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Background Pulmonary fibrosis (PF) is caused by a heterogeneous group of diseases, with a high inter-individual variability in disease trajectory. Identifying disease progression in patients with PF has impact on clinical management decisions. However, strategies to early identify and predict disease progression for these patients are currently lacking. In this study, we aim to assess long-term FVC change in patients with PF measured with home spirometry, and evaluate the feasibility of a multinational patient-led registry in PF. In addition, we will assess validity of patient-reported outcomes (PROMs) for the different subgroups of patients with PF. Methods In this international, prospective, multicenter, observational study, we aim to include 700 patients across seven European countries. Patients will monitor their disease course for a period of two years using an online home monitoring program (I-FILE), which includes home spirometry, pulse oximetry, and PROMs. Results will be directly sent to the hospital via the online application. Patients will be asked to perform daily home spirometry and pulse oximetry in the first three months, followed by once weekly measurements for a period of two years. PROMs will be completed in the online I-FILE application every six months, including the King’s brief Interstitial Lung Disease Health Status, The EuroQol five dimensions five-level, Visual Analogue Scales on cough, dyspnea, fatigue and general complaints, Leicester Cough Questionnaire, Fatigue Assessment Scale, Work Productivity and Activity Impairment Questionnaire, Global Rating of Change Scale, and Living with Pulmonary Fibrosis questionnaire. Discussion This study will provide much needed insights in disease trajectories of the different subgroups of patients with PF. Simultaneously, the I-FILE study will yield valuable information on the use and feasibility of home-based data collection. This international patient-led registry will facilitate trans-border collaboration to further optimize care and research for patients with PF. Trial registration: The study was registered on the 12th of March 2020 in the International Clinical Trial Registry, www.clinicaltrials.gov; Identifier: NCT04304898.

Background Patients with serious respiratory illness and their caregivers suffer considerable burdens and palliative care is a fundamental right for anyone who needs it However the overwhelming majority of patients do not receive timely palliative care before the end of life despite robust evidence for improved outcomes Goals This policy statement by the American Thoracic Society ATS and partnering societies advocates for improved integration of high quality palliative care early in the care continuum for patients with serious respiratory illness and their caregivers and provides clinicians and policymakers with a framework to accomplish this Methods An international and interprofessional expert committee including patients and caregivers achieved consensus across a diverse working group representing pulmonary critical care palliative care bioethics health law and policy geriatrics nursing physiotherapy social work pharmacy patient advocacy psychology and sociology Results The committee developed fundamental values principles and policy recommendations for integrating palliative care in serious respiratory illness care across seven domains 1 delivery models 2 comprehensive symptom assessment and management 3 advance care planning and goals of care discussions 4 caregiver support 5 health disparities 6 mass casualty events and emergency preparedness and 7 research priorities The recommendations encourage timely integration of palliative care promote innovative primary and secondary or specialist palliative care delivery models and advocate for research and policy initiatives to improve the availability and quality of palliative care for patients and their caregivers Conclusions This multisociety policy statement establishes a framework for early palliative care in serious respiratory illness and provides guidance for pulmonary critical care clinicians and policymakers for its proactive integration Copyright 2022 by the American Thoracic Society

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is increasingly recognized as the consequence of a pathological reparative response of the developing lung to both antenatal and postnatal injury. According to this view, the pathogenesis of BPD is multifactorial and heterogeneous with different patterns of antenatal stress (endotypes) that combine with varying postnatal insults and might distinctively damage the development of airways, lung parenchyma, interstitium, lymphatic system, and pulmonary vasculature. This results in different clinical phenotypes of BPD. There is no clear consensus on which are the endotypes of prematurity but the combination of clinical information with placental and bacteriological data enables the identification of two main pathways leading to birth before 32 weeks of gestation: (1) infection/inflammation and (2) dysfunctional placentation. Regarding BPD phenotypes, the following have been proposed: parenchymal, peripheral airway, central airway, interstitial, congestive, vascular, and mixed phenotype. In line with the approach of personalized medicine, endotyping prematurity and phenotyping BPD will facilitate the design of more targeted therapeutic and prognostic approaches.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease with an unknown cause. Uncertainties still remain regarding the pathogenesis of IPF, and the prognosis of this disease is poor despite some recent improvements in treatment. Radiation induced lung injury (RILI) is a common complication and a dose-limiting toxicity of thoracic radiotherapy. Importantly, IPF is a crucial risk factor for pulmonary toxicity after thoracic radiotherapy. Although IPF is not universally accepted as a definite contraindication for thoracic radiotherapy at present, it has been shown that IPF can increase the risk of severe and fatal complications after thoracic radiotherapy. Proton beam therapy has shown promising results in reducing the incidence of thoracic radiotherapy related life-threatening complications in IPF patients, but the current evidence is not sufficient to recommend the standard use of it. Many similarities are noticeable between IPF and RILI in terms of pathogenesis and underlying mechanisms. Better understanding of the mechanisms of IPF and RILI may enable clinicians to provide safer and more effective thoracic radiotherapy treatments in cancer patients with IPF. In this review, we summarize the current knowledge of IPF, present the importance of IPF in radiation oncology practice, and highlight the similarities and relationship between IPF and RILI. (C) 2020 Elsevier B.V. All rights reserved.

Thoracic involvement is one of the main determinants of morbidity and mortality in patients with autoimmune rheumatic diseases (ARDs), with different prevalence and manifestations according to the underlying disease. Interstitial lung disease (ILD) is the most common pulmonary complication, particularly in patients with systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIMs) and rheumatoid arthritis (RA). Other thoracic manifestations include pulmonary arterial hypertension (PAH), mostly in patients with SSc, airway disease, mainly in RA, and pleural involvement, which is common in systemic lupus erythematosus and RA, but rare in other ARDs.In this review, we summarize and critically discuss the current knowledge on thoracic involvement in ARDs, with emphasis on disease pathogenesis and management. Immunosuppression is the mainstay of therapy, particularly for ARDs-ILD, but it should be reserved to patients with clinically significant disease or at risk of progressive disease. Therefore, a thorough, multidisciplinary assessment to determine disease activity and degree of impairment is required to optimize patient management. Nevertheless, the management of thoracic involvement—particularly ILD—is challenging due to the heterogeneity of disease pathogenesis, the variety of patterns of interstitial pneumonia and the paucity of randomized controlled clinical trials of pharmacological intervention. Further studies are needed to better understand the pathogenesis of these conditions, which in turn is instrumental to the development of more efficacious therapies.

