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)

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.

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.

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.

Anti-Aminoacyl Transfer-RNA-Synthetases (Anti-tRNA) Autoantibodies Associated with Interstitial Lung Disease: Pulmonary Disease Progression has a Persistent Elevation of the Th17 Cytokine Profile.

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-1ß, IL-6, IL-12, IL-18, and TNF-α, compared to patients without disease progression (no progressors patients, NPP). IL-17A, IL-1ß, 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.

An Open-label Study With Pirfenidone on Chronic Hypersensitivity Pneumonitis / Estudio abierto con pirfenidona en neumonitis por hipersensibilidad crónica

BACKGROUND: Chronic hypersensitivity pneumonitis (cHP) represents a severe lung disease often evolving to fibrosis with the subsequent destruction of the lung parenchyma. There are no approved therapies with confirmed efficacy to deal with this disease. METHODS: We performed an open-label, proof of concept study, to evaluate the efficacy and safety of pirfenidone added to immunosuppressive drugs on the treatment of cHP. We included 22 patients assigned to two groups: Group 1, nine patients that received prednisone plus azathioprine and Group 2, thirteen patients, received prednisone plus azathioprine and pirfenidone (ClinicalTrials.gov identifier NCT02496182). There were no significant imbalances in clinically relevant baseline characteristics between two study groups. RESULTS: After 1 year of treatment, inclusion of pirfenidone was not associated with improved forced vital capacity (primary end-point). A not significant tendency to show higher improvement of diffusion capacity of the lung for carbon monoxide (DLCO) was observed in the group receiving pirfenidone (p = 0.06). Likewise, a significant improvement in the total score on the SGRQ was found in the group 2 (p = 0.02) without differences in other two questionnaires related to quality of life (ATAQ-IPF and EQ-5D-3L). HRCT showed a decrease of the ground glass attenuation without changes in the fibrotic lesions and without differences between both groups. CONCLUSIONS: These findings suggest that the addition of pirfenidone to the anti-inflammatory treatment in patients with chronic HP may improve the outcome with acceptable safety profile. However, prospective randomized double-blind, placebo-controlled trials in largest cohorts are needed to validate its efficacy

ANTECEDENTES: La neumonitis por hipersensibilidad crónica es una enfermedad pulmonar grave que con frecuencia evoluciona hacia fibrosis, con la ulterior destrucción del parénquima pulmonar. No existen tratamientos aprobados con eficacia confirmada para el manejo de esta enfermedad. MÉTODOS: Llevamos a cabo un estudio preliminar de eficacia, abierto, para evaluar la eficacia y la seguridad de la pirfenidona sumada a los fármacos inmunosupresores en el tratamiento de la neumonitis por hipersensibilidad crónica. Se incluyeron 22 pacientes, que se asignaron a dos grupos: grupo 1, 9 pacientes que recibieron prednisona y azatioprina; y grupo 2, 13 pacientes que recibieron prednisona, azatioprina y pirfenidona (identificador NCT02496182 en ClinicalTrials.gov). No se observaron alteraciones significativas en las características clínicamente relevantes iniciales entre ambos grupos. RESULTADOS: Tras un año de tratamiento, la inclusión de la pirfenidona no se asoció con una mejora de la capacidad vital forzada (objetivo principal). Se observó una tendencia no significativa a mostrar una mayor mejora en la capacidad de difusión de monóxido de carbono (DLCO) por el pulmón en el grupo que recibió pirfenidona (p = 0,06). Asimismo, se encontró una mejora significativa en la puntuación total del cuestionario SGRQ en el grupo 2 (p = 0,02) sin encontrarse diferencias en los otros dos cuestionarios relacionados con la calidad de vida de los pacientes (ATAQ-IPF y EQ-5D-3L). La TAC de alta resolución mostró una disminución de la atenuación en «vidrio deslustrado», sin cambios en las fibrosis y sin diferencias entre ambos grupos. CONCLUSIONES: Estos hallazgos sugieren que añadir pirfenidona al tratamiento antiinflamatorio en pacientes con neumonitis por hipersensibilidad crónica podría mejorar el pronóstico con un perfil de seguridad aceptable. Sin embargo, se necesitan ensayos prospectivos aleatorizados doble ciego y controlados con placebo para validar esta eficacia

Evolution of Pulmonary Function in a Cohort of Patients with Interstitial Lung Disease and Positive for Antisynthetase Antibodies.

