Recommendations for the Treatment of Anti-Melanoma Differentiation-Associated Gene 5-positive Dermatomyositis-Associated Rapidly Progressive Interstitial Lung Disease

Objectives: The study aimed to develop evidence-based recommendations for the treatment of rapidly progressive interstitial lung disease (RPILD) associated with the anti-Melanoma Differentiation-Associated Gene 5-positive dermatomyositis (DM) syndrome. Methods: The task force comprised an expert panel of specialists in rheumatology, intensive care medicine, pulmonology, immunology, and internal medicine. The study was carried out in two phases: identifying key areas in the management of DM-RPILD syndrome and developing a set of recommendations based on a review of the available scientific evidence. Four specific questions focused on different treatment options were identified. Relevant publications in English, Spanish or French up to April 2018 were searched systematically for each topic using PubMed (MEDLINE), EMBASE, and Cochrane Library (Wiley Online). The experts used evidence obtained from these studies to develop recommendations. Results: A total of 134 studies met eligibility criteria and formed the evidentiary basis for the recommendations regarding immunosuppressive therapy and complementary treatments. Overall, there was general agreement on the initial use of combined immunosuppressive therapy. Combination of high-dose glucocorticoids and calcineurin antagonists with or without cyclophosphamide is the first choice. In the case of calcineurin antagonist contraindication or treatment failure, switching or adding other immunosuppressants may be individualized. Plasmapheresis, polymyxin B hemoperfusion and/or intravenous immunoglobulins may be used as rescue options. ECMO should be considered in life-threatening situations while waiting for a clinical response or as a bridge to lung transplant. Conclusions: Thirteen recommendations regarding the treatment of the anti-MDA5 positive DM-RPILD were developed using research-based evidence and expert opinion.This project was supported by Spanish Rheumatology Society and Spanish Society of Internal Medicine (GEAS, Study Group on Autoimmune Diseases)

Myositis autoantibodies in Korean patients with inflammatory myositis: Anti-140-kDa polypeptide antibody is primarily associated with rapidly progressive interstitial lung disease independent of clinically amyopathic dermatomyositis

<p>Abstract</p> <p>Background</p> <p>To investigate the association between myositis autoantibodies and clinical subsets of inflammatory myositis in Korean patients.</p> <p>Methods</p> <p>Immunoprecipitation was performed using the sera of classic polymyositis (PM) (n = 11) and dermatomyositis (DM) (n = 38) patients who met the Bohan and Peter criteria for definite inflammatory myositis. A panel of defined myositis autoantibodies was surveyed to investigate the association between each autoantibody and clinical subsets of inflammatory myositis.</p> <p>Results</p> <p>Either MSAs, anti-p140, or anti-p155/140 antibodies were found in 63.3% (31/49) of the study subjects. Anti-140-kDa-polypeptide (anti-p140) (18.4%, 9/49) and anti-155/140-kDa polypeptide (anti-p155/140) (16.3%, 8/49) antibodies were the most common, followed by anti-Mi2 (14.3%, 7/49), anti-ARS (12.2%, 6/49) and anti-SRP (2.0%, 1/49) antibodies. All MSAs and anti-p140 and anti-p155/140 antibodies were mutually exclusive. Anti-p140 (23.7%, 9/38), anti-p155/140 (21.1%, 8/38), and anti-Mi2 (18.4%, 3/38) antibodies were found exclusively in DM patients. Anti-p140 antibody was associated with rapidly progressive interstitial lung disease (ILD) (p = 0.001), with a sensitivity of 100.0% (4/4) and a specificity of 85.3% (29/34) in DM patients. Anti-p155/140 antibody was associated with cancer-associated DM (p = 0.009), with a sensitivity of 55.6% (5/9) and a specificity of 89.7% (26/29). Cancer-associated survival was significantly worse when anti-p155/140 antibody was present (19.2 ± 7.6 vs. 65.0 ± 3.5 months, p = 0.032). Finally, anti-ARS antibodies were associated with stable or slowly progressive ILD in PM and DM patients (p = 0.005).</p> <p>Conclusions</p> <p>Anti-p140 and anti-p155/140 antibodies were commonly found autoantibodies in Korean patients with inflammatory myositis. Despite the lack of clinically amyopathic DM patients in the study subjects, a strong association was observed between anti-p140 antibody and rapidly progressive ILD. Anti-p155/140 antibody was associated with cancer-associated myositis and poor survival.</p

Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum TimeCourse

Introduction: Increased cardiovascular (CV) morbidity and mortality is observed in inflammatory joint diseases (IJDs) such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. However, the management of CV disease in these conditions is far from being well established.Areas covered: This review summarizes the main epidemiologic, pathophysiological, and clinical risk factors of CV disease associated with IJDs. Less common aspects on early diagnosis and risk stratification of the CV disease in these conditions are also discussed. In Europe, the most commonly used risk algorithm in patients with IJDs is the modified SCORE index based on the revised recommendations proposed by the EULAR task force in 2017.Expert opinion: Early identification of IJD patients at high risk of CV disease is essential. It should include the use of complementary noninvasive imaging techniques. A multidisciplinary approach aimed to improve heart-healthy habits, including strict control of classic CV risk factors is crucial. Adequate management of the underlying IJD is also of main importance since the reduction of disease activity decreases the risk of CV events. Non-steroidal anti-inflammatory drugs may have a lesser harmful effect in IJD than in the general population, due to their anti-inflammatory effects along with other potential beneficial effects.This research was partially funded by FOREUM—Foundation for Research in Rheumatolog

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

Nuevas estrategias en el diagnóstico del cáncer asociado a las dermatomiositis y polimiositis

El diagnóstico de cáncer constituye un indicador de mal pronóstico en pacientes con dermatomiositis (DM) y polimiositis (PM) y se relaciona, además, con una parte importante de la mortalidad observada en estas entidades. Se estima que entre un 15% y un 30% de las DM y PM tienen un comportamiento paraneoplásico. La afectación inflamatoria del músculo y/o la piel parece originarse a partir de una reacción inmunológica cruzada entre antígenos del tejido tumoral (frente a los que se inicia la respuesta inmunitaria) y del músculo. Aunque en la mayor parte de estos casos la neoplasia y la miositis se diagnostican a la vez, un porcentaje significativo de neoplasias no pueden ser diagnosticadas en una primera evaluación, haciéndose únicamente clínicamente evidentes meses o años después del inicio de la miositis. La ausencia de marcadores para determinar que DM y PM tienen una etiología paraneoplásica constituye uno de los principales problemas en la evaluación de estos pacientes, y dificulta la realización de un diagnóstico precoz de las neoplasias que aparece con posterioridad al debut de la miositis, las cuales no es infrecuente que se presenten en forma de enfermedad diseminada. La presente tesis doctoral se ha diseñado con el objetivo de profundizar en esta problemática a partir de la realización de tres estudios independientes que pretenden evaluar posibles marcadores clínicos y serológicos de DM o PM paraneoplásica y la utilidad de nuevas técnicas diagnósticas para el cribado inicial de neoplasia en estas entidades. En un primer lugar se ha procedido al estudio del fenómeno del cáncer en una serie histórica de 85 pacientes con DM (65) y PM (20) atendidos en el servicio de Medicina Interna del Hospital Vall d'Hebron de Barcelona. Tras realizar un análisis descriptivo de la frecuencia de cáncer en la cohorte y valorar las características clínicas asociadas a esta condición, se ha investigado mediante la implementación de técnicas de inmunoprecipitación de proteinas la presencia del nuevo anticuerpo anti-p155, determinándose su grado de relación con las neoplasias. Mediante este estudio se ha conseguido aportar a la bibliografía la segunda serie más larga (hasta la fecha de publicación) de pacientes adultos con DM en los que se ha evaluado esta asociación. Los resultados obtenidos han confirmado en nuestra serie una frecuencia de neoplasia y un comportamiento clínico de las mismas similar al observado en la bibliografía. Se ha identificado también la presencia del anticuerpo anti-p155 en un 23% de pacientes con