Publications
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Kolb M, Crestani B, Maher TM, 2023, Phosphodiesterase 4B inhibition: a potential novel strategy for treating pulmonary fibrosis, European Respiratory Review, Vol: 32, Pages: 1-13, ISSN: 0905-9180
Patients with interstitial lung disease can develop a progressive fibrosing phenotype characterised by an irreversible, progressive decline in lung function despite treatment. Current therapies slow, but do not reverse or stop, disease progression and are associated with side-effects that can cause treatment delay or discontinuation. Most crucially, mortality remains high. There is an unmet need for more efficacious and better-tolerated and -targeted treatments for pulmonary fibrosis. Pan-phosphodiesterase 4 (PDE4) inhibitors have been investigated in respiratory conditions. However, the use of oral inhibitors can be complicated due to class-related systemic adverse events, including diarrhoea and headaches. The PDE4B subtype, which has an important role in inflammation and fibrosis, has been identified in the lungs. Preferentially targeting PDE4B has the potential to drive anti-inflammatory and antifibrotic effects via a subsequent increase in cAMP, but with improved tolerability. Phase I and II trials of a novel PDE4B inhibitor in patients with idiopathic pulmonary fibrosis have shown promising results, stabilising pulmonary function measured by change in forced vital capacity from baseline, while maintaining an acceptable safety profile. Further research into the efficacy and safety of PDE4B inhibitors in larger patient populations and for a longer treatment period is needed.
Strambu IR, Seemayer CA, Fagard LM-CA, et al., 2023, GLPG1205 for idiopathic pulmonary fibrosis: a phase 2 randomised placebo-controlled trial., Eur Respir J, Vol: 61
BACKGROUND: GLPG1205 is a selective functional antagonist of G-protein-coupled receptor 84, which plays an important role in fibrotic processes. This study assessed the efficacy, safety and tolerability of GLPG1205 for treatment of idiopathic pulmonary fibrosis (IPF). METHODS: PINTA (ClinicalTrials.gov: NCT03725852) was a phase 2, randomised, double-blind, placebo-controlled, proof-of-concept trial. Patients with IPF were randomised 2:1 to once-daily oral GLPG1205 100 mg or placebo for 26 weeks and stratified to receive GLPG1205 alone or with local standard of care (nintedanib or pirfenidone). The primary end-point was change from baseline in forced vital capacity (FVC); other end-points were safety and tolerability, and lung volumes measured by imaging (high-resolution computed tomography). The study was not powered for statistical significance. RESULTS: In total, 68 patients received study medication. Least squares mean change from baseline in FVC at week 26 was -33.68 (95% CI -112.0-44.68) mL with GLPG1205 and -76.00 (95% CI -170.7-18.71) mL with placebo (least squares mean difference 42.33 (95% CI -81.84-166.5) mL; p=0.50). Lung volumes by imaging declined -58.30 versus -262.72 mL (whole lung) and -33.68 versus -135.48 mL (lower lobes) with GLPG1205 versus placebo, respectively. Treatment with GLPG1205 versus placebo resulted in higher proportions of serious and severe treatment-emergent adverse events and treatment-emergent discontinuations, most apparent with nintedanib. CONCLUSIONS: Treatment with GLPG1205 did not result in a significant difference in FVC decline versus placebo. GLPG1205 demonstrated a poorer safety and tolerability profile than placebo.
