Project description:Systemic sclerosis (SSc), or scleroderma, is a heterogeneous and complex autoimmune disease characterized by varying degrees of skin and organ fibrosis and obliterative vasculopathy. The disease results in significant morbidity and mortality, and to date, available treatments are limited. Lung involvement is the leading cause of death of patients with SSc. Over the past year, significant advances have been made in our understanding of SSc-associated lung disease, and this review attempts to encapsulate these most recent findings and place them in context.We divide our discussion of the most recent literature into the following: first, clinical aspects of SSc lung management, including classification, imaging, biomarkers, and treatment; second, promising new animal models that may improve our ability to accurately study this disease; and third, studies that advance or change our understanding of SSc lung disease pathogenesis, thereby raising the potential for new targets for therapeutic intervention.Recent advances have resulted in a better understanding of SSc-associated lung disease, the development of new in-vivo models for exploring disease pathogenesis, and the identification of potential novel targets for the development of therapies.
Project description:This article reviews the most important articles published in interstitial lung disease, as reviewed during the Clinical Year in Review session at the 2012 annual European Respiratory Society Congress in Vienna, Austria. Since the recent international guidelines for the management of idiopathic pulmonary fibrosis (IPF), important new evidence is available. The anti-fibrotic drug pirfenidone has been recently approved in Europe. Other pharmacological agents, especially nintedanib, are still being tested. The so-called triple combination therapy, anticoagulation therapy and endothelin receptor antagonists, especially ambrisentan, are either harmful or ineffective in IPF and are not recommended as treatment. Although the clinical course of IPF is highly variable, novel tools have been developed for individual prediction of prognosis. Acute exacerbations of IPF are associated with increased mortality and may occur with higher frequency in IPF patients with associated pulmonary hypertension. Interstitial lung disease associated with connective tissue disease has been definitely established to have a better long-term survival than IPF. A subset of patients present with symptoms and/or biological autoimmune features, but do not fulfil diagnostic criteria for a given autoimmune disease; this condition is associated with a higher prevalence of nonspecific interstitial pneumonia pattern, female sex and younger age, although survival relevance is unclear.
Project description:Interstitial lung diseases are a group of diffuse parenchymal lung disorders associated with substantial morbidity and mortality. Knowledge achieved in recent years has resulted in the publication of the new classification of idiopathic interstitial pneumonias, according to which there are three groups: major, rare and unclassified. The novelty of the new classification comes from the fact that difficult to classify entities can be treated according to the disease behaviour classification. Idiopathic pulmonary fibrosis is the most lethal amongst the interstitial lung diseases and presents high heterogeneity in clinical behaviour. A number of biomarkers have been proposed in order to predict the course of the disease and group patients with the same characteristics in clinical trials. Early diagnosis and disease stratification is also important in the field of other interstitial lung diseases.
Project description:Purpose of reviewRheumatoid arthritis-associated interstitial lung disease (RA-ILD) is one of the most serious extra-articular RA manifestations. RA-ILD is associated with worse physical function, lower quality of life, and increased mortality. RA-ILD is comprised of heterogeneous subtypes characterized by inflammation and fibrosis. Diagnosis can be difficult since the presentation of RA-ILD is characterized by non-specific symptoms and imaging findings. Management of RA-ILD is also challenging due to difficulty in precisely measuring pulmonary disease activity and response to treatment in patients who may also have articular inflammation. We provide a current overview of RA-ILD focusing on prevalence, risk factors, and treatment.Recent findingsResearch interest in RA-ILD has increased in recent years. Some studies suggest that RA-ILD prevalence may be increasing; this may be due to underlying biologic drivers or increases in imaging and recognition. Novel RA-ILD risk factors include the MUC5B promotor variant, articular disease activity, autoantibodies, and biomarkers of damaged pulmonary parenchyma. Treatment should focus on controlling RA disease activity, which emerging data suggest may reduce RA-ILD risk. Immunomodulatory and antifibrotic drugs may also treat RA-ILD.SummaryRA-ILD is an underrecognized and serious manifestation of RA, but important progress is being made in identifying risk factors and treatment.
