Abstract
Introduction
Clinical practice guidelines recommend autoimmune serological testing in patients newly diagnosed with interstitial lung disease of apparently unknown cause who may have idiopathic pulmonary fibrosis (IPF), in order to exclude connective tissue disease (CTD). Autoantibody positivity has been associated with unique patient profiles and prognosis in patients with IPF who otherwise lack a CTD diagnosis.
Methods
This post-hoc analysis of patients with IPF from the Phase III ASCEND trial (NCT01366209) evaluated the association of antinuclear antibodies (ANA), rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) status with baseline disease characteristics, disease progression [percent predicted forced vital capacity (%FVC), forced vital capacity (FVC) volume and progression-free survival (PFS)], and treatment outcomes with pirfenidone and placebo (%FVC, FVC and PFS).
Results
Of 555 participants, 244/514 (47.5%) were ANA positive (ANA+), 83/514 (16.1%) had high ANA+ (ANA titre ≥ 1:160 or positive nucleolar- or centromere-staining patterns), 60/555 (10.8%) were RF positive (RF+) and/or anti-CCP positive (anti-CCP+) and 270/514 (52.5%) were autoantibody negative (AAb−). Baseline demographics and characteristics were generally comparable between autoantibody subgroups. Although not statistically significant, more placebo-treated participants with ANA+ or high ANA+ had a decline from baseline to Week 52 of ≥ 10% in %FVC or death (48.7% and 55.9%, respectively) or in FVC volume or death (48.7% and 47.1%, respectively) compared with the AAb− group (%FVC or death: 42.0%; FVC volume or death: 42.0%). The RF+ and/or anti-CCP+ group was similar to AAb−. No differences were observed in PFS. A treatment benefit for pirfenidone versus placebo was observed regardless of autoantibody status [PFS: ANA+ HR (95% CI): 0.56 (0.37 to 0.86), P = 0.007; AAb− HR (95% CI): 0.50 (0.32 to 0.78), P = 0.002].
Conclusion
IPF disease course did not differ by autoantibody status in ASCEND. Pirfenidone had a treatment benefit regardless of the presence of ANA.
Trial Registration
ClinicalTrials.gov identifier, NCT01366209.
Plain Language Summary
People with idiopathic pulmonary fibrosis sometimes have abnormal antibodies, called autoantibodies, in their blood. Uncommonly, autoantibodies may mistakenly target the person’s own tissues, including the lungs. It is unknown whether these autoantibodies cause idiopathic pulmonary fibrosis or make it worse. This analysis looked at data from the ASCEND clinical trial in people with idiopathic pulmonary fibrosis, who were split randomly into two groups to receive tablets of either a medicine called pirfenidone or a placebo for 52 weeks. One goal was to see whether people with certain autoantibodies called antinuclear antibodies (‘ANA’ for short), rheumatoid factor (‘RF’) and anti-cyclic citrullinated peptide (‘anti-CCP’) had different traits from people without autoantibodies, such as age, race or smoking history. Other goals were to see if autoantibodies affected (1) how well people’s lungs worked during the trial, (2) how quickly people’s idiopathic pulmonary fibrosis got worse or they died and (3) how well pirfenidone worked. The analysis showed that most traits were similar in people with and without autoantibodies. In people who received placebo, the change in lung function during the trial was not different for people with ANA, RF or anti-CCP compared with people with no autoantibodies. People who received pirfenidone were less likely to have worsening lung function, or die, than people who received placebo, regardless of whether or not they had autoantibodies. Doctors evaluating patients with idiopathic pulmonary fibrosis should consider the impact of autoantibodies and feel confident that pirfenidone is effective regardless of whether or not autoantibodies are present.