Oldham JM, Allen RJ, Lorenzo-Salazar JM, et al., 2023, PCSK6 and survival in idiopathic pulmonary fibrosis., American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. OBJECTIVE: To identify and validate molecular determinants of IPF survival. METHODS: A staged genome-wide association study (GWAS) was performed using paired genomic and survival data. Stage I cases were drawn from centers across the US and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplant-free survival (TFS). Stage I variants with nominal significance (p<5x10-5) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (p<5x10-8). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. MAIN RESULTS: After quality controls, 1481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of proprotein convertase subtilisin/kexin type 6 (PCSK6) reaching genome-wide significance (HR 4.11; 95%CI 2.54-6.67; p=9.45x10-9). PCSK6 protein was highly expressed in IPF lung parenchyma. PCSK6 lung staining intensity, peripheral blood gene expression and plasma concentration were associated with reduced transplant-free survival. CONCLUSIONS: We identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein plays a potentially important role in IPF progression. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/lic
Kreuter M, Hoffmann-Vold A-M, Matucci-Cerinic M, et al., 2023, Impact of lung function and baseline clinical characteristics on patient-reported outcome measures in systemic sclerosis-associated interstitial lung disease, Rheumatology, Vol: 62, Pages: S143-S153, ISSN: 1462-0324
OBJECTIVE: The SENSCIS® trial demonstrated a significant reduction of lung function decline in patients with systemic sclerosis (SSc)-associated interstitial lung disease (SSc-ILD) treated with nintedanib, but no significant effect on health-related quality of life (HRQoL). To assess whether SSc/SSc-ILD severity and large changes in lung function correlate with HRQoL, a post-hoc analysis of SENSCIS®, aggregating treatment arms, was undertaken. METHODS: Patient-reported outcome (PRO) measures (St. George's Respiratory Questionnaire [SGRQ], Functional Assessment of Chronic Illness Therapy [FACIT]-Dyspnoea, and Health Assessment Questionnaire-Disability Index [HAQ-DI], incorporating the Scleroderma Health Assessment Questionnaire visual analogue scale [SHAQ VAS]) at baseline and week 52 were assessed for associations to SSc-ILD severity. RESULTS: At baseline and at week 52, forced vital capacity (FVC) <70% predicted was associated with worse PRO measure scores compared with FVC ≥70% predicted (week 52: SGRQ 45.1 vs 34.0 [p< 0.0001]; FACIT-Dyspnoea 48.9 vs 44.5 [p< 0.0001]; HAQ-DI 0.7 vs 0.6 [p< 0.0228]; SHAQ VAS breathing problems 3.6 vs 2.6 [p< 0.0001]). Patients with diffuse cutaneous SSc and other characteristics associated with SSc-ILD severity had worse PRO measure scores. Patients requiring oxygen or with >30% fibrosis on high-resolution computed tomography at baseline demonstrated worse PRO measure scores at week 52. After 1 year, patients with a major (>10%) improvement/worsening in FVC demonstrated corresponding improvement/worsening in SGRQ and other PRO measures, significant for the SGRQ symptom domain (p< 0.001). CONCLUSION: Severe SSc-ILD and major deteriorations in lung function have important impacts on HRQoL. Treatments that slow lung function decline and prevent severe SSc-ILD are important to preserve HRQoL. TRIAL REGISTRATION: clinicaltrials.gov, www.clinicaltrials.gov, NCT02597933.
Khanna D, Maher TM, Volkmann ER, et al., 2023, Effect of nintedanib in patients with systemic sclerosis-associated interstitial lung disease and risk factors for rapid progression, RMD OPEN, Vol: 9, ISSN: 2056-5933
Peljto AL, Blumhagen RZ, Walts AD, et al., 2023, Idiopathic pulmonary fibrosis is associated with common genetic variants and limited rare variants, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X
Rationale: Idiopathic pulmonary fibrosis is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to non-genetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants genome-wide may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ≤0.01) within genes or regions. We also identified individual variants that are influential within genes and estimated the heritability of IPF based on rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP-heritability of IPF was estimated to be 32% (s.e. 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.
Wijsenbeek MS, Moor CC, Johannson KA, et al., 2023, Home monitoring in interstitial lung diseases, The Lancet Respiratory Medicine, Vol: 11, Pages: 97-110, ISSN: 2213-2600
The widespread use of smartphones and the internet has enabled self-monitoring and more hybrid-care models. The COVID-19 pandemic has further accelerated remote monitoring, including in the heterogenous and often vulnerable group of patients with interstitial lung diseases (ILDs). Home monitoring in ILD has the potential to improve access to specialist care, reduce the burden on health-care systems, improve quality of life for patients, identify acute and chronic disease worsening, guide treatment decisions, and simplify clinical trials. Home spirometry has been used in ILD for several years and studies with other devices (such as pulse oximeters, activity trackers, and cough monitors) have emerged. At the same time, challenges have surfaced, including technical, analytical, and implementational issues. In this Series paper, we provide an overview of experiences with home monitoring in ILD, address the challenges and limitations for both care and research, and provide future perspectives. VIDEO ABSTRACT.
