Differences in the pattern of muscular and extramuscular involvement in patients with inflammatory myopathy according to the clinical groups and specific autoantibodies

Abstract

Inflammatory myopathy (IM) is a heterogeneous group of diseases characterized by muscle weakness and inflammatory infiltrates on the muscle biopsy. But muscle involvement is not always present and other organs and tissues like the lung, skin, and joints are also commonly affected. Patients with IM presented with specific autoantibodies, that target nuclear or cytoplasmic proteins and are 90% specific for IM. Moreover, it has been described that these autoantibodies correlate with the clinical phenotype. This PhD is composed of three studies based on the hypothesis that a systematic analysis of retrospective data using magnetic resonance imaging (MRI) of the muscles could provide clear data about the diagnostic and prognostic utility of these technique in the understanding of the evolution of IM. Moreover, we hypothesized that using high resolution manometry (HRM) to analyze esophageal involvement could shed a light on the pathophysiology of this process in patients with IM, and help to assess the necessity of treating these type of manifestations in patients with myositis. Our third hypothesis was that a myositis classification based on autoantibodies may be useful to assess the prognosis of patients with antisynthetase syndrome (ASyS). The general objectives of this PhD were as follows: 1. To study muscle and esophageal involvement in IM through thigh magnetic resonance imaging (t-MRI) and HRM. 2. To define the pattern of muscle and esophageal involvement in IM patients, and compare the differences in those patterns among the IM clinical and serological subtypes. 3. To establish the utility of t-MRI to distinguish the IM subsets. 4. To study the prevalence, rate of appearance and severity of clinical features in patients with different ASyS autoantibodies, and assess if autoantibodies as well as epidemiological features like sex and race have a role in ASyS prognosis. To assess these objectives, we performed three studies. 1) A cross-sectional study including all Johns Hopkins Myositis Longitudinal Cohort subjects with a tMRI who fulfilled criteria for IM to define the pattern of muscle involvement in patients with immune-mediated necrotizing myopathy (IMNM) compared with other IM subtypes and to compare patients with IMNM with different autoantibodies. 2) Another cross-sectional study including patients with IM from the Vall d’Hebron Hospital, to examine the prevalence of HRM findings and esophageal symptoms among clinical and serological groups of patients with polymyositis (PM) and dermatomysitis (DM), and to define the features of esophageal involvement in IM and compare their prevalence among IM patients with different autoantibodies. 3) A cohort study including all Johns Hopkins Myositis Longitudinal Cohort subjects positive for any ASyS autoantibodies to assess the prevalence, rate of appearance, and severity of clinical features in patients with different ASyS autoantibodies. As general conclusions of the above-mentioned studies, we found that: 1. Different clinical and serological IM groups present characteristic patterns of muscle and esophageal involvement as assessed in t-MRI and HRM, respectively. 2. IMNM, and specially patients with anti-SRP autoantibodies, present with more severe muscle involvement than the other IM subsets. 3. t-MRI patterns are specific, but not sensitive to distinguish the different IM subsets. 4. An early therapeutic intervention is necessary in IM patients, due to the early fatty replacement that spreads to additional muscle groups more quickly during the early phases of the disease. 5. Esophageal involvement is common in IM patients, but it correlates poorly with esophageal symptoms. 6. ASyS autoantibodies as well as race are useful prognostic markers in ASyS patients.

Las MI son un grupo heterogéneo de enfermedades caracterizadas por debilidad e infiltrado inflamatorio en la biopsia muscular. Algunos pacientes con IM presentan autoanticuerpos específicos y ha sido descrito que éstos se correlacionan con el fenotipo clínico. Este doctorado se compone de tres estudios con los siguientes objetivos generales: 1) Estudiar la afectación muscular y esofágica en MI a través de imágenes de resonancia magnética nuclear del muslo (m-RMN) y manometría esofágica de alta resolución (MAR). 2) Definir el patrón de afectación muscular y esofágica en pacientes con MI y comparar las diferencias en esos patrones entre los subtipos clínicos y serológicos de MI. 3) Establecer la utilidad de m-RMN para distinguir los subtipos de MI. 4) Estudiar la prevalencia, la tasa de aparición y la gravedad de las características clínicas en pacientes con diferentes autoanticuerpos antisintetasa, y evaluar éstos y las características epidemiológicas como el sexo y la raza tienen un papel en el pronóstico del síndrome antisintetasa (SAS). Para evaluar estos objetivos realizamos tres estudios. Un estudio transversal que incluyó todos los sujetos de la cohorte longitudinal de pacientes con MI del Hospital Johns Hopkins que tuviesen una m-RMN. Otro estudio transversal que incluyó pacientes con MI del Hospital Vall d'Hebron; y un estudio de cohortes que incluye todos los pacientes de la cohorte longitudinal de pacientes con MI del Hospital Johns Hopkins que fueran positivos para cualquier autoanticuerpo antisintetasa. De estos estudios obtuvimos las siguientes conclusiones: 1. Diferentes grupos de MI presentan patrones característicos de afectación muscular y esofágica en la m-RMN y la MAR. 2. Los pacientes con miopatía necrotizante, y especialmente pacientes con autoanticuerpos anti-SRP, presentan una afectación muscular más severa que los otros subtipos MI. 3. Los patrones de m-RMN son específicos, pero no son sensibles para distinguir los diferentes subtipos de MI. 4. Una intervención terapéutica temprana es necesaria en pacientes con MI, debido al recambio graso que ocurre en los primeros estadios de la enfermedad. 5. La afectación esofágica es común en pacientes con MI, pero se correlaciona pobremente con síntomas esofágicos. 6. El tipo de autoanticuerpo antisintetasa, así como la raza son marcadores de pronóstico útiles en pacientes con SAS.