Objectives Nailfold videocapillaroscopy (NVC) plays a well-established role in differentiating primary from secondary RP due to SSc. However, the association of NVC with novel severe organ involvement/progression in SSc has never been evaluated in a multicentre, multinational study, which we now perform for the first time. Methods Follow-up data from 334 SSc patients [265 women; 18 limited SSc (lSSc)/203 lcSSc/113 dcSSc] registered between November 2008 and January 2016 by seven tertiary centres in the EUSTAR-database, were analysed. Novel severe organ involvement/progression was defined as new/progressive involvement of the peripheral vasculature, lungs, heart, skin, gastrointestinal tract, kidneys, musculoskeletal system, or death, at the 12- or 24-month follow-up. NVC images at enrolment were quantitatively and qualitatively evaluated according to the standardized definitions of the EULAR Study Group on Microcirculation in Rheumatic Diseases. Uni- and multivariable logistic regression modelling (ULR, MLR) was performed. Results Of the 334 included SSc patients, 257 (76.9%) developed novel overall severe organ involvement/progression. Following MLR, normal capillary density was associated with less-frequent novel overall severe organ involvement/progression [odds ratio (OR) = 0.77, P Conclusions Our results suggest that NVC may be a promising biomarker in SSc, certainly warranting further investigation. Despite the participation of tertiary centres, which follow their patients in a standardized way, we were underpowered to detect associations with infrequent severe organ involvement/progression.

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International audience; In eukaryotic cells, the balance between the synthesis and the degradation decides the steady-state levels of messenger RNAs (mRNA). The removal of adenosine residues from the poly(A) tail, called deadenylation, is the first and the most crucial step in the process of mRNA degradation. Poly (A)-specific ribonuclease (PARN) is one such enzyme that catalyses the process of deadenylation. Although PARN has been primarily known as the regulator of the mRNA stability, recent evidence clearly suggests several other functions of PARN, including a role in embryogenesis, oocyte maturation, cell-cycle progression, telomere biology, non-coding RNA maturation and ribosome biogenesis. Also, deregulated PARN activity is shown to be a hallmark of specific disease conditions. Pathogenic variants in the RN gene have been observed in various cancers and inherited bone marrow failure syndromes. The focus in this review is to highlight the emerging functions of PARN, particularly in the context of human diseases.

Health-related quality of life (HRQoL), though rarely considered as a primary endpoint in clinical trials, may be the single outcome reflective of patient priorities when living with a health condition. HRQoL is a multi-dimensional concept that reflects the degree to which a health condition interferes with participation in and fulfillment of important life areas. HRQoL is intended to capture the composite degree of physical, physiologic, psychological, and social impairment resulting from symptom burden, patient-perceived disease severity, and treatment side effects. Diminished HRQoL expectedly correlates to worsening disability and death; but interventions addressing HRQoL are linked to increased survival. Sarcoidosis, being a multi-organ system disease, is associated with a diffuse array of manifestations resulting in multiple symptoms, complications, and medication-related side effects that are linked to reduced HRQoL. Diminished HRQoL in sarcoidosis is related to decreased physical function, pain, significant loss of income, absence from work, and strain on personal relationships. Symptom distress can result clearly from a sarcoidosis manifestation (e.g., ocular pain, breathlessness, cough) but may also be non-specific, such as pain or fatigue. More complex, a single non-specific symptom, e.g., fatigue may be directly sarcoidosis-derived (e.g., inflammatory state, neurologic, hormonal, cardiopulmonary), medication-related (e.g., anemia, sleeplessness, weight gain, sub-clinical infection), or an indirect complication (e.g., sleep apnea, physical deconditioning, depression). Identifying and distinguishing underlying causes of impaired HRQoL provides opportunity for treatment strategies that can greatly impact a patient’s function, well-being, and disease outcomes. Herein, we present a reference manual that describes the current state of knowledge in sarcoidosis-related HRQoL and distinguish between diverse causes of symptom distress and other influences on sarcoidosis-related HRQoL. We provide tools to assess, investigate, and diagnose compromised HRQoL and its influencers. Strategies to address modifiable HRQoL factors through palliation of symptoms and methods to improve the sarcoidosis health profile are outlined; as well as a proposed research agenda in sarcoidosis-related HRQoL.

Health-related quality of life (HRQoL), though rarely considered as a primary endpoint in clinical trials, may be the single outcome reflective of patient priorities when living with a health condition. HRQoL is a multi-dimensional concept that reflects the degree to which a health condition interferes with participation in and fulfillment of important life areas. HRQoL is intended to capture the composite degree of physical, physiologic, psychological, and social impairment resulting from symptom burden, patient-perceived disease severity, and treatment side effects. Diminished HRQoL expectedly correlates to worsening disability and death; but interventions addressing HRQoL are linked to increased survival. Sarcoidosis, being a multi-organ system disease, is associated with a diffuse array of manifestations resulting in multiple symptoms, complications, and medication-related side effects that are linked to reduced HRQoL. Diminished HRQoL in sarcoidosis is related to decreased physical function, pain, significant loss of income, absence from work, and strain on personal relationships. Symptom distress can result clearly from a sarcoidosis manifestation (e.g., ocular pain, breathlessness, cough) but may also be non-specific, such as pain or fatigue. More complex, a single non-specific symptom, e.g., fatigue may be directly sarcoidosis-derived (e.g., inflammatory state, neurologic, hormonal, cardiopulmonary), medication-related (e.g., anemia, sleeplessness, weight gain, sub-clinical infection), or an indirect complication (e.g., sleep apnea, physical deconditioning, depression). Identifying and distinguishing underlying causes of impaired HRQoL provides opportunity for treatment strategies that can greatly impact a patient's function, well-being, and disease outcomes. Herein, we present a reference manual that describes the current state of knowledge in sarcoidosis-related HRQoL and distinguish between diverse causes of symptom distress and other influences on sarcoidosis-related HRQoL. We provide tools to assess, investigate, and diagnose compromised HRQoL and its influencers. Strategies to address modifiable HRQoL factors through palliation of symptoms and methods to improve the sarcoidosis health profile are outlined; as well as a proposed research agenda in sarcoidosis-related HRQoL.

The CIRO Academy in Horn (the Netherlands) organised a 2-day meeting to present and discuss the studies published in 2017 pertaining to key priority areas of respiratory and critical care medicine. This review summarises studies focussing on pulmonary rehabilitation and exercise training, physical activity, chronic respiratory failure and palliative respiratory care published in 2017.

