Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases

Although these conditions are rare, a proportion of patients with interstitial lung diseases (ILDs) may develop a progressive-fibrosing phenotype. Progressive fibrosis is associated with worsening respiratory symptoms, lung function decline, limited response to immunomodulatory therapies, decreased quality of life and, potentially, early death. Idiopathic pulmonary fibrosis may be regarded as a model for other progressive-fibrosing ILDs. Here we focus on other ILDs that may present a progressive-fibrosing phenotype, namely idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, connective tissue disease-associated ILDs (e.g. rheumatoid arthritis-related ILD), fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis and ILDs related to other occupational exposures. Differential diagnosis of these ILDs can be challenging, and requires detailed consideration of clinical, radiological and histopathological features. Accurate and early diagnosis is crucial to ensure that patients are treated optimally

Four-factor risk score for the prediction of interstitial lung disease in rheumatoid arthritis

Objective Interstitial lung disease (ILD) is one of the commonest systemic complications in patients with rheumatoid arthritis (RA) and carries a signifcant morbidity and mortality burden. We aimed to identify key variables to risk-stratify RA patients in order to identify those at increased risk of developing ILD. We propose a probability score based on the identifcation of these variables. Methods A retrospective, multicentre study using clinical data collected between 2010 and 2020, across 20 centres. Results A total of 430 RA (210 with ILD confrmed on high-resolution computed tomography (HRCT)) patients were evaluated. We explored several independent variables for the risk of developing ILD in RA and found that the key signifcant variables were smoking (past or present), older age and positive rheumatoid factor/anti-cyclic citrullinated peptide. Multivariate logistic regression models were used to form a scoring system for categorising patients into high and low risk on a scale of 0–9 points and a cut-of score of 5, based on the area under the receiver operating characteristic curve of 0.76 (CI 95% 0.71–0.82). This yielded a sensitivity of 86% and a specifcity of 58%. High-risk patients should be considered for investigation with HRCT and monitored closely. Conclusion We have proposed a new model for identifying RA patients at risk of developing ILD. This approach identifed four simple clinical variables: age, anti-cyclic citrullinated peptide antibodies, Rheumatoid factor and smoking, which allowed development of a predictive scoring system for the presence of ILD in patients with RA

Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations

This book aims to summarize the latest advances in the rheumatic diseases, particularly regarding their pathophysiology and targeted therapy, with a focus on the recent efforts of vascular and pulmonary manifestations in order to anticipate new and future directions of these research topics. Rheumatic diseases represent a heterogeneous group of severe autoimmune disorders. The present Special Issue aims to provide an overview of the diversity and complexity of vascular and pulmonary manifestations of rheumatic diseases and to highlight gaps in our knowledge of how to effectively manage them. Despite their significant morbidity, we have a limited understanding of their pathogenesis. The eleven published articles reported here underline the complexity of rheumatic diseases and the difficulty of managing them. The manuscripts provide an overview of the pathophysiology and current management approach of these disorders, highlighting tools that assist with diagnosis, risk stratification, and therapy. A significant number of articles have reported innovative and effective treatments for the most frequent and debilitating complications of rheumatic diseases. The book emphasizes the importance of multidisciplinary teams using the skills of laboratory researchers, clinicians, radiologists, and pathologists. Furthermore, recent findings are presented and discussed, highlighting strategies to combat worsening symptoms of rheumatic diseases. The research described in this book provide an extremely useful example of the results achieved in the field of anti-rheumatic drug development. Detailed information on new breakthroughs can be found in this book. We strongly encourage a wide group of readers to explore the book that we are presenting for inspiration to develop new approaches to the diagnosis and treatment of rheumatic diseases

Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations

This e-book summarises the latest advances in the rheumatic diseases with a focus on the recent efforts of vascular and pulmonary manifestations and anticipate the new and future directions of these research topic. Rheumatic diseases represent a heterogeneous group of severe autoimmune disorders. The present Special Issue aims to provide an overview of the complexity of vascular and pulmonary manifestations of rheumatologic diseases and helps in knowledge to manage them. The eleven published articles here collected underline the complexity of rheumatic diseases and the difficult to treated them. The manuscripts provide an overview of the pathophysiology and current treatment regimes of these disorders, highlighting tools which assist with diagnosis, risk stratification and therapy. Finally, we underline the importance of a multidisciplinary team working using the skills of clinicians, radiologists, and pathologists

Systemic sclerosis. Novel molecular and epidemiological features of disease.

