented in nucleotide databases, and an accurate, robust taxonomy has been established. However, the effectiveness of DNA barcoding for identification is expected to be limited for understudied taxa or regions. One such region is Antarctica, where, despite the importance of lichens and lichenized fungi identification, their genetic diversity is far from characterized. The aim of this exploratory study was to survey the lichenized fungi diversity of King George Island using a fungal barcode marker as an initial identification tool. Samples were collected unrestricted to specific taxa in coastal areas near Admiralty Bay. Most samples were identified using the barcode marker and verified up to the species or genus level with a high degree of similarity. A posterior morphological evaluation focused on samples with novel barcodes allowed for the identification of unknown Austrolecia, Buellia, and Lecidea s.l. species. These results contribute to better represent the lichenized fungi diversity in understudied regions such as Antarctica by increasing the richness of the nucleotide databases. Furthermore, the approach used in this study is valuable for exploratory surveys in understudied regions to guide taxonomic efforts towards species recognition and discovery.

The HLA-DRB1*07 Allele Is Associated with Interstitial Lung Abnormalities (ILA) and Subpleural Location in a Mexican Mestizo Population.

Interstitial lung abnormalities (ILA) are defined as the presence of different patterns of increased lung density, including ground glass attenuation and reticular opacities on chest high-resolution computed tomography (HRCT). In this study, we included 90 subjects with ILA and 189 healthy controls (HC) from our Aging Lung Program. We found that subjects with ILA are older, have a significant smoking history, and have worse pulmonary function than HC (p < 0.05). When we evaluated the allele frequencies of the human leukocyte antigen (HLA) system, we found that HLA-DRB1*07 was associated with a higher risk for ILA (p < 0.05, OR = 1.95, 95% CI = 1.06-3.57). When we compared subjects with subpleural ILA vs. HC, the association with HLA-DRB1*07 became stronger than the whole ILA group (p < 0.05, OR = 2.29, 95% CI = 1.24-4.25). Furthermore, subjects with subpleural ILA and central ILA display differences in allele frequencies with HLA-DRB1*14 (3.33% vs. 13.33%, p < 0.05) and *15 (3.33% vs. 20%, p < 0.05). Our findings indicate that the HLA-DRB1*07 allele contributes to the risk of ILA, especially those of subpleural locations.

IFNAR2 relevance in the clinical outcome of individuals with severe COVID-19.

Interferons (IFNs) are a group of cytokines with antiviral, antiproliferative, antiangiogenic, and immunomodulatory activities. Type I IFNs amplify and propagate the antiviral response by interacting with their receptors, IFNAR1 and IFNAR2. In COVID-19, the IFNAR2 (interferon alpha and beta receptor subunit 2) gene has been associated with the severity of the disease, but the soluble receptor (sIFNAR2) levels have not been investigated. We aimed to evaluate the association of IFNAR2 variants (rs2236757, rs1051393, rs3153, rs2834158, and rs2229207) with COVID-19 mortality and to assess if there was a relation between the genetic variants and/or the clinical outcome, with the levels of sIFNAR2 in plasma samples from hospitalized individuals with severe COVID-19. We included 1,202 subjects with severe COVID-19. The genetic variants were determined by employing Taqman® assays. The levels of sIFNAR2 were determined with ELISA in plasma samples from a subgroup of 351 individuals. The rs2236757, rs3153, rs1051393, and rs2834158 variants were associated with mortality risk among patients with severe COVID-19. Higher levels of sIFNAR2 were observed in survivors of COVID-19 compared to the group of non-survivors, which was not related to the studied IFNAR2 genetic variants. IFNAR2, both gene, and soluble protein, are relevant in the clinical outcome of patients hospitalized with severe COVID-19.

COVID-19 Survivor Patients Carrying the Rs35705950 Risk Allele in MUC5B Have Higher Plasma Levels of Mucin 5B.