Idiopathic inflammatory myopathies (IIM) are a group of diseases characterized by immune-mediated muscular lesions that may be associated with extra-muscular manifestations involving skin, lungs, heart or joints. Four main groups of IIM can be distinguished: dermatomyositis (DM), overlap myositis including mainly anti-synthetase syndrome (ASS), immune mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Myositis-specific autoantibodies (MSA) are increasingly recognized as valuable tools for diagnosis, classification and prognosis of IIM. For example, ASS is associated with anti-aminoacyl tRNA synthetase antibodies (anti-Jo-1, PL-7, PL-12, …), IMNM with anti-SRP and anti-HMGCR; IBM with anti-cytosolic 5'nucleotidase 1A (cN1A), and DM with anti-Mi-2, anti-MDA-5, anti-TIF-1γ, anti-NXP-2 and anti-SAE. Moreover, anti-MDA-5 is associated with amyopathic myositis and interstitial lung disease and anti-TIF-1γ and anti-NXP-2 with juvenile DM as well as malignancy in patients >40 years. Most MSA have initially been discovered by immunoprecipitation. In routine laboratories, however, MSA are screened for by indirect immunofluorescence and identified by (automated) monospecific immunoassays or by multispecific immunoassays (mainly line/dot immunoassays). Validation of these (multispecific) assays is a challenge as the antibodies are rare and the assays diverse. In this review, we give an overview of the (clinical) performance characteristics of monospecific assays as well as of multispecific assays for detection of MSA. Although most assays are clinically useful, there are differences between techniques and between manufacturers. We discuss that efforts are needed to harmonize and standardize detection of MSA. ispartof: AUTOIMMUNITY REVIEWS vol:18 issue:3 pages:293-305 ispartof: location:Netherlands status: published

Idiopathic inflammatory myopathies (IIM) are a group of diseases characterized by immune-mediated muscular lesions that may be associated with extra-muscular manifestations involving skin, lungs, heart or joints. Four main groups of IIM can be distinguished: dermatomyositis (DM), overlap myositis including mainly anti-synthetase syndrome (ASS), immune mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Myositis-specific autoantibodies (MSA) are increasingly recognized as valuable tools for diagnosis, classification and prognosis of IIM. For example, ASS is associated with anti-aminoacyl tRNA synthetase antibodies (anti-Jo-1, PL-7, PL-12,...), IMNM with anti-SRP and anti-HMGCR; IBM with anti-cytosolic 5'nucleotidase 1A (cN1A), and DM with anti-Mi-2, anti-MDA-5, anti-TIF-1y, anti-NXP-2 and anti-SAE. Moreover, anti-MDA-5 is associated with amyopathic myositis and interstitial lung disease and anti-TIF-1y and anti-NXP-2 with juvenile DM as well as malignancy in patients > 40 years. Most MSA have initially been discovered by immunoprecipitation. In routine laboratories, however, MSA are screened for by indirect immunofluorescence and identified by (automated) monospecific immunoassays or by multispecific immunoassays (mainly line/dot immunoassays). Validation of these (multispecific) assays is a challenge as the antibodies are rare and the assays diverse. In this review, we give an overview of the (clinical) performance characteristics of monospecific assays as well as of multispecific assays for detection of MSA. Although most assays are clinically useful, there are differences between techniques and between manufacturers. We discuss that efforts are needed to harmonize and standardize detection of MSA.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with great variability in disease severity and rate of progression. The need for a reliable, sensitive, and objective biomarker to track disease progression and response to therapy remains a great challenge in IPF clinical trials. Over the past decade, quantitative computed tomography (QCT) has emerged as an area of intensive research to address this need. We have gathered a group of pulmonologists, radiologists and scientists with expertise in this area to define the current status and future promise of this imaging technique in the evaluation and management of IPF. In this Pulmonary Perspective, we review the development and validation of six computer-based QCT methods and offer insight into the optimal use of an imaging-based biomarker as a tool for prognostication, prediction of response to therapy, and potential surrogate endpoint in future therapeutic trials.

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is increasingly recognized as the consequence of a pathological reparative response of the developing lung to both antenatal and postnatal injury. According to this view, the pathogenesis of BPD is multifactorial and heterogeneous with different patterns of antenatal stress (endotypes) that combine with varying postnatal insults and might distinctively damage the development of airways, lung parenchyma, interstitium, lymphatic system, and pulmonary vasculature. This results in different clinical phenotypes of BPD. There is no clear consensus on which are the endotypes of prematurity but the combination of clinical information with placental and bacteriological data enables the identification of two main pathways leading to birth before 32 weeks of gestation: (1) infection/inflammation and (2) dysfunctional placentation. Regarding BPD phenotypes, the following have been proposed: parenchymal, peripheral airway, central airway, interstitial, congestive, vascular, and mixed phenotype. In line with the approach of personalized medicine, endotyping prematurity and phenotyping BPD will facilitate the design of more targeted therapeutic and prognostic approaches.

Juvenile systemic sclerosis (JSSc) is a rare disease of childhood and currently no international consensus exists with regard to its assessment and treatment. This SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) initiative, based on expert opinion informed by the best available evidence, provides recommendations for the assessment and treatment of patients with JSSc with a view to improving their outcome. Experts focused attention not only on the skin assessment but also on the early signs of internal organ involvement whose proper treatment can significantly affect the long-term outcome. A score for disease severity is proposed in order to perform a structured assessment of outcome over time but a validation in a wider patient population is recommended. Finally, a stepwise treatment approach is proposed in order to unify the standard of care throughout Europe with the aim to reduce morbidity and mortality in this disease. European Agency for Health and Consumers (EAHC) [20111202] The SHARE project was supported by a grant from the European Agency for Health and Consumers (EAHC), grant number 20111202.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease with an unknown cause. Uncertainties still remain regarding the pathogenesis of IPF, and the prognosis of this disease is poor despite some recent improvements in treatment. Radiation induced lung injury (RILI) is a common complication and a dose-limiting toxicity of thoracic radiotherapy. Importantly, IPF is a crucial risk factor for pulmonary toxicity after thoracic radiotherapy. Although IPF is not universally accepted as a definite contraindication for thoracic radiotherapy at present, it has been shown that IPF can increase the risk of severe and fatal complications after thoracic radiotherapy. Proton beam therapy has shown promising results in reducing the incidence of thoracic radiotherapy related life-threatening complications in IPF patients, but the current evidence is not sufficient to recommend the standard use of it. Many similarities are noticeable between IPF and RILI in terms of pathogenesis and underlying mechanisms. Better understanding of the mechanisms of IPF and RILI may enable clinicians to provide safer and more effective thoracic radiotherapy treatments in cancer patients with IPF. In this review, we summarize the current knowledge of IPF, present the importance of IPF in radiation oncology practice, and highlight the similarities and relationship between IPF and RILI. (C) 2020 Elsevier B.V. All rights reserved.