Systemic sclerosis (SSc) is a systemic rheumatic disease with significant mortality and morbidity. Different estimations of disease prevalence and incidence have been presented from various parts of the world. While lung involvement is a common cause of SSc-related death, a majority of SSc patients suffer from symptoms originating in the gastrointestinal (GI) tract. By combining data from a population based register with individual case ascertainment, we investigated the epidemiology of SSc in a defined region in southern Sweden comprising one million adult inhabitants. The investigation was performed by using classification criteria presented in 1980 and in 2013 respectively. SSc prevalence was estimated to 305 per million and the annual incidence 19 per million and year by application of the 2013 classification criteria. We show that the novel criteria identify SSc subjects who were overlooked by the previous criteria. Usage of either criteria set resulted in prevalence estimates that are higher than previous reports from northern Europe, but similar to reports from southern Europe. Cartilage oligomeric matrix protein (COMP) is a promising biomarker of skin fibrosis in SSc. We have investigated the potential for S-COMP to serve as a biomarker for SSc associated lung fibrosis and as a predictor of SSc survival. S-COMP showed only minimal associations with the development or presence of pulmonary fibrosis. SSc patients with pathological S-COMP in early SSc were at an increased risk of death. To further explore the mechanisms behind COMP and fibrosis, we investigated skin fibrosis in mice deficient in COMP. These mice were not resistant to skin fibrosis. GI disease is a common visceral manifestation of SSc. The inflammatory protein complex S100A8/A9, also known as calprotectin, has been associated with several rheumatic diseases. Faecal calprotectin (FC) is a validated biomarker in inflammatory bowel disease. We have explored the biomarker potential of FC in SSc. FC correlated with SSc manifestations in the GI tract. FCs showed little variation upon repeated testing. FC was higher in SSc compared to other rheumatic diseases. The development of inflammation and fibrosis was investigated in reference to S100A8/A9 in an experimental mouse model. S100A8 and S100A9 were found to localise to inflamed and fibrotic skin tissue. Using the same model, we could not identify any significant reduction of inflammation or fibrosis in S100A9 deficient mice. I suggest that FC, a feasible biomarker already available in routine clinical care, could be a valid biomarker of GI disease in SSc. Further studies are warranted to elucidate the mechanisms behind pathological FC testing in SSc

Pulmonary Function Test in Rheumatoid Arthritis Patients without Extra Articular Manifestations

