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Cottin V, Tomassetti S, Valenzuela C, et al., 2022, Integrating Clinical Probability into the Diagnostic Approach to Idiopathic Pulmonary Fibrosis An International Working Group Perspective, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 206, Pages: 247-259, ISSN: 1073-449X
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Maher TM, 2022, Biomarkers for Interstitial Lung Abnormalities: A Stepping-stone Toward Idiopathic Pulmonary Fibrosis Prevention?, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 206, Pages: 244-246, ISSN: 1073-449X
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Allen RJ, Stockwell A, Oldham JM, et al., 2022, Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis, THORAX, Vol: 77, Pages: 829-833, ISSN: 0040-6376
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Maher TM, Bourdin A, Volkmann ER, et al., 2022, Decline in forced vital capacity in subjects with systemic sclerosis-associated interstitial lung disease in the SENSCIS trial compared with healthy reference subjects, Respiratory Research, Vol: 23, ISSN: 1465-9921
BACKGROUND: The forced vital capacity (FVC) of healthy individuals depends on their age, sex, ethnicity and height. Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterised by loss of FVC. We compared FVC values in the subjects with SSc-ILD in the SENSCIS trial of nintedanib versus placebo with values from hypothetical matched healthy references. METHODS: The SENSCIS trial enrolled subjects with SSc with first non-Raynaud symptom in the prior ≤ 7 years, extent of fibrotic ILD on HRCT ≥ 10%, and FVC ≥ 40% predicted. FVC at baseline and decline in FVC over 52 weeks were compared with FVC values in hypothetical healthy reference subjects matched 1:1 to the subjects in the trial for age, sex, ethnicity and height, determined using equations published by the European Respiratory Society Global Lung Function Initiative. RESULTS: At baseline, mean (SD) FVC was 2460 (737) mL in the nintedanib group (n = 287) compared with 3403 (787) mL in the hypothetical matched healthy references. Mean (SD) FVC was 2544 (817) mL in the placebo group (n = 286) compared with 3516 (887) mL in the hypothetical matched healthy references. Mean (SE) changes in FVC at week 52, i.e., age-related loss of lung function, in the hypothetical healthy references matched to the nintedanib and placebo groups, respectively, were - 26.3 (0.5) mL and - 25.8 (0.5) mL. The difference in the change in FVC at week 52 between the nintedanib group and the hypothetical healthy references was 26.6 mL (95% CI: 1.2, 52.0; p = 0.04). The difference in the change in FVC at week 52 between the placebo group and the hypothetical healthy references was 77.5 mL (95% CI: 51.4, 103.7; p < 0.0001). CONCLUSIONS: Subjects with SSc-ILD in the SENSCIS trial had impaired lung function at baseline and experienced further deterioration over 52 wee
Zhang D, Povysil G, Kobeissy PH, et al., 2022, Rare and common variants in KIF15 contribute to genetic risk of idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 206, ISSN: 1073-449X
RATIONALE: Genetic studies of Idiopathic Pulmonary Fibrosis (IPF) have improved our understanding of this disease, but not all causal loci have been identified. OBJECTIVE: 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 functional studies, and examined human lung single cell RNA sequencing data. MEASUREMENT AND MAIN RESULTS: Gene burden analysis of 1,725 cases and 23,509 controls identified heterozygous rare deleterious variants in KIF15, a kinesin involved in spindle separation during mitosis, and three telomere-related genes (TERT, RTEL1, PARN). KIF15 was implicated in autosomal dominant models of rare deleterious variants (OR 4.9 [95%CI 2.7, 8.8] P=2.55x10-7) and rare protein-truncating variants (OR 7.6 [3.3, 17.1], P=8.12x10-7). Meta-analysis of the discovery and replication cohorts, including 2,966 cases and 29,817 controls, confirm the involvement of KIF15, plus the three telomere-related genes. A common variant within a KIF15 intron (rs74341405, OR 1.6 [1.4, 1.9], P=5.63x10-10) 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 IPF patients. CONCLUSIONS: Both rare deleterious variants and common variants in KIF15 link a non-telomerase pathway of cell proliferation with IPF susceptibility.