MUC5B rs35705950 (G/T) is strongly associated with idiopathic pulmonary fibrosis (IPF) and also contributes to the risk of interstitial lung disease (ILD) in rheumatoid arthritis (RA-ILD) and chronic hypersensitivity pneumonitis (CHP). Due to this, we evaluated the implication of MUC5B rs35705950 in antisynthetase syndrome (ASSD), a pathology characterised by a high ILD incidence. 160 patients with ASSD (142 with ILD associated with ASSD [ASSD-ILD+]), 232 with ILD unrelated to ASSD (comprising 161 IPF, 27 RA-ILD and 44 CHP) and 534 healthy controls were genotyped. MUC5B rs35705950 frequency did not significantly differ between ASSD-ILD+ patients and healthy controls nor when ASSD patients were stratified according to the presence/absence of anti Jo-1 antibodies or ILD. No significant differences in MUC5B rs35705950 were also observed in ASSD-ILD+ patients with a usual interstitial pneumonia (UIP) pattern when compared to those with a non-UIP pattern. However, a statistically significant decrease of MUC5B rs35705950 GT, TT and T frequencies in ASSD-ILD+ patients compared to patients with ILD unrelated to ASSD was observed. In summary, our study does not support a role of MUC5B rs35705950 in ASSD. It also indicates that there are genetic differences between ILD associated with and that unrelated to ASSD, This study was partially supported by grants from the Foundation for Research in Rheumatology (FOREUM). RL-M is a recipient of a Miguel Servet type I programme fellowship from the ‘Instituto de Salud Carlos III’ (ISCIII), cofunded by the European Social Fund (ESF, ‘Investing in your future’) (grant CP16/00033). SR-M is supported by funds of the RETICS Program (RD16/0012/0009), co-funded by the European Regional Development Fund (ERDF). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). VM is supported by funds of a Miguel Servet type I programme (grant CP16/00033) (ISCIII, co-funded by ESF). LL-G is supported by funds of PI18/00042 (ISCIII, co-funded by ERDF). OG is Staff Personnel of Xunta de Galicia (Servizo Galego de Saude, SERGAS) through a research-staff stabilization contract (ISCIII/SERGAS). OG,is member of RETICS Programme, RD16/0012/0014 (RIER: Red de Investigación en Inflamación y Enfermedades Reumáticas) via Instituto de Salud Carlos III (ISCIII) and FEDER. The work of OG (PI17/00409), was funded by Instituto de Salud Carlos III and FEDER. OG is a beneficiary of a project funded by Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme (Project number 734899). OG is beneficiary of a grant funded by Xunta de Galicia, Consellería de Educación, Universidade e Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN), GPC IN607B2019/10

Contains fulltext : 244673.pdf (Publisher’s version ) (Open Access) Many therapies have been investigated for systemic sclerosis-associated interstitial lung disease (SSc-ILD), including immunosuppressive therapies, antifibrotic agents, immunomodulators and monoclonal antibodies. There is a high unmet medical need to better understand the current evidence for treatment efficacy and safety. This systematic review aims to present the existing literature on different drug treatments investigated for SSc-ILD and to critically assess the level of evidence for these drugs. A systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A structured literature search was performed for clinical trials and observational studies on the treatment of SSc-ILD with pharmaceutical interventions from 1 January 1990 to 15 December 2020. The quality of each reference was assessed using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria. A total of 77 references were reviewed and 13 different treatments were identified. We found high-quality evidence for the use of cyclophosphamide, nintedanib, mycophenolate and tocilizumab. Therefore, we would posit that the clinical community has four valid options for treatment of SSc-ILD. Further research is mandatory to provide more evidence for the optimal treatment strategy in SSc-ILD, including the optimal time to initiate treatment, selection of patients for treatment and upfront combination therapy.

Introduction Simvastatin has previously been associated with drug-induced interstitial lung disease. In this retrospective observational study, cases with non-specific interstitial pneumonia (NSIP) or idiopathic pulmonary fibrosis (IPF) with simvastatin-associated pulmonary toxicity (n = 34) were evaluated. Objective To identify whether variations in genes encoding cytochrome P450 (CYP) enzymes or in the SLCO1B1 gene (Solute Carrier Organic anion transporting polypeptide 1B1 gene, encoding the organic anion transporting polypeptide 1B1 [OATP1B1] drug transporter enzyme), and/or characteristics of concomitantly used drugs, predispose patients to simvastatin-associated pulmonary toxicity. Methods Characteristics of concomitantly used drugs and/or variations in the CYP or SLCO1B1 genes and drug–gene interactions were assessed. The outcome after withdrawal of simvastatin and/or switch to another statin was assessed after 6 months. Results Multiple drug use involving either substrates and/or inhibitors of CYP3A4 and/or three or more drugs with the potential to cause acidosis explained the simvastatin-associated toxicity in 70.5% (n = 24) of cases. Cases did not differ significantly from controls regarding CYP3A4, CYP2C9, or OATP1B1 phenotypes, and genetic variation explained only 20.6% (n = 7) of cases. Withdrawal of simvastatin without switching to another statin or with a switch to a hydrophilic statin led to improvement or stabilization in all NSIP cases, whereas all cases who were switched to the lipophilic atorvastatin progressed. Conclusion Simvastatin-associated pulmonary toxicity is multifactorial. For patients with this drug-induced pulmonary toxicity who need to continue taking a statin, switching to a hydrophilic statin should be considered. ClinicalTrials.gov identifier NCT00267800, registered in 2005. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01105-8.

Rationale: The level of diagnostic likelihood at which physicians prescribe antifibrotic therapy without requesting surgical lung biopsy (SLB) in patients suspected of idiopathic pulmonary fibrosis (IPF) is unknown. Objectives: To determine how often physicians advocate SLB in patient subgroups defined by IPF likelihood and risk associated with SLB, and to identify the level of diagnostic likelihood at which physicians prescribe antifibrotic therapy with requesting SLB. Methods: An international cohort of respiratory physicians evaluated 60 cases of interstitial lung disease, giving: 1) differential diagnoses with diagnostic likelihood; 2) a decision on the need for SLB; and 3) initial management. Diagnoses were stratified according to diagnostic likelihood bands described by Ryerson and colleagues. Measurements and Main Results: A total of 404 physicians evaluated the 60 cases (24,240 physician-patient evaluations). IPF was part of the differential diagnosis in 9,958/24,240 (41.1%) of all physician-patient evaluations. SLB was requested in 8.1%, 29.6%, and 48.4% of definite, provisional high-confidence and provisional low-confidence diagnoses of IPF, respectively. In 63.0% of provisional high-confidence IPF diagnoses, antifibrotic therapy was prescribed without requesting SLB. No significant mortality difference was observed between cases given a definite diagnosis of IPF (90-100% diagnostic likelihood) and cases given a provisional high-confidence IPF diagnosis (hazard ratio, 0.97; P = 0.65; 95% confidence interval, 0.90-1.04). Conclusions: Most respiratory physicians prescribe antifibrotic therapy without requesting an SLB if a provisional high-confidence diagnosis or "working diagnosis" of IPF can be made (likelihood>70%). SLB is recommended in only a minority of patients with suspected, but not definite, IPF.

