Decline In Forced Vital Capacity Research Articles

Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study

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. 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. 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). 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 from this analysis. PKN2 inhibitors are currently in development and signify a potential novel therapeutic approach for IPF. Action for Pulmonary Fibrosis, Medical Research Council, Wellcome Trust, and National Institutes of Health National Heart, Lung, and Blood Institute.

Reticulation pattern without honeycombing on high-resolution CT is associated with the risk of disease progression in interstitial lung diseases

BackgroundThe disease course of idiopathic pulmonary fibrosis (IPF) is progressive and occasionally, other types of interstitial lung disease (ILD) may progress similarly to IPF. This study aimed to evaluate risk factors for disease progression within 24 months in patients with various ILDs.MethodsThis prospective study obtained 97 patients with a suspected ILD who underwent a transbronchial lung cryobiopsy. The extent of several high-resolution computed tomography (HRCT) patterns was assessed. Due to the inclusion criteria the study population presented a low extent of honeycombing and definite usual interstitial pneumonia (UIP) pattern on HRCT suggesting an early stage of ILD. Disease progression within 24 months despite treatment was defined as a relative decline of ≥ 10% in forced vital capacity (FVC), or a relative decline in FVC of ≥ 5% and one of the three additional criteria: (1) a decline in diffusion capacity to carbon monoxide (DLCO) ≥ 15%; (2) increased fibrosis on HRCT; (3) progressive symptoms, or progressive symptoms and increased fibrosis on HRCT. The same definition was utilized in patients with IPF and other ILDs. Risk factors for disease progression were evaluated in a multivariable logistic regression model.ResultsDisease progression was revealed in 52% of the patients with ILD, 51% of the patients with IPF, and 53% of the patients with other types of ILD. A high extent of reticulation on HRCT (Odds ratio [OR] 3.11, 95% Confidence interval [CI] 1.21–7.98, P = 0.019) and never smoking (OR 3.11, CI 1.12–8.63, P = 0.029) were associated with disease progression whereas platelet count (OR 2.06 per 100 units increase, CI 0.96–4.45, P = 0.065) did not quite reach statistical significance.ConclusionHigher extent of reticulation on HRCT and never smoking appeared to associate with the risk of disease progression within 24 months in ILD patients without honeycombing. Approximately half of the patients with ILD revealed disease progression, and similar proportions were observed in patients with IPF and in other types of ILD.

Clinical relevance of circulating autoantibodies in idiopathic pulmonary fibrosis; A NAt hard to break.

Patients with idiopathic pulmonary fibrosis are screened for circulating autoantibodies as part of the initial interstitial lung disease workup. Management of seropositive idiopathic pulmonary fibrosis is currently considered no different than that of lone idiopathic pulmonary fibrosis. Emerging data however suggest that the former may possess distinct characteristics in terms of pathophysiology, histopathology, prognosis and amenability to immunomodulation. In that context, the aim of our study was to evaluate the influence of autoantibody status on: (i) the decline of forced vital capacity; (ii) the decline of diffusing capacity of lung for carbon monoxide; and (iii) 3-year survival; in a cohort of 102 idiopathic pulmonary fibrosis patients. In a pilot sub-study, we also sought to evaluate whether changes in antibody status during disease course affect the aforementioned parameters by potentially reflecting activity of the autoimmunity component of the pro-fibrotic mechanism.

Body mass index increase: a risk factor for forced expiratory volume in 1 s decline for overweight and obese adults with asthma.

BackgroundWith increasing prevalence of overweight and obesity, it is important to study how body mass index (BMI) change may affect lung function among subjects with asthma. There are few prospective studies on this topic, especially with separate analyses of those with normal and high BMI. The aim of the present study was to prospectively study the association between annual BMI change and annual lung function decline, separately among those with normal initial BMI and overweight/obesity, in an adult asthma cohort.MethodsA population-based adult asthma cohort was examined at study entry between 1986 and 2001 and at follow-up between 2012 and 2014 (n=945). Annual BMI change was analysed in association with annual decline in forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC separately in those with normal weight (BMI 18.5–24.9) and overweight/obese subjects (BMI ≥25) at study entry. Regression models were used to adjust for sex, age, smoking, inhaled corticosteroids use and occupational exposure to gas, dust or fumes.ResultsOverweight/obese subjects had lower FEV1 and FVC but slower annual FEV1 and FVC decline compared to those with normal weight. After adjustment through regression modelling, the association between BMI change with FEV1 and FVC decline remained significant for both BMI groups, but with stronger associations among the overweight/obese (FEV1 B[Overweight/obese]=−25 mL versus B[normal weight]=−15 mL). However, when including only those with BMI increase during follow-up, the associations remained significant among those with overweight/obesity, but not in the normal-weight group. No associations were seen for FEV1/FVC.ConclusionsBMI increase is associated with faster FEV1 and FVC decline among overweight and obese adults with asthma in comparison with their normal-weight counterparts.