BACKGROUND: Genetic susceptibility to infectious diseases is partly due to the variation in the human genome, and COVID-19 is not the exception. This study aimed to identify whether risk alleles of known genes linked with emphysema (SERPINA1) and pulmonary fibrosis (MUC5B) are associated with severe COVID-19, and whether plasma mucin 5B differs according to patients' outcomes. MATERIALS AND METHODS: We included 1258 Mexican subjects diagnosed with COVID-19. We genotyped rs2892474 and rs17580 of the SERPINA1 gene and rs35705950 of MUC5B. Based on the rs35705950 genotypes, mucin 5B plasma protein levels were quantified. RESULTS: Homozygous for the risk alleles of the three polymorphisms were found in less than 5% of the study population, but no statistically significant difference in the genotype or allele association analysis. At the protein level, non-survivors carrying one or two copies of the risk allele rs35705950 in MUC5B (GT + TT) had lower levels of mucin 5B compared to the survivors (0.0 vs. 0.17 ng/mL, p = 0.0013). CONCLUSION: The polymorphisms rs28929474 and rs17580 of SERPINA1 and rs35705950 of MUC5B are not associated with the risk of severe COVID-19 in the Mexican population. COVID-19 survivor patients bearing one or two copies of the rs35705950 risk allele have higher plasma levels of mucin 5B.

Latin American Registry of Idiopathic Pulmonary Fibrosis (REFIPI): Clinical Characteristics, Evolution and Treatment.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and frequently fatal disease. Currently there are national and multinational registries in Europe, United States, Australia and China to better understand the magnitude of the problem and the characteristics of the IPF patients. However, there are no national or regional registries in Latin America, so the objective of this study was to carry out a Latin American registry that would allow the identification of IPF patients in our region. METHODOLOGY: A system consisting of 3 levels of control was designed, ensuring that patients met the diagnostic criteria for IPF according to international guidelines ATS/ERS/ALAT/JRS 2011. Demographic, clinical, serological, functional, tomographic, histological and treatment variables were recorded through a digital platform. RESULTS: 761 IPF patients from 14 Latin American countries were included for analysis, 74.7% were male, with a mean age of 71.9+8.3 years. In general there was a long period of symptoms before definitive diagnosis (median 1 year). In functional tests, an average reduction of FVC (70.9%) and DLCO (53.7%) was detected. 72% received at least one antifibrotic drug (pirfenidone or nintedanib) and 11.2% of the patients had an acute exacerbation, of which 38 (45.2%) died from this cause. CONCLUSIONS: Like other registries, we found that there is difficulty in the recognition and excessive delay in the diagnosis of IPF in Latin America. Most of the patients in REFIPI received antifibrotics; these were well tolerated and associated with fewer adverse events than those reported in clinical trials.

Interstitial lung disease progression in patients with anti-aminoacyl transfer-RNA-synthetase autoantibodies is characterized by higher levels of sCD163.

BACKGROUND: Patients with anti-tRNA autoantibodies are characterized by arthritis, mechanic´s hands, fever, Raynaud´s phenomenon, and interstitial lung disease (ILD), in at least two clinical scenarios: the antisynthetase syndrome (ASSD) and interstitial pneumonia with autoimmune features (IPAF). The anti-tRNA-ILD treatment is centered on the administration of corticosteroids and a wide variety of immunosuppressive drugs; however, the effectiveness of the treatment depends on factors not fully understood. This research work aimed to quantify the serum levels of two molecules related to pulmonary fibrosis and explore their relationship with the progression of ILD associated with ASSD METHODOLOGY: Serum levels of sCD163 and TGF-ß1 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 RESULTS: Forty patients were included (anti-Jo1, anti-PL7, anti-PL12, and anti-Ej). Five patients (12.5%) had ILD progression and were characterized by higher levels of sCD163 at baseline. Baseline sCD163 serum levels showed good discriminatory capacity in patients with ILD progression. On the other hand, at follow-up, serum TGF-ß1 levels significantly increased in both patients' groups, with and without progression CONCLUSION: Basal levels of sCD163 were higher in patients who later developed ILD progression and kinetics of both molecules suggests the participation of M2 macrophages in the development of ILD.

SERPINE1 rs6092 Variant Is Related to Plasma Coagulation Proteins in Patients with Severe COVID-19 from a Tertiary Care Hospital.