DM, describiéndose, de forma concordante con lo previamente reportado, una intensa asociación del mismo con aquellas miositis en las que se asume un origen paraneoplásico. En un segundo lugar, mediante una revisión sistemática y un metanálisis de todos los trabajos publicados sobre el tema se ha investigado la utilidad de la determinación del anticuerpo anti-p155 como test diagnóstico de miositis paraneoplásica. Mediante este estudio se ha podido caracterizar mejor y definir las propiedades de este anticuerpo cuando se utiliza para esta finalidad, quedando patente su potencial relevancia clínica en el cribado de neoplasia y la planificación de estrategias de seguimiento en estas entidades. Finalmente, se ha evaluado mediante un estudio prospectivo multicéntrico la utilidad del FDG-PET/TC para la detección precoz de neoplasias en pacientes con un diagnóstico reciente de DM y PM, demostrándose que esta exploración tiene una sensibilidad y especificidad similar a la observada con las estrategias de cribado convencionales. A partir de los resultados anteriores se propone finalmente una nueva estrategia de evaluación de neoplasia de pacientes con DM y PM tanto al inicio de la enfermedad como en su seguimiento.Dermatomyositis (DM) and polymyositis (PM) are often associated with cancer, which considerably determine the prognosis and is one of the main causes of mortality in this population. The incidence of cancer in published series of patients with idiopathic inflammatory myopathy (IIM) ranges from 15% to 30%. Inflammation in skin and muscle in patients with cancer-associated myositis (CAM) is supposed to appear as a paraneoplastic phenomenon secondary to an immune response directed to similar antigens present both in cancer and muscle tissues. As cancer can develop before, concurrently, or subsequent to the onset of IIM, cancer screening is now mandatory routine practice in patients with IIM. Nevertheless, there is no consensus as to the method or frequency with which patients should be tested to rule out neoplasm at diagnosis or during the follow-up. Clinical, analytical, and treatment response features that have been proposed as positive and negative predictive markers of malignancy are of uncertain usefulness in clinical practice. The aim of this doctoral thesis is to go in depth this topic through three different studies where clinical and new serologic and imaging techniques for CAM diagnosis are evaluated. In the first study we analyze the presence of cancer and the new myositis-specific autoantibody anti-p155 (determined by protein immunoprecipitation assays with HeLa cells) in a large cohort of patients with IIM and describe a number of clinical, serologic and laboratory features of CAM and p155-positive patients. The incidence of CAM in our series is similar than previously reported (19% in the complete cohort and 22% in DM group). Only the shawl sign shows a significant association with CAM. Anti-p155 is present in 23% of DM patients with a clear association with CAM, with an odds ratio of 23 (95% confidence interval, 5,23-101,2). The second study is a systematic review and meta-analysis of the published studies on this subject (including our first study) to ascertain the accuracy of anti-p155 for diagnosing CAM in DM. In this study the diagnostic value of anti-p155 for detecting paraneoplastic DM has been more precisely characterized, with a sensitivity and specificity of 78% and 89% respectively. Our data indicate an important potential role for negative anti-p155 results, which indicate a low probability of CAM in adult DM patients, and supports the usefulness of this antibody for diagnosing CAM and guiding patient management. The third study is a multicenter, 3-year prospective study including 55 consecutive patients with IIM, where the value of whole-body [18F] fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/TC) for diagnosing occult malignant disease in patients with myositis is compared to broad conventional cancer screening. According to our results FDG-PET/TC is not superior to broad convencional screening to diagnose occult cancer in myositis. Finally a new algorithm for the diagnosis of malignancy in myositis is proposed