This guideline were initiated by DEBRA International; financial support was provided by DEBRA Austria. The generous assistance of Rebecca Bodan, Lisa Brains, Sharon Cassidy and Kelsey Townsend-Miller is gratefully acknowledged in providing patient or lay input into this guideline. The authors acknowledge the guidance of Kattya Mayre-Chilton (DEDRA International). Johann Bauer (Paracelsus University and EB House, Salzburg, Austria), Christine Bodemer (Hôpital Universitaire Necker, Paris, France), Judith Fischer (Institute of Human Genetics, University of Freiburg, Germany), Jemima Mellerio (St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, U.K.), Francis Palisson (Universidad del Desarrollo and DEBRA, Chile), Eli Sprecher (Department of Dermatology, Tel Aviv Sourasky Medical Center, Israel) and Jouni Uitto, Leila Youssefian and Hassan Vahidnezhad (all from the Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, U.S.A.) are acknowledged as reviewers.

Recurrent severe bacterial and fungal infections are characteristic features of the rare genetic immunodeficiency disorder chronic granulomatous disease (CGD). The disease usually manifests within the first years of life with an incidence of 1 in approximately 200,000 live births. The incidence is higher in Iran and Morocco where it reaches 1.5 per 100,000 live births. Mutations have been described in the 5 subunits of NADPH oxidase, mostly in gp91phox and p47phox, with fewer mutations reported in p67phox, p22phox, and p40phox. These mutations cause loss of superoxide production in phagocytic cells. CYBB, the gene encoding the large gp91phox subunit of the transmembrane component cytochrome b558 of the NADPH oxidase complex, is localized on the X-chromosome. Genetic defects in CYBB are responsible for the disease in the majority of male CGD patients. CGD is associated with the development of granulomatous reactions in the skin, lungs, bones, and lymph nodes, and chronic infections may be seen in the liver, gastrointestinal tract, brain, and eyes. There is usually a history of repeated infections, including inflammation of the lymph glands, skin infections, and pneumonia. There may also be a persistent runny nose, inflammation of the skin, and inflammation of the mucous membranes of the mouth. Gastrointestinal problems can also occur, including diarrhea, abdominal pain, and perianal abscesses. Infection of the bones, brain abscesses, obstruction of the genitourinary tract and/or gastrointestinal tract due to the formation of granulomatous tissue, and delayed growth are also symptomatic of CGD. The prevention of infectious complications in patients with CGD involves targeted prophylaxis against opportunistic microorganisms such as Staphylococcus aureus, Klebsiella spp., Salmonella spp. and Aspergillus spp. In this review, we provide an update on organ involvement and the association with specific isolated microorganisms in CGD patients.

PubMed: 31227488, Objectives Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database. Methods Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12±3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression. Results Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model. Conclusions The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ., Bayer Bayer, United Kingdom Université Paris Descartes Li Ka Shing Foundation, LKSF University of Michigan, U-M, 1Department of Rheumatology and the Centre of experimental Rheumatology, University Hospital Zurich, Zurich, switzerland 2Graf Biostatistics, Winterthur, switzerland 3Big Data institute, li Ka shing Centre for Health information and Discovery, nuffield Department of Medicine, University of Oxford, Oxford, UK 4Rheumatology a Department, Paris Descartes University, sorbonne Paris Cité, Cochin Hospital, Paris, France 5Data science and analytics, Bayer plc, Reading, UK 6UCl Division of Medicine, Royal Free Campus, london, UK 7Division of Rheumatology, Department of internal Medicine, University of Michigan scleroderma Program, University of Michigan, ann arbor, Michigan, Usa 8Department of experimental and Clinical Medicine, University of Florence, Florence, italy 9Bayer Us llC, Whippany, new Jersey, Usa 10Department of Medicine, Division of Rheumatology, University of Western Ontario, st. Joseph’s Health Care, london, Ontario, Canada Acknowledgements The R-code for the linear Mi-lassO was received from Qixuan Chen.21 Medical writing assistance was provided by adelphi Communications ltd (Bollington, UK), funded by Bayer aG (Berlin, Germany)., Contributors study conception and design, acquisition of data, analysis and interpretation of data and drafting and revising the article: OD and MB; analysis and interpretation of data: OD, MB, Rs and nG. all authors have critically reviewed and approved the final submitted version to be published. Funding This study was supported by a grant from Bayer aG. Bayer employees are coauthors of this paper and supported the study design and interpretation of the data, but otherwise Bayer had no influence on the study., Competing interests MOB declares no conflict of interest. OD has had consultancy relationships with actelion, Bayer, Biogen idec, Boehringer ingelheim, Chemomab, espeRare foundation, Genentech/Roche, GsK, inventiva, italfarmaco, lilly, medac, Medimmune, Mitsubishi Tanabe Pharma, Pharmacyclics, novartis, Pfizer, sanofi, sinoxa and UCB in the area of potential treatments of scleroderma and its complications. OD has received research funding from actelion, Bayer, Boehringer ingelheim, Mitsubishi Tanabe Pharma and Roche in the area of potential treatments of scleroderma and its complications. OD has a patent for mir-29 licensed for the treatment of systemic sclerosis. DK has consultancy relationships and/or has received grant/research support from Bayer, Bristol-Myers squibb, Boehringer ingelheim, Genentech/Roche, niH, Pfizer, sanofi-aventis Pharmaceuticals, actelion Pharmaceuticals Us, Chemomab, Corbus, Covis, Cytori, eicos, eMD serono, Gilead, GlaxosmithKline, and UCB Pharma. He is a shareholder of eicos. CPD has consultancy relationships with and/or has received speakers’ bureau fees from actelion Pharmaceuticals Us, Bayer aG, GlaxosmithKline, Csl Behring, Merck serono, Roche Pharmaceuticals, Genentech and Biogen iDeC inc., inventiva, sanofi-aventis Pharmaceuticals and Boehringer ingelheim. JeP has consultancy relationships with and/or has received grant/research support from actelion, Bayer aG, Bristol-Myers squibb, Merck, Pfizer inc. and Roche. MM-C has consultancy relationships and/ or has received grant/research support from Pfizer, Bristol-Myers squibb, actelion, UCB Pharma, Bayer, Chemomab, Genentech/Roche, inventiva and lilly. Ya has consultancy relationships with and/or has received grant/research support from actelion, Pharmaceuticals Us, Bayer aG, Bristol-Myers squibb, inventiva, Medac, Pfizer inc., Roche Pharmaceuticals, Genentech and Biogen iDeC inc., sanofi-aventis Pharmaceuticals and servier. JdOP and JC are employees of Bayer. nTG has nothing to disclose.

