Zinpentraxin Alfa for Idiopathic Pulmonary Fibrosis: The Randomized Phase III STARSCAPE Trial.

Rationale: A phase II trial reported clinical benefit over 28 weeks in patients with idiopathic pulmonary fibrosis (IPF) who received zinpentraxin alfa. Objectives: To investigate the efficacy and safety of zinpentraxin alfa in patients with IPF in a phase III trial. Methods: This 52-week phase III, double-blind, placebo-controlled, pivotal trial was conducted at 275 sites in 29 countries. Patients with IPF were randomized 1:1 to intravenous placebo or zinpentraxin alfa 10 mg/kg every 4 weeks. The primary endpoint was absolute change from baseline to Week 52 in FVC. Secondary endpoints included absolute change from baseline to Week 52 in percent predicted FVC and 6-minute walk distance. Safety was monitored via adverse events. Post hoc analysis of the phase II and phase III data explored changes in FVC and their impact on the efficacy results. Measurements and Main Results: Of 664 randomized patients, 333 were assigned to placebo and 331 to zinpentraxin alfa. Four of the 664 randomized patients were never administered study drug. The trial was terminated early after a prespecified futility analysis that demonstrated no treatment benefit of zinpentraxin alfa over placebo. In the final analysis, absolute change from baseline to Week 52 in FVC was similar between placebo and zinpentraxin alfa (-214.89 ml and -235.72 ml; P = 0.5420); there were no apparent treatment effects on secondary endpoints. Overall, 72.3% and 74.6% of patients receiving placebo and zinpentraxin alfa, respectively, experienced one or more adverse events. Post hoc analysis revealed that extreme FVC decline in two placebo-treated patients resulted in the clinical benefit of zinpentraxin alfa reported by phase II. Conclusions: Zinpentraxin alfa treatment did not benefit patients with IPF over placebo. Learnings from this program may help improve decision making around trials in IPF. Clinical trial registered with www.clinicaltrials.gov (NCT04552899).

Treatment of Systemic Sclerosis-associated Interstitial Lung Disease: Evidence-based Recommendations. An Official American Thoracic Society Clinical Practice Guideline.

Background: Interstitial lung disease (ILD) is a significant cause of morbidity and mortality in patients with systemic sclerosis (SSc). To date, clinical practice guidelines regarding treatment for patients with SSc-ILD are primarily consensus based. Methods: An international expert guideline committee composed of 24 individuals with expertise in rheumatology, SSc, pulmonology, ILD, or methodology, and with personal experience with SSc-ILD, discussed systematic reviews of the published evidence assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Predetermined conflict-of-interest management strategies were applied, and recommendations were made for or against specific treatment interventions exclusively by the nonconflicted panelists. The confidence in effect estimates, importance of outcomes studied, balance of desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention, and implications for health equity were all considered in making the recommendations. This was in accordance with the American Thoracic Society guideline development process, which is in compliance with the Institute of Medicine standards for trustworthy guidelines. Results: For treatment of patients with SSc-ILD, the committee: 1) recommends the use of mycophenolate; 2) recommends further research into the safety and efficacy of (a) pirfenidone and (b) the combination of pirfenidone plus mycophenolate; and 3) suggests the use of (a) cyclophosphamide, (b) rituximab, (c) tocilizumab, (d) nintedanib, and (e) the combination of nintedanib plus mycophenolate. Conclusions: The recommendations herein provide an evidence-based clinical practice guideline for the treatment of patients with SSc-ILD and are intended to serve as the basis for informed and shared decision making by clinicians and patients.

Meaningful Endpoints for Idiopathic Pulmonary Fibrosis (IPF) Clinical Trials: Emphasis on 'Feels, Functions, Survives'. Report of a Collaborative Discussion in a Symposium with Direct Engagement from Representatives of Patients, Investigators, the National Institutes of Health, a Patient Advocacy Organization, and a Regulatory Agency.

Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.

Pulmonary Fibrosis Stakeholder Summit: A Joint NHLBI, Three Lakes Foundation, and Pulmonary Fibrosis Foundation Workshop Report.

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.

Prognostic and predictive markers of systemic sclerosis-associated interstitial lung disease in a clinical trial and long-term observational cohort.