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Why carry out this study? |
Autoantibody signatures of patients with idiopathic pulmonary fibrosis (IPF) without diagnosed connective tissue disease may be linked with specific disease characteristics and prognosis. |
This post-hoc analysis of data from the ASCEND trial aimed to determine the association between the presence of common autoantibodies and baseline disease characteristics, disease progression and treatment outcomes in patients with IPF who were randomised to receive pirfenidone or placebo. |
What was learned from the study? |
In the current analysis, baseline characteristics and disease course shared similarities by autoantibody status. |
Among patients receiving placebo, no significant differences were observed in the evaluated efficacy endpoints for patients who were ANA+, RF+ or anti-CCP+ when compared with autoantibody-negative patients. |
By comparing treatment arms, clinical outcomes and management of patients with IPF remain unchanged in those with autoantibody positivity in the absence of other clinical features of systemic autoimmune rheumatic disease. |
Introduction
Interstitial lung disease (ILD) is a large and heterogeneous group of pulmonary disorders; some are associated with an underlying autoimmune aetiology and some are linked to environmental exposures, whereas others have unknown causes [1, 2]. It can be challenging to differentiate between different types of ILD due to overlapping clinical, radiological and pathological presentations [1]. Diagnostic guidelines recommend that patients with suspected idiopathic pulmonary fibrosis (IPF), the most common and severe form of ILD, undergo autoantibody testing as part of the initial evaluation to assess for autoimmune-mediated diseases [3,4,5]. In previous studies, autoantibodies such as antinuclear antibodies (ANA), rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) have been reported in 22–33% of patients with IPF in the absence of connective tissue disease (CTD) on initial evaluation, with one study reporting that up to 10% of patients with IPF progressed to CTD [6,7,8]. However, the link between markers of autoimmunity and disease characteristics is not fully understood and may be an important factor to consider in the initial diagnosis and management of patients with IPF [1, 3] who do not otherwise manifest clinically with CTD.
Previous studies have suggested that differences in autoantibody status may be associated with unique patient profiles and differences in prognosis in patients with IPF, and that the presence of autoantibodies in IPF may represent a novel subgroup of patients, but this evidence is based on limited patient numbers, short follow-up duration and a lack of robust clinical data [6, 7, 9, 10]. Here, in this post-hoc analysis, we aimed to determine the association between autoantibody status and baseline disease characteristics, disease progression and treatment outcomes in patients with IPF who were randomised to receive pirfenidone or placebo in ASCEND, a large, well-characterised Phase III clinical trial.
Methods
The trial design of ASCEND (NCT01366209) has been previously reported [11]. In brief, ASCEND was a randomised, double-blind, placebo-controlled Phase III trial in which 555 patients with IPF were randomised to receive either oral pirfenidone (2403 mg/day; n = 278) or placebo (n = 277) for 52 weeks.
Eligible participants were aged 40–80 years and had a centrally confirmed diagnosis of IPF with findings on high-resolution computed tomography (HRCT) of the chest indicating either definite or possible usual interstitial pneumonia (UIP), with a surgical lung biopsy to confirm the presence of definite or probable UIP in the latter group. Patients with diagnosis of any CTD, including scleroderma, polymyositis/dermatomyositis, systemic lupus erythematosus (SLE) or rheumatoid arthritis, or any known explanation for ILD, including sarcoidosis and hypersensitivity pneumonitis, were excluded [11]. In addition, participants were recruited if they had 50–90% of percent predicted forced vital capacity (%FVC), 30–90% of percent predicted carbon monoxide diffusing capacity (%DLco), forced expiratory volume in 1 s/forced vital capacity (FVC) ratio of ≥ 0.80 and a 6-min walk distance (6MWD) of ≥ 150 m. All participants randomised to pirfenidone or placebo in the ASCEND trial with any autoantibody result at screening were included in this post-hoc analysis.
The ASCEND trial was conducted in compliance with Good Clinical Practice as described in FDA regulations and the 1996 International Council for Harmonisation document, in consistence with the principles stated in the Declaration of Helsinki. The protocol for the ASCEND trial was approved by the institutional review board or ethics committee at each participating centre and all patients provided written informed consent for participation in the trial. No prospective data were collected during this post-hoc analysis; therefore, ethical approval was not required.