Introduction Pulmonary fibrosis (PF) and its most common form, idiopathic pulmonary fibrosis (IPF), are chronic, progressive diseases resulting in increasing loss of lung function and impaired quality of life and survival. The aim of this joint expert and patient statement was to highlight the most pressing common unmet needs of patients with PF/IPF, putting forward recommendations to improve the quality of life and health outcomes throughout the patient journey. Methods Two online surveys for patients and healthcare professionals (HCPs) were conducted by the European Idiopathic Pulmonary Fibrosis and Related Disorders Federation (EU-IPFF) in 14 European countries. Results The surveys were answered by 286 patients and 69 HCPs, including physicians and nurses. Delays in diagnosis and timely access to interstitial lung disease specialists and pharmacological treatment have been identified as important gaps in care. Additionally, patients and HCPs reported that a greater focus on symptom-centred management, adequate information, trial information and increasing awareness of PF/IPF is required. Conclusions The surveys offer important insights into the current unmet needs of PF/IPF patients. Interventions at different points of the care pathway are needed to improve patient experience., This joint expert and patient statement highlights the most pressing common unmet needs of patients with pulmonary fibrosis, and puts forward recommendations to improve the quality of life and health outcomes throughout the patient journey http://bit.ly/34cTOeo

Patients with common variable immunodeficiency (CVID) can develop immune dysregulation complications such as autoimmunity, lymphoproliferation, enteritis, and malignancy, which cause significant morbidity and mortality. We aimed to (i) assess the potential of serum proteomics in stratifying patients with immune dysregulation using two independent cohorts and (ii) identify cytokine and chemokine signaling pathways that underlie immune dysregulation in CVID. A panel of 180 markers was measured in two multicenter CVID cohorts using Olink Protein Extension Assay technology. A classification algorithm was trained to distinguish CVID with immune dysregulation (CVIDid, n = 14) from CVID with infections only (CVIDio, n = 16) in the training cohort, and validated on a second testing cohort (CVIDid n = 23, CVIDio n = 24). Differential expression in both cohorts was used to determine relevant signaling pathways. An elastic net classifier using MILR1, LILRB4, IL10, IL12RB1, and CD83 could discriminate between CVIDid and CVIDio patients with a sensitivity of 0.83, specificity of 0.75, and area under the curve of 0.73 in an independent testing cohort. Activated pathways (fold change > 1.5, FDR-adjusted p

Many patients with idiopathic pulmonary fibrosis (IPF) complain of chronic refractory cough. Chronic cough is a distressing and disabling symptom with a major impact on quality of life. During recent years, progress has been made in gaining insight into the pathogenesis of cough in IPF, which is most probably “multifactorial” and influenced by mechanical, biochemical and neurosensory changes, with an important role for comorbidities as well. Clinical trials of cough treatment in IPF are emerging, and cough is increasingly included as a secondary end-point in trials assessing new compounds for IPF. It is important that such studies include adequate end-points to assess cough both objectively and subjectively. This article summarises the latest insights into chronic cough in IPF. It describes the different theories regarding the pathophysiology of cough, reviews the different methods to assess cough and deals with recent and future developments in the treatment of cough in IPF.

Introduction: Primary Sjogren's syndrome (pSS) is a disabling auto-immune disease, affecting exocrine glands and several organs.Areas covered: In this review we analyze the safety of therapies used in pSS. Symptomatic treatment is widely applied due to the good supportive effect and good safety profile. Systemic stimulation of tears and saliva can be successful in pSS. However, cumbersome adverse events can influence the tolerability of this therapy. Evidence for the effectiveness of synthetic DMARDs therapies in pSS is limited, while there is a risk of adverse events. Several studies on biologic DMARD treatment of pSS patients have shown promising efficacy and safety results.Expert opinion: The safety of symptomatic treatment of pSS is very good. However, systemic therapy is necessary to achieve long-term relieve and prevention of organ-damage. Synthetic DMARDs have not shown much efficacy in earlier studies, and their benefits do not weigh up to the possible harms, while biologic DMARDs show promising results regarding efficacy and cause mostly mild adverse events. Many questions remain unanswered regarding safety of DMARDs in pSS. There is a need for well designed studies, in which safety should be evaluated in a uniform manner to be able to compare the results between studies.

Introduction: Primary Sjogren's syndrome (pSS) is a disabling auto-immune disease, affecting exocrine glands and several organs.Areas covered: In this review we analyze the safety of therapies used in pSS. Symptomatic treatment is widely applied due to the good supportive effect and good safety profile. Systemic stimulation of tears and saliva can be successful in pSS. However, cumbersome adverse events can influence the tolerability of this therapy. Evidence for the effectiveness of synthetic DMARDs therapies in pSS is limited, while there is a risk of adverse events. Several studies on biologic DMARD treatment of pSS patients have shown promising efficacy and safety results.Expert opinion: The safety of symptomatic treatment of pSS is very good. However, systemic therapy is necessary to achieve long-term relieve and prevention of organ-damage. Synthetic DMARDs have not shown much efficacy in earlier studies, and their benefits do not weigh up to the possible harms, while biologic DMARDs show promising results regarding efficacy and cause mostly mild adverse events. Many questions remain unanswered regarding safety of DMARDs in pSS. There is a need for well designed studies, in which safety should be evaluated in a uniform manner to be able to compare the results between studies.