Maher TM, Tudor VA, Saunders P, et al., 2023, Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial, The Lancet Respiratory Medicine, Vol: 11, Pages: 45-54, ISSN: 2213-2600
BACKGROUND: Rituximab is often used as rescue therapy in interstitial lung disease (ILD) associated with connective tissue disease (CTD), but has not been studied in clinical trials. This study aimed to assess whether rituximab is superior to cyclophosphamide as a treatment for severe or progressive CTD associated ILD. METHODS: We conducted a randomised, double-blind, double-dummy, phase 2b trial to assess the superiority of rituximab compared with cyclophosphamide. Patients aged 18-80 years with severe or progressive ILD related to scleroderma, idiopathic inflammatory myositis, or mixed CTD, recruited across 11 specialist ILD or rheumatology centres in the UK, were randomly assigned (1:1) to receive rituximab (1000 mg at weeks 0 and 2 intravenously) or cyclophosphamide (600 mg/m2 body surface area every 4 weeks intravenously for six doses). The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks compared with baseline, analysed using a mixed-effects model with random intercepts, adjusted for baseline FVC and CTD type. Prespecified secondary endpoints reported in this Article were change in FVC at 48 weeks versus baseline; changes from baseline in 6 min walk distance, diffusing capacity of the lung for carbon monoxide (DLCO), physician-assessed global disease activity (GDA) score, and quality-of-life scores on the St George's Respiratory Questionnaire (SGRQ), King's Brief Interstitial Lung Disease (KBILD) questionnaire, and European Quality of Life Five-Dimension (EQ-5D) questionnaire at 24 and 48 weeks; overall survival, progression-free survival, and time to treatment failure; and corticosteroid use. All endpoints were analysed in the modified intention-to-treat population, which comprised all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT01862926). FINDINGS: Between Dec 1, 2014, and March 31, 2020, we screened 145 participants, of whom 101 participants were randomly allocated
Solomon JJ, Danoff SK, Woodhead FA, et al., 2023, Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study., Lancet Respir Med, Vol: 11, Pages: 87-96
BACKGROUND: Interstitial lung disease is a known complication of rheumatoid arthritis, with a lifetime risk of developing the disease in any individual of 7·7%. We aimed to assess the safety, tolerability, and efficacy of pirfenidone for the treatment of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). METHODS: TRAIL1 was a randomised, double-blind, placebo-controlled, phase 2 trial done in 34 academic centres specialising in interstitial lung disease in four countries (the UK, the USA, Australia, and Canada). Adults aged 18-85 years were eligible for inclusion if they met the 2010 American College of Rheumatology and European Alliance of Associations for Rheumatology criteria for rheumatoid arthritis and had interstitial lung disease on a high-resolution CT scan imaging and, when available, lung biopsy. Exclusion criteria include smoking, clinical history of other known causes of interstitial lung disease, and coexistant clinically significant COPD or asthma. Patients were randomly assigned (1:1) to receive 2403 mg oral pirfenidone (pirfenidone group) or placebo (placebo group) daily. The primary endpoint was the incidence of the composite endpoint of a decline from baseline in percent predicted forced vital capacity (FVC%) of 10% or more or death during the 52-week treatment period assessed in the intention-to-treat population. Key secondary endpoints included change in absolute and FVC% over 52 weeks, the proportion of patients with a decline in FVC% of 10% or more, and the frequency of progression as defined by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02808871. FINDINGS: From May 15, 2017, to March 31, 2020, 231 patients were assessed for inclusion, of whom 123 patients were randomly assigned (63 [51%] to the pirfenidone group and 60 [49%] to the placebo group). The trial was stopped early (March 31, 2020) d
Allen RJ, Oldham JM, Jenkins DA, et al., 2023, Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study, The Lancet Respiratory Medicine, Vol: 11, Pages: 65-73, ISSN: 2213-2600