OBJECTIVE: To describe the evolution of the pulmonary function in patients with interstitial lung disease (ILD) who are positive for at least 1 of the antisynthetase antibodies (ASAB) after medical treatment, and to compare whether the evolution of pulmonary function is associated with the type of ASAB. METHODS: Patients with ILD and positive for at least 1 of the ASAB (anti-Jo1, anti-PL7, anti-PL12, anti-EJ, or anti-OJ) were included. The clinical evolution, time until death or censoring, and improvement of lung disease were registered. RESULTS: The study included 118 patients. Most of the patients had a high extent of ground glass opacities in high-resolution computed tomography (HRCT) and low extent of fibrosis. In the final evaluation of pulmonary function (median 749.5 days of followup), 67% of the patients had lung disease improvement. The improvement occurred within the first 6 months after initiating medical treatment; thereafter, pulmonary function remained stable in most of the patients. A decrease of the extent of ground glass opacities was demonstrated in HRCT at followup in those patients with pulmonary improvement. No differences were observed in the percentage of patients who achieved improvement between the ASAB groups, or in survival. CONCLUSION: Improvement of pulmonary function was observed in 67% of the patients. Improvement was observed in all ASAB groups and occurred within 6 months after initiating medical treatment.

An Open-label Study With Pirfenidone on Chronic Hypersensitivity Pneumonitis.

BACKGROUND: Chronic hypersensitivity pneumonitis (cHP) represents a severe lung disease often evolving to fibrosis with the subsequent destruction of the lung parenchyma. There are no approved therapies with confirmed efficacy to deal with this disease. METHODS: We performed an open-label, proof of concept study, to evaluate the efficacy and safety of pirfenidone added to immunosuppressive drugs on the treatment of cHP. We included 22 patients assigned to two groups: Group 1, nine patients that received prednisone plus azathioprine and Group 2, thirteen patients, received prednisone plus azathioprine and pirfenidone (ClinicalTrials.gov identifier NCT02496182). There were no significant imbalances in clinically relevant baseline characteristics between two study groups. RESULTS: After 1 year of treatment, inclusion of pirfenidone was not associated with improved forced vital capacity (primary end-point). A not significant tendency to show higher improvement of diffusion capacity of the lung for carbon monoxide (DLCO) was observed in the group receiving pirfenidone (p=0.06). Likewise, a significant improvement in the total score on the SGRQ was found in the group 2 (p=0.02) without differences in other two questionnaires related to quality of life (ATAQ-IPF and EQ-5D-3L). HRCT showed a decrease of the ground glass attenuation without changes in the fibrotic lesions and without differences between both groups. CONCLUSIONS: These findings suggest that the addition of pirfenidone to the anti-inflammatory treatment in patients with chronic HP may improve the outcome with acceptable safety profile. However, prospective randomized double-blind, placebo-controlled trials in largest cohorts are needed to validate its efficacy.

Enfermedad indiferenciada del tejido conectivo y enfermedad pulmonar intersticial: intentando definir patrones / Undifferentiated connective tissue disease and interstitial lung disease: trying to define patterns

Objetivos. Agrupar a los pacientes con enfermedad pulmonar intersticial (EPI) asociada a enfermedad indiferenciada del tejido conectivo (EITC) según la presencia o no de ciertas manifestaciones clínicas o inmunológicas, esperando encontrar diferentes expresiones tomográficas o funcionales. Métodos. Estudio de cohortes retrospectivas. Se incluyeron pacientes que cumplían criterios de Kinder para EITC. Se consideraron variables predictoras: manifestaciones «altamente específicas de enfermedad del tejido conectivo (ETC)» (Raynaud, xeroftalmia o artritis), títulos altos de anticuerpos antinucleares (ANA) (mayores a 1:320) y patrones específicos de ANA (centromérico, citoplásmico y nucleolar). El cambio en la capacidad vital forzada% (CVF%) en el tiempo y el patrón en TCAR fueron las variables de resultado estudiadas. Resultados. Se incluyeron 66 pacientes. Veintinueve presentaron al menos una manifestación «altamente específica de ETC» (43,94%), 16 ANA específico (28,57%) y 29 ANA alto título (43,94%). Aquellos con manifestaciones «altamente específicas de ETC» presentaron menor frecuencia de sexo masculino (10,34% vs 48,65%, p<0,001), menor edad en años (media 52 [DE14,58] vs 62,08 [9,46], p<0,001) y menor mediana de declinación de CVF% (1[RIC −1 a 10] vs −6 [RIC −16 a −4], p<0,006). En el análisis de regresión lineal múltiple la presencia de manifestaciones «altamente específicas de ETC» se asoció con mejoría en CVF% (coeficiente B de 13,25 [IC95% 2,41 a 24,09]). No encontramos asociaciones en cuanto al patrón en TACAR. Conclusiones. La presencia de manifestaciones «altamente específicas de ETC» se asoció con sexo femenino, menor edad al inicio y una evolución más favorable en cuanto a la CVF%, lo cual evidencia el impacto de las manifestaciones clínicas en la evolución de estos pacientes (AU)

