ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is an incurable interstitial lung disease characterized by fibrosis. Two FDA-approved drugs, pirfenidone and nintedanib, only modestly prolong survival. In this study, we asked whether levels of select circulating biomarkers in patients with IPF demonstrated changes in response to treatment over time and whether treatment with pirfenidone and nintedanib led to differential biomarker expression. Serial plasma samples from 48 patients with IPF on usual treatment and six healthy volunteers were analyzed to identify differentially expressed blood protein. Hypothesis-driven potential biomarker selection was based on recent literature, internal preclinical data, and the PROLIFIC Consortium (Schafer P. 6th Annual IPF Summit. Boston, MA, 2022) proposed biomarkers of pulmonary fibrosis. We compared our findings to public databases to provide insights into relevant signaling pathways in IPF. Of the 26 proteins measured, we found that 11 (SP-D, TIMP1, MMP7, CYFRA21-1, YKL40, CA125, sICAM, IP-10, MDC, CXCL13) were significantly elevated in patients with IPF compared with healthy volunteers but their levels did not significantly change over time. In the IPF samples, seven proteins were elevated in the treatment group compared with the no-treatment group. However, protein profiles were not distinguishable between patients on pirfenidone versus nintedanib. We demonstrated that most proteins differentially detected in our samples were predicted to be secreted from the lung epithelial or interstitial compartments. However, a significant minority of the proteins are not known to be transcriptionally expressed by lung cells, suggesting an ongoing systemic response. Understanding the contributions of the systemic response in IPF may be important as new therapeutics are developed.NEW & NOTEWORTHY In this study, we confirmed protein expression differences in only a subset of predicted biomarkers from IPF and control subjects. Most differentially expressed proteins were predicted to be secreted from lung cells. However, a significant minority of the proteins are not known to be transcriptionally expressed by lung cells, suggesting an ongoing systemic response. The contributions of the systemic response in IPF may be important as new therapeutics are developed.
Subject(s)
Antigens, Neoplasm , Idiopathic Pulmonary Fibrosis , Keratin-19 , Humans , Idiopathic Pulmonary Fibrosis/pathology , Lung/metabolism , Fibrosis , BiomarkersABSTRACT
Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which novel therapies are needed. External controls (ECs) could enhance IPF trial efficiency, but the direct comparability of ECs versus concurrent controls is unknown. Objectives: To develop IPF ECs by fit-for-purpose data standards to historical randomized clinical trial (RCT), multicenter registry (Pulmonary Fibrosis Foundation Patient Registry), and electronic health record (EHR) data and to evaluate endpoint comparability among ECs and the phase II RCT of BMS-986020. Methods: After data curation, the rate of change in FVC from baseline to 26 weeks among participants receiving BMS-986020 600 mg twice daily was compared with the BMS-placebo arm and ECs using mixed-effects models with inverse probability weights. Measurements and Main Results: At 26 weeks, the rates of change in FVC were -32.71 ml for BMS-986020 and -130.09 ml for BMS-placebo (difference, 97.4 ml; 95% confidence interval [CI], 24.6-170.2), replicating the original BMS-986020 RCT. RCT ECs showed treatment effect point estimates within the 95% CI of the original BMS-986020 RCT. Pulmonary Fibrosis Foundation Patient Registry ECs and EHR ECs experienced a slower rate of FVC decline compared with the BMS-placebo arm, resulting in treatment-effect point estimates outside of the 95% CI of the original BMS-986020 RCT. Conclusions: IPF ECs generated from historical RCT placebo arms result in comparable primary treatment effects to that of the original clinical trial, whereas ECs from real-world data sources, including registry or EHR data, do not. RCT ECs may serve as a potentially useful supplement to future IPF RCTs.
Subject(s)
Idiopathic Pulmonary Fibrosis , Information Sources , Humans , Vital Capacity , Idiopathic Pulmonary Fibrosis/drug therapy , Lung , Treatment Outcome , Disease ProgressionABSTRACT
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with limited treatment options. A phase 2 trial (NCT01766817) showed that twice-daily treatment with BMS-986020, a lysophosphatidic acid receptor 1 (LPA1) antagonist, significantly decreased the slope of forced vital capacity (FVC) decline over 26 weeks compared with placebo in patients with IPF. This analysis aimed to better understand the impact of LPA1 antagonism on extracellular matrix (ECM)-neoepitope biomarkers and lung function through a post hoc analysis of the phase 2 study, along with an in vitro fibrogenesis model. METHODS: Serum levels of nine ECM-neoepitope biomarkers were measured in patients with IPF. The association of biomarkers with baseline and change from baseline FVC and quantitative lung fibrosis as measured with high-resolution computed tomography, and differences between treatment arms using linear mixed models, were assessed. The Scar-in-a-Jar in vitro fibrogenesis model was used to further elucidate the antifibrotic mechanism of BMS-986020. RESULTS: In 140 patients with IPF, baseline ECM-neoepitope biomarker levels did not predict FVC progression but was significantly correlated with baseline FVC and lung fibrosis measurements. Most serum ECM-neoepitope biomarker levels were significantly reduced following BMS-986020 treatment compared with placebo, and several of the reductions correlated with FVC and/or lung fibrosis improvement. In the Scar-in-a-Jar in vitro model, BMS-986020 potently inhibited LPA1-induced fibrogenesis. CONCLUSIONS: BMS-986020 reduced serum ECM-neoepitope biomarkers, which were previously associated with IPF prognosis. In vitro, LPA promoted fibrogenesis, which was LPA1 dependent and inhibited by BMS-986020. Together these data elucidate a novel antifibrotic mechanism of action for pharmacological LPA1 blockade. Trial registration ClinicalTrials.gov identifier: NCT01766817; First posted: January 11, 2013; https://clinicaltrials.gov/ct2/show/NCT01766817 .
Subject(s)
Collagen/drug effects , Idiopathic Pulmonary Fibrosis/drug therapy , Receptors, Lysophosphatidic Acid/antagonists & inhibitors , Respiratory System Agents/administration & dosage , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Collagen/metabolism , Epitopes/blood , Female , Humans , Idiopathic Pulmonary Fibrosis/pathology , In Vitro Techniques , Male , Middle Aged , Models, Biological , Vital Capacity/drug effectsABSTRACT
INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a poor prognosis. Treatment with antifibrotic agents can slow, but not halt, disease progression, and treatment discontinuation because of adverse events is common. Fibrotic diseases such as these can be mediated by lysophosphatidic acid (LPA), which signals via six LPA receptors (LPA1-6). Signalling via LPA1 appears to be fundamental in the pathogenesis of fibrotic diseases. BMS-986278, a second-generation LPA1 antagonist, is currently in phase 2 development as a therapy for IPF and PF-ILD. METHODS AND ANALYSIS: This phase 2, randomised, double-blind, placebo-controlled, parallel-group, international trial will include adults with IPF or PF-ILD. The trial will consist of a 42-day screening period, a 26-week placebo-controlled treatment period, an optional 26-week active-treatment extension period, and a 28-day post-treatment follow-up. Patients in both the IPF (n=240) and PF-ILD (n=120) cohorts will be randomised 1:1:1 to receive 30 mg or 60 mg BMS-986278, or placebo, administered orally two times per day for 26 weeks in the placebo-controlled treatment period. The primary endpoint is rate of change in per cent predicted forced vital capacity from baseline to week 26 in the IPF cohort. ETHICS AND DISSEMINATION: This study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT04308681.
Subject(s)
Idiopathic Pulmonary Fibrosis , Receptors, Lysophosphatidic Acid , Adult , Humans , Idiopathic Pulmonary Fibrosis/diagnosis , Idiopathic Pulmonary Fibrosis/drug therapy , Lysophospholipids/therapeutic use , Receptors, Lysophosphatidic Acid/therapeutic use , Vital CapacityABSTRACT
Contemporary studies of systemic sclerosis (SSc) consistently demonstrate that interstitial lung (ILD) is a leading cause of disease-related death. This review summarizes morbidity and mortality outcomes in SSc-ILD patients from high-quality observational and interventional studies over the last 50 years. The data presented suggest a trend for improved morbidity and mortality outcomes among present day SSc-ILD patients. Specifically, SSc-ILD patients appear to be living longer from the time of the initial diagnosis. Despite improved survival, the number one cause of death for most SSc-ILD patients remains respiratory failure from ILD. This review describes the most important demographic, clinical, and biological factors, which affect mortality in SSc-ILD, and could be used to help stratify patients for closer monitoring and more aggressive initial treatment. The review concludes with an overview of future research needed to (1) understand how to personalize the care of SSc-ILD patients to improve morbidity and mortality outcomes; and (2) investigate whether novel therapeutic interventions (e.g., anti-fibrotics, hematopoetic stem-cell transplantation) offer any meaningful long-term survival advantage over the current standard of care.
ABSTRACT
BACKGROUND/OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Interstitial lung disease (ILD) is an extra-articular manifestation of RA. We investigated incidence rates of ILD in patients with RA, receiving tofacitinib 5 or 10 mg twice daily, and identified potential risk factors for ILD. METHODS: This post hoc analysis comprised a pooled analysis of patients receiving tofacitinib 5 or 10 mg twice daily or placebo from 2 phase (P)1, 10 P2, 6 P3, 1 P3b/4, and 2 long-term extension studies. Interstitial lung disease events were adjudicated as "probable" (supportive clinical evidence) or "possible" (no supportive clinical evidence) compatible adverse events. Incidence rates (patients with events per 100 patient-years) were calculated for ILD events. RESULTS: Of 7061 patients (patient-years of exposure = 23,393.7), 42 (0.6%) had an ILD event; median time to ILD event was 1144 days. Incidence rates for ILD with both tofacitinib doses were 0.18 per 100 patient-years. Incidence rates generally remained stable over time. There were 17 of 42 serious adverse events (40.5%) of ILD; for all ILD events (serious and nonserious), 35 of 42 events (83.3%) were mild to moderate in severity. A multivariable Cox regression analysis identified age 65 years or older (hazard ratio 2.43 [95% confidence interval, 1.13-5.21]), current smokers (2.89 [1.33-6.26]), and Disease Activity Score in 28 joints-erythrocyte sedimentation rate score (1.30 [1.04-1.61]) as significant risk factors for ILD events. CONCLUSIONS: Across P1/2/3/4/long-term extension studies, incidence rates for ILD events were 0.18 following tofacitinib treatment, and ILD events were associated with known risk factors for ILD in RA.
Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Lung Diseases, Interstitial , Aged , Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/epidemiology , Humans , Incidence , Lung Diseases, Interstitial/chemically induced , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/epidemiology , Piperidines , Pyrimidines , Pyrroles/adverse effects , Treatment OutcomeABSTRACT
BACKGROUND: At present, no approved pharmacotherapies are available for unclassifiable interstitial lung disease (ILD), which is characterised by progressive fibrosis of the lung. We aimed to assess the efficacy and safety of pirfenidone in patients with progressive fibrosing unclassifiable ILD. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 70 centres in Australia, Belgium, Canada, Czech Republic, Denmark, Germany, Greece, Ireland, Israel, Italy, Poland, Portugal, Spain, and the UK. Eligible patients (aged ≥18-85 years) had progressive fibrosing unclassifiable ILD, a percent predicted forced vital capacity (FVC) of 45% or higher and percent predicted carbon monoxide diffusing capacity (DLco) of 30% or higher, more than 10% fibrosis on high-resolution CT, and a high-resolution CT from the previous 12 months. Patients were randomly assigned (1:1) to 2403 mg oral pirfenidone daily or placebo using a central validated interactive voice or web-based response system, stratified by concomitant mycophenolate mofetil use and presence or absence of interstitial pneumonia with autoimmune features. Investigators, site personnel, and patients were masked to treatment assignment. The primary endpoint was mean predicted change in FVC from baseline over 24 weeks, measured by daily home spirometry. Secondary endpoints were change in FVC measured by site spirometry, proportion of patients who had a more than 5% or more than 10% absolute or relative decline in percent predicted FVC measured by clinic-based spirometry, change in percent predicted DLco, change in 6-min walk distance (6MWD), change in University of California San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) score, change in Leicester Cough Questionnaire score, change in cough visual analogue scale, and changes in total and subscores of the St George's Respiratory Questionnaire (SGRQ), all of which were compared with baseline. Additional secondary endpoints included proportion of patients who had non-elective hospitalisation (respiratory and all-cause) and acute exacerbations, and progression-free survival. Efficacy was analysed in the intention-to-treat (ITT) population, which included all randomly assigned patients. Safety was assessed in the safety analysis set, which included all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03099187, and is no longer recruiting. FINDINGS: Between May 15, 2017, and June 5, 2018, 253 patients were randomly assigned to receive 2403 mg pirfenidone (n=127) or placebo (n=126) and were included in the ITT analysis set. Analysis of the primary endpoint was affected by intraindividual variability in home spirometry values, which prevented application of the prespecified statistical model. Over 24 weeks, predicted median change in FVC measured by home spirometry was -87·7 mL (Q1-Q3 -338·1 to 148·6) in the pirfenidone group versus -157·1 mL (-370·9 to 70·1) in the placebo group. Over 24 weeks, predicted mean change in FVC measured by site spirometry was lower in patients given pirfenidone than placebo (treatment difference 95·3 mL [95% CI 35·9 to 154·6], p=0·002). Compared with the placebo group, patients in the pirfenidone group were less likely to have a decline in FVC of more than 5% (odds ratio [OR] 0·42 [95% CI 0·25 to 0·69], p=0·001) or more than 10% (OR 0·44 [0·23 to 0·84], p=0·011). At week 24, mean change in DLco from baseline was -0·7% (SD 7·1) for the pirfenidone group and -2·5% (8·8) for the placebo group, and mean change in 6MWD from baseline was -2·0 m (68·1) for the pirfenidone group and -26·7 m (79·3) for the placebo group. Changes from baseline in UCSD-SOBQ, Leicester Cough Questionnaire score, cough visual analogue scale, and SGRQ scores were similar between the pirfenidone and placebo groups at week 24. Analysis of acute exacerbations, hospital admissions, and time to death from respiratory causes during the study yielded no meaningful results due to a small number of events. No differences in progression-free survival were identified between the pirfenidone and placebo groups, irrespective of the definition of progression-free survival used. Treatment-emergent adverse events were reported in 120 (94%) of 127 patients in the pirfenidone group and 101 (81%) of 124 patients in the placebo group. Serious treatment-emergent adverse events were reported in 18 (14%) patients in the pirfenidone group and 20 (16%) patients in the placebo group. The most common treatment-related treatment-emergent adverse events were gastrointestinal disorders (60 [47%] in the pirfenidone group vs 32 [26%] in the placebo group), fatigue (16 [13%] vs 12 [10%]), and rash (13 [10%] vs nine [7%]). INTERPRETATION: Although the planned statistical model could not be applied to the primary endpoint data, analysis of key secondary endpoints suggests that patients with progressive fibrosing unclassifiable ILD could benefit from pirfenidone treatment, which has an acceptable safety and tolerability profile. These findings support further investigation of pirfenidone as an effective treatment for patients with progressive fibrotic unclassifiable ILD. FUNDING: F Hoffmann-La Roche.
Subject(s)
Lung Diseases, Interstitial/drug therapy , Pulmonary Fibrosis/drug therapy , Pyridones/therapeutic use , Aged , Double-Blind Method , Drug Therapy, Combination , Europe , Female , Humans , Lung/drug effects , Lung Diseases, Interstitial/etiology , Lung Diseases, Interstitial/mortality , Male , Middle Aged , Mycophenolic Acid/therapeutic use , Progression-Free Survival , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/mortality , Respiratory Function Tests , Treatment Outcome , Vital Capacity/drug effectsABSTRACT
Systemic sclerosis (SSc) is a progressive and often devastating disease characterized by autoimmune dysfunction, vasculopathy, and fibrosis. Interstitial lung disease (ILD) is identified in the majority of patients with SSc and is the leading cause of SSc-related mortality. Although clinical manifestations and ILD severity vary among patients, lung function typically declines to the greatest extent during the first 3-4 years after disease onset. We aim to provide an overview of SSc-associated ILD (SSc-ILD) with a focus on current and emerging tools for early diagnosis of ILD and current and novel treatments under investigation. Early detection of ILD provides the opportunity for early therapeutic intervention, which could improve patient outcomes. Thoracic high-resolution computed tomography is the most effective method of identifying ILD in patients with SSc; it enables detection of mild lung abnormalities and plays an important role in monitoring disease progression. Cyclophosphamide and mycophenolate mofetil are the most commonly prescribed treatments for SSc-ILD. Recently, nintedanib (an antifibrotic) was approved by the Food and Drug Administration for patients with SSc-ILD; it is indicated for slowing the rate of decline in pulmonary function. However, there is a need for additional effective and well-tolerated disease-modifying therapy. Ongoing studies are evaluating other antifibrotics and novel agents. We envision that early detection of lung involvement, combined with the emergence and integration of novel therapies, will lead to improved outcomes in patients with SSc-ILD.
ABSTRACT
OBJECTIVE: To describe the phenotypic characteristics and natural history of patients with autoimmune forms of interstitial lung disease (ILD). METHODS: Retrospective, descriptive, single-center study of patients with autoimmune forms of ILD evaluated between February 2008 and August 2014. All data were extracted from the electronic medical record. Longitudinal changes in forced vital capacity (FVC%) and diffusion capacity for carbon monoxide (DLco%) in percent predicted were analyzed and time-to-event analyses for death were performed using Cox regression. RESULTS: Of the entire cohort (n = 243), systemic sclerosis (SSc)-associated ILD (n = 88, 36%), interstitial pneumonia with autoimmune features (IPAF, n = 56, 23%), rheumatoid arthritis (RA)-associated ILD (n = 42, 17%), and idiopathic inflammatory myopathy (IIM)-associated ILD (n = 26, 11%) were the most common phenotypes. The SSc-ILD, IIM-ILD, and IPAF groups had similar features: average age in the mid-50s, strongly female predominant and more likely to have nonspecific interstitial pneumonia (NSIP). In contrast, RA-ILD patients were older, gender balanced, more likely to be past smokers and were UIP predominant. Adjusted longitudinal lung function was stable during a median follow-up period of nearly 4 years and the independent predictors for death were older age (p = 0.003), male sex (p = 0.019), and lower FVC (p = < 0.001). CONCLUSIONS: The predominant phenotypes of autoimmune ILD were SSc-ILD, IPAF, RA-ILD, and IIM-ILD. In contrast to the other subsets, those with RA-ILD may be older, gender balanced, with more smoking history, and higher proportion of UIP. Longitudinal lung function was stable among the groups and younger age, female gender, and better lung function were associated with improved survival.
Subject(s)
Autoimmune Diseases/physiopathology , Lung Diseases, Interstitial/physiopathology , Lung/physiopathology , Pulmonary Diffusing Capacity/physiology , Adult , Age Distribution , Age Factors , Aged , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/epidemiology , Autoimmune Diseases/epidemiology , Autoimmune Diseases/etiology , Carbon Monoxide , Disease Progression , Female , Forced Expiratory Volume , Humans , Lung/diagnostic imaging , Lung Diseases, Interstitial/diagnostic imaging , Lung Diseases, Interstitial/epidemiology , Lung Diseases, Interstitial/etiology , Male , Middle Aged , Myositis/complications , Myositis/epidemiology , Proportional Hazards Models , Retrospective Studies , Scleroderma, Systemic/complications , Scleroderma, Systemic/epidemiology , Sex Factors , Smoking/epidemiology , Survival Rate , Tomography, X-Ray Computed , Total Lung Capacity , Vital CapacityABSTRACT
Interstitial lung disease (ILD) is a common manifestation of systemic autoimmune diseases and a leading cause of death in these patients. A proportion of patients with autoimmune ILDs develop a progressive fibrosing form of ILD, characterized by increasing fibrosis on high-resolution computed tomography, worsening of lung function, and early mortality. Autoimmune disease-related ILDs have a variable clinical course and not all patients will require treatment, but all patients should be monitored for signs of progression. Apart from systemic sclerosis-associated ILD, the limited evidence to support the efficacy of immunosuppression as a treatment for ILDs is based mainly on small retrospective series and expert opinion. Non-clinical data suggest that there are commonalities in the mechanisms that drive progressive fibrosis in ILDs with an immunological trigger as in other forms of progressive fibrosing ILD. This suggests that nintedanib and pirfenidone, drugs known to slow disease progression in patients with idiopathic pulmonary fibrosis, may also slow the progression of ILD associated with systemic autoimmune diseases. In the SENSCIS® trial, nintedanib reduced the rate of ILD progression in patients with systemic sclerosis-associated ILD. The results of other large clinical trials will provide further insights into the role of anti-fibrotic therapies in the treatment of autoimmune disease-related ILDs.
Subject(s)
Autoimmune Diseases/complications , Lung Diseases, Interstitial/complications , Lung/physiopathology , Pulmonary Fibrosis/complications , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/therapy , Autoimmune Diseases/therapy , Clinical Trials as Topic , Disease Progression , Humans , Immunosuppression Therapy/adverse effects , Indoles/therapeutic use , Kaplan-Meier Estimate , Lung Diseases, Interstitial/therapy , Phenotype , Pulmonary Fibrosis/therapy , Pyridones/therapeutic use , Risk Factors , Tomography, X-Ray ComputedABSTRACT
The European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease put forth the research classification interstitial pneumonia with autoimmune features as a step toward uniformly describing these patients. Diverse nomenclature and classification schemes had been proposed to characterize them. This classification has provided uniform nomenclature and criteria, fostering interdisciplinary engagement and research. Longitudinal surveillance is needed; some patients evolve to a defined connective tissue disease. This review discusses cohort studies of interstitial pneumonia with autoimmune features and what they have taught us about the phenotype, and offers insights into future directions.
Subject(s)
Autoimmune Diseases/etiology , Lung Diseases, Interstitial/immunology , Autoimmune Diseases/pathology , Humans , Retrospective StudiesABSTRACT
Objective: Some patients with interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) develop a progressive fibrosing phenotype. We investigated the diagnosis and management of non-IPF ILDs using data from a survey of physicians and from US insurance claims. Methods: Pulmonologists, rheumatologists and internists in France, Germany, Italy, Japan, Spain, UK and US who had managed ≥10 patients with non-IPF ILDs in the past year, including those with progressive fibrosing ILDs, completed an online survey. Data on US insurance and prescription claims were obtained from a repository that aggregates data on claims routed from providers or pharmacies to payers. Results: In May-June 2017, 243 pulmonologists, 203 rheumatologists and 40 internists completed an online survey. Respondents estimated that 18-32% of patients diagnosed with non-IPF ILDs develop progressive fibrosis and that time from symptom onset to death in these patients was 61-80 months. Drug treatment was given to 50-75% of patients with non-IPF progressive fibrosing ILDs. Reasons for patients not being treated included that physicians considered patients to have mild or slowly progressing disease, or did not believe that available treatments are effective or well tolerated. Corticosteroids were the preferred first-line treatment for all types of non-IPF ILD. There was considerable heterogeneity in preferences for second- and third-line treatments. US insurance claims data from 3823 patients indicated that, in 2016, 50-75% of patients with ILDs received drug treatment (mostly corticosteroids) for their ILD. Conclusions: Physicians estimate that 18-32% of patients diagnosed with non-IPF ILDs develop a progressive fibrosing phenotype and that these patients experience significant delays in the diagnosis of ILD and the detection of progressive fibrosis. Between 25% and 50% of patients with progressive fibrosing ILDs do not receive drug therapy. There is an unmet need for effective and well tolerated treatments for progressive fibrosing ILDs.
Subject(s)
Idiopathic Pulmonary Fibrosis/diagnosis , Idiopathic Pulmonary Fibrosis/therapy , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/therapy , Disease Progression , Humans , PhenotypeSubject(s)
Autoimmune Diseases/drug therapy , Autoimmune Diseases/etiology , Immunosuppressive Agents/therapeutic use , Lung Diseases, Interstitial/etiology , Myositis, Inclusion Body/complications , Myositis, Inclusion Body/pathology , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , Biopsy, Needle , Follow-Up Studies , Humans , Immunohistochemistry , Lung Diseases, Interstitial/immunology , Lung Diseases, Interstitial/pathology , Male , Middle Aged , Muscle Strength/physiology , Mycophenolic Acid/therapeutic use , Myositis, Inclusion Body/diagnostic imaging , Prednisone/therapeutic use , Rare Diseases , Recovery of Function , Respiratory Function Tests , Risk Assessment , Tomography, X-Ray Computed/methods , Treatment OutcomeABSTRACT
BACKGROUND: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52. RESULTS: A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was -52.4 ml per year in the nintedanib group and -93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P = 0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of -0.21 (95% CI, -0.94 to 0.53; P = 0.58) and 1.69 (95% CI, -0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group. CONCLUSIONS: Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo. (Funded by Boehringer Ingelheim; SENSCIS ClinicalTrials.gov number, NCT02597933.).
Subject(s)
Enzyme Inhibitors/therapeutic use , Indoles/therapeutic use , Lung Diseases, Interstitial/drug therapy , Protein-Tyrosine Kinases/antagonists & inhibitors , Scleroderma, Systemic/complications , Administration, Oral , Adult , Diarrhea/chemically induced , Disease Progression , Double-Blind Method , Enzyme Inhibitors/adverse effects , Female , Humans , Indoles/adverse effects , Lung Diseases, Interstitial/etiology , Lung Diseases, Interstitial/physiopathology , Male , Middle Aged , Scleroderma, Systemic/drug therapy , Vital CapacityABSTRACT
INTRODUCTION: Interstitial lung disease (ILD) is a common manifestation of scleroderma/systemic sclerosis (SSc). However, the direct and indirect economic burdens of SSc-ILD remain unclear. This study assessed and compared healthcare resource utilization (HRU), direct healthcare costs, work loss, and indirect costs between patients with SSc-ILD and matched controls with neither SSc nor ILD in the USA. METHODS: Data were obtained from a large US commercial claims database (2005-2015). Patients (at least 18 years old) had at least one SSc diagnosis in the inpatient (IP) or emergency room (ER) setting or at least two SSc diagnoses in another setting, and at least one diagnosis of ILD in the IP or ER setting or at least two diagnoses of ILD in another setting. Controls with neither SSc nor ILD were matched 5:1 to patients with SSc-ILD. Comparisons were conducted using Wilcoxon signed-rank and McNemar's tests and adjusted odds ratios (ORs) and incidence rate ratios (IRRs). RESULTS: A total of 479 SSc-ILD patients and 2395 matched controls were included (52 SSc-ILD patients and 260 matched controls for work loss and indirect cost analyses). Patients with SSc-ILD had significantly higher HRU and costs, IP admissions (adjusted IRR = 5.6), IP hospitalization days (adjusted IRR = 12.0), ER visits (adjusted IRR = 2.8), OP visits (adjusted IRR = 3.1), and days of work loss (adjusted IRR = 4.5). The adjusted difference in annual direct healthcare costs was $28,632 (SSc-ILD, $33,195; controls, $4562) and that in indirect costs was $4735 (SSc-ILD, $5640; controls, $906) (all p < 0.0001). CONCLUSION: SSc-ILD patients had significantly higher HRU, work loss, and direct and indirect costs compared to matched controls with neither SSc nor ILD. FUNDING: Boehringer Ingelheim Pharmaceuticals, Inc.
Subject(s)
Health Resources/economics , Insurance, Health/economics , Lung Diseases, Interstitial/economics , Lung Diseases, Interstitial/therapy , Scleroderma, Systemic/economics , Scleroderma, Systemic/therapy , Adult , Comorbidity , Cost of Illness , Data Analysis , Databases, Factual , Female , Health Care Costs/statistics & numerical data , Health Resources/statistics & numerical data , Hospitalization/economics , Humans , Lung Diseases, Interstitial/epidemiology , Male , Middle Aged , Retrospective Studies , Scleroderma, Systemic/epidemiologyABSTRACT
Patients with certain types of fibrosing interstitial lung disease (ILD) are at risk of developing a progressive phenotype characterised by self-sustaining fibrosis, decline in lung function, worsening quality of life, and early mortality. It has been proposed that such progressive fibrosing ILDs, which show commonalities in clinical behaviour and in the pathogenetic mechanisms that drive progressive fibrosis, may be "lumped" together for the purposes of clinical research and, potentially, for treatment. At present, no drugs are approved for the treatment of ILDs other than nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis. For other progressive fibrosing ILDs, the mainstay of drug therapy is immunosuppression. However, it is postulated that, once the response to lung injury in fibrosing ILDs has reached the stage at which fibrosis has become progressive and self-sustaining, targeted antifibrotic therapy would be required to slow disease progression. Nintedanib, an intracellular inhibitor of tyrosine kinases, has shown antifibrotic, anti-inflammatory and vascular remodelling effects in several non-clinical models of fibrosis, irrespective of the trigger for the injury. Ongoing clinical trials will provide insight into the role of antifibrotic treatment with nintedanib or pirfenidone in the management of fibrosing ILDs with a progressive phenotype.
Subject(s)
Lung Diseases, Interstitial , Lung , Pulmonary Fibrosis , Disease Progression , Health Status , Humans , Indoles/therapeutic use , Lung/drug effects , Lung/pathology , Lung/physiopathology , Lung Diseases, Interstitial/drug therapy , Lung Diseases, Interstitial/mortality , Lung Diseases, Interstitial/pathology , Lung Diseases, Interstitial/physiopathology , Phenotype , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/mortality , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/physiopathology , Pyridones/therapeutic use , Quality of Life , Respiratory System Agents/therapeutic use , Risk Factors , Severity of Illness Index , Treatment OutcomeSubject(s)
Idiopathic Interstitial Pneumonias/immunology , Idiopathic Interstitial Pneumonias/pathology , Idiopathic Pulmonary Fibrosis/pathology , Tomography, X-Ray Computed/methods , Biomarkers/analysis , Biopsy, Needle , Diagnosis, Differential , Dyspnea/diagnosis , Dyspnea/etiology , Humans , Idiopathic Interstitial Pneumonias/diagnostic imaging , Idiopathic Pulmonary Fibrosis/diagnostic imaging , Idiopathic Pulmonary Fibrosis/immunology , Immunohistochemistry , Lung Diseases, Interstitial/diagnostic imaging , Lung Diseases, Interstitial/immunology , Lung Diseases, Interstitial/pathology , Male , Middle Aged , Risk AssessmentABSTRACT
OBJECTIVE: To quantify healthcare resource utilization (HRU), work loss, and annual direct and indirect healthcare costs among patients with systemic sclerosis (SSc) compared to matched controls in the United States. METHODS: Data were obtained from a large US commercial claims database. Patients were ≥ 18 years old at the index date (first SSc diagnosis) and had ≥ 1 SSc diagnosis in the inpatient (IP) or emergency room (ER) setting, or ≥ 2 SSc diagnoses on 2 different dates in the outpatient (OP) setting between January 1, 2005, and March 31, 2015; continuous enrollment was required during the followup period (12 months after the index date). Individuals with no SSc diagnoses were matched 1:1 to patients with SSc. Wilcoxon signed-rank and McNemar tests were used for comparisons and regressions with generalized estimating equations for adjusted OR (aOR) and incidence rate ratios (IRR) between 2 cohorts. RESULTS: There were 2192 pairs of patients with SSc and matched controls included (mean age 57.6 yrs; 84.3% female); of these, 233 were eligible for work loss/indirect cost analyses. Compared to matched controls, patients with SSc had significantly higher HRU and costs during the 1-year followup period, IP admissions (adjusted IRR = 2.4), IP hospitalization days (adjusted IRR = 3.1), ER visits (adjusted IRR = 2.0), OP visits (adjusted IRR = 2.3), and days of work loss (adjusted IRR = 2.6). The adjusted difference in annual direct and indirect costs was US$12,820 and $3103, respectively (all p < 0.0001). CONCLUSION: Patients with SSc had a high direct and indirect economic burden postdiagnosis.
Subject(s)
Health Expenditures , Hospitalization/economics , Insurance, Health , Patient Acceptance of Health Care , Scleroderma, Systemic/economics , Adult , Aged , Cost of Illness , Female , Health Resources/economics , Humans , Male , Middle Aged , Retrospective Studies , United StatesABSTRACT
Interstitial pneumonia with autoimmune features (IPAF) is a research classification proposed by the European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease as an initial step to uniformly define, identify, and study patients with interstitial lung disease (ILD) who have features of autoimmunity, yet fall short of a characterizable connective tissue disease. Since its publication in July 2015, there has been substantial interest in IPAF. Centers from around the world have published their findings of retrospectively identified cohorts of patients who fulfill IPAF criteria, suggestions for modification of the criteria have been offered, and patients who fulfill IPAF criteria are being included as a subset in the ongoing phase II multicenter unclassifiable ILD treatment trial with pirfenidone. The IPAF designation represents an important first step toward studying and furthering our understanding of the natural history of this cohort of patients with ILD using uniform nomenclature and a standardized set of criteria. Prospective evaluations and, ideally, interdisciplinary and multicenter collaborations will inform best practices for treatment and management and will guide future refinement to the IPAF criteria. This review focuses on the relevant background that led to the development of IPAF, summarizes the proposed criteria, discusses cohort studies of patients with IPAF published to date and what they have taught us about the IPAF phenotype, and offers insights into future directions in this arena. Clinical trial registered with www.clinicaltrials.gov (NCT03099187).