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Background/objective Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Interstitial lung disease (ILD) is an extra-articular manifestation of RA. We investigated incidence rates of ILD in patients with RA, receiving tofacitinib 5 or 10 mg twice daily, and identified potential risk factors for ILD. Methods This post hoc analysis comprised a pooled analysis of patients receiving tofacitinib 5 or 10 mg twice daily or placebo from 2 phase (P)1, 10 P2, 6 P3, 1 P3b/4, and 2 long-term extension studies. Interstitial lung disease events were adjudicated as "probable" (supportive clinical evidence) or "possible" (no supportive clinical evidence) compatible adverse events. Incidence rates (patients with events per 100 patient-years) were calculated for ILD events. Results Of 7061 patients (patient-years of exposure = 23,393.7), 42 (0.6%) had an ILD event; median time to ILD event was 1144 days. Incidence rates for ILD with both tofacitinib doses were 0.18 per 100 patient-years. Incidence rates generally remained stable over time. There were 17 of 42 serious adverse events (40.5%) of ILD; for all ILD events (serious and nonserious), 35 of 42 events (83.3%) were mild to moderate in severity. A multivariable Cox regression analysis identified age 65 years or older (hazard ratio 2.43 [95% confidence interval, 1.13-5.21]), current smokers (2.89 [1.33-6.26]), and Disease Activity Score in 28 joints-erythrocyte sedimentation rate score (1.30 [1.04-1.61]) as significant risk factors for ILD events. Conclusions Across P1/2/3/4/long-term extension studies, incidence rates for ILD events were 0.18 following tofacitinib treatment, and ILD events were associated with known risk factors for ILD in RA.

Contemporary studies of systemic sclerosis consistently demonstrate that interstitial lung disease is a leading cause of disease-related death. This review summarizes morbidity and mortality outcomes in systemic sclerosis-related interstitial lung disease patients from high-quality observational and interventional studies over the last 50 years. The data presented suggest a trend for improved morbidity and mortality outcomes among present day systemic sclerosis–associated interstitial lung disease patients. Specifically, systemic sclerosis–associated interstitial lung disease patients appear to be living longer from the time of the initial diagnosis. Despite improved survival, the number one cause of death for most systemic sclerosis–associated interstitial lung disease patients remains respiratory failure from interstitial lung disease. This review describes the most important demographic, clinical, and biological factors, which affect mortality in systemic sclerosis–associated interstitial lung disease, and could be used to help stratify patients for closer monitoring and more aggressive initial treatment. The review concludes with an overview of future research needed to (1) understand how to personalize the care of systemic sclerosis–associated interstitial lung disease patients to improve morbidity and mortality outcomes; and (2) investigate whether novel therapeutic interventions (e.g. anti-fibrotics, hematopoietic stem cell transplantation) offer any meaningful long-term survival advantage over the current standard of care.

Systemic sclerosis (SSc) is a progressive and often devastating disease characterized by autoimmune dysfunction, vasculopathy, and fibrosis. Interstitial lung disease (ILD) is identified in the majority of patients with SSc and is the leading cause of SSc-related mortality. Although clinical manifestations and ILD severity vary among patients, lung function typically declines to the greatest extent during the first 3-4 years after disease onset. We aim to provide an overview of SSc-associated ILD (SSc-ILD) with a focus on current and emerging tools for early diagnosis of ILD and current and novel treatments under investigation. Early detection of ILD provides the opportunity for early therapeutic intervention, which could improve patient outcomes. Thoracic high-resolution computed tomography is the most effective method of identifying ILD in patients with SSc; it enables detection of mild lung abnormalities and plays an important role in monitoring disease progression. Cyclophosphamide and mycophenolate mofetil are the most commonly prescribed treatments for SSc-ILD. Recently, nintedanib (an antifibrotic) was approved by the Food and Drug Administration for patients with SSc-ILD; it is indicated for slowing the rate of decline in pulmonary function. However, there is a need for additional effective and well-tolerated disease-modifying therapy. Ongoing studies are evaluating other antifibrotics and novel agents. We envision that early detection of lung involvement, combined with the emergence and integration of novel therapies, will lead to improved outcomes in patients with SSc-ILD.

IntroductionIdiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a poor prognosis. Treatment with antifibrotic agents can slow, but not halt, disease progression, and treatment discontinuation because of adverse events is common. Fibrotic diseases such as these can be mediated by lysophosphatidic acid (LPA), which signals via six LPA receptors (LPA1–6). Signalling via LPA1 appears to be fundamental in the pathogenesis of fibrotic diseases. BMS-986278, a second-generation LPA1 antagonist, is currently in phase 2 development as a therapy for IPF and PF-ILD.Methods and analysisThis phase 2, randomised, double-blind, placebo-controlled, parallel-group, international trial will include adults with IPF or PF-ILD. The trial will consist of a 42-day screening period, a 26-week placebo-controlled treatment period, an optional 26-week active-treatment extension period, and a 28-day post-treatment follow-up. Patients in both the IPF (n=240) and PF-ILD (n=120) cohorts will be randomised 1:1:1 to receive 30 mg or 60 mg BMS-986278, or placebo, administered orally two times per day for 26 weeks in the placebo-controlled treatment period. The primary endpoint is rate of change in per cent predicted forced vital capacity from baseline to week 26 in the IPF cohort.Ethics and disseminationThis study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication.Trial registration numberNCT04308681.

Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with limited treatment options. A phase 2 trial (NCT01766817) showed that twice-daily treatment with BMS-986020, a lysophosphatidic acid receptor 1 (LPASerum levels of nine ECM-neoepitope biomarkers were measured in patients with IPF. The association of biomarkers with baseline and change from baseline FVC and quantitative lung fibrosis as measured with high-resolution computed tomography, and differences between treatment arms using linear mixed models, were assessed. The Scar-in-a-Jar in vitro fibrogenesis model was used to further elucidate the antifibrotic mechanism of BMS-986020.In 140 patients with IPF, baseline ECM-neoepitope biomarker levels did not predict FVC progression but was significantly correlated with baseline FVC and lung fibrosis measurements. Most serum ECM-neoepitope biomarker levels were significantly reduced following BMS-986020 treatment compared with placebo, and several of the reductions correlated with FVC and/or lung fibrosis improvement. In the Scar-in-a-Jar in vitro model, BMS-986020 potently inhibited LPABMS-986020 reduced serum ECM-neoepitope biomarkers, which were previously associated with IPF prognosis. In vitro, LPA promoted fibrogenesis, which was LPA