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease characterised by progressive scarring leading to alveolar stiffness, reduced lung capacity, and impeded gas transfer. We aimed to identify genetic variants associated with declining lung capacity or declining gas transfer after diagnosis of IPF. METHODS: We did a genome-wide meta-analysis of longitudinal measures of forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) in individuals diagnosed with IPF. Individuals were recruited to three studies between June, 1996, and August, 2017, from across centres in the US, UK, and Spain. Suggestively significant variants were investigated further in an additional independent study (CleanUP-IPF). All four studies diagnosed cases following American Thoracic Society/European Respiratory Society guidelines. Variants were defined as significantly associated if they had a meta-analysis p<5 × 10-8 when meta-analysing across all discovery and follow-up studies, had consistent direction of effects across all four studies, and were nominally significant (p<0·05) in each study. FINDINGS: 1329 individuals with a total of 5216 measures were included in the FVC analysis. 975 individuals with a total of 3361 measures were included in the DLCO analysis. For the discovery genome-wide analyses, 7 611 174 genetic variants were included in the FVC analysis and 7 536 843 in the DLCO analysis. One variant (rs115982800) located in an antisense RNA gene for protein kinase N2 (PKN2) showed a genome-wide significant association with FVC decline (-140 mL/year per risk allele [95% CI -180 to -100]; p=9·14 × 10-12). INTERPRETATION: Our analysis identifies a genetic variant associated with disease progression, which might highlight a new biological mechanism for IPF. We found that PKN2, a Rho and Rac effector protein, is the most likely gene of interest fro
van der Vis JJ, Prasse A, Renzoni EA, et al., 2022, MUC5B rs35705950 minor allele associates with older age and better survival in idiopathic pulmonary fibrosis, Respirology, ISSN: 1323-7799
Background and Objective:The minor T-allele of the MUC5B promoter polymorphism rs35705950 is strongly associated with idiopathic pulmonary fibrosis (IPF). However, conflicting results have been reported on the relationship between the MUC5B minor allele and survival and it is unknown whether a specific subgroup of IPF patients might benefit from MUC5B minor allele carriage. We investigated the association between MUC5B rs35705950, survival and patient characteristics in a real-world population of European IPF patients.Methods:In this retrospective study, 1751 patients with IPF from 8 European centres were included. MUC5B rs35705950 genotype, demographics, clinical characteristics at diagnosis and survival data were analysed.Results:In a multi-variate Cox proportional hazard model the MUC5B minor allele was a significant independent predictor of survival when adjusted for age, sex, high resolution computed tomography pattern, smoking behaviour and pulmonary function tests in IPF. MUC5B minor allele carriers were significantly older at diagnosis (p = 0.001). The percentage of MUC5B minor allele carriers increased significantly with age from 44% in patients aged <56 year, to 63% in patients aged >75. In IPF patients aged <56, the MUC5B minor allele was not associated with survival. In IPF patients aged ≥56, survival was significantly better for MUC5B minor allele carriers (45 months [CI: 42–49]) compared to non-carriers (29 months [CI: 26–33]; p = 4 × 10−12).Conclusion:MUC5B minor allele carriage associates with a better median transplant-free survival of 16 months in the European IPF population aged over 56 years. MUC5B genotype status might aid disease prognostication in clinical management of IPF patients.
Richeldi L, Azuma A, Cottin V, et al., 2022, Plain language summary: Clinical study of BI 1015550 as a potential treatment for idiopathic pulmonary fibrosis., J Comp Eff Res
WHAT IS THIS SUMMARY ABOUT?: This plain language summary describes the main findings from a trial in people with idiopathic pulmonary fibrosis (also called IPF) that was recently published in the New England Journal of Medicine. IPF is a rare disease, where the lungs become more and more scarred, with breathing and oxygen uptake becoming increasingly difficult. This trial looked at the medication BI 1015550 as a potential treatment for IPF. It compared BI 1015550 to placebo (a dummy drug that does not contain any active ingredients) to investigate the effectiveness of the drug in treating people with IPF. The study also looked at the additional medical issues (referred to as adverse events) reported during the study. Some participants took approved treatments to reduce scarring (nintedanib or pirfenidone), and some did not. WHAT WERE THE RESULTS?: Overall, 147 people with IPF from 22 countries took part in the trial. The results showed that BI 1015550 prevented lung function from decreasing in people with IPF. There was no difference in the percentage of patients with medical issues rated as severe by the study physician with BI 1015550 or placebo. However, more people treated with BI 1015550 had diarrhoea. Among those treated with BI 1015550, 13 participants stopped their treatment due to medical issues, whereas treatment was not stopped due to medical issues for any participants treated with placebo. WHAT DO THE RESULTS MEAN?: These results provide evidence that BI 1015550 prevents lung function from worsening in people with IPF. Further clinical studies will be conducted in the future to test BI 1015550 in a larger group of people with IPF and other forms of lung scarring that get worse over time, and for a longer time period.