Post-Hoc Analysis
Peripheral blood samples collected at screening were used to determine the presence of the following autoantibodies: ANA, RF and anti-CCP. Autoantibody status was defined by the following titres and staining patterns:
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1.
ANA-positive (ANA+) participants had ANA titre ≥ 1:40 or nucleolar-staining pattern or centromere-staining pattern as defined by previous studies, regardless of RF or anti-CCP positivity [2, 12].
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a.
Participants with high ANA+ levels (H-ANA+) had ANA titre ≥ 1:160 or a positive nucleolar-staining pattern or centromere-staining pattern (regardless of titre level), both of which were independent of RF or anti-CCP positivity; a previous study suggests the ≥ 1:160 cutoff would be likely to exclude 95% of individuals without systemic sclerosis, SLE or Sjogren’s syndrome [12].
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b.
Participants with low ANA+ levels had ANA titre ≥ 1:40 to < 1:160 and absence of both nucleolar-staining pattern and centromere-staining pattern, regardless of RF or anti-CCP positivity; a previous study suggests that an ANA cutoff level of 1:40 could have diagnostic value, and a survey of laboratories participating in the College of American Pathologists’ Proficiency Testing Programme suggests that a majority of US laboratories use this traditional cutoff for reporting ANA positivity [12, 13].
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a.
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2.
RF-positive (RF+) participants had RF titre ≥ 20 IU/mL.
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3.
Anti-CCP–positive (anti-CCP+) participants had anti-CCP titre ≥ 20 IU/mL.
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4.
Autoantibody-negative (AAb−, triple negative) participants had ANA titre < 1:40, “negative” titre with an absence of nucleolar-staining pattern or centromere-staining pattern, and negative RF (< 20 IU/mL) and negative anti-CCP (< 20 IU/mL) titres.
The endpoints of the current analysis focused on participants who were classified as ANA+, H-ANA+, RF+ and/or anti-CCP+ and AAb−. The endpoints included:
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1.
Summaries of the demographic and baseline characteristics organised by autoantibody subgroup and/or treatment arm.
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2.
Changes in %FVC from baseline to Week 52, determined using a fixed effect rank analysis of covariance, where the outcome variable was standardised ranked change from baseline, and fixed effect was either the participant ANA status, treatment arm or RF/anti-CCP status. The ranked baseline %FVC was included as a covariate (deaths were ranked worst according to time until death).
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3.
Changes in FVC volume (litres) from baseline to Week 52, determined using the same approach as for the %FVC and by ranking the relative change in volume defined as (Week 52 FVC volume − baseline FVC volume)/baseline FVC volume.
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4.
Estimation of progression-free survival (PFS), defined as first occurrence of death, confirmed ≥ 10% decline from baseline in %FVC or confirmed ≥ 50 m decline from baseline in 6MWD. The decline in either %FVC or 6MWD was confirmed at two consecutive assessments at least 6 weeks apart. PFS was analysed using the product limit method log-rank test and a proportional hazards model with treatment as a covariate. ANA status or RF/anti-CCP status was used to estimate the hazard ratio (HR) and Kaplan–Meier estimates were used to summarise PFS time.
Data from participants receiving placebo were analysed to determine the effect of autoantibody status (ANA+, H-ANA+, RF+ and/or anti-CCP+, or AAb−) on the course of disease, whereas data from participants receiving pirfenidone versus those receiving placebo were analysed to assess the impact of autoantibody status (ANA+ or AAb−) on response to treatment. P values for autoantibody-positive groups versus the AAb− group were calculated using Pearson’s chi-squared test. Comparisons of some subgroups of placebo- or pirfenidone-treated participants (e.g., those who were H-ANA+ and RF+ and/or anti-CCP+) were not included in the analysis due to their small sample size.
Results
Autoantibody Analysis
All 555 enrolled participants from the ASCEND trial had autoantibody data available for analysis (Table 1). In total, 514 participants were tested for the presence of ANA, of whom 47.5% (244/514) were classed as ANA+ and 16.1% (83/514) of participants were further categorised as H-ANA+. Additionally, 10.8% (60/555) participants were classed as RF+ and/or anti-CCP+. Overall, 52.5% (270/514) of participants were classed as AAb−, i.e., had a confirmed negative status for all the tested autoantibodies.