INTRODUCTION: Rheumatoid Arthritis is one of the commonest Auto immune disorder affecting females commonly and smoking males. Asians are more proned. HLA DR4 is the MHC involved. The triggering factors are smoking, porphyromonas gingivalis (bacteria) and post mycoplasma pneumonia. In RA, there occurs Acute synovitis in the early followed by chronic synovitis and finally to erosive arthritis which is irreversible. The mechanism is mediated by release of all proteolytic enzymes causing fibrous deposition and finally leading to ankylosis which is a fixed deformity. One of the important extraarticular manifestation is involvement of pulmonary system. The manifestations observed so far are pleuritis followed by transudate pleural effusion and interstitial lung disease (particularly smokers). Hence a PULMONARY FUNCTION TEST is carried among the affected individuals of Rheumatoid Arthritis to get a inference. The detailed analysis of this test help us in understanding the incidence of pulmonary manifestation of rheumatoid arthristis, its effect on respiratory volumes and aid us in further management. AIMS AND OBJECTIVES: 1. To know the incidence of pulmonary manifestation of Rheumatoid Arthritis. 2. To know its effects over pulmonary system. 3. To assess further improvement in treating our patients. METHODOLOGY: This prospective cross sectional study is carried out in RHEUMATOID ARTHRIATIS patients (clinically and serologically confirmed) with respect to inclusion and exclusion criteria, who attend the Rheumatology outpatient clinic or in General Medicine ward of Tirunelveli Medical College and Hospital between April 2010 and April 2019Written informed consent was obtained from the patients selected for the study. They have been elaborated history and subjected to clininal examination. Routine investigations and RA factor were done. Then the patient subjected to perform Pulmonary function testing in the Thoracic Department Tirunelveli Medical College. RESULTS: Out of 100 patients studied 83% were females and 17% were males.32% had pulmonary abnormalities on screening with pulmonary function tests. Mild restriction is the most common pulmonary abnormality seen followed by mild obstruction. Mean age for development of pulmonary abnormality is 45.3 years and is significant by unpaired test. Pulmonary function test in patients with additional risk factors like diabetes, smoking is found to be abnormal. CONCLUSION: Our study highlighted the pulmonary function abnormalities in RA population without any pulmonary disease. The commonest defect pattern seen is mild restrictive pattern followed by obstructive pattern. In most patients the ventilatory defects were mild. There was increased prevalence of abnormal pulmonary function test in patients with additional risk factor like diabetes and hypertension. Rheumatoid disease activity by CDAI score, Age, Duration of disease, Duration of treatment, Diabetes, Hypertension, Smoking were found as predictors of pulmonary impairment as determined by Spirometry

Pilot study: prognostic biomarkers for interstitial lung disease in systemic sclerosis

Interstitial lung disease is one of the main causes of mortality in Systemic Sclerosis. The course of the disease is clinically variable where patients can suffer from a range of stable disease to rapid progressive clinical deterioration. Therefore, it is important to identify biomarkers that can predict the clinical course of patients in order to provide early treatment. We evaluated 1129 proteins utilizing novel high-throughput SOMAlogic proteomic technology from the serum of 13 LSSc, 13 progressive ILD and 11 stable ILD patients. Calpain-1 was significantly elevated in progressive ILD patients (median 15129 RFU, 11091-24561) compared to LSSc patients (12759, 9904-15498, p=0.0015) and stable ILD patients (11876, 10271-14249, p=0.0005). Coagulation Factor V was significantly lower in the progressive ILD patients (7161 RFU, 2140-8296) compared to LSSc patients (10311 RFU, 6396-12260, p=0.001) and stable ILD patients (9646 RFU, 6510-11941, p=0.0016). The combination of Coagulation Factor V and Calpain-1 produced an area under the curve of 0.97 (95% CI, 0.921-0.99), sensitivity of 99% and specificity of 91% for the identification of progressive ILD. We have identified a combination of proteins that show potential to be prognostic biomarkers for ILD in SSc.2016-12-31T00:00:00

Biomarkers in systemic sclerosis.

Systemic sclerosis is an autoimmune inflammatory disorder of unknown etiologycharacterized b y pronounced fibroproliferative alterations in the microvasculature, and frequent cellular and humoral immunity abnormalities, culminating in a severe and often progressive fibrotic process. Numerous biomarkers reflecting the three main pathogenetic mechanisms in systemic sclerosis have been described; however, aside from several disease-specific autoantibodies, other biomarkers have not been thoroughly validated and require further study. Thus, there is an unmet need for validated biomarkers for diagnosis, disease classification, and evaluation of organ involvement and therapeutic response in systemic sclerosis