Podolanczuk AJ, Kim JS, Cooper CB, et al., 2022, Design and rationale for the prospective treatment efficacy in IPF using genotype for NAC selection (PRECISIONS) clinical trial, BMC Pulmonary Medicine, Vol: 22, ISSN: 1471-2466
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. N-acetylcysteine (NAC) is a well-tolerated, inexpensive treatment with antioxidant and anti-fibrotic properties. The National Heart, Lung, and Blood Institute (NHLBI)-sponsored PANTHER (Prednisone Azathioprine and NAC therapy in IPF) trial confirmed the harmful effects of immunosuppression in IPF, and did not show a benefit to treatment with NAC. However, a post hoc analysis revealed a potential beneficial effect of NAC in a subgroup of individuals carrying a specific genetic variant, TOLLIP rs3750920 TT genotype, present in about 25% of patients with IPF. Here, we present the design and rationale for the Phase III, multi-center, randomized, double-blind, placebo-controlled Prospective Treatment Efficacy in IPF Using Genotype for NAC Selection (PRECISIONS) clinical trial. METHODS: The PRECISIONS trial will randomize 200 patients with IPF and the TOLLIP rs3750920 TT genotype 1:1 to oral N-acetylcysteine (600 mg tablets taken three times a day) or placebo for a 24-month duration. The primary endpoint is the composite of time to 10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or death from any cause. Secondary endpoints include change in patient-reported outcome scores and proportion of participants with treatment-emergent adverse events. Biospecimens, including blood, buccal, and fecal will be collected longitudinally for future research purposes. Study participants will be offered enrollment in a home spirometry substudy, which explores time to 10% relative FVC decline measured at home, and its comparison with study visit FVC. DISCUSSION: The sentinel observation of a potential pharmacogenetic interaction between NAC and TOLLIP polymorphism highlights the urgent, unmet need for better, molecularly focused, and precise therapeutic strategies in IPF. The PRECISIONS clinical trial is the first study
Fainberg HP, Oldham JM, Molyneau PL, et al., 2022, Forced vital capacity trajectories in patients with idiopathic pulmonary fibrosis: a secondary analysis of a multicentre, prospective, observational cohort, The Lancet Digital Health, Vol: 4, Pages: e862-e872, ISSN: 2589-7500
BACKGROUND: Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease with a variable clinical trajectory. Decline in forced vital capacity (FVC) is the main indicator of progression; however, missingness prevents long-term analysis of patterns in lung function. We aimed to identify distinct clusters of lung function trajectory among patients with idiopathic pulmonary fibrosis using machine learning techniques. METHODS: We did a secondary analysis of longitudinal data on FVC collected from a cohort of patients with idiopathic pulmonary fibrosis from the PROFILE study; a multicentre, prospective, observational cohort study. We evaluated the imputation performance of conventional and machine learning techniques to impute missing data and then analysed the fully imputed dataset by unsupervised clustering using self-organising maps. We compared anthropometric features, genomic associations, serum biomarkers, and clinical outcomes between clusters. We also performed a replication of the analysis on data from a cohort of patients with idiopathic pulmonary fibrosis from an independent dataset, obtained from the Chicago Consortium. FINDINGS: 415 (71%) of 581 participants recruited into the PROFILE study were eligible for further analysis. An unsupervised machine learning algorithm had the lowest imputation error among tested methods, and self-organising maps identified four distinct clusters (1-4), which was confirmed by sensitivity analysis. Cluster 1 comprised 140 (34%) participants and was associated with a disease trajectory showing a linear decline in FVC over 3 years. Cluster 2 comprised 100 (24%) participants and was associated with a trajectory showing an initial improvement in FVC before subsequently decreasing. Cluster 3 comprised 113 (27%) participants and was associated with a trajectory showing an initial decline in FVC before subsequent stabilisation. Cluster 4 comprised 62 (15%) participants and was associated with a trajectory showing stable lung
De Zorzi E, Spagnolo P, Cocconcelli E, et al., 2022, Thoracic involvement in systemic autoimmune rheumatic diseases: pathogenesis and management, Clinical Reviews in Allergy and Immunology, Vol: 63, Pages: 472-489, ISSN: 1080-0549
Thoracic involvement is one of the main determinants of morbidity and mortality in patients with autoimmune rheumatic diseases (ARDs), with different prevalence and manifestations according to the underlying disease. Interstitial lung disease (ILD) is the most common pulmonary complication, particularly in patients with systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIMs) and rheumatoid arthritis (RA). Other thoracic manifestations include pulmonary arterial hypertension (PAH), mostly in patients with SSc, airway disease, mainly in RA, and pleural involvement, which is common in systemic lupus erythematosus and RA, but rare in other ARDs.In this review, we summarize and critically discuss the current knowledge on thoracic involvement in ARDs, with emphasis on disease pathogenesis and management. Immunosuppression is the mainstay of therapy, particularly for ARDs-ILD, but it should be reserved to patients with clinically significant disease or at risk of progressive disease. Therefore, a thorough, multidisciplinary assessment to determine disease activity and degree of impairment is required to optimize patient management. Nevertheless, the management of thoracic involvement-particularly ILD-is challenging due to the heterogeneity of disease pathogenesis, the variety of patterns of interstitial pneumonia and the paucity of randomized controlled clinical trials of pharmacological intervention. Further studies are needed to better understand the pathogenesis of these conditions, which in turn is instrumental to the development of more efficacious therapies.