Molina-Molina M, Kreuter M, Cottin V, et al., 2022, Efficacy of pirfenidone vs. placebo in unclassifiable interstitial lung disease, by surgical lung biopsy status: data from a post-hoc analysis, Frontiers in Medicine, Vol: 9, ISSN: 2296-858X
Approximately 12-13% of patients with interstitial lung disease (ILD) are diagnosed with unclassifiable ILD (uILD), often despite thorough evaluation. A recent Phase 2 study (NCT03099187) described a significant effect of pirfenidone vs. placebo on forced vital capacity (FVC) measured by site spirometry in patients with progressive fibrosing uILD (hereafter referred to as the pirfenidone in uILD study). Here, we present the results from a post-hoc analysis of this study to assess patient baseline characteristics and the efficacy of pirfenidone vs. placebo analyzed by surgical lung biopsy (SLB) status. Mean FVC (mL) change over 24 weeks was included as a post-hoc efficacy outcome. Of 253 randomized patients, 88 (34.8%) had a SLB and 165 (65.2%) did not. Baseline characteristics were generally similar between SLB subgroups; however, patients who had a SLB were slightly younger and had a higher 6-min walk distance than those without a SLB. Mean FVC change over 24 weeks for pirfenidone vs. placebo was -90.9 vs. -146.3 mL, respectively, in patients who had a SLB, and 8.2 vs. -85.3 mL, respectively, in patients without a SLB. Overall, the results from the post-hoc analysis identified that pirfenidone may be an effective treatment in progressive fibrosing uILD over 24 weeks, irrespective of SLB status; however, caution should be taken when interpreting these data due to several limitations. There are differences in the treatment effect of pirfenidone between the subgroups that require further pathological and radiological investigation. In this manuscript, we also descriptively compared baseline characteristics from the overall pirfenidone in uILD study population with other uILD populations reported in the literature, with the aim of understanding if there are any similarities or differences within these cohorts. Most baseline characteristics for patients in the pirfenidone in uILD study were within the ranges reported in the literature; however, ranges were wide, highlig
Oldham JM, Lee CT, Wu Z, et al., 2022, Lung function trajectory in progressive fibrosing interstitial lung disease, European Respiratory Journal, Vol: 59, ISSN: 0903-1936
Proposed criteria for progressive fibrosing interstitial lung disease (PF-ILD) have been linked to increased mortality risk, but lung function trajectory after satisfying individual criterion remains unknown. Because survival is rarely employed as the primary endpoint in therapeutic trials, identifying PF-ILD criteria that best predict subsequent change in forced vital capacity (FVC) could improve clinical trial design. A retrospective, multi-center longitudinal cohort analysis was performed in consecutive patients with fibrotic connective tissue disease-associated ILD (CTD-ILD), chronic hypersensitivity pneumonitis and idiopathic interstitial pneumonia at three US centers (test cohort) and one UK center (validation cohort). One-year change in FVC after satisfying proposed PF-ILD criteria was estimated using joint modeling. Subgroup analyses were performed to determine whether results varied across key subgroups. One thousand two hundred twenty-seven patients were included, with CTD-ILD predominating. Six of nine PF-ILD criteria were associated with differential one-year change in FVC, with radiologic progression of fibrosis, alone and in combination with other features, associated with the largest subsequent decline in FVC. Findings varied significantly by ILD subtype, with CTD-ILD demonstrating little change in FVC after satisfying most PF-ILD criteria, while other ILDs showed significantly larger changes. Findings did not vary after stratification by radiologic pattern or exposure to immunosuppressant therapy. Near-term change in FVC after satisfying proposed PF-ILD criteria was heterogeneous depending on the criterion assessed and was strongly influenced by ILD subtype. These findings may inform future clinical trial design and suggest ILD subtype should be taken into consideration when applying PF-ILD criteria.