Baseline demographics and characteristics by autoantibody status (ANA+, H-ANA+, RF+ and/or anti-CCP+ and AAb−) for all participants are presented in Table 2 and for participants receiving pirfenidone or placebo are presented in Table 3. Key baseline demographics and characteristics were broadly similar between participants who were ANA+ and those who were AAb− (Table 2). However, there was a higher proportion of American Indian or Alaska Native participants in the ANA+ (8.6%) and RF+ and/or anti-CCP+ (8.3%) groups versus the AAb− (3.3%) group. There was also a greater proportion of women in the H-ANA+ (27.7%) and RF+ and/or anti-CCP+ (31.7%) groups versus the AAb− (20.0%) group (Table 2). Additionally, when compared with the AAb− group, the H-ANA+ group had a lower proportion of current smokers (51.8% vs. 64.1%), a lower proportion of patients requiring supplemental oxygen (19.4% vs. 30.4%) and a lower 6MWD (400.0 m vs. 424.0 m) (Table 2).
Disease Course in Placebo-Treated Participants
Overall, the disease course in placebo-treated participants was similar regardless of autoantibody status. Numerically, a greater proportion of participants in the ANA+ and H-ANA+ groups had a decline from baseline to Week 52 of ≥ 10% in %FVC or death (48.7% and 55.9%, respectively) or in FVC volume or death (48.7% and 47.1%, respectively) compared with the AAb− group (%FVC or death: 42.0%; FVC volume or death: 42.0%) (Fig. 1). However, there were no statistically significant differences in decline in %FVC or death or in FVC volume or death between the AAb− group and the ANA+ and H-ANA+ groups (Fig. 1). The proportions of patients with decline in %FVC or death or in FVC volume or death, in the RF+ and/or anti-CCP+ group were similar to those in the AAb− groups, again with no statistically significant difference (Fig. 1). There was no difference in PFS between the ANA+ group versus the AAb− group [HR (95% confidence interval [CI]): 1.14 (0.78 to 1.66); P = 0.5] (Fig. 2A) or between the H-ANA+ group versus the AAb− group [HR (95% CI): 1.22 (0.69 to 2.17); P = 0.5] (Fig. 2B). Due to small sample sizes, analysis of PFS for the H-ANA+ and RF+ and/or anti-CCP+ groups was not performed.
Response to Pirfenidone Treatment
Clinically relevant trends towards a treatment effect for pirfenidone over placebo were observed for patients who were ANA+. Numerically lower proportions of participants with ANA+ who received pirfenidone than who received placebo had decline in %FVC or death, or decline in FVC volume or death, although this difference did not reach statistical significance for either endpoint (%FVC or death: pirfenidone 37.2% vs. placebo 48.7%, P = 0.093; FVC volume or death: pirfenidone 35.7% vs. placebo 48.7%, P = 0.053) (Fig. 3). In the AAb− group, there was a statistically significant benefit of pirfenidone over placebo for both decline in %FVC or death and decline in FVC volume or death (both endpoints: pirfenidone 29.1% vs. placebo 42.0%, P = 0.039) (Fig. 3). PFS was statistically significantly higher for participants receiving pirfenidone compared with those receiving placebo in both the ANA+ group [HR (95% CI): 0.56 (0.37 to 0.86); P = 0.007; Fig. 4A] and the AAb− group [HR (95% CI): 0.50 (0.32 to 0.78); P = 0.002; Fig. 4B]. Due to small sample sizes, analysis of PFS for the H-ANA+ group and the RF+ and/or anti-CCP+ group was not performed.