Maher TM, Schiffman C, Kreuter M, et al., 2022, A review of the challenges, learnings and future directions of home handheld spirometry in interstitial lung disease, Respiratory Research, Vol: 23, ISSN: 1465-9921
BackgroundPatients with interstitial lung disease (ILD) require regular physician visits and referral to specialist ILD clinics. Difficulties or delays in accessing care can limit opportunities to monitor disease trajectory and response to treatment, and the COVID-19 pandemic has added to these challenges. Therefore, home monitoring technologies, such as home handheld spirometry, have gained increased attention as they may help to improve access to care for patients with ILD. However, while several studies have shown that home handheld spirometry in ILD is acceptable for most patients, data from clinical trials are not sufficiently robust to support its use as a primary endpoint. This review discusses the challenges that were encountered with handheld spirometry across three recent ILD studies, which included home spirometry as a primary endpoint, and highlights where further optimisation and research into home handheld spirometry in ILD is required.Abstract bodyRate of decline in forced vital capacity (FVC) as measured by daily home handheld spirometry versus site spirometry was of primary interest in three recently completed studies: STARLINER (NCT03261037), STARMAP and a Phase II study of pirfenidone in progressive fibrosing unclassifiable ILD (NCT03099187). Unanticipated practical and technical issues led to problems with estimating FVC decline. In all three studies, cross-sectional correlations for home handheld versus site spirometry were strong/moderate at baseline and later timepoints, but longitudinal correlations were weak. Other issues observed with the home handheld spirometry data included: high within-patient variability in home handheld FVC measurements; implausible longitudinal patterns in the home handheld spirometry data that were not reflected in site spirometry; and extreme estimated rates of FVC change.ConclusionsHome handheld spirometry in ILD requires further optimisation and research to ensure accurate and reliable FVC measurements before it
Chung KF, Birring SS, Morice AH, et al., 2022, Tackling the neuropathic cough of idiopathic pulmonary fibrosis (IPF): more needs to be done, Lung: an international journal on lungs, airways and breathing, Vol: 200, Pages: 673-675, ISSN: 0341-2040
Up to 80% of patients with idiopathic pulmonary fibrosis (IPF) suffer from a chronic cough, which may be the first symptom of the disease. Cough has been reported to be an independent predictor of disease progression [1] and is associated with reduced quality of life (QoL), because from the patients’ point of view, it causes physical and emotional distress with chest pain, hoarse voice, incontinence, and sleep disturbance [2, 3]. In addition, cough QoL scores have been independently associated with a higher risk of hospitalisation, lung transplantation and death at 1 year [4]. Therefore, control of cough in IPF remains an important priority.