Molyneaux PL, Fahy WA, Byrne AJ, et al., 2022, CYFRA 21-1 predicts progression in IPF: a prospective longitudinal analysis of the PROFILE cohort, American Journal of Respiratory and Critical Care Medicine, Vol: 205, Pages: 1440-1448, ISSN: 1073-449X
OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a progressive and inevitably fatal condition for which there are a lack of effective biomarkers to guide therapeutic decision making. RATIONALE: To determine the relationship between serum levels of the cytokeratin fragment CYFRA 21-1 and disease progression and mortality in individuals with IPF enrolled in the PROFILE study. METHODS: CYFRA 21-1 was identified by immunohistochemistry in samples of human lung. Concentrations of CYFRA 21-1 were measured using an Elisa-based assay in serum, collected at baseline, 1- and 3-months, from 491 individuals with an incident diagnosis of IPF enrolled in the PROFILE study and from 100 control subjects. Study subjects were followed for a minimum of 3 years. MEASUREMENTS AND MAIN RESULTS: CYFRA 21-1 localises to hyperplastic epithelium in IPF lung. CYFRA 21-1 levels were significantly higher in IPF subjects compared to healthy controls in both discovery (n=132) (control 0.96±0.81 ng/mL versus IPF; 2.34±2.15 ng/mL, p < 0.0001) and validation (n=359) (control; 2.21±1.54 ng/mL and IPF; 4.13±2.77 ng/mL, p<0.0001) cohorts. Baseline levels of CYFRA 21-1 distinguished individuals at risk of 12-month disease progression (C-statistic 0.70 (95% CI 0.61-0.79), p < 0.0001) and were predictive of overall-mortality (HR 1.12 (1.06-1.19) per 1 ng/mL increase in CYFRA 21-1, p=0.0001). Furthermore, 3-month change in levels of CYFRA 21-1 separately predicted 12-month and overall survival in both the discovery and validation cohorts. CONCLUSIONS: CYFRA 21-1, a marker of epithelial damage and turnover, has the potential to be an important prognostic and therapeutic biomarker in individuals with IPF.
Khanna D, Maher T, Volkmann E, et al., 2022, EFFECT OF NINTEDANIB IN PATIENTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (SSC-ILD) AND RISK FACTORS FOR RAPID DECLINE IN FORCED VITAL CAPACITY: FURTHER ANALYSES OF THE SENSCIS TRIAL, Publisher: BMJ PUBLISHING GROUP, Pages: 102-103, ISSN: 0003-4967
Maher T, Bourdin A, Volkmann E, et al., 2022, "EFFECTIVE LUNG AGE" IN SUBJECTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (SSC-ILD) IN THE SENSCIS TRIAL, EULAR European Congress of Rheumatology (EULAR), Publisher: BMJ PUBLISHING GROUP, Pages: 447-447, ISSN: 0003-4967
Assassi S, Kuwana M, Denton CP, et al., 2022, EFFECTS OF NINTEDANIB ON CIRCULATING BIOMARKERS IN SUBJECTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (SSC-ILD), Publisher: BMJ PUBLISHING GROUP, Pages: 719-720, ISSN: 0003-4967
Molyneaux PL, Maher TM, authors of CYFRA 21-1 predicts progression in IPF; a prospective longitudinal analysis of the PROFILE cohort, 2022, Reply to: the need for a CYFRA 21-1 cut-off value to predict clinical progression of IPF in clinical practice., American Journal of Respiratory and Critical Care Medicine, Vol: 206, Pages: 649-650, ISSN: 1073-449X
Kraven LM, Taylor AR, Molyneaux PL, et al., 2022, Cluster analysis of transcriptomic datasets to identify endotypes of idiopathic pulmonary fibrosis, Thorax, Vol: 78, Pages: 551-558, ISSN: 0040-6376
Background Considerable clinical heterogeneity in idiopathic pulmonary fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes would improve our understanding of the pathogenesis of IPF and could allow for a biomarker-driven personalised medicine approach. We aimed to identify clinically distinct groups of patients with IPF that could represent distinct disease endotypes.Methods We co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases).Findings We identified three clusters of patients with IPF with statistically significant differences in lung function (p=0.009) and mortality (p=0.009) between groups. Gene enrichment analysis implicated mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: HR 4.25, 95% CI 2.14 to 8.46, p=3.7×10−5).Interpretation We have identified blood gene expression signatures capable of discerning groups of patients with IPF with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.