Systemic sclerosis (SSc) is an orphan disease characterised by autoimmunity, fibrosis of the skin and internal organs, and vasculopathy. SSc may be associated with high morbidity and mortality. In this narrative review we summarise the results of a systematic literature research, which was performed as part of the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases project, aimed at evaluating existing clinical practice guidelines or recommendations. Only in the domains ‘Vascular & Ulcers’ (ie, non-pharmacological approach to digital ulcer), ‘PAH’ (ie, screening and treatment), ‘Treatment’ and ‘Juveniles’ (ie, evaluation of juveniles with Raynaud’s phenomenon) evidence-based and consensus-based guidelines could be included. Hence there is a preponderance of unmet needs in SSc referring to the diagnosis and (non-)pharmacological treatment of several SSc-specific complications. Patients with SSc experience significant uncertainty concerning SSc-related taxonomy, management (both pharmacological and non-pharmacological) and education. Day-to-day impact of the disease (loss of self-esteem, fatigue, sexual dysfunction, and occupational, nutritional and relational problems) is underestimated and needs evaluation.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease of unknown cause. Current evidence suggests that it arises in genetically susceptible individuals as a consequence of an aberrant wound-healing response following repetitive alveolar injury. Overt respiratory infection and immunosuppression carry a high mortality, while polymorphisms in genes related to epithelial integrity and host defence predispose to IPF. Recent advances in sequencing technologies have allowed the use of molecular microbial technologies to characterise the respiratory microbiota in patients with IPF. Studies have suggested that changes in the overall bacterial burden are related to disease progression and highlighted significant differences between the microbiota in IPF subjects and healthy controls. Indeed differences in the microbiota between IPF patients may differentiate those with stable compared to progressive disease. As our understanding of the IPF microbiome evolves, along with refinement and advances in sampling and sequencing methodologies we may be able to use microbial signatures as a biomarker to guide prognostication and even treatment stratification in this devastating disease.

Health-related quality of life or health status is significantly impaired in bronchiectasis. There is a paucity of brief, simple-to-use, disease-specific health status measures. The aim of this study was to develop and validate the Bronchiectasis Health Questionnaire (BHQ), a new health status measure that is brief and generates a single overall score.Patients with bronchiectasis were recruited from two outpatient clinics, during a clinically stable stage. The development of the questionnaire followed three phases: item generation and item reduction using Rasch analysis, validation, and repeatability testing. The BHQ was translated into 11 languages using standardised methodology.206 patients with bronchiectasis completed a preliminary 65-item questionnaire. 55 items were removed due to redundancy or poor fit to the Rasch model. The final version of the BHQ consisted of 10 items. Internal consistency was good (Cronbach's α=0.85). Convergent validity of the BHQ with the St George's Respiratory Questionnaire was high (r= −0.82; pversus no colonisation (p=0.048). The BHQ was highly repeatable after 2 weeks (intraclass correlation coefficient 0.89).The BHQ is a brief, valid and repeatable, self-completed health status questionnaire for bronchiectasis that generates a single total score. It can be used in the clinic to assess bronchiectasis from the patient's perspective.

RATIONALE: In the absence of a surgical lung biopsy, patients diagnosed with idiopathic pulmonary fibrosis (IPF) in clinical practice could participate in the INPULSIS® trials of nintedanib if they had honeycombing and/or traction bronchiectasis plus reticulation, without atypical features of usual interstitial pneumonia (UIP), on high-resolution computed tomography (HRCT). Thus the patients in these trials represented patients with definite UIP and a large subgroup of patients with possible UIP. OBJECTIVE: We investigated the potential impact of diagnostic subgroups on the progression of IPF and effect of nintedanib. METHODS: Post-hoc subgroup analysis of patients with honeycombing on HRCT and/or confirmation of UIP by biopsy versus patients without either, using pooled data from the INPULSIS® trials. MEASUREMENTS AND MAIN RESULTS: 723 (68.1%) patients had honeycombing and/or biopsy and 338 (31.9%) had no honeycombing or biopsy. In these subgroups, respectively, the adjusted annual rate of decline in forced vital capacity (FVC) in patients treated with placebo was -225.7 mL/year and -221.0 mL/year, and the nintedanib versus placebo difference in adjusted annual rate of decline in FVC was 117.0 mL/year (95% CI: 76.3, 157.8) and 98.9 mL/year (95% CI: 36.4, 161.5). There was no significant treatment-by-subgroup interaction (p=0.8139). Adverse events were similar between subgroups. CONCLUSION: Patients with IPF diagnosed in clinical practice who have possible UIP with traction bronchiectasis on HRCT and have not undergone surgical lung biopsy have disease that progresses in a similar way, and responds similarly to nintedanib, as patients with honeycombing on HRCT and/or confirmation of UIP by biopsy. Clinical trial registration available at www.clinicaltrials.gov, IDs NCT01335464 and NCT01335477.

The complexity of central breathing disturbances during sleep has become increasingly obvious. They present as central sleep apnoeas (CSAs) and hypopnoeas, periodic breathing with apnoeas, or irregular breathing in patients with cardiovascular, other internal or neurological disorders, and can emerge under positive airway pressure treatment or opioid use, or at high altitude. As yet, there is insufficient knowledge on the clinical features, pathophysiological background and consecutive algorithms for stepped-care treatment. Most recently, it has been discussed intensively if CSA in heart failure is a “marker” of disease severity or a “mediator” of disease progression, and if and which type of positive airway pressure therapy is indicated. In addition, disturbances of respiratory drive or the translation of central impulses may result in hypoventilation, associated with cerebral or neuromuscular diseases, or severe diseases of lung or thorax. These statements report the results of an European Respiratory Society Task Force addressing actual diagnostic and therapeutic standards. The statements are based on a systematic review of the literature and a systematic two-step decision process. Although the Task Force does not make recommendations, it describes its current practice of treatment of CSA in heart failure and hypoventilation.

Idiopathic pulmonary fibrosis (IPF) is a fatal progressive lung disease occurring in adults. In the last decade, the results of a number of clinical trials based on the updated disease classification have been published. The registration of pirfenidone and nintedanib, the first two pharmacological treatment options approved for IPF, marks a new chapter in the management of patients with this disease. Other nonpharmacological treatments such as lung transplantation, rehabilitation and palliation have also been shown to be beneficial for these patients. In this review, past and present management is discussed based on a comprehensive literature search. A treatment algorithm is presented based on available evidence and our overall clinical experience. In addition, unmet needs with regard to treatment are highlighted and discussed. We describe the development of various treatment options for IPF from the first consensus to recent guidelines based on evidence from large-scale, multinational, randomized clinical trials, which have led to registration of the first drugs for IPF.