Project description:Interstitial lung disease (ILD) is frequently a complication of rheumatoid arthritis (RA) as an extra-articular manifestation which has a poor prognosis. Acute-onset diffuse ILD (AoDILD) occasionally occurs in RA and includes acute exacerbation of ILD, drug-induced ILD, and Pneumocystis pneumonia. AoDILD also confers a poor prognosis in RA. Previously-established biomarkers for ILD include Krebs von den lungen-6 and surfactant protein-D originally defined in patients with idiopathic pulmonary fibrosis; the sensitivity of these markers for RA-associated ILD (RA-ILD) is low. Although many studies on ILD markers have been performed in idiopathic pulmonary fibrosis, only a few validation studies in RA-ILD or AoDILD have been reported. Biomarkers for RA-ILD and AoDILD are thus still required. Recently, genomic, cytokine, antibody, and metabolomic profiles of RA-ILD or AoDILD have been investigated with the aim of improving biomarkers. In this review, we summarize current preliminary data on these potential biomarkers for RA-ILD or AoDILD. The development of biomarkers on RA-ILD has only just begun. When validated, such candidate biomarkers will provide valuable information on pathogenesis, prognosis, and drug responses in RA-ILD in future.
Project description:Interstitial lung disease (ILD) is comprised of a heterogeneous group of disorders with highly variable natural histories and response to therapies. Pharmacogenetics focuses on the variability in drug response because of the presence of genetic factors that influence drug metabolism or disease activity. In this article, we review relevant drug-specific and disease-specific polymorphisms that may influence therapeutic response, and then highlight a recently identified drug-gene interaction in patients with idiopathic pulmonary fibrosis (IPF).The emergence of high-throughput genomic technology has allowed for identification of gene polymorphisms associated with susceptibility to specific disease states, including IPF and several connective tissue diseases known to cause ILD. IPF risk loci span a diverse group of genes, while most associated with connective tissue disease are critical to immune signaling. A recent pharmacogenetic analysis of patients enrolled in an IPF clinical trial identified a variant within TOLLIP to be associated with differential response to N-acetylcysteine therapy.Though few pharmacogenetic investigations have been conducted in patients with ILD to date, ample opportunities for pharmacogenetic exploration exist in this patient population. Such exploration will advance our understanding of specific ILDs and help usher in an era of personalized medicine.
Project description:There has been tremendous progress in the approach to childhood interstitial lung diseases (chILD), with particular recognition that interstitial lung disease (ILD) in infants is often distinct from the forms that occur in older children and adults. Diagnosis is challenging because of the rarity of ILD and the fact that the presenting symptoms of ILD often overlap those of common respiratory disorders. This review summarizes the newly published recommendations for diagnosis and management, and highlights the recent scientific advances in several specific forms of chILD.Clinical practice guidelines emphasize the role for chest computed tomography, genetic testing, and lung biopsy in the diagnostic evaluation of children with suspected ILD. Recent studies have better defined the characteristics and molecular understanding of several different forms of ILD, including neuroendocrine cell hyperplasia of infancy and ILD, due to mutations in genes affecting surfactant production and metabolism. Despite significant progress, definitive therapies are often lacking.chILD encompasses a collection of rare, diffuse lung diseases. Timely recognition of children with suspected ILD and initiation of appropriate diagnostic evaluations will facilitate medical management. Systematic approaches to clinical care and further studies are needed to improve the outcomes of children with these rare disorders.
Project description:Systemic sclerosis is a heterogeneous disease of unknown etiology with limited effective therapies. It is characterized by autoimmunity, vasculopathy, and fibrosis and is clinically manifested by multiorgan involvement. Interstitial lung disease is a common complication of systemic sclerosis and is associated with significant morbidity and mortality. The diagnosis of interstitial lung disease hinges on careful clinical evaluation and pulmonary function tests and high-resolution computed tomography. Effective therapeutic options are still limited. Several experimental therapies are currently in early-phase clinical trials and show promise.
Project description:Interstitial lung diseases (ILD) encompass a group of conditions involving fibrosis and/or inflammation of the pulmonary parenchyma. Telomeres are repetitive DNA sequences at chromosome ends which protect against genome instability. At each cell division, telomeres shorten, but the telomerase complex partially counteracts progressive loss of telomeres by catalysing the synthesis of telomeric repeats. Once critical telomere shortening is reached, cell cycle arrest or apoptosis are triggered. Telomeres progressively shorten with age. A number of rare genetic mutations have been identified in genes encoding for components of the telomerase complex, including telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), in familial and, less frequently, in sporadic fibrotic ILDs. Defects in telomerase result in extremely short telomeres. More rapidly progressive disease is observed in fibrotic ILD patients with telomere gene mutations, regardless of underlying diagnosis. Associations with common single nucleotide polymorphisms in telomere related genes have also been demonstrated for various ILDs. Shorter peripheral blood telomere lengths compared to age-matched healthy individuals are found in a proportion of patients with fibrotic ILDs, and in idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (HP) have been linked to worse survival, independently of disease severity. Greater susceptibility to immunosuppressant-induced side effects in patients with short telomeres has been described in patients with IPF and with fibrotic HP. Here, we discuss recent evidence for the involvement of telomere length and genetic variations in the development, progression, and treatment of fibrotic ILDs.