Anti-PL-7 (anti-threonyl-tRNA synthetase) antisynthetase syndrome: clinical manifestations in a series of patients from a European multicenter study (EUMYONET) and review of the literature

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Healthcare workers hospitalized due to COVID-19 have no higher risk of death than general population. Data from the Spanish SEMI-COVID-19 Registry

Aim To determine whether healthcare workers (HCW) hospitalized in Spain due to COVID-19 have a worse prognosis than non-healthcare workers (NHCW). Methods Observational cohort study based on the SEMI-COVID-19 Registry, a nationwide registry that collects sociodemographic, clinical, laboratory, and treatment data on patients hospitalised with COVID-19 in Spain. Patients aged 20-65 years were selected. A multivariate logistic regression model was performed to identify factors associated with mortality. Results As of 22 May 2020, 4393 patients were included, of whom 419 (9.5%) were HCW. Median (interquartile range) age of HCW was 52 (15) years and 62.4% were women. Prevalence of comorbidities and severe radiological findings upon admission were less frequent in HCW. There were no difference in need of respiratory support and admission to intensive care unit, but occurrence of sepsis and in-hospital mortality was lower in HCW (1.7% vs. 3.9%; p = 0.024 and 0.7% vs. 4.8%; p<0.001 respectively). Age, male sex and comorbidity, were independently associated with higher in-hospital mortality and healthcare working with lower mortality (OR 0.211, 95%CI 0.067-0.667, p = 0.008). 30-days survival was higher in HCW (0.968 vs. 0.851 p<0.001). Conclusions Hospitalized COVID-19 HCW had fewer comorbidities and a better prognosis than NHCW. Our results suggest that professional exposure to COVID-19 in HCW does not carry more clinical severity nor mortality

Disease Specific Autoantibodies in Idiopathic Inflammatory Myopathies

Idiopathic inflammatory myopathies represent still a diagnostic and therapeutic challenge in different disciplines including neurology, rheumatology, and dermatology. In recent years, the spectrum of idiopathic inflammatory myopathies has been significantly extended and the different manifestations were described in more detail leading to new classification criteria. A major breakthrough has also occurred with respect to new biomarkers especially with the characterization of new autoantibody-antigen systems, which can be separated in myositis specific antibodies and myositis associated antibodies. These markers are detectable in approximately 80% of patients and facilitate not only the diagnostic procedures, but provide also important information on stratification of patients with respect to organ involvement, risk of cancer and overall prognosis of disease. Therefore, it is not only of importance to know the significance of these markers and to be familiar with the optimal diagnostic tests, but also with potential limitations in detection. This article focuses mainly on antibodies which are specific for myositis providing an overview on the targeted antigens, the available detection procedures and clinical association. As major tasks for the near future, the need of an international standardization is discussed for detection methods of autoantibodies in idiopathic inflammatory myopathies. Furthermore, additional investigations are required to improve stratification of patients with idiopathic inflammatory myopathies according to their antibody profile with respect to response to different treatment options

