ABSTRACT
OBJECTIVES: The predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease [ILD]) as well as the low frequency of muscle signs in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease. METHODS: To characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5-; n = 190/201) based on selected variables, collected retrospectively, without any missing data. RESULTS: Within anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; p < 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologic symptoms (arthralgia; 82.6%; p < 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%; p < 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%; p < 0.0001), and an intermediate prognosis. Raynaud phenomenon, arthralgia/arthritis, and sex permit the cluster appurtenance (83.3% correct estimation). Nevertheless, an unsupervised analysis confirmed that anti-MDA5 antibody delineates an independent group of patients (e.g., dermatomyositis skin rash, skin ulcers, calcinosis, mechanic's hands, ILD, arthralgia/arthritis, and high mortality rate) distinct from anti-MDA5- patients with myositis. CONCLUSION: Anti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist.
Subject(s)
Biological Variation, Population , Dermatomyositis/classification , Dermatomyositis/immunology , Interferon-Induced Helicase, IFIH1/immunology , Adult , Autoantibodies/immunology , Autoantigens/immunology , Dermatomyositis/complications , Female , Humans , Lung Diseases/etiology , Male , Middle Aged , Retrospective Studies , Rheumatic Diseases/etiology , Vascular Diseases/etiologySubject(s)
Anti-Infective Agents/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Pneumocystis carinii/isolation & purification , Pneumonia, Pneumocystis/etiology , Aged , Humans , Lung/diagnostic imaging , Male , Middle Aged , Pneumonia, Pneumocystis/diagnosis , Pneumonia, Pneumocystis/drug therapy , Pneumonia, Pneumocystis/microbiology , Tomography, X-Ray ComputedABSTRACT
Idiopathic pulmonary fibrosis (IPF), the most common and severe interstitial lung disease, remains a great challenge for clinicians. The natural history of the disease is incompletely understood and its prognosis is as devastating as that of many cancers. The most recent international consensus conference on IPF does not recommend any specific medical treatment and underlines the role of symptomatic care and management of co-morbidities, as well as lung transplantation, which should be openly discussed with the patient, if applicable, without delay. The lack of efficacy observed with steroids and immunosuppressive agents argues the current pathogenic hypothesis consistent with an abnormal alveolar epithelium wound healing after repeated injury. Thus, a need for anti-fibrosing and epithelial protective drugs emerged. Considerable progress has been made regarding the validation of relevant endpoints for clinical trials on IPF and pathogenesis, these two aspects of research being a framework for the exploration of new therapeutic approaches. Pirfenidone is the first drug that has been approved by health-care system for IPF treatment in Japan and in Europe. Many novel and promising drugs based on recent targets are under investigation. Combined therapies targeting different pathogenic pathways may represent the future for the treatment of IPF.
Subject(s)
Idiopathic Pulmonary Fibrosis/therapy , Therapies, Investigational/methods , Adrenal Cortex Hormones/therapeutic use , Clinical Trials as Topic , Humans , Idiopathic Pulmonary Fibrosis/diagnosis , Idiopathic Pulmonary Fibrosis/epidemiology , Idiopathic Pulmonary Fibrosis/etiology , Immunosuppressive Agents/therapeutic use , Models, Biological , Practice Guidelines as Topic , Therapies, Investigational/trendsABSTRACT
Bcl-2 is an anti-apoptotic molecule preventing oxidative stress damage and cell death. We have previously shown that Bcl-2 is able to prevent hyperoxia-induced cell death when overexpressed in a murine fibrosarcoma cell line L929. We hypothesized that its specific overexpression in pulmonary epithelial type II cells could prevent hyperoxia-induced lung injury by protecting the epithelial side of the alveolo-capillary barrier. In the present work, we first showed that in vitro Bcl-2 can rescue murine pulmonary epithelial cells (MLE12) from oxygen-induced cell apoptosis, as shown by analysis of LDH release, annexin V/propidium staining, and caspase-3 activity. We then generated transgenic mice overexpressing specifically Bcl-2 in lung epithelial type II cells under surfactant protein C (SP-C) promoter (Tg-Bcl-2) and exposed them to hyperoxia. Bcl-2 did not hinder hyperoxia-induced mitochondria and DNA oxidative damage of type II cell in vivo. Accordingly, lung damage was identical in both Tg-Bcl-2 and littermate mice strains, as measured by lung weight, bronchoalveolar lavage, and protein content. Nevertheless, we observed a significant lower number of TUNEL-positive cells in type II cells isolated from Tg-Bcl-2 mice exposed to hyperoxia compared with cells isolated from littermate mice. In summary, these results show that although Bcl-2 overexpression is able to prevent hyperoxia-induced cell death at single cell level in vitro and ex vivo, it is not sufficient to prevent cell death of parenchymal cells and to protect the lung from acute damage in mice.