Quantitative computed tomography predicts outcomes in idiopathic pulmonary fibrosis.

Prediction of disease course in patients with progressive pulmonary fibrosis remains challenging. The purpose of this study was to assess the prognostic value of lung fibrosis extent quantified at computed tomography (CT) using data-driven texture analysis (DTA) in a large cohort of well-characterized patients with idiopathic pulmonary fibrosis (IPF) enrolled in a national registry. This retrospective analysis included participants in the Australian IPF Registry with available CT between 2007 and 2016. CT scans were analysed using the DTA method to quantify the extent of lung fibrosis. Demographics, longitudinal pulmonary function and quantitative CT metrics were compared using descriptive statistics. Linear mixed models, and Cox analyses adjusted for age, gender, BMI, smoking history and treatment with anti-fibrotics were performed to assess the relationships between baseline DTA, pulmonary function metrics and outcomes. CT scans of 393 participants were analysed, 221 of which had available pulmonary function testing obtained within 90 days of CT. Linear mixed-effect modelling showed that baseline DTA score was significantly associated with annual rate of decline in forced vital capacity and diffusing capacity of carbon monoxide. In multivariable Cox proportional hazard models, greater extent of lung fibrosis was associated with poorer transplant-free survival (hazard ratio [HR] 1.20, p< 0.0001) and progression-free survival (HR 1.14, p< 0.0001). In a multi-centre observational registry of patients with IPF, the extent of fibrotic abnormality on baseline CT quantified using DTA is associated with outcomes independent of pulmonary function.

Effect of Nintedanib on Progression of Systemic Sclerosis‐Associated Interstitial Lung Disease Over 100 Weeks: Data From a Randomized Controlled Trial

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.

Long-term outcomes of edaravone in amyotrophic lateral sclerosis in South Korea: 72-week observational study

BackgroundAmyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease characterized by the gradual loss of upper and lower motor neurons that leads to progressive muscle atrophy and weakness. Edaravone, a free-radical scavenger, was approved as an ALS treatment in 2015 in South Korea.MethodsThis study investigated the long-term effects and safety of edaravone by reviewing the medical records of 16 Korean patients with ALS who received extended edaravone between 2015 and 2021 in a single tertiary ALS center.ResultsAmong sixteen patients, eleven patients underwent extended edaravone therapy for more than 18 cycles (72 weeks). The mean monthly changes in the revised ALS Functional Rating Scale (ALSFRS-R) were − 0.96 ± 0.83 (0–24 weeks), − 0.70 ± 0.76 (24–48 weeks), − 1.18 ± 1.67 (48–72 weeks), and − 0.81 ± 0.60 (0–72 weeks). The mean decline in forced vital capacity (FVC) was 17.4 ± 24.1. The changes were significant in both ALSFRS-R (p < 0.001) and FVC (p = 0.048); however, the mean change in compound muscle action potential of phrenic nerves was not. Patients experienced only minor adverse events, which were well tolerated.ConclusionsThis study verifies previous reported outcomes of edaravone in 16 Korean ALS patients, indicating a modest effect with a favorable safety profile.

Decline in forced vital capacity in subjects with systemic sclerosis-associated interstitial lung disease in the SENSCIS trial compared with healthy reference subjects

BackgroundThe 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.MethodsThe 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.ResultsAt 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).ConclusionsSubjects with SSc-ILD in the SENSCIS trial had impaired lung function at baseline and experienced further deterioration over 52 weeks. The decline in FVC in the placebo group was four-fold greater than in a hypothetical group of matched healthy references, whereas the decline in FVC in patients who received nintedanib was two-fold greater than in hypothetical healthy references. These data highlight the clinical relevance of the slowing of FVC decline provided by nintedanib.Trial registration Registered 5 November 2015, https://clinicaltrials.gov/ct2/show/NCT02597933.