Richeldi L, Azuma A, Cottin V, et al., 2022, Trial of a preferential phosphodiesterase 4B inhibitor for idiopathic pulmonary fibrosis., New England Journal of Medicine, Vol: 386, Pages: 2178-2187, ISSN: 0028-4793
BACKGROUND: Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis. METHODS: In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent. RESULTS: A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, -39.1 to 50.5) in the BI 1015550 group and -81.7 ml (95% credible interval, -133.5 to -44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, -32.8 to 38.2) in the BI 1015550 group and -59.2 ml (95% credible interval, -111.8 to -17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups. CONCLUSIONS: In this placebo-controlled trial, treatment with BI 1015550, either alone or with ba
Bonella F, Cottin V, Valenzuela C, et al., 2022, Meta-analysis of effect of nintedanib on reducing FVC decline across interstitial lung diseases, Advances in Therapy, Vol: 14/5/22, Pages: 3392-3402, ISSN: 0741-238X
INTRODUCTION: The effect of nintedanib on slowing the rate of decline in forced vital capacity (FVC) has been investigated in randomized placebo-controlled trials in subjects with idiopathic pulmonary fibrosis (IPF), other progressive fibrosing interstitial lung diseases (ILDs), and ILD associated with systemic sclerosis (SSc-ILD). We assessed the consistency of the effect of nintedanib on the rate of decline in FVC over 52 weeks across four placebo-controlled phase III trials. METHODS: We used data on FVC decline from the INPULSIS-1 and INPULSIS-2 trials in subjects with IPF, the INBUILD trial in subjects with progressing fibrosing ILDs other than IPF, and the SENSCIS trial in subjects with SSc-ILD. In each trial, the primary endpoint was the annual rate of decline in FVC (mL/year) assessed over 52 weeks. We performed fixed effect and random effects meta-analyses based on the relative treatment effect of nintedanib versus placebo on the rate of decline in FVC (mL/year) over 52 weeks. Heterogeneity of the relative treatment effect of nintedanib across populations was assessed using the I2 statistic, τ2 and corresponding p value from a Q test for heterogeneity. RESULTS: The combined analysis comprised 1257 subjects treated with nintedanib and 1042 subjects who received placebo. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks by 51.0% (95% CI 39.1, 63.0) compared with placebo. The relative effect (95% CI) was the same using the fixed effect and random effects models. There was no evidence of heterogeneity in the relative treatment effect of nintedanib across the populations studied (I2 = 0%, τ2 = 0, p = 0.93). CONCLUSIONS: A meta-analysis of data from four placebo-controlled trials demonstrated that nintedanib approximately halved the rate of decline in FVC over 52 weeks across subjects with different forms of pulmonary fibrosis, with no evidence of het
Hu X, Kim J, Ma S, et al., 2022, Integrating Gene Expression with Genome-Wide Association Summary Statistics to Identify Genes Associated with Idiopathic Pulmonary Fibrosis Survival, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Maher TM, Tudor V, Saunders P, et al., 2022, Rituximab versus Cyclophosphamide for the Treatment of Connective Tissue Disease Associated Interstitial Lung Disease ( RECITAL): A Multi-Centre Randomised Controlled Trial, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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Sand JM, Frederiksen P, Leeming DJ, et al., 2022, An Epithelial Damage-Induced Repair Response May Be Assessed by a Serological Basement Membrane Collagen Biomarker and Is Related to IPF Progression, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Raghu G, Remy-Jardin M, Richeldi L, et al., 2022, Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 205, Pages: E18-E47, ISSN: 1073-449X
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- Citations: 345
Fainberg H, Allen R, Kraven L, et al., 2022, Analysis of Forced Vital Capacity (FVC) Trajectories in Idiopathic Pulmonary Fibrosis (IPF) Identifies Four Distinct Clusters of Disease Behaviour, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Maher TM, Jenkins RG, Bonella F, et al., 2022, Effects of Nintedanib on Circulating Biomarkers in Subjects with Progressive Fibrosing Interstitial Lung Diseases (ILDs), International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Martinez FJ, Wijsenbeek MS, Raghu G, et al., 2022, Phase 2B study of inhaled RVT-1601 for chronic cough in idiopathic pulmonary fibrosis A multicenter, randomized, placebo-controlled study (SCENIC trial), American Journal of Respiratory and Critical Care Medicine, Vol: 205, Pages: 1084-1092, ISSN: 1073-449X
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.