To describe the phenotypic characteristics and natural history of patients with autoimmune forms of interstitial lung disease (ILD). Retrospective, descriptive, single-center study of patients with autoimmune forms of ILD evaluated between February 2008 and August 2014. All data were extracted from the electronic medical record. Longitudinal changes in forced vital capacity (FVC%) and diffusion capacity for carbon monoxide (DLco%) in percent predicted were analyzed and time-to-event analyses for death were performed using Cox regression. Of the entire cohort (n = 243), systemic sclerosis (SSc)-associated ILD (n = 88, 36%), interstitial pneumonia with autoimmune features (IPAF, n = 56, 23%), rheumatoid arthritis (RA)-associated ILD (n = 42, 17%), and idiopathic inflammatory myopathy (IIM)-associated ILD (n = 26, 11%) were the most common phenotypes. The SSc-ILD, IIM-ILD, and IPAF groups had similar features: average age in the mid-50s, strongly female predominant and more likely to have nonspecific interstitial pneumonia (NSIP). In contrast, RA-ILD patients were older, gender balanced, more likely to be past smokers and were UIP predominant. Adjusted longitudinal lung function was stable during a median follow-up period of nearly 4 years and the independent predictors for death were older age (p = 0.003), male sex (p = 0.019), and lower FVC (p =

The European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease put forth the research classification interstitial pneumonia with autoimmune features as a step toward uniformly describing these patients. Diverse nomenclature and classification schemes had been proposed to characterize them. This classification has provided uniform nomenclature and criteria, fostering interdisciplinary engagement and research. Longitudinal surveillance is needed; some patients evolve to a defined connective tissue disease. This review discusses cohort studies of interstitial pneumonia with autoimmune features and what they have taught us about the phenotype, and offers insights into future directions.

Interstitial lung disease (ILD) is a common manifestation of systemic autoimmune diseases and a leading cause of death in these patients. A proportion of patients with autoimmune ILDs develop a progressive fibrosing form of ILD, characterized by increasing fibrosis on high-resolution computed tomography, worsening of lung function, and early mortality. Autoimmune disease–related ILDs have a variable clinical course and not all patients will require treatment, but all patients should be monitored for signs of progression. Apart from systemic sclerosis–associated ILD, the limited evidence to support the efficacy of immunosuppression as a treatment for ILDs is based mainly on small retrospective series and expert opinion. Non-clinical data suggest that there are commonalities in the mechanisms that drive progressive fibrosis in ILDs with an immunological trigger as in other forms of progressive fibrosing ILD. This suggests that nintedanib and pirfenidone, drugs known to slow disease progression in patients with idiopathic pulmonary fibrosis, may also slow the progression of ILD associated with systemic autoimmune diseases. In the SENSCIS® trial, nintedanib reduced the rate of ILD progression in patients with systemic sclerosis–associated ILD. The results of other large clinical trials will provide further insights into the role of anti-fibrotic therapies in the treatment of autoimmune disease–related ILDs.

Introduction Interstitial lung disease (ILD) is a common manifestation of scleroderma/systemic sclerosis (SSc). However, the direct and indirect economic burdens of SSc-ILD remain unclear. This study assessed and compared healthcare resource utilization (HRU), direct healthcare costs, work loss, and indirect costs between patients with SSc-ILD and matched controls with neither SSc nor ILD in the USA. Methods Data were obtained from a large US commercial claims database (2005–2015). Patients (at least 18 years old) had at least one SSc diagnosis in the inpatient (IP) or emergency room (ER) setting or at least two SSc diagnoses in another setting, and at least one diagnosis of ILD in the IP or ER setting or at least two diagnoses of ILD in another setting. Controls with neither SSc nor ILD were matched 5:1 to patients with SSc-ILD. Comparisons were conducted using Wilcoxon signed-rank and McNemar’s tests and adjusted odds ratios (ORs) and incidence rate ratios (IRRs). Results A total of 479 SSc-ILD patients and 2395 matched controls were included (52 SSc-ILD patients and 260 matched controls for work loss and indirect cost analyses). Patients with SSc-ILD had significantly higher HRU and costs, IP admissions (adjusted IRR = 5.6), IP hospitalization days (adjusted IRR = 12.0), ER visits (adjusted IRR = 2.8), OP visits (adjusted IRR = 3.1), and days of work loss (adjusted IRR = 4.5). The adjusted difference in annual direct healthcare costs was $28,632 (SSc-ILD, $33,195; controls, $4562) and that in indirect costs was $4735 (SSc-ILD, $5640; controls, $906) (all p

Lung involvement in connective tissue diseases is associated with substantial morbidity and mortality, most commonly in the form of interstitial lung disease, and can occur in any of these disorders. Patterns of interstitial lung disease in patients with connective tissue disease are similar to those seen in idiopathic interstitial pneumonias, such as idiopathic pulmonary fibrosis. It may be difficult to distinguish between the 2 ailments, particularly when interstitial lung disease presents before extrapulmonary manifestations of the underlying connective tissue disease. There are important clinical implications in achieving this distinction. Given the complexities inherent in the management of these patients, a multidisciplinary evaluation is needed to optimize the diagnostic process and management strategies. The aim of this article was to summarize an approach to diagnosis and management based on the opinion of experts on this topic.

Introduction: Two antifibrotic medications (pirfenidone and nintedanib) were approved for the treatment of idiopathic pulmonary fibrosis (IPF) in the US in 2014. However, few studies have examined the real-world prevalence or patient (pt) characteristics associated with use of these therapies. Objectives: To analyze real-world data to determine the prevalence and characteristics of IPF pts treated with nintedanib or pirfenidone. Methods: Adult pts with an incident IPF diagnosis (based on ICD codes) between 10/01/14 and 03/31/18 in the US-based Optum Clinformatics Data Mart database were included. The index date was the initial IPF diagnosis date. Pts with other interstitial lung disease diagnoses were excluded. Rate of antifibrotic therapy use within 12 months of index was calculated. Baseline demographics, comorbid conditions, physician specialty, and healthcare utilization were compared between pts who did and did not receive antifibrotic therapy. Results: Among 2,925 identified IPF pts, 351 (12%) received antifibrotic therapy within 12 months. These pts were younger (73.2 vs 76.4 years), more likely to be male (65.0% vs 50.2%), and had a lower Charlson Comorbidity Index score (0.70 vs 1.16) than those who did not receive antifibrotic therapy (all p Conclusions: The uptake of antifibrotic medications appears to have been slow and the majority of real-world IPF patients remain untreated with these agents, indicating that the unmet need remains high in IPF.