Limited efficacy of nintedanib for idiopathic pleuroparenchymal fibroelastosis.

The antifibrotic agent nintedanib has been reported to effectively prevent the decline in forced vital capacity (FVC) in a broad range of interstitial lung diseases. However, the efficacy of nintedanib against idiopathic pleuroparenchymal fibroelastosis (iPPFE) remains unclear. We retrospectively examined patients with idiopathic PPFE or idiopathic pulmonary fibrosis (IPF) who received nintedanib for more than 6 months. We evaluated annual changes in %FVC, radiological PPFE lesions, and body weight before and during nintedanib treatment. To investigate radiological PPFE lesions, we examined the fibrosis score, which was defined as the mean percentage of the high attenuation area in the whole lung parenchyma using three axial computed tomography images. Overall, 15 patients with iPPFE and 27 patients with IPF were included in the present study. In patients with IPF, the annual rate of decline in %FVC was significantly lower during nintedanib treatment than that before treatment (-2.01%/year [-7.64 to 3.21] versus -7.64%/year [-10.8 to -4.44], p=0.031). Meanwhile, in patients with iPPFE, the annual rate of decline in %FVC during nintedanib treatment was higher than that before treatment (-18.0%/year [-21.6 to -12.7] versus -9.40%/year [-12.3 to -8.23], p=0.109). In addition, nintedanib treatment failed to inhibit the annual rate of increase in fibrosis score in patients with iPPFE (6.53/year [1.18-15.3] during treatment versus 2.70/year [0.27-12.2] before treatment, p=0.175). Nintedanib efficacy may be limited in patients with iPPFE.

Combination of Prednisolone and Calcineurin Inhibitors Prevents Lung Function Decline in Patients with Anti-aminoacyl-tRNA Synthetase Antibody-Positive Polymyositis/Dermatomyositis.

Anti-aminoacyl-tRNA synthetase antibody-positive polymyositis/dermatomyositis-associ ated interstitial lung disease (ARS-ILD) has a good prognosis, with few cases progressing to respiratory failure. This study aimed to determine factors predictive of lung function changes in patients with ARS-ILD. We retrospectively studied 49 patients with ARS-ILD treated at Kurume University Hospital Hospital between 2000 and 2018. We followed 30 patients for more than 2 years after prednisolone (PSL) therapy, with or without calcineurin inhibitors (CNIs), evaluating clinical, physiological, computed tomography, pulmonary func tion, and serological data. After treatment for 24 months, no significant differences were noted between clinical parameters and improvement in forced vital capacity (FVC), %FVC, % carbon monoxide diffusing capacity/alveolar volume (%DLCO), and %DLCO/alveolar volume. Conversely, the annual change of %FVC significantly correlated with the Medical Research Council dyspnea scale grade and %FVC at the first visit and treatment. Furthermore, the annual change of %DLCO/VA significantly correlated with the duration from the first visit to treatment initiation. Compared with PSL monotherapy, combining PSL and CNI showed greater mitigation of %FVC decline. The time from onset of ARS-ILD to the first visit is critical for preventing a decline in lung function, and as such, patients should be monitored carefully.

The effect of COVID-19 on transplant function and development of CLAD in lung transplant patients: A multicenter experience.