Maher TM, Schlecker C, Luedtke D, et al., 2022, Phase I studies of BI 1015550, a preferential phosphodiesterase 4B inhibitor, in healthy males and patients with idiopathic pulmonary fibrosis, ERJ Open Research, Vol: 8, ISSN: 2312-0541
Introduction: BI 1015550 is a phosphodiesterase 4 (PDE4) inhibitor that has antifibrotic properties. Phase I and Ic studies were conducted to investigate the safety, tolerability and pharmacokinetics of BI 1015550 in healthy male subjects and patients with idiopathic pulmonary fibrosis (IPF).Methods: In the phase I study, 42 subjects were partially randomised to receive placebo or BI 1015550 in single rising doses of 36 mg and 48 mg, or multiple rising doses of 6 mg and 12 mg twice daily over 14 days. In the phase Ic study, 15 patients with IPF were randomised to receive 18 mg BI 1015550 or placebo twice daily for up to 12 weeks. For both studies, the primary endpoint was the number of subjects with drug-related adverse events (AEs).Results: In the Phase I study, drug-related AEs were reported for 50.0% of healthy male subjects treated with a single dose of BI 1015550, compared with 16.7% receiving placebo. For those receiving multiple doses, drug-related AEs were reported for 37.5% of those treated with BI 1015550 and 12.5% receiving placebo. The most frequently reported AEs by organ class were nervous system disorders, which were largely driven by headache. In the Phase Ic study, drug-related AEs were reported in 90.0% of patients treated with BI 1015550, compared with 60.0% of those receiving placebo. The most frequent AEs by organ class were gastrointestinal AEs.Conclusions: BI 1015550 had an acceptable safety profile in healthy male subjects and male and female patients with IPF, supporting further development in larger trials.
Zhang D, Povysil G, Newton CA, et al., 2022, Genome-wide enrichment of TERT rare variants in Idiopathic Pulmonary Fibrosis patients of Latino ancestry, American Journal of Respiratory and Critical Care Medicine, Vol: 206, Pages: 903-905, ISSN: 1073-449X
Genome-wide rare variant studies of IPF patients of non-European ancestry have been understudied. Here, we evaluate the enrichment of rare genetic variants of 241 unrelated non-European cases, representing individuals of Latino, African, South Asian, East Asian, and Other Admixed ancestry. Gene burden analysis of deleterious rare (protein-truncating and missense) variants demonstrate an excess of TERT rare damaging variants (OR 67.1, 95% CI [23.1, 195.0], P = 9.4 x 10-14) in non-European subjects. Analysis by ancestry demonstrated an excess of rare, damaging TERT variants in the Latino subgroup (OR 80.9, 95% CI [17.3, 383.8], P = 2.6 x 10-8). Although the non-European group did not show enrichment of PARN, RTEL1, and KIF15 rare deleterious variants, these groups all showed a trend in the same direction as the European ancestry group. For TERT and KIF15, the inclusion of IPF patients of non-European ancestry led to a higher odds ratios and increased evidence in favor of rare deleterious variant contributions, thus demonstrating the increased power of multi-ethnic studies over single-ethnicity studies. To our knowledge, this is the first study that confirms the involvement of rare deleterious TERT variants for IPF patients of Latino and non-European ancestry. To better understand the genetic underpinnings of IPF patients of all ancestries, additional work will be needed to broaden patient recruitment to normalize imbalances.
Assassi S, Distler O, Allanore Y, et al., 2022, Effect of nintedanib on progression of systemic sclerosis-associated interstitial lung disease over 100 weeks: data from a randomized controlled trial, ACR Open Rheumatology, Vol: 10, Pages: 837-844, ISSN: 2578-5745
ObjectiveIn the SENSCIS trial, participants with systemic sclerosis-associated interstitial lung disease (SSc-ILD) were randomized to receive nintedanib or placebo until the last participant reached week 52 but for 100 weeks or less. Nintedanib reduced the rate of decline in forced vital capacity (FVC) (ml/year) over 52 weeks by 44% (41 ml [95% confidence interval (95% CI): 2.9-79.0]) versus placebo. We investigated the effect of nintedanib over the whole SENSCIS trial.MethodsThe annual rate of decline in FVC (ml/year) over the whole trial was assessed descriptively using 1) on-treatment data plus off-treatment data from participants who prematurely discontinued treatment (intent-to-treat analysis) and 2) only on-treatment data to assess the effect of nintedanib in participants who remained on treatment.ResultsIn the intent-to-treat analysis, the adjusted mean (SE) annual rate of decline in FVC over 100 weeks was −54.9 (11.1) and −88.8 (10.9) ml/year in the nintedanib (n = 287) and placebo (n = 288) groups, respectively (difference 34.0 ml/year [95% CI: 3.4-64.5]). In the on-treatment analysis, the adjusted mean (SE) annual rate of decline in FVC over 100 weeks was −55.1 (12.3) and −94.0 (11.7) ml/year in the nintedanib (n = 286) and placebo (n = 288) groups, respectively (difference 38.9 ml/year [95% CI: 5.6-72.1]). The adverse event profile of nintedanib over 100 weeks was consistent with that observed over 52 weeks.ConclusionNintedanib provides a sustained benefit on slowing the progression of SSc-ILD over 100 weeks, with adverse events that are manageable for most patients.