Nuevos Conceptos en el Síndrome por Anticuerpos Antisintetasa

El síndrome por anticuerpos antisintetasa (SAS) es una entidad autoinmune que comprende la presencia de un anticuerpo antisintetasa (AAS), principalmente anti-Jo-1, anti-PL-7 y anti-PL-12 y al menos una de las siguientes características clínicas: miositis, enfermedad pulmonar intersticial –EPI-, artritis, fiebre, fenómeno de Raynaud y “manos de mecánico”. La rareza del síndrome y los pocos estudios al respecto hacen que aún existan múltiples interrogantes en torno a la etiopatogenia, tratamiento y pronóstico del mismo. Mediante la realización de cuatro estudios independientes, esta Tesis Doctoral intentará dar respuesta a varias de estas cuestiones. En el primero se analiza las características clínicas de una cohorte de 59 pacientes con SAS, poniendo especial énfasis en la descripción y evolución de la EPI. Se analiza además la supervivencia de la cohorte, de manera global y por subgrupos, comparándola con las series publicadas. Los resultados muestran una alta frecuencia de EPI, pero sin poder confirmar que ésta sea un factor de mal pronóstico; los únicos factores que predicen una menor supervivencia son el descenso de la capacidad vital forzada (CVF) ≥ 10% durante el seguimiento y la presencia de hipertensión arterial pulmonar. La supervivencia global de la serie a los 5 y 10 años es del 83% y 80%. No se observan diferencias en cuanto a la supervivencia respecto a los pacientes con miositis sin AAS. Se objetiva una alta frecuencia de pericarditis especialmente en pacientes con anti-PL-7. En el segundo estudio se analiza la exposición ocupacional en pacientes con SAS, y su relación con la presencia y evolución de la EPI. Los resultados muestran una alta exposición laboral (50%), más elevada que en la población de referencia y que en los pacientes con miositis sin AAS. El estudio sugiere que la exposición ambiental podría desempeñar un papel en la etiopatogenia del síndrome. El tercer trabajo estudia la eficacia de los inhibidores de la calcineurina (IC) (ciclosporina y tacrólimus) en una serie de 15 pacientes con EPI asociada a SAS. Tras el seguimiento, 13 de ellos presentaron una mejoría y/o estabilización del funcionalismo pulmonar. Estos resultados indican que los IC podrían ser una buena opción terapéutica en los pacientes con SAS. En el último trabajo, un estudio multicéntrico europeo, se describen las características clínicas y de laboratorio de una cohorte de 18 pacientes con anti-PL-7, y se comparar con las series publicadas previamente. Los resultados indican que tal y como ocurre con otros anticuerpos antisintetasa, la miositis y la EPI son manifestaciones frecuentes del SAS. El hallazgo de una alta prevalencia de pericarditis en estos pacientes (50%), no descrito hasta la fecha, implica que es posible que existan nuevas manifestaciones en estos pacientes. En conclusión, los estudios muestran que la EPI es una manifestación frecuente que ocurre en casi el 80% de los casos de SAS, pero la existencia de la misma de por sí sola no implica un pronóstico negativo. El descenso ≥ 10% en la CVF y la presencia de hipertensión arterial pulmonar son datos asociados a una mayor mortalidad. La supervivencia acumulada a los 10 años es del 80%. Identificamos una alta prevalencia de exposición ocupacional en nuestra cohorte, la cual podría ser desencadenante del síndrome. Además de las características clínicas clásicas, objetivamos una alta prevalencia de pericarditis en los pacientes con anti-PL-7, un nuevo