BackgroundConcerns have been raised on the impact of coronavirus disease (COVID-19) on lung transplant (LTx) patients. The aim of this study was to evaluate the transplant function pre- and post-COVID-19 in LTx patients.MethodsData were retrospectively collected from LTx patients with confirmed COVID-19 from all 3 Dutch transplant centers, between February 2020 and September 2021. Spirometry results were collected pre-COVID-19, 3- and 6-months post infection.ResultsSeventy-four LTx patients were included. Forty-two (57%) patients were admitted, 19 (26%) to the intensive care unit (ICU). The in-hospital mortality was 20%. Twelve out of 19 ICU patients died (63%), a further 3 died on general wards. Patients with available spirometry (78% at 3 months, 65% at 6 months) showed a significant decline in mean forced expiratory volume in 1 second (FEV1) (ΔFEV1 138 ± 39 ml, p = 0.001), and forced vital capacity (FVC) (ΔFVC 233 ±74 ml, p = 0.000) 3 months post infection. Lung function improved slightly from 3 to 6 months after COVID-19 (ΔFEV1 24 ± 38 ml; ΔFVC 100 ± 46 ml), but remained significantly lower than pre-COVID-19 values (ΔFEV1 86 ml ± 36 ml, p = 0.021; ΔFVC 117 ± 35 ml, p = 0.012). FEV1/FVC was > 0.70.ConclusionsIn LTx patients COVID-19 results in high mortality in hospitalized patients. Lung function declined 3 months after infection and gradually improved at 6 months, but remained significantly lower compared to pre-COVID-19 values. The more significant decline in FVC than in FEV1 and FEV1/FVC > 70%, suggested a more restrictive pattern.

Clinical relevance of rheumatoid factor and anti-citrullinated peptides in fibrotic interstitial lung disease.

Rheumatoid arthritis (RA) is a frequent cause of interstitial lung disease (ILD); however, the impact of rheumatoid factor and anti-citrullinated peptide antibody seropositivity in ILD without connective tissue disease (CTD) is unclear. We examined the association of seropositivity with ILD progression, mortality and response to immunosuppression in non-CTD ILD. A total of 1570 non-CTD patients (with idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, interstitial pneumonia with autoimmune features or unclassifiable ILD) and 181 RA-ILD patients were included from a prospective registry. Longitudinal forced vital capacity (FVC), transplant-free survival and incidence of progressive fibrosing-ILD (PF-ILD) were compared between seronegative non-CTD ILD (reference group), seropositive non-CTD ILD and RA-ILD using linear mixed-effect and Cox proportional hazards models adjusted for age, sex, smoking pack-years and baseline FVC. Interaction between seropositivity and immunosuppression on FVC decline was assessed in patients with ≥6months of follow-up before and after the treatment. Two hundred and seventeen (13.8%) patients with seropositive non-CTD ILD had similar rates of FVC decline and transplant-free survival compared to seronegative non-CTD ILD, but more frequently met the criteria for PF-ILD (hazard ratio [HR]=1.35, p= 0.004). RA-ILD had slower FVC decline (p= 0.03), less PF-ILD (HR=0.75, p= 0.03) and lower likelihood of lung transplant or death (HR=0.66, p= 0.01) compared to seronegative non-CTD ILD. No interaction was found between seropositivity and treatment on FVC decline in non-CTD ILD. Seropositivity in non-CTD ILD was not associated with improved outcomes or treatment response, highlighting the importance of other disease features in determining prognosis and predicting response to immunosuppression.

Neutrophil lymphocyte ratio as an indicator for disease progression in Idiopathic Pulmonary Fibrosis

RationaleIdiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease. Patients present at different stages and disease course is varied. Blood monocytes have been linked to all-cause mortality, and neutrophils...

Safety and tolerability of pirfenidone in asbestosis: a prospective multicenter study

BackgroundPirfenidone slows down disease progression in idiopathic pulmonary fibrosis (IPF). Recent studies suggest a treatment effect in progressive pulmonary fibrosis other than IPF. However, the safety and effectiveness of pirfenidone in asbestosis patients remain unclear. In this study, we aimed to investigate the safety, tolerability and efficacy of pirfenidone in asbestosis patients with a progressive phenotype.MethodsThis was a multicenter prospective study in asbestosis patients with progressive lung function decline. After a 12-week observational period, patients were treated with pirfenidone 801 mg three times a day. Symptoms and adverse events were evaluated weekly and patients completed online patient-reported outcomes measures. At baseline, start of therapy, 12 and 24 weeks, in hospital measurement of lung function and a 6 min walking test were performed. Additionally, patients performed daily home spirometry measurements.ResultsIn total, 10 patients were included of whom 6 patients (66.7%) experienced any adverse events during the study period. Most frequently reported adverse events were fatigue, rash, anorexia and cough, which mostly occurred intermittently and were reported as not very bothersome. No significant changes in hospital pulmonary function (forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO), 6 min walking test or patient-reported outcomes measures before and after start of pirfenidone were found. Home spirometry demonstrated a FVC decline in 12 weeks before start of pirfenidone, while FVC did not decline during the 24 week treatment phase, but this difference was not statistically significant.ConclusionsTreatment with pirfenidone in asbestosis has an acceptable safety and tolerability profile and home spirometry data suggest this antifibrotic treatment might attenuate FVC decline in progressive asbestosis.Trial registration MEC-2018-1392; EudraCT number: 2018-001781-41