Nuevas estrategias en el diagnóstico del cáncer asociado a las dermatomiositis y polimiositis

Descripció del recurs: el 01 setembre 2012El diagnóstico de cáncer constituye un indicador de mal pronóstico en pacientes con dermatomiositis (DM) y polimiositis (PM) y se relaciona, además, con una parte importante de la mortalidad observada en estas entidades. Se estima que entre un 15% y un 30% de las DM y PM tienen un comportamiento paraneoplásico. La afectación inflamatoria del músculo y/o la piel parece originarse a partir de una reacción inmunológica cruzada entre antígenos del tejido tumoral (frente a los que se inicia la respuesta inmunitaria) y del músculo. Aunque en la mayor parte de estos casos la neoplasia y la miositis se diagnostican a la vez, un porcentaje significativo de neoplasias no pueden ser diagnosticadas en una primera evaluación, haciéndose únicamente clínicamente evidentes meses o años después del inicio de la miositis. La ausencia de marcadores para determinar que DM y PM tienen una etiología paraneoplásica constituye uno de los principales problemas en la evaluación de estos pacientes, y dificulta la realización de un diagnóstico precoz de las neoplasias que aparece con posterioridad al debut de la miositis, las cuales no es infrecuente que se presenten en forma de enfermedad diseminada. La presente tesis doctoral se ha diseñado con el objetivo de profundizar en esta problemática a partir de la realización de tres estudios independientes que pretenden evaluar posibles marcadores clínicos y serológicos de DM o PM paraneoplásica y la utilidad de nuevas técnicas diagnósticas para el cribado inicial de neoplasia en estas entidades. En un primer lugar se ha procedido al estudio del fenómeno del cáncer en una serie histórica de 85 pacientes con DM (65) y PM (20) atendidos en el servicio de Medicina Interna del Hospital Vall d'Hebron de Barcelona. Tras realizar un análisis descriptivo de la frecuencia de cáncer en la cohorte y valorar las características clínicas asociadas a esta condición, se ha investigado mediante la implementación de técnicas de inmunoprecipitación de proteinas la presencia del nuevo anticuerpo anti-p155, determinándose su grado de relación con las neoplasias. Mediante este estudio se ha conseguido aportar a la bibliografía la segunda serie más larga (hasta la fecha de publicación) de pacientes adultos con DM en los que se ha evaluado esta asociación. Los resultados obtenidos han confirmado en nuestra serie una frecuencia de neoplasia y un comportamiento clínico de las mismas similar al observado en la bibliografía. Se ha identificado también la presencia del anticuerpo anti-p155 en un 23% de pacientes con DM, describiéndose, de forma concordante con lo previamente reportado, una intensa asociación del mismo con aquellas miositis en las que se asume un origen paraneoplásico. En un segundo lugar, mediante una revisión sistemática y un metanálisis de todos los trabajos publicados sobre el tema se ha investigado la utilidad de la determinación del anticuerpo anti-p155 como test diagnóstico de miositis paraneoplásica. Mediante este estudio se ha podido caracterizar mejor y definir las propiedades de este anticuerpo cuando se utiliza para esta finalidad, quedando patente su potencial relevancia clínica en el cribado de neoplasia y la planificación de estrategias de seguimiento en estas entidades. Finalmente, se ha evaluado mediante un estudio prospectivo multicéntrico la utilidad del FDG-PET/TC para la detección precoz de neoplasias en pacientes con un diagnóstico reciente de DM y PM, demostrándose que esta exploración tiene una sensibilidad y especificidad similar a la observada con las estrategias de cribado convencionales. A partir de los resultados anteriores se propone finalmente una nueva estrategia de evaluación de neoplasia de pacientes con DM y PM tanto al inicio de la enfermedad como en su seguimiento.Dermatomyositis (DM) and polymyositis (PM) are often associated with cancer, which considerably determine the prognosis and is one of the main causes of mortality in this population. The incidence of cancer in published series of patients with idiopathic inflammatory myopathy (IIM) ranges from 15% to 30%. Inflammation in skin and muscle in patients with cancer-associated myositis (CAM) is supposed to appear as a paraneoplastic phenomenon secondary to an immune response directed to similar antigens present both in cancer and muscle tissues. As cancer can develop before, concurrently, or subsequent to the onset of IIM, cancer screening is now mandatory routine practice in patients with IIM. Nevertheless, there is no consensus as to the method or frequency with which patients should be tested to rule out neoplasm at diagnosis or during the follow-up. Clinical, analytical, and treatment response features that have been proposed as positive and negative predictive markers of malignancy are of uncertain usefulness in clinical practice. The aim of this doctoral thesis is to go in depth this topic through three different studies where clinical and new serologic and imaging techniques for CAM diagnosis are evaluated. In the first study we analyze the presence of cancer and the new myositis-specific autoantibody anti-p155 (determined by protein immunoprecipitation assays with HeLa cells) in a large cohort of patients with IIM and describe a number of clinical, serologic and laboratory features of CAM and p155-positive patients. The incidence of CAM in our series is similar than previously reported (19% in the complete cohort and 22% in DM group). Only the shawl sign shows a significant association with CAM. Anti-p155 is present in 23% of DM patients with a clear association with CAM, with an odds ratio of 23 (95% confidence interval, 5,23-101,2). The second study is a systematic review and meta-analysis of the published studies on this subject (including our first study) to ascertain the accuracy of anti-p155 for diagnosing CAM in DM. In this study the diagnostic value of anti-p155 for detecting paraneoplastic DM has been more precisely characterized, with a sensitivity and specificity of 78% and 89% respectively. Our data indicate an important potential role for negative anti-p155 results, which indicate a low probability of CAM in adult DM patients, and supports the usefulness of this antibody for diagnosing CAM and guiding patient management. The third study is a multicenter, 3-year prospective study including 55 consecutive patients with IIM, where the value of whole-body [18F] fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/TC) for diagnosing occult malignant disease in patients with myositis is compared to broad conventional cancer screening. According to our results FDG-PET/TC is not superior to broad convencional screening to diagnose occult cancer in myositis. Finally a new algorithm for the diagnosis of malignancy in myositis is proposed