Objectives. To identify clinical or immunological features in patients with undifferentiated connective tissue disease (UCTD) associated interstitial lung disease (ILD), in order to group them and recognize different functional and high resolution computed tomography (HRCT) behavior. Methods. Retrospective cohort study. Patients meeting Kinder criteria for UCTD were included. We defined the following predictive variables: ‘highly specific’ connective tissue disease (CTD) manifestations (Raynaud's phenomenon, dry eyes or arthritis), high antinuclear antibody (ANA) titer (above 1: 320), and ‘specific’ ANA staining patterns (centromere, cytoplasmic and nucleolar patterns). We evaluated the following outcomes: change in the percentage of the predicted forced vital capacity (FVC%) during the follow-up period, and HRCT pattern. Results. Sixty-six patients were included. Twenty-nine (43.94%) showed at least one ‘highly specific’ CTD manifestation, 16 (28.57%) had a ‘specific’ ANA staining pattern and 29 (43.94%) high ANA titer. Patients with ‘highly specific’ CTD manifestations were younger (mean [SD] 52 years [14.58] vs 62.08 years [9.46], P<.001), were more likely men (10.34% vs 48.65%, P<.001) and showed a smaller decline of the FVC% (median [interquartile range] 1% [−1 to 10] vs -6% [−16 to −4], P<.006). In the multivariate analysis, the presence of highly specific manifestations was associated with improvement in the FVC% (B coefficient of 13.25 [95% confidence interval, 2.41 to 24.09]). No association was observed in relation to the HRCT pattern. Conclusion. The presence of ‘highly specific’ CTD manifestations was associated with female sex, younger age and better functional behavior. These findings highlight the impact of the clinical features in the outcome of patients with UCTD ILD (AU)

Enfermedad pulmonar intersticial temprana en poliangitis microscópica: reporte de un caso y revisión de la literatura / Early interstitial lung disease in microscopic polyangiitis: case report and literature review

La poliangeítis microscópica (PAM) es una enfermedad sistémica incluida en la clasificación de Chapel Hill 2012 como vasculitis necrosante que afecta capilares, vénulas y arteriolas. Usualmente expresa anticuerpos anti-citoplasma de neutrófilo (ANCA), con patrón perinuclear en la inmunofluorescencia, y correlación con los anticuerpos anti-mieloperoxidasa (MPO). La capilaritis con hemorragia alveolar es la manifestación más usual de afección pulmonar. La enfermedad pulmonar intersticial (EPI) es infrecuente, siendo la neumonía intersticial común el patrón predominante, sin embargo, otros patrones como la neumonía organizada han sido descritos. No existen pautas de tratamiento de los pacientes con EPI y vasculitis asociada a ANCA (VAA); actualmente son tratados con las bases de las vasculitis de vasos pequeños. El pronóstico de esta asociación es incierto, con posibilidad de recaídas y de curso fatal. A continuación se presenta un caso en el que neumopatía intersticial fue la primera manifestación de una PAM, sin hemorragia alveolar, con posterior involucro renal, y con el tratamiento instaurado presenta mejoría clínica significativa (AU)

Microscopic polyangiitis (MPA) is a systemic disease included in the Chapel Hill 2012 Classification as necrotizing vasculitis affecting capillaries, venules and arterioles. It usually expresses antineutrophil cytoplasmic antibodies (ANCA) and has a perinuclear immunofluorescence pattern and correlation with anti-myeloperoxidase (MPO) antibodies. Capillaritis with alveolar hemorrhage is the most common manifestation of lung disease. Interstitial lung disease (ILD) is uncommon, with usual interstitial pneumonia being the predominant pattern. However, other patterns such as organizing pneumonia have been described. No guidelines exist for treating patients with ILD and, currently, ANCA-associated vasculitis (AAV) is managed along the lines of small vessel vasculitis. The prognosis with this association is uncertain, with possibilities of relapse and a fatal outcome. We present a case in which ILD was the first manifestation of MPA, without alveolar hemorrhage, with subsequent renal involvement and, in which, the established treatment produced a significant clinical improvement (AU)

Early interstitial lung disease in microscopic polyangiitis: Case report and literature review. / Enfermedad pulmonar intersticial temprana en poliangitis microscópica: reporte de un caso y revisión de la literatura.