Maher TM, Bossert S, Evans-Marsi M, et al., 2022, Safety, Tolerability and Pharmacokinetics of BI 1015550 in Patients with Idiopathic Pulmonary Fibrosis, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Kreuter M, Maher TM, 2022, <i>Fatum Inexorabile</i>: Do Monocytes Predict the Fate of Interstitial Lung Abnormalities?, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 205, Pages: 743-744, ISSN: 1073-449X
Clynick B, Corte TJ, Jo HE, et al., 2022, Biomarker signatures for progressive idiopathic pulmonary fibrosis, European Respiratory Journal, Vol: 59, ISSN: 0903-1936
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease in which circulatory biomarkers have the potential for guiding management in clinical practice. We assessed the prognostic role of serum biomarkers in three independent IPF cohorts: Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR), Trent Lung Fibrosis (TLF) and Prospective Observation of Fibrosis in the Lung Clinical Endpoints (PROFILE). METHODS: In the AIPFR cohort, candidate proteins were assessed by ELISA as well as in an unbiased proteomic approach. LASSO (least absolute shrinkage and selection operator) regression was used to restrict the selection of markers that best accounted for the progressor phenotype at 1 year in the AIPFR cohort, and subsequently prospectively selected for replication in the validation TLF cohort and assessed retrospectively in the PROFILE cohort. Four significantly replicating biomarkers were aggregated into a progression index model based on tertiles of circulating concentrations. RESULTS: 189 participants were included in the AIPFR cohort, 205 participants from the TLF cohort and 122 participants from the PROFILE cohort. Differential biomarker expression was observed by ELISA and replicated for osteopontin, matrix metallopeptidase-7, intercellular adhesion molecule-1 and periostin for those with a progressor phenotype at 1 year. Proteomic data did not replicate. The progression index in the AIPFR, TLF and PROFILE cohorts predicted risk of progression, mortality and progression-free survival. A statistical model incorporating the progression index demonstrated the capacity to distinguish disease progression at 12 months, which was increased beyond the clinical GAP (gender, age and physiology) score model alone in all cohorts, and significantly so within the incidence-based TLF and PROFILE cohorts. CONCLUSION: A panel of circulatory biomarkers can provide potentially valuable clinical assistance in the prognosis of IPF patients.
Nolan CM, Polgar O, Schofield SJ, et al., 2022, Pulmonary rehabilitation in idiopathic pulmonary fibrosis and COPD: a propensity matched real-world study, Chest, Vol: 161, Pages: 728-737, ISSN: 0012-3692
BACKGROUND: The adherence to and clinical efficacy of pulmonary rehabilitation in idiopathic pulmonary fibrosis (IPF), particularly in comparison to people with chronic obstructive pulmonary disease (COPD), remains uncertain. The objectives of this real-world study were to compare the responses of patients with IPF with a matched group of patients with COPD undergoing the same supervised, outpatient pulmonary rehabilitation program, and to determine whether pulmonary rehabilitation is associated with survival in IPF. RESEARCH QUESTION: Do people with IPF improve to the same extent with pulmonary rehabilitation as a matched group of individuals with COPD, and are non-completion of and/or non-response to pulmonary rehabilitation associated with one-year all-cause mortality in IPF? STUDY DESIGN AND METHODS: Using propensity score matching, 163 patients with IPF were matched 1:1 with a control group of 163 patients with COPD referred to pulmonary rehabilitation. We compared between-group pulmonary rehabilitation completion rates and response. Survival status in the IPF cohort was recorded over one-year following pulmonary rehabilitation discharge. Cox proportional-hazards regression explored the association between pulmonary rehabilitation status and all-cause mortality. RESULTS: Similar pulmonary rehabilitation completion rates (IPF: 69%; COPD: 63%; p=0.24) and improvements in exercise response were observed in both groups with no significant mean (95% confidence interval (CI)) between-group differences in incremental shuttle walk (ISW) change (2 (-18 to 22) meters). Pulmonary rehabilitation non-completion (hazard ratio (HR) (95%CI) 5.62 (2.24 to 14.08)) and non-response (HR (95%CI) 3.91 (1.54 to 9.93)) were independently associated with increased one-year all-cause mortality in IPF. INTERPRETATION: Compared with a matched group of patients with COPD, this real-word study demonstrates that patients with IPF have similar completion rates and magnitude of response to pul
Wu Z, Banya W, Chaudhuri N, et al., 2022, PAciFy Cough-a multicentre, double-blind, placebo-controlled, crossover trial of morphine sulphate for the treatment of pulmonary Fibrosis Cough, Trials, Vol: 23, ISSN: 1745-6215