Sjögren's syndrome (SjS) is a systemic autoimmune disease that mainly affects the exocrine glands, leading to generalized mucosal dryness. However, primary SjS may initially present with non-sicca (systemic) manifestations. When these features appear before the onset of an overt sicca syndrome, we may talk of an underlying 'occult' SjS. The European League Against Rheumatism (EULAR) has promoted and supported an international collaborative study group (EULAR-SS Task Force) aimed at developing consensual recommendations to provide a homogeneous approach to the patient with primary SjS presenting with systemic involvement. This review summarizes the key factors that should be taken into account in the diagnostic approach in a patient with suspected SjS according to the main clinical patterns of presentation, and is especially focused on organ-specific systemic disease presentations, including a consensus set of recommendations in order to reach an early diagnosis. Close collaboration with the different specialties involved through a comprehensive multidisciplinary approach is essential in SjS patients presenting with systemic involvements.

Cardiac scars, often dubbed 'dead tissue', are very much alive, with heterocellular activity contributing to the maintenance of structural and mechanical integrity following heart injury. To form a scar, non-myocytes such as fibroblasts are recruited from intra- and extra-cardiac sources. Fibroblasts perform important autocrine and paracrine signaling functions. They also establish mechanical and, as is increasingly evident, electrical junctions with other cells. While fibroblasts were previously thought to act simply as electrical insulators, they may be electrically connected among themselves and, under some circumstances, to other cells including cardiomyocytes. A better understanding of these biophysical interactions will help to target scar structure and function, and will facilitate the development of novel therapies aimed at modifying scar properties for patient benefit.

The idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of chronic disorders that include dermatomyositis (DM), polymyositis (PM), sporadic inclusion body myositis (IBM) and necrotizing autoimmune myopathy (NAM). They represent distinct pathological entities that, most often, share predominant inflammation in muscle tissue. Many of the immunopathogenic processes behind the IIM remain poorly understood, but the crucial role of cytokines as essential regulators of the intramuscular build-up of inflammation is undisputed. This review describes the extensive cytokine network within IIM muscle, characterized by strong expression of Tumor Necrosis Factors (TNFα, LTβ, BAFF), Interferons (IFNα/β/γ), Interleukins (IL-1/6/12/15/18/23) and Chemokines (CXCL9/10/11/13, CCL2/3/4/8/19/21). Current therapeutic strategies and the exploration of potential disease modifying agents based on manipulation of the cytokine network are provided. Reported responses to anti-TNFα treatment in IIM are conflicting and new onset DM/PM has been described after administration of anti-TNFα agents to treat other diseases, pointing to the complex effects of TNFα neutralization. Treatment with anti-IFNα has been shown to suppress the IFN type 1 gene signature in DM/PM patients and improve muscle strength. Beneficial effects of anti-IL-1 and anti-IL-6 therapy have also been reported. Cytokine profiling in IIM aids the development of therapeutic strategies and provides approaches to subtype patients for treatment outcome prediction. peerReviewed

Patient-centredness is an accepted term and is perceived by healthcare professionals to be morally and ethically desirable. We are motivated by the belief that this approach will improve the patient-professional experience of the decision-making process and improve health outcomes. We acknowledge that patients, either as participants or as co-investigators, have positive contributions to make to research. As the idiopathic pulmonary fibrosis (IPF) community enters a new era of clinical research activity we consider that there is greater capacity for patient involvement and partnership. Patient involvement in research can be optimised through collaborations in the research design, study conduct, and dissemination. There is increasing interest in using patient- reported outcomes (PROs), such as health-related quality of life, and symptoms measures to inform decision-making and ensure patient perspectives are taken into account. PROs are an essential component of specialist IPF services, to monitor and improve care delivery and to measure and benchmark performance. In clinical trials, PROs can additionally be used to define entry criteria, evaluate efficacy of an intervention, and evaluate adverse events. We suggest that there is a much wider scope for including patient-centred PROs in clinical research and for creative thought in developing patient co-investigator roles. Participation in research activity requires highly refined decision-making processes, particularly in a condition such as IPF, which has an often unpredictable trajectory. The IPF research landscape has changed and the design and conduct of clinical trials in IPF requires some radical rethinking. It is accepted that involving patients in the role of co-investigators will impact the research questions we ask and result in study designs that are patient-centred. IPF clinical trials have been hindered by the lack of availability of validated, disease-specific questionnaires. A conservative approach appears to have been taken to the inclusion of generic symptom or quality of life measures as PRO endpoints. Thus, the impact of new drugs on the quality of life of research participants demonstrates only minimal benefit. It is time to refocus on a patient-centred approach with regards to the co-investigator role, PRO development, and research participants.

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The purpose of this study was to investigate the relationship between bronchoalveolar lavage (BAL)-derived parameters of interstitial lung disease and clinical and lung function parameters in 34 patients with sarcoidosis and 23 patients with idiopathic pulmonary fibrosis (IPF). BAL findings of healthy individuals served as controls. Cell content and differentiation of BAL fluid were determined. Oxygen radical (O2-) production of BAL cells and of blood polymorphonuclear (PMN) cells was measured. Phenotypes of lung and blood lymphocytes were determined by immunoperoxidase staining. In addition, lung function was assessed, chest X-rays were made and serum ACE was measured. Lymphocyte alveolitis in sarcoidosis was associated with increased alveolar macrophage (AM) O2- production (P < 0.025 vs. sarcoidosis with normal lymphocyte counts). Patients with extrapulmonary sarcoidosis had higher CD4/CD8 ratios in BAL (P < 0.025) and shorter disease duration (P < 0.01) than those with strictly pulmonary sarcoidosis. Disease duration in sarcoidosis correlated inversely with the number of BAL cells (r = -0.38, P < 0.05), the relative and absolute number of lymphocytes in BAL fluid (r = -0.34, P < 0.05 and r = -0.44, P < 0.01, respectively) and the percentage of CD4-positive cells and the CD4/CD8 ratio (r = -0.43, P < 0.05 and r = -0.48, P < 0.025, respectively). Although significant increases in O2- production by BAL cells were observed in both IPF and sarcoidosis, only in sarcoidosis was a higher AM O2- production associated with a significantly lower total lung capacity (r = -0.67, P < 0.005) and pulmonary diffusing capacity TLCO (r = -0.50, P < 0.05). In conclusion, our findings show that lung lymphocyte phenotypes differ among patients with pulmonary and extrapulmonary sarcoidosis and that O2- production is upregulated in active sarcoidosis. In addition, our findings suggest that different relationships between BAL data and lung function in patients with sarcoidosis and IPF may be explained by differences in disease duration. In IPF, disease duration is likely to be underestimated because of its insidious onset. In sarcoidosis, the presence of extrapulmonary symptoms, helpful to establish an early diagnosis, is associated with significant BAL lymphocytosis.