An impaired coagulation process has been described in patients with severe or critical coronavirus disease (COVID-19). Nevertheless, the implication of coagulation-related genes has not been explored. We aimed to evaluate the impact of F5 rs6025 and SERPINE1 rs6092 on invasive mechanical ventilation (IMV) requirement and the levels of coagulation proteins among patients with severe COVID-19. Four-hundred fifty-five patients with severe COVID-19 were genotyped using TaqMan assays. Coagulation-related proteins (P-Selectin, D-dimer, P-selectin glycoprotein ligand-1, tissue plasminogen activator [tPA], plasminogen activator inhibitor-1, and Factor IX) were assessed by cytometric bead arrays in one- and two-time determinations. Accordingly, SERPINE1 rs6092, P-Selectin (GG 385 pg/mL vs. AG+AA 632 pg/mL, p = 0.0037), and tPA (GG 1858 pg/mL vs. AG+AA 2546 pg/mL, p = 0.0284) levels were different. Patients carrying the CT F5-rs6025 genotype exhibited lower levels of factor IX (CC 17,136 pg/mL vs. CT 10,247 pg/mL, p = 0.0355). Coagulation proteins were also different among IMV patients than non-IMV. PSGL-1 levels were significantly increased in the late stage of COVID-19 (>10 days). The frequencies of F5 rs6025 and SERPINE1 rs6092 variants were not different among IMV and non-IMV. The SERPINE1 rs6092 variant is related to the impaired coagulation process in patients with COVID-19 severe.

TNFRSF1B and TNF Variants Are Associated With Differences in Levels of Soluble Tumor Necrosis Factor Receptors in Patients With Severe COVID-19.

BACKGROUND: The impact of genetic variants in the expression of tumor necrosis factor-α (TNF-α) and its receptors in coronavirus disease 2019 (COVID-19) severity has not been previously explored. We evaluated the association of TNF (rs1800629 and rs361525), TNFRSF1A (rs767455 and rs1800693), and TNFRSF1B (rs1061622 and rs3397) variants with COVID-19 severity, assessed as invasive mechanical ventilation (IMV) requirement, and the plasma levels of soluble TNF-α, TNFR1, and TNFR2 in patients with severe COVID-19. METHODS: The genetic study included 1353 patients. Taqman assays were used to assess the genetic variants. ELISA was used to determine soluble TNF-α, TNFR1, and TNFR2 in plasma samples from 334 patients. RESULTS: Patients carrying TT (TNFRSF1B rs3397) exhibited lower PaO2/FiO2 levels than those with CT + CC genotypes. Differences in plasma levels of TNFR1 and TNFR2 were observed according to the genotype of TNFRSF1B rs1061622, TNF rs1800629, and rs361525. According to the studied genetic variants, there were no differences in the soluble TNF-α levels. Higher soluble TNFR1 and TNFR2 levels were detected in patients with COVID-19 requiring IMV. CONCLUSIONS: Genetic variants in TNF and TNFRSFB1 influence the plasma levels of soluble TNFR1 and TNFR2, implicated in COVID-19 severity.

Rheumatoid arthritis-related interstitial lung disease (RA-ILD): a possible association between disease activity and prognosis.

OBJECTIVES: We hypothesized that RA disease activity might be associated with the survival of RA-ILD patients. To evaluate this possibility, we analyzed data on disease activity during follow-up in an RA-ILD cohort and compared disease activity between surviving patients and those who died during follow-up. METHODS: RA-ILD patients referred for medical evaluation and treatment at a single center, with CDAI scores during all follow up were included. We estimated the HR of the mean of the CDAI score during follow-up with survival. Also, we compared the survival function of patients with high disease activity (CDAI scores ≥ 22) during all follow-up with those with moderate and low disease activity. RESULTS: Thirty-seven patients were included. The mean of the CDAI score during follow-up was higher in death patients (median 30.8 ± 18.5 Vs. 16.8 ± 11.3), and a single unit increase in the mean of the CDAI score was associated with non-survival, HR:1.07 (95% CI: 1.02 -1.12). Patients with high disease activity during all follow-up (CDAI scores > 22) had lower survival function in comparison with moderate and low disease activity (P = 0.042). CONCLUSION: The results of the study suggest that higher RA disease activity is associated with a worse prognosis of RA-ILD patients. The hypothesis that high disease activity is associated with worse survival in RA-ILD patients must be evaluated in more extensive cohort studies and clinical trials. KEY POINTS: • RA-ILD patients with high disease activity during follow-up had a worse prognosis than those with moderate or low disease activity. • The study results suggest the hypothesis that patients with RA-ILD must be treated with a treat to target strategy, with the aim of remission or low RA disease activity.