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease that leads to lung scarring. Cough is reported by 85% of patients with IPF and can be a distressing symptom with a significant impact on patients' quality of life. There are no proven effective therapies for IPF-related cough. Whilst morphine is frequently used as a palliative agent for breathlessness in IPF, its effects on cough have never been tested. PAciFy Cough is a multicenter, double-blind, placebo-controlled, crossover trial of morphine sulphate for the treatment of cough in IPF. METHODS: We will recruit 44 subjects with IPF prospectively from three interstitial lung disease units in the UK, namely the Royal Brompton Hospital, Manchester University NHS Foundation Trust (MFT) and Aintree University Hospital NHS Foundation Trust. Patients will be randomised (1:1) to either placebo twice daily or morphine sulphate 5 mg twice daily for 14 days. They will then crossover after a 7-day washout period. The primary endpoint is the percent change in daytime cough frequency (coughs per hour) from baseline as assessed by objective cough monitoring at day 14 of treatment. DISCUSSION: This multicentre, randomised trial will assess the effect of opioids on cough counts and cough associated quality of life in IPF subjects. If proven to be an effective intervention, it represents a readily available treatment for patients. TRIAL REGISTRATION: The study was approved by the UK Medicines and Healthcare Regulatory Agency (Ref: CTA 21268/0224/001-0001 - EUDRACT 2019-003571-19 - Protocol Number RBH2019/001) on 08 April 2020, in compliance with the European Clinical Trials Directive and the Medicines for Human Use (Clinical Trials) Regulations 2004 and its subsequent amendments. The study was provided with ethical approval by the London Brent Research Ethics Committee (Ref: 20/LO/0368) on 21 May 2020 and is registered with clinicaltrials.gov (NCT04429516) on 12 June 2020, available at https://cli
Khan F, Howard L, Hearson G, et al., 2022, Clinical utility of home versus hospital spirometry in fibrotic ILD: evaluation following INJUSTIS interim analysis, Annals of the American Thoracic Society, Vol: 19, Pages: 506-510, ISSN: 1546-3222
Boustani K, Ghai P, Invernizzi R, et al., 2022, Autoantibodies are present in the bronchoalveolar lavage but not circulation in patients with fibrotic interstitial lung disease, ERJ Open Research, Vol: 8, Pages: 1-10, ISSN: 2312-0541
Fibrotic interstitial lung disease (fILD) has previously been associated with the presence of autoantibody. While studies have focused on systemic autoimmunity, the role of local autoantibodies in the airways remains unknown. We therefore extensively characterised the airway and peripheral autoantibody profiles in patients with fILD and assessed association with disease severity and outcome.Bronchoalveolar lavage (BAL) was collected from a cohort of fILD patients and total BAL antibody concentrations were quantified. An autoantigen microarray was used to measure IgG and IgA autoantibodies against 122 autoantigens in BAL from 40 idiopathic pulmonary fibrosis (IPF), 20 chronic hypersensitivity pneumonitis (CHP), 20 connective tissue disease-associated ILD (CTD-ILD) patients and 20 controls.A subset of patients with fILD but not healthy controls had a local autoimmune signature in their BAL that was not present systemically, regardless of disease. The proportion of patients with IPF with a local autoantibody signature was comparable to that of CTD-ILD, which has a known autoimmune pathology, identifying a potentially novel subset of patients. The presence of an airway autoimmune signature was not associated with reduced survival probability or changes in lung function
Maher TM, Brown KK, Kreuter M, et al., 2022, Effects of nintedanib by inclusion criteria for progression of interstitial lung disease, European Respiratory Journal, Vol: 59, Pages: 1-10, ISSN: 0903-1936
The INBUILD trial investigated nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs). We investigated decline in forced vital capacity (FVC) in subgroups based on the inclusion criteria for ILD progression.Subjects had a fibrosing ILD other than idiopathic pulmonary fibrosis and met these criteria for ILD progression within the 24 months before screening despite management deemed appropriate in clinical practice: Group A, relative decline in FVC ≥10% predicted; Group B, relative decline in FVC ≥5-<10% predicted with worsened respiratory symptoms and/or increased extent of fibrosis on HRCT; Group C, worsened respiratory symptoms and increased extent of fibrosis on HRCT only.In the placebo group, the rates of FVC decline over 52 weeks in Groups A, B and C, respectively, were -241.9, -133.1 and -115.3 mL·year-1 in the overall population (p=0.0002 for subgroup-by-time interaction) and -288.9, -156.2 and -100.1 mL·year-1 among subjects with a usual interstitial pneumonia [UIP]-like fibrotic pattern on HRCT (p=0.0005 for subgroup-by-time interaction). Nintedanib had a greater absolute effect on reducing the rate of FVC decline in Group A than Group B or C. However, the relative effect of nintedanib versus placebo was consistent across the subgroups (p>0.05 for heterogeneity).In conclusion, the inclusion criteria used in the INBUILD trial, based on FVC decline or worsening of symptoms and extent of fibrosis on HRCT, were effective at identifying patients with progressive fibrosing ILDs. Nintedanib reduced the rate of decline in FVC across the subgroups based on the inclusion criteria related to ILD progression.
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