Microscopic polyangiitis (MPA) is a systemic disease included in the Chapel Hill 2012 Classification as necrotizing vasculitis affecting capillaries, venules and arterioles. It usually expresses antineutrophil cytoplasmic antibodies (ANCA) and has a perinuclear immunofluorescence pattern and correlation with anti-myeloperoxidase (MPO) antibodies. Capillaritis with alveolar hemorrhage is the most common manifestation of lung disease. Interstitial lung disease (ILD) is uncommon, with usual interstitial pneumonia being the predominant pattern. However, other patterns such as organizing pneumonia have been described. No guidelines exist for treating patients with ILD and, currently, ANCA-associated vasculitis (AAV) is managed along the lines of small vessel vasculitis. The prognosis with this association is uncertain, with possibilities of relapse and a fatal outcome. We present a case in which ILD was the first manifestation of MPA, without alveolar hemorrhage, with subsequent renal involvement and, in which, the established treatment produced a significant clinical improvement.

A multichannel acoustic approach to define a pulmonary pathology as combined pulmonary fibrosis and emphysema syndrome.

Interstitial lung diseases (ILDs) have been increasing their relevance in loss of lives according to a recent world wide medical information. Idiopathic pulmonary fibrosis (IPF) and combined pulmonary fibrosis and emphysema syndrome (CPFES) belong to ILD class with the latter having a limited survival prognosis. In clinical environment high resolution computed tomography (HRCT) is used to detect CPFE; however, there is still controversy about the amount of emphysema observed in HRCT to declare CPFES. Consequently, to help in the diagnosis of CPFES to develop an alternative technique seems to be attractive. In this study, we propose a multichannel acoustic approach to discriminate between IPF and CPFES parameterizing the multichannel lung sounds information linearly and classifying it by neural networks (NN). The NN performance using different features provided values above 90% in the validation phase. Furthermore, to test the trained NN, the proposed approach was applied on new data from five patients 3 diagnosed by experts as CPFES and 2 with IPF. The univariate autoregressive model obtained the best classification followed by the feature vector formed by the percentile frequencies augmented by the total power of the acoustic information. Results indicate that multichannel acoustic analysis is promising to discern between these two ILDs.

Pulmonary Involvement in Systemic Vasculitis.

PURPOSE OF REVIEW: The purpose of this study is to describe the most relevant advances concerning lung involvement in the ANCA-associated vasculitides (excluding eosinophilic granulomatosis with polyangiitis which may have different disease mechanisms). Focus is on pathophysiology, recent important imagenological procedures, treatment, and outcome. RECENT FINDINGS: Emerging information exists on potential newly investigated diagnostic procedures (v.g. transbronchial cryobiopsies), detailed tomographic abnormalities, the potential favorable role of rituximab and the still uncertain one of plasma exchange in the treatment, and the increasing description of interstitial lung disease. Survival is reduced in case of both, diffuse alveolar hemorrhage and diffuse parenchymal disease. There is the need to expand the knowledge concerning better long-term treatment options with specific regimes, and to incorporate other measures regarding integral treatment in patients afflicted with lung involvement these maladies, as the outcome seems adverse in this scenario.

Small airway dysfunction in chronic hypersensitivity pneumonitis.