Impact of the revised definition on incidence and outcomes of acute exacerbation of idiopathic pulmonary fibrosis

The revised definition of acute exacerbation (AE) in idiopathic pulmonary fibrosis (IPF) was proposed in 2016, but changes in the incidence and impact on prognosis of the re-defined AE compared to those of the previous definition remain unclear. Clinical data of 445 patients with IPF (biopsy proven cases: 165) were retrospectively reviewed. The median follow-up period was 36.8 months and 17.5% (n = 78) experienced AE more than once. The 1- and 3-year incidence rates of AE were 6.7% and 16.6%, respectively, and idiopathic AE accounted for 82.1% of AE. Older age, lower diffusing capacity of the lung for carbon monoxide and 10% relative decline in forced vital capacity for 6 months were independently associated with AE. The in-hospital mortality rate following AE was 29.5%. In the multivariable analysis, AE was independently associated with poor prognosis in patients with IPF. Compared to the old definition, the revised definition relatively increased the incidence of AE by 20.4% and decreased the in-hospital mortality by 10.1%. Our results suggest that the revised definition affects approximately 20% increase in the incidences and 10% reduction in the in-hospital mortality of AE defined by the past definition.

POS0070 CONTINUED TREATMENT WITH NINTEDANIB IN PATIENTS WITH LIMITED CUTANEOUS SYSTEMIC SCLEROSIS (lcSSc) AND INTERSTITIAL LUNG DISEASE (ILD)

POS0070 CONTINUED TREATMENT WITH NINTEDANIB IN PATIENTS WITH LIMITED CUTANEOUS SYSTEMIC SCLEROSIS (lcSSc) AND INTERSTITIAL LUNG DISEASE (ILD)

Meta-Analysis of Effect of Nintedanib on Reducing FVC Decline Across Interstitial Lung Diseases.

IntroductionThe 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.MethodsWe 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.ResultsThe 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).ConclusionsA 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 heterogeneity in its relative treatment effect across patient populations.Graphical abstract

Safety and tolerability of nintedanib in patients with progressive fibrosing interstitial lung diseases: data from the randomized controlled INBUILD trial

BackgroundIn the INBUILD trial in patients with progressive fibrosing interstitial lung diseases (ILDs), nintedanib reduced the rate of decline in forced vital capacity compared with placebo, with side-effects that were manageable for most patients. We used data from the INBUILD trial to characterize further the safety and tolerability of nintedanib.MethodsPatients with fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF), who had experienced progression of ILD within the 24 months before screening despite management deemed appropriate in clinical practice, were randomized to receive nintedanib 150 mg twice daily or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg twice daily. We assessed adverse events and dose adjustments over the whole trial.ResultsA total of 332 patients received nintedanib and 331 received placebo. Median exposure to trial drug was 17.4 months in both treatment groups. Adverse events led to treatment discontinuation in 22.0% of patients treated with nintedanib and 14.5% of patients who received placebo. The most frequent adverse event was diarrhea, reported in 72.3% of patients in the nintedanib group and 25.7% of patients in the placebo group. Diarrhea led to treatment discontinuation in 6.3% of patients in the nintedanib group and 0.3% of the placebo group. In the nintedanib and placebo groups, respectively, 48.2% and 15.7% of patients had ≥ 1 dose reduction and/or treatment interruption. Serious adverse events were reported in 44.3% of patients in the nintedanib group and 49.5% of patients in the placebo group. The adverse event profile of nintedanib was generally consistent across subgroups based on age, sex, race and weight, but nausea, vomiting and dose reductions were more common among female than male patients.ConclusionsThe adverse event profile of nintedanib in patients with progressive fibrosing ILDs other than IPF is consistent with its established safety and tolerability profile in patients with IPF and characterized mainly by gastrointestinal events, particularly diarrhea. Management of adverse events using symptomatic therapies and dose adjustment is important to minimize the impact of adverse events and help patients remain on therapy.Trial registration Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178Graphical A video abstract summarizing the key results presented in this manuscript is available at: https://www.globalmedcomms.com/respiratory/cottin/INBUILDsafety.