Roofeh D, Brown KK, Kazerooni EA, et al., 2022, Systemic sclerosis associated interstitial lung disease: a conceptual framework for subclinical, clinical and progressive disease, RHEUMATOLOGY, ISSN: 1462-0324
Denton CP, Goh NS, Humphries SM, et al., 2022, Extent of fibrosis and lung function decline in patients with systemic sclerosis and interstitial lung disease: data from the SENSCIS trial, Rheumatology, ISSN: 1462-0324
OBJECTIVE: To assess associations between the extent of fibrotic interstitial lung disease (ILD) and forced vital capacity (FVC) at baseline and change in FVC over 52 weeks in patients with systemic sclerosis-associated ILD (SSc-ILD) in the SENSCIS trial. METHODS: We used generalised additive models, which involve few assumptions and allow for interaction between non-linear effects, to assess associations between the extent of fibrotic ILD on high-resolution computed tomography (HRCT), and the interplay of extent of fibrotic ILD on HRCT and FVC % predicted, at baseline and FVC decline over 52 weeks. RESULTS: In the placebo group (n = 288), there was weak evidence of a modest association between a greater extent of fibrotic ILD at baseline and a greater decline in FVC % predicted at week 52 (r: -0.09 [95% CI -0.2, 0.03]). Higher values of both the extent of fibrotic ILD and FVC % predicted at baseline tended to be associated with greater decline in FVC % predicted at week 52. In the nintedanib group (n = 288), there was no evidence of an association between the extent of fibrotic ILD at baseline and decline in FVC % predicted at week 52 (r: 0.01 [95% CI: -0.11, 0.12]) or between the interplay of extent of fibrotic ILD and FVC % predicted at baseline and decline in FVC % predicted at week 52. CONCLUSION: Data from the SENSCIS trial suggest that patients with SSc-ILD are at risk of ILD progression and benefit from nintedanib largely irrespective of their extent of fibrotic ILD at baseline. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02597933.
van der Vis J, Prasse A, Renzoni E, et al., 2022, Association of mUC5B rs35705950 minor allele with age and survival in European patients with Idiopathic Pulmonary Fibrosis, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wiqvist K, Ingelsten M, Jevnikar Z, et al., 2022, A transcriptomic, metabolic and phenotypic study of the anti-fibrotic effects of PGE2 in IPF lung fibroblasts and macrophages, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Maher TM, Nambiar AM, Wells AU, 2022, The role of precision medicine in interstitial lung disease, European Respiratory Journal, Vol: 60, ISSN: 0903-1936
The management of interstitial lung disease (ILD) may benefit from a conceptual shift. Increased understanding of this complex and heterogeneous group of disorders over the past 20 years has highlighted the need for individualised treatment strategies that encompass diagnostic classification and disease behaviour. Biomarker-based approaches to precision medicine hold the greatest promise. Robust, large-scale biomarker-based technologies supporting ILD diagnosis have been developed, and future applications relating to staging, prognosis and assessment of treatment response are emerging. Artificial intelligence may redefine our ability to base prognostic evaluation on both diagnosis and underlying disease processes, sharpening individualised treatment algorithms to a level not previously achieved. Compared with therapeutic areas such as oncology, precision medicine in ILD is still in its infancy. However, the heterogeneous nature of ILD suggests that many relevant molecular, environmental and behavioural targets may serve as useful biomarkers if we are willing to invest in their identification and validation.
Maher TM, 2022, A clinical short-cut to identifying short telomeres in idiopathic pulmonary fibrosis?, RESPIROLOGY, Vol: 27, Pages: 916-917, ISSN: 1323-7799
Richeldi L, Stowasser S, Maher TM, 2022, Trial of a phosphodiesterase 4 inhibitor for idiopathic pulmonary fibrosis. reply., New England Journal of Medicine, Vol: 387, Pages: 762-762, ISSN: 0028-4793
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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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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- Citations: 6
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
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