Objective.Interstitial lung disease (ILD) is commonly associated with rheumatoid arthritis (RA) and can have significant morbidity and mortality. The objective of this study was to calculate the prevalence, incidence, healthcare costs, and mortality of RA-related ILD (RA-ILD) in the United States.Methods.This retrospective cohort analysis used the Truven Health MarketScan Commercial and Medicare Supplemental health insurance databases from 2003 to 2014 and the Social Security Administration death database. Patients with RA-ILD were selected based on diagnoses on medical claims. Outcomes were 1-year prevalence and incidence of RA-ILD among the general enrollee population, all-cause and respiratory-related healthcare costs (2014 US$), and all-cause survival for a subset of newly diagnosed patients with vital status information. This analysis was descriptive. No statistical testing was conducted.Results.Prevalence of RA-ILD ranged from 3.2 to 6.0 cases per 100,000 people across the 10-year period and incidence ranged from 2.7 to 3.8 cases per 100,000 people. There were 750 incident patients with 5 years of followup data. Over that time, 72% had an inpatient admission and 76% had an emergency room visit. Mean total 5-year costs were US$173,405 per patient (SD $158,837). Annual per-patient costs were highest in years 1 and 5. At 5 years after first diagnosis in the data, 35.9% of patients had died.Conclusion.Prevalence of RA-ILD increased over time. For patients who could be followed over a 5-year period, healthcare use and costs were somewhat stable over time, but were substantial. RA-ILD is associated with decreased survival.

Background Disease-specific patient-reported outcome (PRO) instruments are important in assessing the impact of disease and treatment. The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire is the first instrument for quantifying pulmonary arterial hypertension (PAH) symptoms and impacts developed according to the 2009 US Food and Drug Administration PRO guidance; previous qualitative research in patients with PAH supported its initial content validity. Methods Content finalization and psychometric validation were conducted by using data from A Study of Macitentan in Pulmonary Arterial Hypertension to Validate the PAH-SYMPACT (SYMPHONY), a single-arm, 16-week trial with macitentan 10 mg in US patients with PAH. Item performance, Rasch analysis, and factor analyses were used to select the final item content of the PRO and to define its domain structure. Internal consistency, test-retest reliability, known-group and construct validity, sensitivity to change, and influence of oxygen on item performance were evaluated. Results Data from 278 patients (79% female; mean age: 60 years) were analyzed. Following removal of redundant/misfitting items, the final questionnaire has 11 symptom items across two domains (cardiopulmonary and cardiovascular symptoms) and 11 impact items across two domains (physical and cognitive/emotional impacts). Differential item function analysis confirmed that PRO scoring is unaffected by oxygen use. For all four domains, internal consistency reliability was high (Cronbach's alpha > 0.80), and scores were highly reproducible in stable patients (intraclass correlation coefficient: 0.84-0.94). Correlations with the Cambridge Pulmonary Hypertension Outcome Review questionnaire and the 36-item Medical Outcomes Study Short Form Survey were moderate to high ([r] = 0.34-0.80). The questionnaire differentiated well between patients with varying disease severity levels and was sensitive to improvements in clinician- and patient-reported disease severity. Conclusions The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire is a brief, disease-specific PRO instrument possessing good psychometric properties that can be administered in clinical practice and clinical studies. Trial Registry ClinicalTrials.gov; No.: NCT01841762; URL: www.clinicaltrials.gov.

Digital ulcers (DU) are a common clinical problem in systemic sclerosis (SSc); however, there is no standardization of local wound care protocols for management of these lesions. There is a well-recognized need to develop and standardize non-pharmacological management of DU in patients with SSc, and to adopt these protocols in future clinical trials that focus on DU healing. The purpose of this review is to outline the types of DU that occur in SSc, and provide an update on the principles of wound management for these lesions based on the current literature and expert opinion.

Background Systemic sclerosis (SSc), or systemic scleroderma, is a chronic multisystem autoimmune disease characterised by widespread vascular injury and progressive fibrosis of the skin and internal organs. Patients with SSc have decreased survival, with pulmonary involvement as the main cause of death. Current treatments for SSc manage a range of symptoms but not the cause of the disease. Our review describes the humanistic and cost burden of SSc. Methods A structured review of the literature was conducted, using predefined search strategies to search PubMed, Embase, and the Cochrane Library. Grey literature searches also were conducted. Results In total, 2226 articles were identified in the databases and 52 were included; an additional 10 sources were included from the grey literature. The review identified six studies reporting relevant cost estimates conducted in five different countries and four studies that assessed the humanistic burden of SSc. Total direct annual medical costs per patient for Europe varied from €3544 to €8452. For Canada, these costs were reported to be from Can$5038 to Can$10,673. In the United States, the total direct health care costs were reported to be US$17,365 to US$18,396. Different key drivers of direct costs were reported, including hospitalisations, outpatients, and medication. The total annual costs per patient were reported at Can$18,453 in Canada and varied from €11,074 to €22,459 in Europe. Indirect costs represented the largest component of the total costs. EQ-5D utility scores were lower for patients with SSc than those observed in the general population, with reported mean values of 0.49 and 0.68, respectively. The average value of the Health Assessment Questionnaire for patients with SSc was significantly higher than the control population (0.94), and the average value of the SF-36 was significantly lower than the control population: 49.99 for the physical dimension and 58.42 for the mental dimension. Conclusions Overall, there is a paucity of information on the burden of SSc. Nonetheless, our review indicates that the quality of life of patients with SSc is considerably lower than that of the general population. In addition, SSc places a considerable economic burden on health care systems and society as a whole.

Introduction: There are no approved therapies for patients with uILD, who may have irreversible ILD. We evaluated efficacy and safety of pirfenidone in patients with progressive fibrosing uILD. Methods: This was a double-blind, randomised, placebo-controlled Phase II trial (NCT03099187). The primary endpoint was predicted FVC change over 24 weeks measured by daily home spirometry; secondary endpoints included changes in FVC (measured at site visits), DLco and 6MWD. Safety was also assessed. Results: 253 patients were randomised and 251 were treated (n=127 pirfenidone; n=124 placebo). Analysis of the primary endpoint was impacted by high intra-individual variability in home spirometry values in both treatment groups, amplified in patients with short observation periods, which prevented application of the planned statistical model. Median (Q1, Q3) FVC change (home spirometry) over 24 weeks was –87.7 mL (–338.1, 148.6) and –157.1 mL (–370.9, 70.1) in pirfenidone and placebo groups, respectively (Table). FVC change measured at site visits considerably favoured pirfenidone over placebo; results for DLco and 6MWD generally trended towards pirfenidone (Table). AE reporting reflected the known safety profile of pirfenidone. Conclusions: The planned statistical model could not be applied to the primary endpoint data. Results of key secondary endpoints suggest patients with progressive fibrosing uILD benefit from pirfenidone.