hallazgo que debería de ser estudiado. Finalmente, los IC deberían de ser considerados una buena opción terapéutica para el manejo de la EPI asociada al SAS.Antisynthetase syndrome (ASS) is a rare autoimmune disorder that consists on a variety of clinical manifestations (myositis, interstitial lung disease –ILD- arthritis, fever, Raynaud´s phenomenon and “mechanic´s hands”) and the presence of an antisynthetase antibody (ASA), being the most common anti-Jo-1, anti-PL-12, anti-PL7. Due to the rarity of this syndrome, little is known about several aspects of the disease such as ethiopatogenic mechanisms, differences between autoantibodies and survival or mortality rates. This doctoral thesis, divided in four studies and based on a series of 59 patients with ASS, will try to answer some of these questions. The aim of the first study is to describe and analyse the clinical characteristics of 59 patients with ASS, focusing on the ILD, and to analyse the survival of the series. Our results show that ILD is a major complication of the ASS, but its presence does not imply a bad prognosis. A more than 10% decrease in forced vital capacity (FVC) in the follow-up and the presence of pulmonary hypertension are the only two prognostic factors associated with lower survival rates. Cumulative survival at 5 and 10 years are 83 and 80% respectively, but no differences were found when compared with a group of patients with myositis without ASA. An unusually high frequency of pericarditis was assessed in patients with anti-PL-7 antibodies. On the second study we investigate the occupational exposure in patients with ASS, finding a high occupational exposure (up to 50%), much higher of that in the reference population and in patients with myositis without ASA. This study suggests that occupational exposure could be implied in the onset and development of the ASS. The third study analyses the effect of calcineurin inhibitors (CI) (cyclosporine and tacrolimus) in 15 patients with ASS associated ILD. A more than 10% increase in FVC was observed in 13 patients (80% refractory cases and 10% first-line therapy). Our study shows that CI are useful in the treatment o ASS associated ILD, not only in refractory cases but also as a first-line therapy. In the last study, a European multicenter study (Eumyonet), we describe clinical and laboratory characteristics of a cohort of 18 European anti-PL-7 patients, and compare them to previously reported cases. All patients had myositis, and 56% had ILD. Interestingly, 50% of them showed pericarditis. Our results indicate that as in other subsets of ASS, myositis and ILD are common features of the anti-PL-7 AAS syndrome, and we should also add pericarditis as a possible manifestation related to anti-PL-7 antibodies. In conclusion, our studies suggest that ASS is a heterogeneous syndrome. ILD is a common manifestation that occurs in up to 80% of the cases, but the poor prognosis depends not on its presence but on a decrease of more than 10% in FVC. Our results show that overall survival rates are better than those reported previously, with 80% of cumulative survival at 10 years. We identify a high occupational exposure rate in our patients, which could be a trigger in the development of the ASS. Apart from the classic clinical characteristics, we found a high prevalence of pericarditis in our anti-PL-7 patient series, a novel finding that should be further investigated. Finally, CI should be considered as good therapeutic option for managing ASS associated ILD

Nuevos conceptos en el síndrome por anticuerpos antisintetasa

El síndrome por anticuerpos antisintetasa (SAS) es una entidad autoinmune que comprende la presencia de un anticuerpo antisintetasa (AAS), principalmente anti-Jo-1, anti-PL-7 y anti-PL-12 y al menos una de las siguientes características clínicas: miositis, enfermedad pulmonar intersticial -EPI-, artritis, fiebre, fenómeno de Raynaud y "manos de mecánico". La rareza del síndrome y los pocos estudios al respecto hacen que aún existan múltiples interrogantes en torno a la etiopatogenia, tratamiento y pronóstico del mismo. Mediante la realización de cuatro estudios independientes, esta Tesis Doctoral intentará dar respuesta a varias de estas cuestiones. En el primero se analiza las características clínicas de una cohorte de 59 pacientes con SAS, poniendo especial énfasis en la descripción y evolución de la EPI. Se analiza además la supervivencia de la cohorte, de manera global y por subgrupos, comparándola con las series publicadas. Los resultados muestran una alta frecuencia de EPI, pero sin poder confirmar que ésta sea un factor de mal pronóstico; los únicos factores que predicen una menor supervivencia son el descenso de la capacidad vital forzada (CVF) ≥ 10% durante el seguimiento y la presencia de hipertensión arterial pulmonar. La supervivencia global de la serie a los 5 y 10 años es del 83% y 80%. No se observan diferencias en cuanto a la supervivencia respecto a los pacientes con miositis sin AAS. Se objetiva una alta frecuencia de pericarditis especialmente en pacientes con anti-PL-7. En el segundo estudio se analiza la exposición ocupacional en pacientes con SAS, y su relación con la presencia y evolución de la EPI. Los resultados muestran una alta exposición laboral (50%), más elevada que en la población de referencia y que en los pacientes con miositis sin AAS. El estudio sugiere que la exposición ambiental podría desempeñar un papel en la etiopatogenia del síndrome. El tercer trabajo estudia la eficacia de los inhibidores de la calcineurina (IC) (ciclosporina y tacrólimus) en una serie de 15 pacientes con EPI asociada a SAS. Tras el seguimiento, 13 de ellos presentaron una mejoría y/o estabilización del funcionalismo pulmonar. Estos resultados indican que los IC podrían ser una buena opción terapéutica en los pacientes con SAS. En el último trabajo, un estudio multicéntrico europeo, se describen las características clínicas y de laboratorio de una cohorte de 18 pacientes con anti-PL-7, y se comparar con las series publicadas previamente. Los resultados indican que tal y como ocurre con otros anticuerpos antisintetasa, la miositis y la EPI son manifestaciones frecuentes del SAS. El hallazgo de una alta prevalencia de pericarditis en estos pacientes (50%), no descrito hasta la fecha, implica que es posible que existan nuevas manifestaciones en estos pacientes. En conclusión, los estudios muestran que la EPI es una manifestación frecuente que ocurre en casi el 80% de los casos de SAS, pero la existencia de la misma de por sí sola no implica un pronóstico negativo. El descenso ≥ 10% en la CVF y la presencia de hipertensión arterial pulmonar son datos asociados a una mayor mortalidad. La supervivencia acumulada a los 10 años es del 80%. Identificamos una alta prevalencia de exposición ocupacional en nuestra cohorte, la cual podría ser desencadenante del síndrome. Además de las características clínicas clásicas, objetivamos una alta prevalencia de pericarditis en los pacientes con anti-PL-7, un nuevo hallazgo que debería de ser estudiado. Finalmente, los IC deberían de ser considerados una buena opción terapéutica para el manejo de la EPI asociada al SAS.Antisynthetase syndrome (ASS) is a rare autoimmune disorder that consists on a variety of clinical manifestations (myositis, interstitial lung disease -ILD- arthritis, fever, Raynaud's phenomenon and "mechanic's hands") and the presence of an antisynthetase antibody (ASA), being the most common anti-Jo-1, anti-PL-12, anti-PL7. Due to the rarity of this syndrome, little is known about several aspects of the disease such as ethiopatogenic mechanisms, differences between autoantibodies and survival or mortality rates. This doctoral thesis, divided in four studies and based on a series of 59 patients with ASS, will try to answer some of these questions. The aim of the first study is to describe and analyse the clinical characteristics of 59 patients with ASS, focusing on the ILD, and to analyse the survival of the series. Our results show that ILD is a major complication of the ASS, but its presence does not imply a bad prognosis. A more than 10% decrease in forced vital capacity (FVC) in the follow-up and the presence of pulmonary hypertension are the only two prognostic factors associated with lower survival rates. Cumulative survival at 5 and 10 years are 83 and 80% respectively, but no differences were found when compared with a group of patients with myositis without ASA. An unusually high frequency of pericarditis was assessed in patients with anti-PL-7 antibodies. On the second study we investigate the occupational exposure in patients with ASS, finding a high occupational exposure (up to 50%), much higher of that in the reference population and in patients with myositis without ASA. This study suggests that occupational exposure could be implied in the onset and development of the ASS. The third study analyses the effect of calcineurin inhibitors (CI) (cyclosporine and tacrolimus) in 15 patients with ASS associated ILD. A more than 10% increase in FVC was observed in 13 patients (80% refractory cases and 10% first-line therapy). Our study shows that CI are useful in the treatment o ASS associated ILD, not only in refractory cases but also as a first-line therapy. In the last study, a European multicenter study (Eumyonet), we describe clinical and laboratory characteristics of a cohort of 18 European anti-PL-7 patients, and compare them to previously reported cases. All patients had myositis, and 56% had ILD. Interestingly, 50% of them showed pericarditis. Our results indicate that as in other subsets of ASS, myositis and ILD are common features of the anti-PL-7 AAS syndrome, and we should also add pericarditis as a possible manifestation related to anti-PL-7 antibodies. In conclusion, our studies suggest that ASS is a heterogeneous syndrome. ILD is a common manifestation that occurs in up to 80% of the cases, but the poor prognosis depends not on its presence but on a decrease of more than 10% in FVC. Our results show that overall survival rates are better than those reported previously, with 80% of cumulative survival at 10 years. We identify a high occupational exposure rate in our patients, which could be a trigger in the development of the ASS. Apart from the classic clinical characteristics, we found a high prevalence of pericarditis in our anti-PL-7 patient series, a novel finding that should be further investigated. Finally, CI should be considered as good therapeutic option for managing ASS associated ILD