Characterization of immune specificities in idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIM or myositis) are a group of rheumatic autoimmune diseases characterised by skeletal muscle inflammation and weakness, and are associated with high morbidity and mortality. The diagnosis integrates several subgroups of muscular disorders with autoimmune backgrounds, where identifying myositis-specific and associated autoantibodies play an essential role. The spectrum of these autoantibodies may reflect different clinicopathological mechanisms involved in the disease for the various subgroups of IIM. The high heterogeneity and complexity in myositis represent a clinical challenge and due to the rarity of the disease, the pathophysiological mechanism behind IIM remains elusive. The aims of this thesis were to 1) study the mechanisms of disease associated with the group of IIM and anti-Jo-1 autoantibodies in terms of T cell functionality and local autoantibody production; 2) to gain a deeper understanding of T cell infiltrate in the muscle tissue at a single-cell level; 3) to characterise the autoantibody subgroups and identify new associations of risk HLA alleles, and 4) to study the prevalence of anti-FHL1 autoantibody and clinical manifestations in cross-sectional and longitudinal cohorts. In Paper I, we identified histidyl–tRNA synthetase (HisRS) reactive CD4+ T cells in the bronchoalveolar lavage fluid and germinal centre-like structures in the lungs of patients with IIM/anti-synthetase syndrome and the HLA-DRB1*03 allele. Thereby, we identified a potential link between autoreactive T cells and the formation of autoantibodies originating from the lung. In Paper II and V, we detected anti-four-and-a-half-LIM domain 1 (FHL1) autoantibodies in patients with IIM from Australia and Sweden in a cross-sectional and longitudinal approach. In Paper V, we also evaluated the autoantibody levels against FHL1 over time and reported the correlation between FHL1 levels and disease severity. We found that anti-FHL1 autoantibodies were present in patients with IIM who were previously autoantibody-negative, thus adding a novel autoantibody that supports IIM diagnosis. In Paper III, we classified IIM autoantibody co-expression patterns and determined the underlying HLA allele variations. In Paper IV, we used single-cell mRNA sequencing to explore T cell infiltration in the muscle of patients with IIM. We identified a muscle T cell signature containing genes associated with tissue homing and tissue residency. Moreover, we identified immunosuppression-resistant T cell clones in blood and muscle. In conclusion, this thesis contributes to the understanding of the pathophysiology of IIM from the perspective of the tissue-specific T cells, HLA variations, and autoantibodies diversity. Our findings also propose new avenues for further research, which could facilitate the development of a personalised treatment or new biomarkers

Frailty in Rheumatic Diseases

Frailty is a syndrome characterized by the decline in the physiologic reserve and function of several systems, leading to increased vulnerability and adverse health outcomes. While common in the elderly, recent studies have underlined the higher prevalence of frailty in chronic diseases, independent of age. The pathophysiological mechanisms that contribute to frailty have not been completely understood, although significant progresses have recently been made. In this context, chronic inflammation is likely to play a pivotal role, both directly and indirectly through other systems, such as the musculoskeletal, endocrine, and neurological systems. Rheumatic diseases are characterized by chronic inflammation and accumulation of deficits during time. Therefore, studies have recently started to explore the link between frailty and rheumatic diseases, and in this review, we report what has been described so far. Frailty is dynamic and potentially reversible with 8.3%\u201317.9% of older adults spontaneously improving their frailty status over time. Muscle strength is likely the most significant influencing factor which could be improved with training thus pointing at the need to maintain physical activity. Not surprisingly, frailty is more prevalent in patients affected by rheumatic diseases than in healthy controls, regardless of age and is associated with high disease activity to affect the clinical outcomes, largely due to chronic inflammation. More importantly, the treatment of the underlying condition may prevent frailty. Scales to assess frailty in patients affected by rheumatic diseases have been proposed, but larger casuistries are needed to validate disease-specific indexes, which could allow more accurate prognostic estimates than demographic and disease-related variables alone. Frail patients can be more vulnerable and more difficult to treat, due to the risk of side effects, therefore frailty should be taken into account in clinical decisions. Clinical trials addressing frailty could identify patients who are less likely to tolerate potentially toxic medications and might benefit from more conservative regimens. In conclusion, the implementation of the concept of frailty in rheumatology will allow a better understanding of the patient global health, a finest risk stratification and a more individualized management strategy