Summary Background At present, no approved pharmacotherapies are available for unclassifiable interstitial lung disease (ILD), which is characterised by progressive fibrosis of the lung. We aimed to assess the efficacy and safety of pirfenidone in patients with progressive fibrosing unclassifiable ILD. Methods We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 70 centres in Australia, Belgium, Canada, Czech Republic, Denmark, Germany, Greece, Ireland, Israel, Italy, Poland, Portugal, Spain, and the UK. Eligible patients (aged ≥18–85 years) had progressive fibrosing unclassifiable ILD, a percent predicted forced vital capacity (FVC) of 45% or higher and percent predicted carbon monoxide diffusing capacity (DLco) of 30% or higher, more than 10% fibrosis on high-resolution CT, and a high-resolution CT from the previous 12 months. Patients were randomly assigned (1:1) to 2403 mg oral pirfenidone daily or placebo using a central validated interactive voice or web-based response system, stratified by concomitant mycophenolate mofetil use and presence or absence of interstitial pneumonia with autoimmune features. Investigators, site personnel, and patients were masked to treatment assignment. The primary endpoint was mean predicted change in FVC from baseline over 24 weeks, measured by daily home spirometry. Secondary endpoints were change in FVC measured by site spirometry, proportion of patients who had a more than 5% or more than 10% absolute or relative decline in percent predicted FVC measured by clinic-based spirometry, change in percent predicted DLco, change in 6-min walk distance (6MWD), change in University of California San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) score, change in Leicester Cough Questionnaire score, change in cough visual analogue scale, and changes in total and subscores of the St George's Respiratory Questionnaire (SGRQ), all of which were compared with baseline. Additional secondary endpoints included proportion of patients who had non-elective hospitalisation (respiratory and all-cause) and acute exacerbations, and progression-free survival. Efficacy was analysed in the intention-to-treat (ITT) population, which included all randomly assigned patients. Safety was assessed in the safety analysis set, which included all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , NCT03099187 , and is no longer recruiting. Findings Between May 15, 2017, and June 5, 2018, 253 patients were randomly assigned to receive 2403 mg pirfenidone (n=127) or placebo (n=126) and were included in the ITT analysis set. Analysis of the primary endpoint was affected by intraindividual variability in home spirometry values, which prevented application of the prespecified statistical model. Over 24 weeks, predicted median change in FVC measured by home spirometry was −87·7 mL (Q1–Q3 −338·1 to 148·6) in the pirfenidone group versus −157·1 mL (−370·9 to 70·1) in the placebo group. Over 24 weeks, predicted mean change in FVC measured by site spirometry was lower in patients given pirfenidone than placebo (treatment difference 95·3 mL [95% CI 35·9 to 154·6], p=0·002). Compared with the placebo group, patients in the pirfenidone group were less likely to have a decline in FVC of more than 5% (odds ratio [OR] 0·42 [95% CI 0·25 to 0·69], p=0·001) or more than 10% (OR 0·44 [0·23 to 0·84], p=0·011). At week 24, mean change in DLco from baseline was −0·7% (SD 7·1) for the pirfenidone group and −2·5% (8·8) for the placebo group, and mean change in 6MWD from baseline was −2·0 m (68·1) for the pirfenidone group and −26·7 m (79·3) for the placebo group. Changes from baseline in UCSD-SOBQ, Leicester Cough Questionnaire score, cough visual analogue scale, and SGRQ scores were similar between the pirfenidone and placebo groups at week 24. Analysis of acute exacerbations, hospital admissions, and time to death from respiratory causes during the study yielded no meaningful results due to a small number of events. No differences in progression-free survival were identified between the pirfenidone and placebo groups, irrespective of the definition of progression-free survival used. Treatment-emergent adverse events were reported in 120 (94%) of 127 patients in the pirfenidone group and 101 (81%) of 124 patients in the placebo group. Serious treatment-emergent adverse events were reported in 18 (14%) patients in the pirfenidone group and 20 (16%) patients in the placebo group. The most common treatment-related treatment-emergent adverse events were gastrointestinal disorders (60 [47%] in the pirfenidone group vs 32 [26%] in the placebo group), fatigue (16 [13%] vs 12 [10%]), and rash (13 [10%] vs nine [7%]). Interpretation Although the planned statistical model could not be applied to the primary endpoint data, analysis of key secondary endpoints suggests that patients with progressive fibrosing unclassifiable ILD could benefit from pirfenidone treatment, which has an acceptable safety and tolerability profile. These findings support further investigation of pirfenidone as an effective treatment for patients with progressive fibrotic unclassifiable ILD. Funding F Hoffmann-La Roche.

Background In patients with idiopathic pulmonary fibrosis (IPF), nintedanib has a manageable adverse event (AE) profile characterised predominantly by gastrointestinal (GI) events. The efficacy and safety of nintedanib versus placebo in patients with SSc-ILD were investigated in the SENSCIS trial (NCT02597933). Objectives To characterise GI AEs associated with nintedanib therapy in the SENSCIS trial. Methods Patients with SSc-ILD with onset of first non-Raynaud symptom Results A total of 576 patients (288 per group) received ≥1 dose of nintedanib or placebo. Over 52 weeks, 13.9% and 7.3% of patients treated with nintedanib and placebo discontinued study treatment due to AEs. The most frequent AEs in patients treated with nintedanib were diarrhoea (75.7% vs 31.6%), nausea (31.6% vs 13.5%) and vomiting (24.7% vs 10.4%). Serious diarrhoea AEs were reported in 2 patients (0.7%) in each group, and serious vomiting AEs were reported in 2 patients (0.7%) in the placebo group and none in the nintedanib group. Of the 218 nintedanib-treated patients who experienced a diarrhoea AE, most experienced events that were at worst of mild (49.5%) or moderate (45.0%) intensity, most (70.2%) experienced 1 or 2 events, and the duration of diarrhoea AEs was ≤9 days for 50% of the events reported over 52 weeks. Among nintedanib-treated patients who experienced ≥1 diarrhoea AE, 26.1% had a permanent dose reduction and 9.2% discontinued study drug due to the AE. Among the 91 patients in the placebo group who experienced ≥1 diarrhoea AE, the duration of diarrhoea AEs was ≤3 days for 50% of the events reported over 52 weeks, 2.2% had a permanent dose reduction and 1.1% discontinued study drug due to the AE. Conclusion In patients with SSc-ILD, the gastrointestinal AEs associated with nintedanib were manageable for most patients and consistent with its known safety and tolerability profile in patients with IPF. Disclosure of Interests Toby Maher Grant/research support from: Received funds from BI advisory board participation and conference travel. Received research funding and/or consulting fees or other remuneration from GSK, UCB, AstraZeneca, Roche, Bayer, Biogen Idec, Cipla, Prometic, and Sanumed. Toby Maher has, via his institution, received industry-academic funding from GlaxoSmithKline RD and has received consultancy fees from Galecto., Kristin Highland Grant/research support from: Kristin Highland is a site PI for the SENSCIS trial (Dr Highland’s institution has the contract for the study) which is funded by Boehringer Ingelheim., Consultant for: Kristin Highland is a paid consultant for Boehringer Ingelheim through her role sitting on the steering committee., Speakers bureau: Kristin Highland is on the speakers’ bureau for Boehringer Ingelheim., Martina Gahlemann Employee of: Employee of Boehringer Ingelheim, Arata Azuma Consultant for: Arata Azuma has received personal fees from Boehringer Ingelheim, Shionogi & Co., Ltd, Taiho Pharmaceutical Co., Ltd, and Asahikasei Pharma Co., Aryeh Fischer Grant/research support from: Aryeh Fischer has received a grant from Boehringer Ingelheim (Consultant/steering committee member/principal investigator on clinical trials)., Consultant for: Aryeh Fischer has received personal fees from Boehringer Ingelheim (Consultant/steering committee member/principal investigator on clinical trials), Genentech-Roche (Consultant/steering committee member/principal investigator on clinical trials), Pfizer (Consultant) and Genentech (Consultant)., Maureen Mayes Grant/research support from: Maureen Mayes is a clinical trial investigator for Boehringer-Ingelheim; Galapagos, Reata, Sanofi, Merck-Serono, Consultant for: Maureen Mayes is a member of scientific advisory boards for Galapagos NV (Pharma), Boehringer-Ingelheim, Mitsubishi-Tanabe, Astellas: Grant Review Board for Actelion., Speakers bureau: Maureen Mayes received personal fees for being a conference speaker on the use of autoantibodies in connective tissue diseases for Medtelligence, Ganesh Raghu Grant/research support from: Ganesh Raghu is the principal investigator for IPF net studies and is a steering committee member for IPF net studies for the NIH., Consultant for: Ganesh Raghu is a consultant for Boehringer Ingelheim, Bellerophan, Biogen, BMS, Fibrogen, Gilead, Nitto, Revistan, Promedior, Sanofi, Veracyte and Roche-Genentech; and a consultant and chair of the DSMB for Avalyn., Wiebke Sauter Employee of: Wiebke Sauter is an employee of Boehringer Ingelheim, Mannaig Girard Employee of: Mannaig Girard is an employee of Boehringer Ingelheim, Margarida Alves Employee of: Employee of Boehringer Ingelheim, Emmanuelle Clerisme-Beaty Employee of: Emmanuelle Clerisme-Beaty is an employee of Boehringer Ingelheim, Veronika Kohlbrenner Employee of: Veronika Kohlbrenner is an employee of Boehringer Ingelheim, Masataka Kuwana Grant/research support from: Actelion, Consultant for: Chugai, Reata, GlaxoSmithKline, Bayer, Boehringer-Ingelheim, Corpus, CSL-Berling, Mochida, Speakers bureau: Actelion, Pfizer, Bayer, Nippon Shinyaku, Chugai, Oliver Distler Grant/research support from: Prof. Distler received research funding from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi Tanabe to investigate potential treatments of scleroderma and its complications, Consultant for: Prof. Distler has/had consultancy relationship within the last 3 years with Actelion, AnaMar, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, iQvia, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Serodapharm and UCB in the area of potential treatments of scleroderma and its complications. In addition, he had/has consultancy relationship within the last 3 years with A. Menarini, Amgen, Abbvie, GSK, Mepha, MSD, Pfizer and UCB in the field of arthritides and related disorders

Background In the SENSCIS trial, nintedanib reduced the progression of interstitial lung disease associated with systemic sclerosis (SSc-ILD) compared with placebo, as demonstrated by a significantly lower rate of decline in forced vital capacity (FVC) over 52 weeks (primary endpoint). Objectives To assess the effect of nintedanib on the rate of decline in FVC in the SENSCIS trial across pre-specified subgroups defined by baseline characteristics. Methods Patients with SSc-ILD with onset of first non-Raynaud symptom Results A total of 576 patients were treated (288 in each group). Most (75.2%) of patients were female, 51.9% had diffuse cutaneous SSc, and 48.4% were taking mycophenolate at baseline. Mean ± SD age was 54.0 ± 12.2 years and 21.4% of patients were aged ≥65 years. Nintedanib had a consistent effect on reducing the rate of FVC decline across pre-specified subgroups defined by baseline characteristics (p>0.05 for all treatment-by-time-by-subgroup interactions) (figure). Conclusion Nintedanib is effective at reducing ILD progression in a broad range of patients with SSc-ILD. Disclosure of Interests Oliver Distler Grant/research support from: Prof. Distler received research funding from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi Tanabe to investigate potential treatments of scleroderma and its complications, Consultant for: Prof. Distler has/had consultancy relationship within the last 3 years with Actelion, AnaMar, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, iQvia, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Serodapharm and UCB in the area of potential treatments of scleroderma and its complications. In addition, he had/has consultancy relationship within the last 3 years with A. Menarini, Amgen, Abbvie, GSK, Mepha, MSD, Pfizer and UCB in the field of arthritides and related disorders, Kristin Highland Grant/research support from: Kristin Highland is a site PI for the SENSCIS trial (Dr Highland’s institution has the contract for the study) which is funded by Boehringer Ingelheim., Consultant for: Kristin Highland is a paid consultant for Boehringer Ingelheim through her role sitting on the steering committee., Speakers bureau: Kristin Highland is on the speakers’ bureau for Boehringer Ingelheim., Martina Gahlemann Employee of: Employee of Boehringer Ingelheim , Arata Azuma Consultant for: Arata Azuma has received personal fees from Boehringer Ingelheim, Shionogi & Co., Ltd, Taiho Pharmaceutical Co., Ltd, and Asahikasei Pharma Co., Aryeh Fischer Grant/research support from: Aryeh Fischer has received a grant from Boehringer Ingelheim (Consultant/steering committee member/principal investigator on clinical trials)., Consultant for: Aryeh Fischer has received personal fees from Boehringer Ingelheim (Consultant/steering committee member/principal investigator on clinical trials), Genentech-Roche (Consultant/steering committee member/principal investigator on clinical trials), Pfizer (Consultant) and Genentech (Consultant)., Maureen Mayes Grant/research support from: Maureen Mayes is a clinical trial investigator for Boehringer-Ingelheim; Galapagos, Reata, Sanofi, Merck-Serono, Consultant for: Maureen Mayes is a member of scientific advisory boards for Galapagos NV (Pharma), Boehringer-Ingelheim, Mitsubishi-Tanabe, Astellas: Grant Review Board for Actelion., Speakers bureau: Maureen Mayes received personal fees for being a conference speaker on the use of autoantibodies in connective tissue diseases for Medtelligence, Ganesh Raghu Grant/research support from: Ganesh Raghu is the principal investigator for IPF net studies and is a steering committee member for IPF net studies for the NIH., Consultant for: Ganesh Raghu is a consultant for Boehringer Ingelheim, Bellerophan, Biogen, BMS, Fibrogen, Gilead, Nitto, Revistan, Promedior, Sanofi, Veracyte and Roche-Genentech; and a consultant and chair of the DSMB for Avalyn., Wiebke Sauter Employee of: Wiebke Sauter is an employee of Boehringer Ingelheim, Mannaig Girard Employee of: Mannaig Girard is an employee of Boehringer Ingelheim, Margarida Alves Employee of: Employee of Boehringer Ingelheim, Emmanuelle Clerisme-Beaty Employee of: Emmanuelle Clerisme-Beaty is an employee of Boehringer Ingelheim, Susanne Stowasser Employee of: Susanne Stowasser is an employee of Boehringer Ingelheim, Masataka Kuwana Grant/research support from: Actelion, Consultant for: Chugai, Reata, GlaxoSmithKline, Bayer, Boehringer-Ingelheim, Corpus, CSL-Berling, Mochida, Speakers bureau: Actelion, Pfizer, Bayer, Nippon Shinyaku, Chugai, Toby M Maher Shareholder of: Has stock options or bond holdings in a for-profit corporation in Apellis, Grant/research support from: Received funds from BI advisory board participation and conference travel. Received research funding and/or consulting fees or other remuneration from GSK, UCB, AstraZeneca, Roche, Bayer, Biogen Idec, Cipla, Prometic, and Sanumed, Consultant for: Toby Maher has received consultancy or speakers fees from Apellis, AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Galapagos, GlaxoSmithKline RD and has received consultancy fees from Galecto

Background Nintedanib has been investigated in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in the SENSCIS trial and idiopathic pulmonary fibrosis (IPF) in the two INPULSIS trials. These patient populations differ in age, sex, disease characteristics and comorbidities. Objectives To compare the safety and tolerability of nintedanib in patients with SSc-ILD and IPF. Methods Adverse events that occurred over 52 weeks of treatment in the SENSCIS and INPULSIS trials were assessed descriptively in subjects who received ≥1 dose of trial drug. Results A total of 576 subjects were treated in the SENSCIS trial (288 nintedanib; 288 placebo) and 1061 in the INPULSIS trials (638 nintedanib; 423 placebo). At baseline, mean (SD) age was 54.0 (12.2) and 66.8 (8.0) years in SENSCIS and INPULSIS, respectively. The proportion of males was 24.8% and 79.3%, respectively. Over 52 weeks, 19.4% and 10.8% of patients treated with nintedanib and placebo discontinued treatment in SENSCIS, compared with 24.5% and 18.9% of patients treated with nintedanib and placebo in INPULSIS. Gastrointestinal adverse events were the most frequently reported adverse events with nintedanib and, as expected based on the underlying disease, were more frequent in patients with SSc-ILD than IPF in both treatment groups (Table). Diarrhoea adverse events were reported in 75.7% and 31.6% of patients treated with nintedanib and placebo in SENSCIS, and 62.4% and 18.4% of patients treated with nintedanib and placebo in INPULSIS, respectively. Conclusion The safety and tolerability profile of nintedanib in patients with SSc-ILD is similar to that observed in patients with IPF. Disclosure of Interests

Interstitial lung disease (ILD), a group of diffuse parenchymal lung disorders classified together based on specific clinical, radiologic, and histopathologic features, is often associated with significant morbidity and mortality and is a common manifestation in connective tissue disease (CTD). ILD often arises within the context of a specific exposure or is associated with an underlying CTD. The CTDs are a spectrum of systemic autoimmune disorders with significant clinical heterogeneity characterized by immune-mediated organ dysfunction, and the lung is a frequent target. All CTD patients are at risk of developing ILD, and those with systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), and rheumatoid arthritis (RA) are at particularly high risk. ILD may develop at any point in the natural history of CTD, is most frequently identified in the setting of an established CTD, and may also be the first clinically apparent manifestation of occult CTD. Determining whether a patient has a diagnosis of CTD-associated ILD is important, as this knowledge may impact treatment decisions, guide surveillance for other concomitant clinical features, and help with assessment of prognosis.

Objective: Some patients with interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) develop a progressive fibrosing phenotype. We investigated the diagnosis and management of non-IPF ILDs using data from a survey of physicians and from US insurance claims. Methods: Pulmonologists, rheumatologists and internists in France, Germany, Italy, Japan, Spain, UK and US who had managed ≥10 patients with non-IPF ILDs in the past year, including those with progressive fibrosing ILDs, completed an online survey. Data on US insurance and prescription claims were obtained from a repository that aggregates data on claims routed from providers or pharmacies to payers. Results: In May–June 2017, 243 pulmonologists, 203 rheumatologists and 40 internists completed an online survey. Respondents estimated that 18–32% of patients diagnosed with non-IPF ILDs develop progressive fibrosis and that time from symptom onset to death in these patients was 61–80 months. Drug treatment was given to 50–75% of patients with non-IPF progressive fibrosing ILDs. Reasons for patients not being treated included that physicians considered patients to have mild or slowly progressing disease, or did not believe that available treatments are effective or well tolerated. Corticosteroids were the preferred first-line treatment for all types of non-IPF ILD. There was considerable heterogeneity in preferences for second- and third-line treatments. US insurance claims data from 3823 patients indicated that, in 2016, 50–75% of patients with ILDs received drug treatment (mostly corticosteroids) for their ILD. Conclusions: Physicians estimate that 18–32% of patients diagnosed with non-IPF ILDs develop a progressive fibrosing phenotype and that these patients experience significant delays in the diagnosis of ILD and the detection of progressive fibrosis. Between 25% and 50% of patients with progressive fibrosing ILDs do not receive drug therapy. There is an unmet need for effective and well tolerated treatments for progressive fibrosing ILDs.

Objective Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and early mortality and is an important complication in patients with connective tissue disease (CTD). Previously, the endothelin A selective receptor antagonist, ambrisentan, demonstrated efficacy and safety in treating patients with PAH due to WHO Group I etiologies. These analyses describe the 3-year efficacy and safety of ambrisentan in patients specifically with CTD associated PAH (CTD-PAH). Methods Patients with CTD-PAH participating in the ARIES-1 and -2 clinical trials and their long-term extension were evaluated. Efficacy evaluations including 6-min walk distance (6MWD), clinical worsening, and survival were collected at routine study visits. Additional analyses of 6MWD categorical (30 m) breakpoints were conducted to determine any relationship between 6MWD and a prognostic threshold for survival. Results 124 patients with CTD-PAH were evaluated. 62.6%, 57.3%, and 58.2% of CTD-PAH patients treated with ambrisentan exhibited increases in 6MWD at 1-, 2-, and 3- years respectively. At 3 years, 64% of patients were free from clinical worsening and 76% of patients were still alive (Kaplan-Meier estimates). Identified factors holding prognostic relevance for survival include: baseline functional class, CTD-PAH subgroup, patient sex, improvement in 6MWD ≥30 m over the first 12 weeks of treatment, the most recent 6MWD, and a 6MWD absolute threshold of 222 m. Conclusion These first analyses of the 3-year treatment of CTD-PAH patients with ambrisentan revealed fewer clinical worsening events and improved survival compared to historical controls. Key exercise parameters were also identified which appear important in guiding treatment.

Objective.Systemic sclerosis-associated interstitial lung disease (SSc-ILD) shares a number of clinical features and pathogenic mechanisms with idiopathic pulmonary fibrosis (IPF). This study was designed to evaluate the tolerability of the IPF treatment pirfenidone in SSc-ILD. The known gastrointestinal, skin, and liver adverse events (AE) of pirfenidone are of importance given the involvement of these organs in SSc.Methods.All patients received pirfenidone and were randomized 1:1 to either a 2- or 4-week titration starting at 801 mg/day and finishing at a maintenance dose of 2403 mg/day. Patients received pirfenidone for 16 weeks in total. Assessments included treatment-emergent AE (TEAE) and exploratory disease outcomes.Results.Sixty-three patients were randomized; 96.8% experienced a TEAE and more patients reported TEAE during the titration versus the maintenance period. The most commonly reported TEAE were consistent with those observed for pirfenidone in IPF (nausea, headache, fatigue) and were similar regardless of titration schedule. More patients discontinued treatment because of TEAE in the 2- versus 4-week titration group (5 vs 1, respectively); all discontinuation events occurred > 3 weeks after reaching the full dose of pirfenidone. Mycophenolate mofetil (MMF), taken by 63.5% of patients in addition to pirfenidone, did not appear to affect tolerability. Exploratory disease outcomes remained largely unchanged.Conclusion.Pirfenidone showed an acceptable tolerability profile in SSc-ILD, although a longer titration may be associated with better tolerability. Tolerability was not affected by concomitant MMF. The present findings support further investigation of pirfenidone in future clinical trials in patients with SSc-ILD. Trial registration: ClinicalTrials.gov; www.clinicaltrials.govNCT01933334.

Interstitial lung diseases, especially lymphoproliferative disorders such as follicular bronchiolitis and lymphoid interstitial pneumonia, are commonly seen in association with Sjögren syndrome. Although the predominant computed tomographic (CT) findings in patients with lymphoid interstitial pneumonia/follicular bronchiolitis include poorly defined centrilobular nodules and ground-glass attenuation, cystic changes can be seen in approximately two-thirds of these patients. The objective of this study was to define the clinical, radiological, and histopathological features of cyst-predominant lymphoid interstitial pneumonia/follicular bronchiolitis in patients with Sjögren syndrome. We present four patients who were referred to our institution with diffuse cystic changes on chest CT imaging. All four had a presumptive diagnosis of lymphangioleiomyomatosis but were subsequently found to have Sjögren syndrome. The diagnosis was established based on the clinical symptoms of xerostomia and xerophthalmia along with serologic detection of antinuclear antibodies, rheumatoid factor, anti-Sjögren's syndrome–related antigen A (SSA)/Ro antibodies, and anti-Sjögren's syndrome–related antigen B (SSB)/La antibodies. The cystic pattern associated with Sjögren syndrome had a characteristic appearance on chest CT images. Typical features included a wide variation in cyst size, internal structure within cysts, geographic simplification of parenchymal architecture producing a “dissolving lung appearance,” perivascular and often basilar-predominant distribution, and frequent association with ground-glass opacities and nodules. In a compatible clinical context, we submit that these findings can be sufficiently distinctive to obviate the need for lung biopsy, even in the absence of confirmatory serological studies or lip biopsy. Clinicians should consider occult Sjögren syndrome in the differential diagnosis of patients presenting with idiopathic diffuse cystic lung disease.

Objective.To quantify healthcare resource utilization (HRU), work loss, and annual direct and indirect healthcare costs among patients with systemic sclerosis (SSc) compared to matched controls in the United States.Methods.Data were obtained from a large US commercial claims database. Patients were ≥ 18 years old at the index date (first SSc diagnosis) and had ≥ 1 SSc diagnosis in the inpatient (IP) or emergency room (ER) setting, or ≥ 2 SSc diagnoses on 2 different dates in the outpatient (OP) setting between January 1, 2005, and March 31, 2015; continuous enrollment was required during the followup period (12 months after the index date). Individuals with no SSc diagnoses were matched 1:1 to patients with SSc. Wilcoxon signed-rank and McNemar tests were used for comparisons and regressions with generalized estimating equations for adjusted OR (aOR) and incidence rate ratios (IRR) between 2 cohorts.Results.There were 2192 pairs of patients with SSc and matched controls included (mean age 57.6 yrs; 84.3% female); of these, 233 were eligible for work loss/indirect cost analyses. Compared to matched controls, patients with SSc had significantly higher HRU and costs during the 1-year followup period, IP admissions (adjusted IRR = 2.4), IP hospitalization days (adjusted IRR = 3.1), ER visits (adjusted IRR = 2.0), OP visits (adjusted IRR = 2.3), and days of work loss (adjusted IRR = 2.6). The adjusted difference in annual direct and indirect costs was US$12,820 and $3103, respectively (all p < 0.0001).Conclusion.Patients with SSc had a high direct and indirect economic burden postdiagnosis.

Background: Idiopathic pulmonary fibrosis (IPF) is the classic fibrosing interstitial lung disease (ILD), but it accounts for Aims and objectives: To assess healthcare resource use and cost in non-IPF PF-ILD. Methods: We analysed US-based medical insurance claims over 3 years (2014–2016). Patients were considered to have ILD if they had ≥2 ILD claims and ≥1 pulmonologist visit during this period. To stabilise the dataset, patients were required to have ≥1 ILD claim per year and ≥2 medical claims in each half of each year. Here, patients with PF-ILD were defined as the subset of patients with non-IPF ILD with ≥4 pulmonologist visits in 2016 or ≥3 more pulmonologist visits in 2016 than in 2014. Results: Of 2517 patients with non-IPF ILD, 15% (n=373) were considered to have PF-ILD. Mean annual medical costs associated with ILD claims (2014–2016) were $35,364 in patients with PF-ILD compared to $20,211 in the overall ILD population. As expected, patients with PF-ILD had more ILD claims in 2016 at physician offices (7.6 vs 4.2) and hospitals (10.5 vs 4.7) compared to all ILD, suggestive of more severe disease with higher overall healthcare utilisation. Conclusion: Patients with PF-ILD have higher healthcare utilisation and costs compared to other ILD patients, highlighting the need for an improved understanding and management of PF-ILD.

IntroductionDespite extensive multidisciplinary team (MDT) assessment, some patients have interstitial lung disease (ILD) that is considered unclassifiable (uILD), for which there are currently no approved treatments. This study will assess the efficacy and safety of the antifibrotic pirfenidone in treating uILD.Methods and analysisThis double-blind, randomised, placebo-controlled phase II trial is enrolling adults with fibrosing ILD, including uILD that fulfils proposed research criteria for interstitial pneumonia with autoimmune features (IPAF), that cannot be classified with moderate or high confidence to any category of ILD following MDT discussion. Study participants must have >10% fibrosis on high-resolution CT scan within the previous 12 months, forced vital capacity (FVC) ≥45% and diffusing capacity of the lung for carbon monoxide ≥30% of predicted values. Study participants will be randomised to receive 801 mg pirfenidone or placebo three times daily for 24 weeks. The efficacy of pirfenidone vs placebo will be assessed by daily measurement of FVC using a handheld spirometer over the treatment period. Other functional parameters, patient-reported outcomes, samples for biomarker analysis and safety endpoints will be collected. Additionally, the study will assess the efficacy and safety of pirfenidone with and without concomitant mycophenolate mofetil treatment and in study participants with or without IPAF.Ethics and disseminationThis trial is being conducted in accordance with the International Conference on Harmonisation E6 guideline for Good Clinical Practice, Declaration of Helsinki and local laws for countries in which the research is conducted.Trial registration numberNCT03099187.

Objective.We sought to identify predictors of mortality and cardiopulmonary hospitalizations in patients at risk for pulmonary hypertension (PH) and enrolled in PHAROS, a prospective cohort study to investigate the natural history of PH in systemic sclerosis (SSc).Methods.The at-risk population for PH was defined by the following entry criteria: echocardiogram systolic pulmonary arterial pressure > 40 mmHg, or DLCO < 55% predicted or ratio of % forced vital capacity/%DLCO > 1.6, measured by pulmonary function testing. Baseline clinical measures were evaluated as predictors of hospitalization and death between 2005 and 2014. Cox proportional hazards models were censored at date of PH onset or latest study visit and adjusted for age, sex, race, and disease duration.Results.Of the 236 at-risk subjects who were followed for a median of 4 years (range 0.4–8.5 yrs), 35 developed PH after entering PHAROS (reclassified as PH group). In the at-risk group, higher mortality was strongly associated with male sex, low %DLCO, exercise oxygen desaturation, anemia, abnormal dyspnea scores, and baseline pericardial effusion. Risks for cardiopulmonary hospitalization were associated with increased dyspnea and pericardial effusions, although PH patients with DLCO < 50% had the highest risk of cardiopulmonary hospitalizations.Conclusion.Risk factors for poor outcome in patients with SSc who are at risk for PH were similar to others with SSc-PH and SSc-pulmonary arterial hypertension, including male sex, DLCO < 50%, exercise oxygen desaturation, and pericardial effusions. This group should undergo right heart catheterization and receive appropriate intervention if PH is confirmed.

Background Pulmonary arterial hypertension (PAH) is a leading cause of death in patients with systemic sclerosis (SSc). The purpose of this study was to assess long-term outcomes in patients with SSc-PAH. Methods Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma is a prospective registry of patients with SSc at high risk for or with incident pulmonary hypertension from right heart catheterization. Incident World Health Organization group I PAH patients were analyzed. Kaplan-Meier survival curves were generated for the overall cohort and those who died of PAH. Multivariate Cox regression models identified predictors of mortality. Results Survival in 160 patients with incident SSc-PAH at 1, 3, 5, and 8 years was 95%, 75%, 63%, and 49%, respectively. PAH accounted for 52% of all deaths. When restricted to deaths from PAH, respective survival rates were 97%, 83%, 76%, and 76%, with 93% of PAH-related deaths occurring within 4 years of diagnosis. Men (hazard ratio [HR], 3.11; 95% CI, 1.38-6.98), diffuse disease (HR, 2.12; 95% CI, 1.13-3.93), systolic pulmonary artery pressure (PAP) on ECG (HR, 1.06 95% CI, 1.01-1.11), mean PAP on right heart catheterization (HR, 1.03; 95% CI, 1.001-1.07), 6-min walk distance (HR, 0.92; 95% CI, 0.86-0.99), and diffusing capacity for carbon monoxide (HR, 0.65; 95% CI, 0.46-0.92) significantly affected survival on multivariate analysis. Conclusions Overall survival in PHAROS was higher than other SSc-PAH cohorts. PAH accounted for more than one-half of deaths and primarily within the first few years after PAH diagnosis. Optimization of treatment for those at greatest risk of early PAH-related death is crucial.

The primary care physician can play key roles in diagnosis, referral, and long-term management.

The term interstitial pneumonia with autoimmune features (IPAF) has been proposed to define patients with interstitial lung disease (ILD) associated with autoimmune signs not classifiable for connective tissue diseases (CTDs). This new definition overcomes previous nomenclatures and provides a uniform structure for prospective studies through specific classification criteria.This work evaluates the characteristics of IPAF patients reported in the literature, to highlight potential limits through a comparative analysis and to suggest better performing classification criteria.Four retrospective studies on the IPAF population have been considered. The study subjects differed in age, sex, smoking habit, ILD pattern and outcomes. Another important difference lies in the diverse items considered in the classification criteria. The retrospective design of the studies and the absence from some of them of a rheumatologist clearly involved in the diagnosis may have influenced the data, but current IPAF criteria seem to include a rather heterogeneous population. To overcome these discrepancies, this review suggests a limitation in the use of single items and the exclusion of extremely specific CTD criteria. This should avoid the definition of IPAF for those diseases at different stages or at early onset. The investigation of a functional or morphological cut-off of pulmonary involvement would be useful.

International audience; BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7x10(-17)). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7x10(-35)) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3x10(-49)). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4x10(-5)), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5x10(-6)). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Societe Francaise de Rhumatologie and others.).

Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus over nomenclature and classification limits the ability to conduct prospective studies of a uniform cohort. The “European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease” was formed to create consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity. The task force proposes the term “interstitial pneumonia with autoimmune features” (IPAF) and offers classification criteria organised around the presence of a combination of features from three domains: a clinical domain consisting of specific extra-thoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic or pulmonary physiologic features. A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD. With IPAF, a sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort. ERS/ATS task force provides nomenclature and classification criteria for patients with IIP and autoimmune features

Pulmonary involvement is a frequent manifestation of connective tissue disease (CTD)-related thoracic disease. It is important to characterize the underlying pattern when pulmonary involvement occurs in a patient with CTD, and to exclude other causes. A systematic approach, evaluating each compartment of the lung (airway, interstitium, pleura, pulmonary vasculature) may be helpful. In complex cases, a multidisciplinary approach should be considered, potentially including the pulmonologist, rheumatologist, radiologist, pathologist, and sometimes the infectious disease specialist or oncologist. New techniques, such as quantitative computed tomography and MRI, are expected to be helpful for evaluation and management of CTD-associated thoracic disease.