BACKGROUND AND OBJECTIVE: Lung biopsies from patients with hypersensitivity pneumonitis (HP) have demonstrated small airway (SA) involvement, but there is no information concerning SA function in HP, and it is unknown whether pharmacological treatment could modify its function. SA function in patients with chronic HP using ultrasonic pneumography (UPG) and impulse oscillometry (IOS) was explored. We also compared initial results with those obtained after 4 weeks of standardized treatment with azathioprine and prednisone. METHODS: The study group consisted of adults with recent diagnoses of HP. All patients completed UPG, IOS, spirometry, body plethysmography, single-breath carbon monoxide diffusing capacity (DLCO ) and the 6-min walk test (6MWT). The fraction of exhaled nitric oxide (FENO ) was obtained to assess eosinophilic airway inflammation. Measurements were taken at diagnosis and after 4 weeks of treatment. RESULTS: A total of 20 consecutive patients (16 women) with chronic HP participated in the study. Median age was 50 years (interquartile range (IQR): 42-54). At diagnosis, the UPG phase 3 slope was abnormally high, consistent with maldistribution of ventilation. For IOS, all patients had low reactance at 5 Hz (X5) and elevated reactance area (AX) reflecting low compliance, and only eight (40%) patients had elevated R5 (resistance at 5 Hz (total)) and R5-20 (resistance at 5 Hz-resistance at 20 Hz (peripheral)) attributed to SA resistance. In contrast, FENO parameters were within normal limits. After treatment, forced vital capacity (FVC), the 6-min walk distance and the distribution of ventilation showed significant improvement, although DLCO did not. CONCLUSION: Patients with chronic HP have SA abnormalities that are partially revealed by the UPG and IOS tests. Lung volumes, but not gas exchange, improved after treatment with azathioprine and prednisone.

Rheumatoid arthritis-related interstitial lung disease (RA-ILD): methotrexate and the severity of lung disease are associated to prognosis.

Interstitial lung disease (ILD) is a severe rheumatoid arthritis (RA) manifestation. The worst survival has been associated with usual interstitial pneumonia (UIP) definitive pattern in high-resolution chest tomography (HRCT) scans. Moreover, the use of methotrexate in RA-ILD is controversial. Our aim was to evaluate prognostic factors including methotrexate in an RA-ILD cohort and their association with survival. RA-ILD patients referred for medical evaluation and treatment at a single center were included. At the baseline, pulmonary function tests were carried out and a HRCT was obtained. A radiologist evaluated the ILD tomographic pattern and the extent of lung disease. Patients were considered as receiving methotrexate therapy if this drug was specifically prescribed for the treatment of RA-ILD at the beginning of follow up. Seventy-eight patients were included. UIP definite pattern in HRCT was not associated to worse survival. Variables associated with mortality reflected the severity of lung disease. Treatment with methotrexate was associated with survival (HR 0.13, 95% CI 0.02-0.64); older patients had worse prognosis (HR 1.04, 95% CI 1.003-1.09). After adjusting for confounding variables, methotrexate was strongly associated with survival. Methotrexate treatment during follow up was associated with survival. The severity of lung disease and not the tomographic pattern is associated with mortality; older patients had worse prognosis.

Interstitial lung disease and myositis-specific and associated autoantibodies: Clinical manifestations, survival and the performance of the new ATS/ERS criteria for interstitial pneumonia with autoimmune features (IPAF).

OBJECTIVE: to describe the clinical manifestations and survival of patients with ILD and myositis-specific and associated autoantibodies, and to evaluate the performance of the new ATS/ERS classification criteria for IPAF. PATIENTS AND METHODS: Patients with ILD and positive in at least one of the following autoantibodies: anti-Jo-1, anti-Ej, anti-PL7, anti-PL 12, anti-PM/SCL 75 and anti-PM/SCL100 were included. Patients were separated into three groups according to their autoantibody profile: 1. Jo-1 positive patients, 2. Non-Jo-1 antisynthetase autoantibody positive patients, and 3. PM/SCL positive patients. Relevant clinical characteristics were registered. Patients were evaluated had they fulfilled Bohan and Peter's criteria (BPC) for inflammatory myopathies. We evaluated the performance of the IPAF ATS/ERS proposal to classify as such the patients that did not fulfilled BPC, and evaluated whether IPAF patients had a worse survival that BPC patients. RESULTS: Sixty-eight patients were included. Jo-1 was the most frequent autoantibody (65%), followed by non Jo1 anti-synthetase autoantibodies (31%). Non-Jo1 patients had lower Creatin Kinase serum levels at the baseline and less frequency of arthritis. Only 50% of patients fulfilled BPC. All patients not complying with BPC did comply with IPAF criteria. There was no difference in survival between IPAF and BPC patients. Anti Jo-1 positive was associated to survival and the extent of lung inflammation was associated to mortality. CONCLUSIONS: Patients differ in clinical manifestations according to the autoantibody profile. All patients not complying with BPC did comply with the new IPAF criteria. There was no difference in survival between BPC and IPAF patients. Jo-1 patients had a better survival. Extent of lung inflammation was associate to mortality.