Enhanced Activity of NLRP3 Inflammasome in the Lung of Patients with Anti-Synthetase Syndrome.

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.

Differential Genomic Profile in TERT, DSP, and FAM13A Between COPD Patients With Emphysema, IPF, and CPFE Syndrome.

Background: Genetic association studies have identified single nucleotide polymorphisms (SNPs) associated with lasting lung diseases such as Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF), as well as the simultaneous presentation, known as Combined Pulmonary Fibrosis and Emphysema (CPFE) Syndrome. It is unknown if these diseases share genetic variants previously described in an independent way. This study aims to identify common or differential variants between COPD, IPF, and CPFE. Materials and methods: The association analysis was carried out through a case-control design in a Mexican mestizo population (n = 828); three patients' groups were included: COPD smokers (COPD-S, n = 178), IPF patients (n = 93), and CPFE patients (n = 16). Also, two comparison groups were analyzed: smokers without COPD (SWOC, n = 367) and healthy subjects belonging to the Mexican Pulmonary Aging Cohort (PAC, n = 174). Five SNPs in four genes previously associated to interstitial and obstructive diseases were selected: rs2609255 (FAM13A), rs2736100 (TERT), rs2076295 (DSP) rs5743890, and rs111521887 (TOLLIP). Genotyping was performed by qPCR using predesigned Taqman probes. Results: In comparing IPF vs. PAC, significant differences were found in the frequency of the rs260955 G allele associated with the IPF risk (OR = 1.68, p = 0.01). Also, the genotypes, GG of rs260955 (OR = 2.86, p = 0.01) and TT of rs2076295 (OR = 1.79, p = 0.03) were associated with an increased risk of IPF; after adjusting by covariables, only the rs260955 G allele remain significant (p = 0.01). For the CPFE vs. PAC comparison, an increased CPFE risk was identified since there is a difference in the rs2736100 C allele (OR = 4.02, p < 0.01; adjusted p < 0.01). For COPD-S, the rs2609255 TG genotype was associated with increased COPD risk after adjusting by covariables. Conclusion: The rs2736100 C allele is associated with decreased IPF risk and confers an increased risk for CPFE. Also, the rs2076295 TT genotype is associated with increased IPF risk, while the GG genotype is associated with CFPE susceptibility. The rs2609255 G allele and GG genotype are associated with IPF susceptibility, while the TG genotype is present in patients with emphysema.

Angiotensin-Converting Enzyme 2 (ACE2) in the Context of Respiratory Diseases and Its Importance in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.

Angiotensin-Converting Enzyme 2 (ACE2) is an 805 amino acid protein encoded by the ACE2 gene expressed in various human cells, especially in those located in the epithelia. The primary function of ACE2 is to produce angiotensin (1-7) from angiotensin II (Ang II). The current research has described the importance of ACE2 and Ang (1-7) in alternative routes of the renin-angiotensin system (RAS) that promote the downregulation of fibrosis, inflammation, and oxidative stress processes in a great variety of diseases, such as hypertension, acute lung injury, liver cirrhosis, and kidney abnormalities. Investigations into the recent outbreak of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have revealed the importance of ACE2 during infection and its role in recognizing viral binding proteins through interactions with specific amino acids of this enzyme. Additionally, the ACE2 expression in several organs has allowed us to understand the clinical picture related to the infection caused by SARS-CoV-2. This review aims to provide context for the functions and importance of ACE2 with regards to SARS-CoV-2 in the general clinical aspect and its impact on other diseases, especially respiratory diseases.

MUC5B promoter variant rs35705950 and rheumatoid arthritis associated interstitial lung disease survival and progression.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: In this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD.