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Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease that causes progressive cough, exertional dyspnea, impaired quality of life, and death. Objectives: Bexotegrast (PLN-74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. Methods: This Phase-2a multicenter, clinical trial randomized participants with IPF to receive, orally and once daily, bexotegrast at 40 mg, 80 mg, 160 mg, or 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in FVC, quantitative lung fibrosis (QLF) extent (%), and changes from baseline in fibrosis-related biomarkers. Measurements and Main Results: Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Participants who were treated with bexotegrast experienced a reduction in FVC decline over 12 weeks compared with those who received placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging, and a decrease in fibrosis-associated biomarkers was observed with bexotegrast versus placebo. Conclusions: Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registered with www.clinicaltrials.gov (NCT04396756).
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Fibrose Pulmonar Idiopática , Indóis , Piridonas , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/fisiopatologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Indóis/uso terapêutico , Piridonas/uso terapêutico , Piridonas/efeitos adversos , Resultado do Tratamento , Método Duplo-Cego , Relação Dose-Resposta a DrogaRESUMO
OBJECTIVES: Physical activity is reduced in patients with interstitial lung disease (ILD) and physical inactivity is related to poor health outcomes. We investigated the effect of a telecoaching intervention to improve physical activity in patients with ILD. METHODS: Eighty patients with ILD were randomized into the intervention or control group. Patients in the intervention group received a 12-week telecoaching program including a step counter, a patient-tailored smartphone application, and coaching calls. Patients in the control group received usual care. Physical activity (primary outcome), physical fitness and quality of life were measured at baseline and 12 weeks later with an accelerometer, 6-min walking test and quadriceps muscle force and the King's Brief Interstitial Lung Disease questionnaire (K-BILD). RESULTS: Participation in telecoaching did not improve physical activity: between-group differences for step count: 386 ± 590 steps/day, p = .52; sedentary time: 4 ± 18 min/day, p = .81; movement intensity: 0.04 ± 0.05 m/s2, p = .45). Between-group differences for the 6-min walking test, quadriceps muscle force and K-BILD were 14 ± 10 m, p = .16; 2 ± 3% predicted, p = .61; 0.8 ± 1.7 points, p = .62 respectively. CONCLUSIONS: Twelve weeks of telecoaching did not improve physical activity, physical fitness or quality of life in patients with ILD. Future physical or behavioural interventions are needed for these patients to improve physical activity.
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Doenças Pulmonares Intersticiais , Tutoria , Humanos , Qualidade de Vida , Doenças Pulmonares Intersticiais/terapia , Exercício Físico , Inquéritos e QuestionáriosRESUMO
This article summarises a selection of scientific highlights in the field of interstitial lung diseases (ILDs) presented at the International Congress of the European Respiratory Society in 2023. Translational and clinical studies focused on the whole spectrum of ILDs, from (ultra)rare ILDs to sarcoidosis, ILDs associated with connective tissue disease and idiopathic pulmonary fibrosis. The main topics of the 2023 Congress presentations were improving the diagnostic process of ILDs, better prediction of disease course and investigation of novel treatment options.
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BACKGROUND: Fibroblast-to-myofibroblast conversion is a major driver of tissue remodelling in organ fibrosis. Distinct lineages of fibroblasts support homeostatic tissue niche functions, yet their specific activation states and phenotypic trajectories during injury and repair have remained unclear. METHODS: We combined spatial transcriptomics, multiplexed immunostainings, longitudinal single-cell RNA-sequencing and genetic lineage tracing to study fibroblast fates during mouse lung regeneration. Our findings were validated in idiopathic pulmonary fibrosis patient tissues in situ as well as in cell differentiation and invasion assays using patient lung fibroblasts. Cell differentiation and invasion assays established a function of SFRP1 in regulating human lung fibroblast invasion in response to transforming growth factor (TGF)ß1. MEASUREMENTS AND MAIN RESULTS: We discovered a transitional fibroblast state characterised by high Sfrp1 expression, derived from both Tcf21-Cre lineage positive and negative cells. Sfrp1 + cells appeared early after injury in peribronchiolar, adventitial and alveolar locations and preceded the emergence of myofibroblasts. We identified lineage-specific paracrine signals and inferred converging transcriptional trajectories towards Sfrp1 + transitional fibroblasts and Cthrc1 + myofibroblasts. TGFß1 downregulated SFRP1 in noninvasive transitional cells and induced their switch to an invasive CTHRC1+ myofibroblast identity. Finally, using loss-of-function studies we showed that SFRP1 modulates TGFß1-induced fibroblast invasion and RHOA pathway activity. CONCLUSIONS: Our study reveals the convergence of spatially and transcriptionally distinct fibroblast lineages into transcriptionally uniform myofibroblasts and identifies SFRP1 as a modulator of TGFß1-driven fibroblast phenotypes in fibrogenesis. These findings are relevant in the context of therapeutic interventions that aim at limiting or reversing fibroblast foci formation.
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Fibrose Pulmonar Idiopática , Miofibroblastos , Camundongos , Animais , Humanos , Miofibroblastos/metabolismo , Fibroblastos/metabolismo , Pulmão/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Diferenciação Celular , Fator de Crescimento Transformador beta1/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismoRESUMO
Background: There is no standard definition of respiratory-related hospitalisation, a common end-point in idiopathic pulmonary fibrosis (IPF) clinical trials. As diverse aetiologies and complicating comorbidities can present similarly, external adjudication is sometimes employed to achieve standardisation of these events. Methods: An algorithm for respiratory-related hospitalisation was developed through a literature review of IPF clinical trials with respiratory-related hospitalisation as an end-point. Experts reviewed the algorithm until a consensus was reached. The algorithm was validated using data from the phase 3 ISABELA trials (clinicaltrials.gov identifiers NCT03711162 and NCT03733444), by assessing concordance between nonadjudicated, investigator-defined, respiratory-related hospitalisations and those defined by the adjudication committee using the algorithm. Results: The algorithm classifies respiratory-related hospitalisation according to cause: extraparenchymal (worsening respiratory symptoms due to left heart failure, volume overload, pulmonary embolism, pneumothorax or trauma); other (respiratory tract infection, right heart failure or exacerbation of COPD); "definite" acute exacerbation of IPF (AEIPF) (worsening respiratory symptoms within 1â month, with radiological or histological evidence of diffuse alveolar damage); or "suspected" AEIPF (as for "definite" AEIPF, but with no radiological or histological evidence of diffuse alveolar damage). Exacerbations ("definite" or "suspected") with identified triggers (infective, post-procedural or traumatic, drug toxicity- or aspiration-related) are classed as "known AEIPF"; "idiopathic AEIPF" refers to exacerbations with no identified trigger. In the ISABELA programme, there was 94% concordance between investigator- and adjudication committee-determined causes of respiratory-related hospitalisation. Conclusion: The algorithm could help to ensure consistency in the reporting of respiratory-related hospitalisation in IPF trials, optimising its utility as an end-point.
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The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes-CAMK2A, CAMK2B, CAMK2G, and CAMK2D-of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now. Here we show that CAMK2D plays an important role in neurodevelopment not only in mice but also in humans. We identified eight individuals harboring heterozygous variants in CAMK2D who display symptoms of intellectual disability, delayed speech, behavioral problems, and dilated cardiomyopathy. The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms. Together, we describe a cohort of individuals with neurodevelopmental disorders and cardiac anomalies, harboring pathogenic variants in CAMK2D, confirming an important role for the CAMK2D isozyme in both heart and brain function.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Cardiomiopatia Dilatada , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Animais , Humanos , Camundongos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Coração , Transtornos do Neurodesenvolvimento/genéticaRESUMO
RATIONALE: Recent data suggest that the localisation of airway epithelial cells in the distal lung in idiopathic pulmonary fibrosis (IPF) may drive pathology. We set out to discover whether chemokines expressed in these ectopic airway epithelial cells may contribute to the pathogenesis of IPF. METHODS: We analysed whole lung and single-cell transcriptomic data obtained from patients with IPF. In addition, we measured chemokine levels in blood, bronchoalveolar lavage (BAL) of IPF patients and air-liquid interface cultures. We employed ex vivo donor and IPF lung fibroblasts and an animal model of pulmonary fibrosis to test the effects of chemokine signalling on fibroblast function. RESULTS: By analysis of whole-lung transcriptomics, protein and BAL, we discovered that CXCL6 (a member of the interleukin-8 family) was increased in patients with IPF. Elevated CXCL6 levels in the BAL of two cohorts of patients with IPF were associated with poor survival (hazard ratio of death or progression 1.89, 95% CI 1.16-3.08; n=179, p=0.01). By immunostaining and single-cell RNA sequencing, CXCL6 was detected in secretory cells. Administration of mCXCL5 (LIX, murine CXCL6 homologue) to mice increased collagen synthesis with and without bleomycin. CXCL6 increased collagen I levels in donor and IPF fibroblasts 4.4-fold and 1.7-fold, respectively. Both silencing of and chemical inhibition of CXCR1/2 blocked the effects of CXCL6 on collagen, while overexpression of CXCR2 increased collagen I levels 4.5-fold in IPF fibroblasts. CONCLUSIONS: CXCL6 is expressed in ectopic airway epithelial cells. Elevated levels of CXCL6 are associated with IPF mortality. CXCL6-driven collagen synthesis represents a functional consequence of ectopic localisation of airway epithelial cells in IPF.
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Fibrose Pulmonar Idiopática , Animais , Humanos , Camundongos , Bleomicina , Quimiocina CXCL6/metabolismo , Quimiocinas/metabolismo , Colágeno/metabolismo , Fibroblastos/metabolismo , Fibrose Pulmonar Idiopática/genética , Pulmão/patologiaRESUMO
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) with coexistent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may associate with reduced forced vital capacity (FVC) declines compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts. METHODS: Visual emphysema presence (>0% emphysema) scored on computed tomography identified CPFE patients (CPFE/non-CPFE: derivation cohort n=317/n=183, replication cohort n=358/n=152), who were subgrouped using 10% or 15% visual emphysema thresholds, and an unsupervised machine-learning model considering emphysema and interstitial lung disease extents. Baseline characteristics, 1-year relative FVC and diffusing capacity of the lung for carbon monoxide (D LCO) decline (linear mixed-effects models), and their associations with mortality (multivariable Cox regression models) were compared across non-CPFE and CPFE subgroups. RESULTS: In both IPF cohorts, CPFE patients with ≥10% emphysema had a greater smoking history and lower baseline D LCO compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with ≥10% emphysema, 1-year D LCO decline showed stronger mortality associations than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials and in subjects subgrouped by ≥15% emphysema and using unsupervised machine learning. Importantly, the unsupervised machine-learning approach identified CPFE patients in whom FVC decline did not associate strongly with mortality. In non-CPFE IPF patients, 1-year FVC declines ≥5% and ≥10% showed strong mortality associations. CONCLUSION: When assessing disease progression in IPF, D LCO decline should be considered in patients with ≥10% emphysema and a ≥5% 1-year relative FVC decline threshold considered in non-CPFE IPF patients.
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Enfisema , Fibrose Pulmonar Idiopática , Enfisema Pulmonar , Humanos , Enfisema Pulmonar/complicações , Pulmão , Fibrose , Enfisema/complicações , Progressão da Doença , Estudos RetrospectivosRESUMO
Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly (MDMHB) is an ultra-rare skeletal dysplasia caused by heterozygous intragenic RUNX2 duplications, comprising either exons 3 to 5 or exons 3 to 6 of RUNX2. In this study, we describe a 14-year-old Belgian boy with metaphyseal dysplasia with maxillary hypoplasia but without brachydactyly. Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance. Exome sequencing led to the identification of a de novo heterozygous tandem duplication within RUNX2, encompassing exons 3 to 7. This duplication is larger than the ones previously reported in MDMHB cases since it extends into the C-terminal activation domain of RUNX2. We review previously reported cases with MDMHB and highlight the resemblance of this disorder with Pyle disease, which may be explained by intersecting molecular pathways between RUNX2 and sFRP4. This study expands our knowledge on the genotypic and phenotypic characteristics of MDMHB and the role of RUNX2 in rare bone disorders.