Actual Size Mismatch in Lung Transplantation for Restrictive Lung Disease

<h3>Purpose</h3> Donor to recipient <i>predicted</i> total lung capacity (TLC) ratio is increasingly used for size matching in lung transplantation. This can overlook significant reductions in the <i>actual</i> TLC frequently seen in restrictive lung diseases. Forced vital capacity (FVC) is a useful surrogate for actual TLC, with proportionate decreases with progression of restrictive conditions. Analyzing donor predicted:recipient actual FVC could better predict actual lung size mismatch. <h3>Methods</h3> The UNOS database was used to identify 7,572 patients with restrictive lung disease undergoing isolated bilateral lung transplantation from 2005 to 2021. Lung size mismatch was quantified by donor:recipient FVC ratio, and patients were divided into quintiles. Multivariable cox regression was used to assess the relationship between size mismatch and all-cause mortality, adjusting for patient, donor and center baseline characteristics including lung allocation score (LAS) and degree of recipient FVC decline. Restricted cubic splines were used to assess the non-linear relationship between the FVC ratio and relative mortality hazard. Median follow-up was 2.6 (range 0-15) years. <h3>Results</h3> The median age of the cohort was 59 (Interquartile range (IQR) 53-64) years, 32.5% (n=2,464) were female and the median LAS was 47.1 (IQR 39.7-67.3). The median FVC ratio was 2.4 (range 1.1-5.3). Overall unadjusted 10-year survival was 37.3% (95% confidence interval (CI) 35.5-39.2). The primary cause of death was graft failure in 19.0% (n=532) cases. The highest quintile of FVC ratio was an independent predictor of mortality in multivariable analysis (hazard ratio 1.2, 95% CI 1.1-1.4). Spline analysis indicated that an FVC ratio >3.45 predicted significantly worse survival (Figure 1), corresponding to the 1,043 (14%) most oversized patients. <h3>Conclusion</h3> Oversizing with respect to FVC results in worse long-term survival despite adjustment for baseline characteristics, emphasizing the importance of considering recipient actual TLC in donor-recipient matching.

Phenotype of limited cutaneous systemic sclerosis patients with positive anti-topoisomerase I antibodies: data from the EUSTAR cohort.

To characterize patients with positive anti-topoisomerase I (ATA) in lcSSc. SSc patients enrolled in the EUSTAR cohort with a disease duration of ≤3 years at database entry were considered. We assessed the risk of major organ involvement in the following groups: ATA-lcSSc vs ACA-lcSSc and vs ANA without specificity (ANA)-lcSSc, and ATA-lcSSc vs ATA-dcSSc. Cox regression models with time-dependent covariates were performed with the following outcomes: new-onset interstitial lung disease (ILD), ILD progression [forced vital capacity (FVC) decline ≥10% and ≥5% vs values at ILD diagnosis), primary myocardial involvement (PMI), pulmonary hypertension (PH), any organ involvement and all-cause mortality. We included 1252 patients [194 ATA-lcSSc (15.5%)], with 7.7 years (s.d. 3.5) of follow-up. ILD risk was higher in ATA-lcSSc vs ACA- and ANA-lcSSc and similar to ATA-dcSSc, although with less frequent restrictive lung disease. The risk of FVC decline ≥10% (35% of ATA-lcSSc) was lower in ATA-lcSSc than in ATA-dcSSc, whereas FVC decline ≥5% occurs similarly between ATA-lcSSc (58% of patients) and other SSc subsets, including ATA-dcSSc. The risk of PMI was similar in ATA-lcSSc and ANA-lcSSc but lower than in ACA-lcSSc; no difference in PH and mortality risk was observed among lcSSc subsets. The risk of any organ involvement, PMI and PH was lower and the mortality tended to be lower in ATA-lcSSc vs ATA-dcSSc. ATA-lcSSc patients have a high risk of ILD, albeit with a lower risk of progression compared with ATA-dcSSc, supporting careful screening for ILD in this subgroup.