Discussion
In this post-hoc analysis of data from the ASCEND trial, we report the impact of autoantibody status on disease progression and treatment responses in patients with IPF. We did not identify any prominent pulmonary physiologic differences in baseline characteristics of participants with IPF who were classed as positive for commonly tested autoantibodies versus AAb−. Some differences were observed between the subgroups of participants with high ANA levels versus AAb−, such as a higher proportion of women and American Indians or Alaska Natives, and a lower proportion of ever smokers and supplemental oxygen users; however, other baseline clinical characteristics (%FVC, %DLco) were comparable between groups. Our findings support those of previous studies of patients with IPF that found broadly similar results in baseline demographics, pulmonary function tests and definite UIP pattern on HRCT based on the presence of autoantibodies [6, 14,15,16].
Among placebo-treated participants, there was no difference in PFS between the AAb− group and the ANA+ or H-ANA+ groups, despite participants who were ANA+ or H-ANA+ being more likely to exhibit a non-statistically significant decline of ≥ 10% in %FVC or FVC volume compared with those who were AAb−. Several studies have previously examined the associations between autoantibody status and outcomes in patients with IPF [6, 9, 14, 16, 17]; however, ours is the largest analysis reporting post-hoc prospective data from a randomised controlled trial. Although data on other autoantibodies were not available for this analysis, an analysis of patients with IPF who were part of the Pulmonary Fibrosis Foundation Patient Registry suggested that baseline characteristics and clinical outcomes were generally similar among patients regardless of baseline seropositivity status across a wide range of autoantibodies, including ANA, RF, anti-CCP, anti-Smith and anti-myositis antibodies [18].
Our analysis, based on a large, well-characterised clinical trial population, indicates that participants responded to pirfenidone treatment regardless of their ANA status, with a treatment effect of pirfenidone over placebo for PFS in both the ANA+ and the AAb− groups. A significant treatment effect was also observed for ≥ 10% percent predicted FVC decline or death and ≥ 10% FVC volume decline or death from baseline to Week 52 in the AAb− group, although this clinically relevant trend in the ANA+ group did not reach statistical significance. These findings mirror those shown in a smaller, 6-month follow-up, retrospective observational study that also reported a pirfenidone treatment effect irrespective of autoantibody status [15].
Diagnostic guidelines recommend that patients with suspected IPF undergo autoantibody testing as part of the initial evaluation, but no consensus was reached about which autoantibodies should be included in screening panels [3]. Initial screening for a broad range of autoantibodies is not deemed mandatory for all patients with suspected IPF, although it could be useful in cases where other potential causes of ILD are clinically suspected [3]. The prognostic value of autoantibodies in patients diagnosed with IPF is not yet fully understood [1], and, as such, it will be important to consider further which autoantibodies should be included in the initial diagnostic screen [3].
Apart from its possible link with autoimmune diseases, ANA positivity has also been described as a factor of ageing, as its prevalence generally increases with age and it also correlates with shorter telomere length, a marker of biological age [19, 20]. Cellular senescence associated with ageing has been described in the pathogenesis of IPF, a disease of the aged population; whether the high prevalence of ANA positivity is merely an association or has pathological implication is unclear [21]. Nevertheless, therapeutic response to pirfenidone remains unaffected by autoantibody positivity in this study.
There are several limitations of this analysis. Firstly, it was a post-hoc exploratory analysis with only 52 weeks of follow-up available. Secondly, data on autoantibodies other than ANA, RF and anti-CCP, change in positivity or titre, and whether participants went on to develop systemic autoimmune rheumatic diseases, were not collected. Thirdly, the small number of participants in certain groups (e.g., H-ANA+, and RF+ and/or anti-CCP+) may limit the interpretation of the data and impact the observed outcomes; therefore, these results should be interpreted with caution. Fourthly, we present here available data for the three commonly evaluated autoantibodies that were included during screening for ASCEND. Diagnostic guidelines suggest screening for the presence of these antibodies in patients with suspected IPF, with evaluation using a full antibody panel reserved for cases where other autoimmune diseases are clinically suspected [3]. We recommend that screening for other disease-related autoantibodies be included in future studies in order to broaden potential analyses. Finally, although we used the placebo arm of the ASCEND trial as a proxy for the natural disease progression in IPF in this analysis, we cannot rule out the presence of a placebo effect in these patients, which could have influenced disease outcomes.
Conclusion
This post-hoc analysis of data from the ASCEND trial in patients with IPF indicates that disease course did not differ by ANA, RF or anti-CCP autoantibody status, although patients in the H-ANA subgroup have differences in certain baseline demographics compared with antibody-negative patients. Importantly, we observed a treatment benefit for pirfenidone regardless of ANA status, particularly in relation to PFS. This analysis underscores that, while some patients with IPF may have autoantibody positivity, in the absence of other clinical features of systemic autoimmune rheumatic disease, clinical outcomes and management remain unchanged.
Data Availability
Qualified researchers may request access to individual patient-level data through the clinical study data request platform (https://vivli.org). Further details on Roche’s criteria for eligible studies are available here (https://vivli.org/members/ourmembers). For further details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here: https://www.roche.com/innovation/process/clinical-trials/data-sharing.
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Acknowledgments
Medical Writing, Editorial, and Other Assistance. Statistical analyses were performed by Jinnie Ko and Yiling Chen of Genentech, Inc. Medical writing support, under the direction of the authors, was provided by Nikoleta Tzioutziou, PhD, formerly of CMC AFFINITY, a division of IPG Health Medical Communications, funded by F. Hoffmann-La Roche, Ltd. in accordance with Good Publication Practice (GPP 2022) guidelines.
Funding
The data and analyses reported in this manuscript are directly derived from research sponsored by F. Hoffmann-La Roche, Ltd./Genetech, Inc. The funder also approved the final version of the manuscript and covered the cost of the journal’s rapid service fee.
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Substantial contributions to the conception or design of the work: Tejaswini Kulkarni, Chad A. Newton, Sachin Gupta, Katerina Samara, Elana J. Bernstein. Data acquisition: Sachin Gupta. Data interpretation: Tejaswini Kulkarni, Chad A. Newton, Sachin Gupta, Katerina Samara, Elana J. Bernstein. All authors were involved in the drafting or critical review of the manuscript for important intellectual content and approved the final version for submission.
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Conflict of Interest
Tejaswini Kulkarni reports consultancy and speaker fees from Boehringer Ingelheim and consultancy fees from Aileron Therapeutics, PureTech LYT-100 Inc., United Therapeutics Corporation and Veracyte. Chad A. Newton reports consultancy fees from Boehringer Ingelheim. Dr. Newton is supported by the National Heart, Lung, and Blood Institute (K23 HL148498). Sachin Gupta is an employee of Genentech, Inc. Katerina Samara is an employee of F. Hoffmann-La Roche, Ltd. Elana J. Bernstein reports grants, consultancy fees and support for meeting attendance from Boehringer Ingelheim. Dr. Bernstein is also supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant number K23 AR075112), the National Heart, Lung, and Blood Institute (grant number R01 HL164758), and the Department of Defence (grant number W81XWH2210163).
Ethical Approval
The ASCEND trial was conducted in compliance with Good Clinical Practice as described in FDA regulations and the 1996 International Council for Harmonisation document, in consistence with the principles stated in the Declaration of Helsinki. The protocol for the ASCEND trial was approved by the institutional review board or ethics committee at each participating centre and all patients provided written informed consent for participation in the trial. No prospective data were collected during this post-hoc analysis; therefore, ethical approval was not required.
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Prior Presentation: Some of the results presented in this manuscript were previously presented as a poster at the ATS 2022 International Conference (13–18 May 2022; San Francisco, CA) and the ERS 2022 International Congress (4–6 September 2022; Barcelona, Spain).
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Kulkarni, T., Newton, C.A., Gupta, S. et al. The Impact of Autoantibodies on Outcomes in Patients with Idiopathic Pulmonary Fibrosis: Post-Hoc Analyses of the Phase III ASCEND Trial. Pulm Ther 10, 331–346 (2024). https://doi.org/10.1007/s41030-024-00267-x
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DOI: https://doi.org/10.1007/s41030-024-00267-x