OBJECTIVES: To explore prognostic and predictive markers of SSc-associated interstitial lung disease (SSc-ILD) outcomes in a phase 3 trial (focuSSced) and prognostic markers in a real-world cohort (SMART). METHODS: The focuSSced SSc-ILD subgroup included 68 of 106 placebo-treated and 68 of 104 tocilizumab-treated patients. The SMART cohort included 505 patients with SSc-ILD. Linear mixed-effect models were used to identify factors associated with change in forced vital capacity (FVC). Kaplan-Meier estimation and Cox regression were used for time-to-event analyses. RESULTS: In placebo-treated focuSSced patients, sex was a significant prognostic factor for FVC decline; males had increased risk for absolute decline ≥10% in percent-predicted FVC (ppFVC) and 0.22% faster weekly FVC decline than females (P = 0.0001). FVC was 9.8% lower in patients with CRP >6 mg/ml vs those with CRP ≤6 mg/ml (P = 0.0059). Tocilizumab reduced the risk for ≥10% decline in ppFVC in patients who were male, had earlier disease (<2 years duration), had IL-6 levels <10 pg/ml, or had anti-topoisomerase antibodies (ATA). In the SMART cohort, prognostic factors for ppFVC <70% were male sex, ATA, and low baseline FVC. Males had 3.3% lower FVC 1 year after disease onset (P < 0.001) and 0.6% faster yearly decline (P = 0.03) than females. CONCLUSION: Prognostic markers in SSc-ILD were similar between focuSSced and SMART. Male sex and inflammatory markers were associated with lower FVC but IL-6 ≥10 pg/ml was not predictive of response to tocilizumab. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02453256.

Pamrevlumab for Idiopathic Pulmonary Fibrosis: The ZEPHYRUS-1 Randomized Clinical Trial.

Importance: Current treatments for idiopathic pulmonary fibrosis slow the rate of lung function decline, but may be associated with adverse events that affect medication adherence. In phase 2 trials, pamrevlumab (a fully human monoclonal antibody that binds to and inhibits connective tissue growth factor activity) attenuated the progression of idiopathic pulmonary fibrosis without substantial adverse events. Objective: To assess the efficacy and safety of pamrevlumab for patients with idiopathic pulmonary fibrosis. Design, Setting, and Participants: Phase 3 randomized clinical trial including 356 patients aged 40 to 85 years with idiopathic pulmonary fibrosis who were not receiving antifibrotic treatment with nintedanib or pirfenidone at enrollment. Patients were recruited from 117 sites in 9 countries between July 18, 2019, and July 29, 2022; the last follow-up encounter occurred on August 28, 2023. Interventions: Pamrevlumab (30 mg/kg administered intravenously every 3 weeks; n = 181) or placebo (n = 175) for 48 weeks. Main Outcomes and Measures: The primary outcome was absolute change in forced vital capacity (FVC) from baseline to week 48. There were 5 secondary outcomes (including time to disease progression, which was defined as a decline of ≥10% in predicted FVC or death). The exploratory outcomes included patient-reported symptoms. Adverse events were reported. Results: Among 356 patients (mean age, 70.5 years; 258 [72.5%] were men; 221 [62.1%] were White), 277 (77.8%) completed the trial. There was no significant between-group difference for absolute change in FVC from baseline to week 48 (least-squares mean, -260 mL [95% CI, -350 to -170 mL] in the pamrevlumab group vs -330 mL [95% CI, -430 to -230 mL] in the placebo group; mean between-group difference, 70 mL [95% CI, -60 to 190 mL], P = .29). There were no significant between-group differences in any of the secondary outcomes or in the patient-reported outcomes. In the pamrevlumab group, there were 160 patients (88.4%) with treatment-related adverse events and 51 patients (28.2%) with serious adverse events vs 151 (86.3%) and 60 (34.3%), respectively, in the placebo group. During the study, 23 patients died in each group (12.7% in the pamrevlumab group vs 13.1% in the placebo group). Conclusions and Relevance: Among patients with idiopathic pulmonary fibrosis treated with pamrevlumab or placebo, there was no statistically significant between-group difference for the primary outcome of absolute change in FVC from baseline to week 48. Trial Registration: ClinicalTrials.gov Identifier: NCT03955146.

Inhaled pirfenidone solution (AP01) for IPF: a randomised, open-label, dose-response trial.

INTRODUCTION: Oral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects, including nausea, rash, photosensitivity, weight loss and fatigue. Reduced doses may be suboptimal in slowing disease progression. METHODS: This phase 1b, randomised, open-label, dose-response trial at 25 sites in six countries (Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12618001838202) assessed safety, tolerability and efficacy of inhaled pirfenidone (AP01) in IPF. Patients diagnosed within 5 years, with forced vital capacity (FVC) 40%-90% predicted, and intolerant, unwilling or ineligible for oral pirfenidone or nintedanib were randomly assigned 1:1 to nebulised AP01 50 mg once per day or 100 mg two times per day for up to 72 weeks. RESULTS: We present results for week 24, the primary endpoint and week 48 for comparability with published trials of antifibrotics. Week 72 data will be reported as a separate analysis pooled with the ongoing open-label extension study. Ninety-one patients (50 mg once per day: n=46, 100 mg two times per day: n=45) were enrolled from May 2019 to April 2020. The most common treatment-related adverse events (frequency, % of patients) were all mild or moderate and included cough (14, 15.4%), rash (11, 12.1%), nausea (8, 8.8%), throat irritation (5, 5.5%), fatigue (4, 4.4%) and taste disorder, dizziness and dyspnoea (three each, 3.3%). Changes in FVC % predicted over 24 and 48 weeks, respectively, were -2.5 (95% CI -5.3 to 0.4, -88 mL) and -4.9 (-7.5 to -2.3,-188 mL) in the 50 mg once per day and 0.6 (-2.2 to 3.4, 10 mL) and -0.4 (-3.2 to 2.3, -34 mL) in the 100 mg two times per day group. DISCUSSION: Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01. Mean FVC % predicted remained stable in the 100 mg two times per day group. Further study of AP01 is warranted. TRIAL REGISTRATION NUMBER: ACTRN12618001838202 Australian New Zealand Clinical Trials Registry.

Idiopathic pulmonary fibrosis: state of the art for 2023.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease characterised by worsening respiratory symptoms and physiological impairment. Increasing awareness of the clinical manifestations of IPF, more widespread use of computed tomography scans and other potential factors have contributed to a rising prevalence of IPF over the last two decades, especially among people over the age of 65 years. Significant advances in the understanding of the pathobiology of IPF have emerged, and multiple genetic and nongenetic contributors have been identified. The individual patient course and the rate of disease progression in IPF are often unpredictable and heterogeneous. The rate of lung function decline is further modified by treatment with antifibrotic therapies, which have been shown to slow down disease progression. The presence of comorbid conditions may increase symptom burden and impact survival. Clinical monitoring at regular intervals to assess for disease progression by worsening symptoms, physiological parameters and/or radiological features is essential to assess the natural disease course and to guide further management, including prompt detection of complications and comorbid conditions that warrant additional treatment considerations, and timely consideration of referral to palliative care and lung transplantation for the appropriate patient. More studies are needed to determine whether early detection of IPF might improve patient outcomes. The purpose of this concise clinical review is to provide an update on IPF diagnosis, epidemiology, natural history and treatment in the context of new knowledge and latest clinical practice guidelines.

Associations of hiatus hernia with CT-based interstitial lung changes: the MESA Lung Study.

BACKGROUND: Hiatus hernia (HH) is prevalent in adults with pulmonary fibrosis. We hypothesised that HH would be associated with markers of lung inflammation and fibrosis among community-dwelling adults and stronger among MUC5B (rs35705950) risk allele carriers. METHODS: In the Multi-Ethnic Study of Atherosclerosis, HH was assessed from cardiac and full-lung computed tomography (CT) scans performed at Exam 1 (2000-2002, n=3342) and Exam 5 (2010-2012, n=3091), respectively. Percentage of high attenuation areas (HAAs; percentage of voxels with attenuation between -600 and -250 HU) was measured from cardiac and lung scans. Interstitial lung abnormalities (ILAs) were examined from Exam 5 scans (n=2380). Regression models were used to examine the associations of HH with HAAs, ILAs and serum matrix metalloproteinase-7 (MMP-7), and adjusted for age, sex, race/ethnicity, educational attainment, smoking, height, weight and scanner parameters for HAA analysis. RESULTS: HH detected from Exam 5 scans was associated with a mean percentage difference in HAAs of 2.23% (95% CI 0.57-3.93%) and an increase of 0.48% (95% CI 0.07-0.89%) per year, particularly in MUC5B risk allele carriers (p-value for interaction=0.02). HH was associated with ILAs among those <80 years of age (OR for ILAs 1.78, 95% CI 1.14-2.80) and higher serum MMP-7 level among smokers (p-value for smoking interaction=0.04). CONCLUSIONS: HH was associated with more HAAs over time, particularly among MUC5B risk allele carriers, and ILAs in younger adults, and may be a risk factor in the early stages of interstitial lung disease.

Systemic sclerosis associated interstitial lung disease: a conceptual framework for subclinical, clinical and progressive disease.

OBJECTIVES: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). METHODS: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. RESULTS: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. CONCLUSIONS: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

Antisynthetase syndrome-related interstitial lung disease (ASyS-ILD): longitudinal imaging findings.

OBJECTIVES: Interstitial lung disease (ILD) impacts mortality in antisynthetase syndrome (ASyS). Computed tomographic (CT) patterns and evolution in ASyS ILD are not well described. We report longitudinal CT patterns in ASyS-ILD and their impact on survival. METHODS: This is a monocentric retrospective study of 47 patients with ASyS-ILD. Longitudinal CT patterns and fibrosis severity (severity of radiographic features indicating fibrosis) were analyzed by two radiologists in consensus. The association between imaging features and survival was examined using univariate Cox regression analysis. RESULTS: In total, 211 CT scans were analyzed with an average of 4 ± 2 CT scans/patient with a median follow-up of 79 months in 47 patients. Non-fibrotic patterns were present initially in 63.8% (n = 30) of patients, while fibrotic patterns occurred in 36.2% (n = 17). The initial non-fibrotic patterns/abnormalities resolved in 23.3% (n = 7), evolved in 6.7% (n = 2), persisted in 13.3% (n = 4), and progressed in 56.7% (n = 17), while initial fibrotic patterns persisted in 82.4% (n = 14) and progressed in 17.6% (n = 3). Radiographic progression of ILD (progression in CT pattern or increased fibrosis severity) occurred in 53.2% (n = 25) of patients. Advanced age and radiographic progression were associated with decreased survival (all p < 0.05). The presence of ground-glass opacities (GGO) and predominant lower lung distribution of abnormalities on initial CTs were associated with increased survival (all p < 0.05). CONCLUSION: Progression occurred in 56.7% of ASyS-ILD patients presenting with non-fibrotic patterns. Fibrotic patterns tended to persist. Age and radiographic progression were associated with reduced survival while the initial presence of GGO and predominant lower lobe distribution were associated with increased survival. KEY POINTS: • In ASyS-ILD, initial non-fibrotic patterns such as OP, cNSIP, or OP-cNSIP tended to progress to fNSIP. • Fibrotic patterns such as fNSIP or UIP in ASyS-ILD tended to persist without pattern changes. • GGO and lower lung predominance on initial CT were associated with better survival while advanced baseline age and radiographic ILD progression during follow-up were associated with decreased survival.

Phase 2B Study of Inhaled RVT-1601 for Chronic Cough in Idiopathic Pulmonary Fibrosis: A Multicenter, Randomized, Placebo-controlled Study (SCENIC Trial).

Rationale: Chronic cough remains a major and often debilitating symptom for patients with idiopathic pulmonary fibrosis (IPF). In a phase 2A study, inhaled RVT-1601 (cromolyn sodium) reduced daytime cough and 24-hour average cough counts in patients with IPF. Objectives: To determine the efficacy, safety, and optimal dose of inhaled RVT-1601 for the treatment of chronic cough in patients with IPF. Methods: In this multicenter, randomized, placebo-controlled phase 2B study, patients with IPF and chronic cough for ⩾8 weeks were randomized (1:1:1:1) to receive 10, 40, and 80 mg RVT-1601 three times daily or placebo for 12 weeks. The primary endpoint was change from baseline to end of treatment in log-transformed 24-hour cough count. Key secondary endpoints were change from baseline in cough severity and cough-specific quality of life. Safety was monitored throughout the study. Measurements and Main Results: The study was prematurely terminated owing to the impact of the coronavirus disease (COVID-19) pandemic. Overall, 108 patients (mean age 71.0 years, 62.9% males) received RVT-1601 10 mg (n = 29), 40 mg (n = 25), 80 mg (n = 27), or matching placebo (n = 27); 61.1% (n = 66) completed double-blind treatment. No statistically significant difference was observed in the least-square mean change from baseline in log-transformed 24-hour average cough count, cough severity, and cough-specific quality of life score between the RVT-1601 groups and the placebo group. The mean percentage change from baseline in 24-hour average cough count was 27.7% in the placebo group. Treatment was generally well tolerated. Conclusions: Treatment with inhaled RVT-1601 (10, 40, and 80 mg three times a day) did not provide benefit over placebo for the treatment of chronic cough in patients with IPF.

Long-Term Safety and Efficacy of Tocilizumab in Early Systemic Sclerosis-Interstitial Lung Disease: Open-Label Extension of a Phase 3 Randomized Controlled Trial.

Rationale: Tocilizumab, an anti-IL-6 receptor antibody, had no statistically significant effect on skin sclerosis but preserved lung function over 48 weeks in patients with early systemic sclerosis (SSc)-associated interstitial lung disease (ILD) in a phase 3 randomized controlled trial. Objectives: Assess long-term safety and efficacy of tocilizumab. Methods: Adults with diffuse cutaneous SSc for ⩽60 months and elevated acute-phase reactants, including those with ILD, received weekly placebo or tocilizumab 162 mg subcutaneously in the 48-week, double-blind period and then open-label tocilizumab from Weeks 48 to 96 (placebo-tocilizumab; continuous-tocilizumab). Measurements and Main Results: Eighty-two of 107 patients in the placebo-tocilizumab group and 85 of 105 patients in the continuous-tocilizumab group completed 96 weeks. Mean age and disease duration were 48 years and 23 months; high-resolution computed tomography revealed ILD in 61%. Mean (95% confidence interval [CI]) change in modified Rodnan skin score from baseline to week 96 was -8.4 (-10.0 to -6.8) for placebo-tocilizumab and -9.6 (-10.9 to -8.4) for continuous-tocilizumab. Mean (95% CI) change in FVC (percent predicted) from baseline to week 96 was -3.3 (-5.1 to -1.5) for placebo-tocilizumab and -0.5 (-2.4 to 1.3) for continuous-tocilizumab among completers and, in a post hoc analysis, -4.1 (-6.7 to -1.6) and -0.6 (-3.1 to 2.0), respectively, among completers with ILD (mean [95% CI] change from Weeks 48 to 96: 0.9 [-0.8 to 2.7] and -0.4 [-2.3 to 1.5], respectively). Rates per 100 patient-years of serious adverse events from Weeks 48 to 96 were 14.8 for placebo-tocilizumab and 15.8 for continuous-tocilizumab. Conclusions: Tocilizumab preserved lung function, slowing decline in FVC, in patients with SSc, including those with ILD. Long-term safety was consistent with the known safety profile of tocilizumab. Clinical trial registered with www.clinicaltrials.gov (NCT02453256).

A Phase IIb Randomized Clinical Study of an Anti-αvß6 Monoclonal Antibody in Idiopathic Pulmonary Fibrosis.

Rationale: Treatment options for idiopathic pulmonary fibrosis (IPF) are limited. Objectives: To evaluate the efficacy and safety of BG00011, an anti-αvß6 IgG1 monoclonal antibody, in the treatment of patients with IPF. Methods: In a phase IIb randomized, double-blind, placebo-controlled trial, patients with IPF (FVC ⩾50% predicted, on or off background therapy) were randomized 1:1 to once-weekly subcutaneous BG00011 56 mg or placebo. The primary endpoint was FVC change from baseline at Week 52. Because of early trial termination (imbalance in adverse events and lack of clinical benefit), endpoints were evaluated at Week 26 as an exploratory analysis. Measurements and Main Results: One hundred six patients were randomized and received at least one dose of BG00011 (n = 54) or placebo (n = 52). At Week 26, there was no significant difference in FVC change from baseline between patients who received BG00011 (n = 20) or placebo (n = 23), least squares mean (SE) -0.097 L (0.0600) versus -0.056 L (0.0593), respectively (P = 0.268). However, after Week 26, patients in the BG00011 group showed a worsening trend. Eight (44.4%) of 18 who received BG00011 and 4 (18.2%) of 22 who received placebo showed worsening of fibrosis on high-resolution computed tomography at the end of treatment. IPF exacerbation/or progression was reported in 13 patients (all in the BG00011 group). Serious adverse events occurred more frequently in BG00011 patients, including four deaths. Conclusions: The results do not support the continued clinical development of BG00011. Further research is warranted to identify new treatment strategies that modify inflammatory and fibrotic pathways in IPF. Clinical trial registered with www.clinicaltrials.gov (NCT03573505).

Rare and Common Variants in KIF15 Contribute to Genetic Risk of Idiopathic Pulmonary Fibrosis.

Rationale: Genetic studies of idiopathic pulmonary fibrosis (IPF) have improved our understanding of this disease, but not all causal loci have been identified. Objectives: To identify genes enriched with rare deleterious variants in IPF and familial pulmonary fibrosis. Methods: We performed gene burden analysis of whole-exome data, tested single variants for disease association, conducted KIF15 (kinesin family member 15) functional studies, and examined human lung single-cell RNA sequencing data. Measurements and Main Results: Gene burden analysis of 1,725 cases and 23,509 control subjects identified heterozygous rare deleterious variants in KIF15, a kinesin involved in spindle separation during mitosis, and three telomere-related genes (TERT [telomerase reverse transcriptase], RTEL1 [regulator of telomere elongation helicase 1], and PARN [poly(A)-specific ribonuclease]). KIF15 was implicated in autosomal-dominant models of rare deleterious variants (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.7-8.8; P = 2.55 × 10-7) and rare protein-truncating variants (OR, 7.6; 95% CI, 3.3-17.1; P = 8.12 × 10-7). Meta-analyses of the discovery and replication cohorts, including 2,966 cases and 29,817 control subjects, confirm the involvement of KIF15 plus the three telomere-related genes. A common variant within a KIF15 intron (rs74341405; OR, 1.6; 95% CI, 1.4-1.9; P = 5.63 × 10-10) is associated with IPF risk, confirming a prior report. Lymphoblastoid cells from individuals heterozygous for the common variant have decreased KIF15 and reduced rates of cell growth. Cell proliferation is dependent on KIF15 in the presence of an inhibitor of Eg5/KIF11, which has partially redundant function. KIF15 is expressed specifically in replicating human lung cells and shows diminished expression in replicating epithelial cells of patients with IPF. Conclusions: Both rare deleterious variants and common variants in KIF15 link a nontelomerase pathway of cell proliferation with IPF susceptibility.

Associations of Monocyte Count and Other Immune Cell Types with Interstitial Lung Abnormalities.

Rationale: Higher blood monocyte counts are associated with worse survival in adults with clinically diagnosed pulmonary fibrosis. Their association with the development and progression of interstitial lung abnormalities (ILA) in humans is unknown. Objectives: We evaluated the associations of blood monocyte count, and other immune cell types, with ILA, high-attenuation areas, and FVC in four independent cohorts. Methods: We included participants with measured monocyte counts and computed tomographic (CT) imaging enrolled in MESA (Multi-Ethnic Study of Atherosclerosis, n = 484), AGES-Reykjavik (Age/Gene Environment Susceptibility Study, n = 3,547), COPDGene (Genetic Epidemiology of COPD, n = 2,719), and the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points, n = 646). Measurements and Main Results: After adjustment for covariates, a 1-SD increment in blood monocyte count was associated with ILA in MESA (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.0-1.8), AGES-Reykjavik (OR, 1.2; 95% CI, 1.1-1.3), COPDGene (OR, 1.3; 95% CI, 1.2-1.4), and ECLIPSE (OR, 1.2; 95% CI, 1.0-1.4). A higher monocyte count was associated with ILA progression over 5 years in AGES-Reykjavik (OR, 1.2; 95% CI, 1.0-1.3). Compared with participants without ILA, there was a higher percentage of activated monocytes among those with ILA in MESA. Higher monocyte count was associated with greater high-attenuation areas in MESA and lower FVC in MESA and COPDGene. Associations of other immune cell types were less consistent. Conclusions: Higher blood monocyte counts were associated with the presence and progression of interstitial lung abnormalities and lower FVC.

Integrating Clinical Probability into the Diagnostic Approach to Idiopathic Pulmonary Fibrosis: An International Working Group Perspective.

Background: When considering the diagnosis of idiopathic pulmonary fibrosis (IPF), experienced clinicians integrate clinical features that help to differentiate IPF from other fibrosing interstitial lung diseases, thus generating a "pre-test" probability of IPF. The aim of this international working group perspective was to summarize these features using a tabulated approach similar to chest HRCT and histopathologic patterns reported in the international guidelines for the diagnosis of IPF, and to help formally incorporate these clinical likelihoods into diagnostic reasoning to facilitate the diagnosis of IPF. Methods: The committee group identified factors that influence the clinical likelihood of a diagnosis of IPF, which was categorized as a pre-test clinical probability of IPF into "high" (70-100%), "intermediate" (30-70%), or "low" (0-30%). After integration of radiological and histopathological features, the post-test probability of diagnosis was categorized into "definite" (90-100%), "high confidence" (70-89%), "low confidence" (51-69%), or "low" (0-50%) probability of IPF. Findings: A conceptual Bayesian framework was created, integrating the clinical likelihood of IPF ("pre-test probability of IPF") with the HRCT pattern, the histopathology pattern when available, and/or the pattern of observed disease behavior, into a "post-test probability of IPF." The diagnostic probability of IPF was expressed using an adapted diagnostic ontology for fibrotic interstitial lung diseases. Interpretation: The present approach will help incorporate the clinical judgment into the diagnosis of IPF, thus facilitating the application of IPF diagnostic guidelines and, ultimately improving diagnostic confidence and reducing the need for invasive diagnostic techniques.

Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline.

Background: This American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax guideline updates prior idiopathic pulmonary fibrosis (IPF) guidelines and addresses the progression of pulmonary fibrosis in patients with interstitial lung diseases (ILDs) other than IPF. Methods: A committee was composed of multidisciplinary experts in ILD, methodologists, and patient representatives. 1) Update of IPF: Radiological and histopathological criteria for IPF were updated by consensus. Questions about transbronchial lung cryobiopsy, genomic classifier testing, antacid medication, and antireflux surgery were informed by systematic reviews and answered with evidence-based recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. 2) Progressive pulmonary fibrosis (PPF): PPF was defined, and then radiological and physiological criteria for PPF were determined by consensus. Questions about pirfenidone and nintedanib were informed by systematic reviews and answered with evidence-based recommendations using the GRADE approach. Results:1) Update of IPF: A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise. No recommendation was made for or against genomic classifier testing. Conditional recommendations were made against antacid medication and antireflux surgery for the treatment of IPF. 2) PPF: PPF was defined as at least two of three criteria (worsening symptoms, radiological progression, and physiological progression) occurring within the past year with no alternative explanation in a patient with an ILD other than IPF. A conditional recommendation was made for nintedanib, and additional research into pirfenidone was recommended. Conclusions: The conditional recommendations in this guideline are intended to provide the basis for rational, informed decisions by clinicians.

Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease.

BACKGROUND: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52. RESULTS: A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was -52.4 ml per year in the nintedanib group and -93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P = 0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of -0.21 (95% CI, -0.94 to 0.53; P = 0.58) and 1.69 (95% CI, -0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group. CONCLUSIONS: Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo. (Funded by Boehringer Ingelheim; SENSCIS ClinicalTrials.gov number, NCT02597933.).

R-scale for pulmonary fibrosis: a simple, visual tool for the assessment of health-related quality of life.

RATIONALE: Patients with idiopathic pulmonary fibrosis (IPF) experience impaired health-related quality of life (HRQoL). Several tools have been developed to objectively assess HRQoL in this patient population, but none are in use in routine clinical practice. OBJECTIVES: To develop a rapid, specific tool that can be used for patients with IPF during routine clinic visits. METHODS: A novel and simple five-item numerical rating scale was developed and compared with two other previously validated tools. 100 consecutive patients with IPF managed at a centre for interstitial lung disease were recruited to complete the Raghu scale for pulmonary fibrosis (R-Scale-PF), King's Brief Interstitial Lung Disease questionnaire (K-BILD), and the EuroQol Five-Dimensional Five-Level questionnaire (EQ-5D-5L) in addition to pulmonary function and 6-min walk tests. MEASUREMENTS AND MAIN RESULTS: All 100 patients successfully completed the three HRQoL tools with 53 completing them again at follow-up visits. Internal consistency was high (Cronbach's α 0.825) with minimal floor/ceiling effect. Concurrent validity of the R-Scale-PF was moderate to high compared with the K-BILD (r=-0.713) and the EQ-5D-5L (r=-0.665). Concurrent validity was moderate with physiologic measures (forced vital capacity, r=-0.307, 6-min walking distance, r=-0.383). The R-Scale-PF demonstrated good known-groups validity when comparing scores across stages of disease severity. CONCLUSIONS: The R-Scale-PF correlates well with the K-BILD and EQ-5D-5L. It is hoped that this novel simple numerical rating scale tool, subject to validation in patients from other centres, will provide an opportunity to objectively measure HRQoL in routine clinical practice for patients with IPF.