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Braquidactilia , Displasia Cleidocraniana , Micrognatismo , Osteocondrodisplasias , Masculino , Humanos , Adolescente , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Proteínas Proto-OncogênicasRESUMO
BACKGROUND AND OBJECTIVE: Real-life data on suspected familial fibrosis, defined as the occurrence of the disease in a patient younger than 50 and/or having at least one relative affected by pulmonary fibrosis remain scarce. METHODS: The Belgian and Luxembourg IPF registry (PROOF-Next) is a multicentric prospective longitudinal and observational study set in Belgium and Luxembourg. We compared characteristics and clinical course of patients with suspected familial pulmonary fibrosis (FPF) and sporadic IPF. RESULTS: We included 618 patients in the analysis, of whom 76 (12%) fulfilled criteria for FPF. They were significantly younger than sIPF (median age (range) 65 (43-87), vs. 72 (51-98), p = 0.0001). Male gender proportion and smoking status did not differ between groups, but the number of pack-year among current and former smokers was lower in FPF (20 vs. 25, p = 0.02). Besides, 87% of FPF and 76% of sIPF were treated with antifibrotic (p = 0.047). Baseline pulmonary function tests were similar in both groups, as well as median time before progression and transplant-free survival. Finally, genetic testing, performed in a minority, led to the identification of 10 telomerase-related gene variants. CONCLUSION: Although younger and exposed to less tobacco, patients with FPF show an equally aggressive progression as observed in sporadic IPF patients. These results warrant early referral of FPF patients to expert centres for optimal management.
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Fibrose Pulmonar Idiopática , Humanos , Masculino , Estudos Prospectivos , Fibrose Pulmonar Idiopática/epidemiologia , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/tratamento farmacológico , Testes de Função Respiratória , Sistema de Registros , Progressão da DoençaRESUMO
Pulmonary fibrosis develops as a consequence of failed regeneration after injury. Analyzing mechanisms of regeneration and fibrogenesis directly in human tissue has been hampered by the lack of organotypic models and analytical techniques. In this work, we coupled ex vivo cytokine and drug perturbations of human precision-cut lung slices (hPCLS) with single-cell RNA sequencing and induced a multilineage circuit of fibrogenic cell states in hPCLS. We showed that these cell states were highly similar to the in vivo cell circuit in a multicohort lung cell atlas from patients with pulmonary fibrosis. Using micro-CT-staged patient tissues, we characterized the appearance and interaction of myofibroblasts, an ectopic endothelial cell state, and basaloid epithelial cells in the thickened alveolar septum of early-stage lung fibrosis. Induction of these states in the hPCLS model provided evidence that the basaloid cell state was derived from alveolar type 2 cells, whereas the ectopic endothelial cell state emerged from capillary cell plasticity. Cell-cell communication routes in patients were largely conserved in hPCLS, and antifibrotic drug treatments showed highly cell type-specific effects. Our work provides an experimental framework for perturbational single-cell genomics directly in human lung tissue that enables analysis of tissue homeostasis, regeneration, and pathology. We further demonstrate that hPCLS offer an avenue for scalable, high-resolution drug testing to accelerate antifibrotic drug development and translation.
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Fibrose Pulmonar , Humanos , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Análise da Expressão Gênica de Célula Única , Pulmão/patologia , Células Epiteliais Alveolares , Células Epiteliais/metabolismoRESUMO
BACKGROUND: Rheumatoid arthritis (RA) is a chronic auto-immune disease, typically affecting the joints, which can also present with lung involvement (pleuritis, interstitial lung disease, pulmonary nodules, etc.). Lung ultrasound (LUS) is an upcoming tool in the detection of these pulmonary manifestations. METHODS: We performed a 72-window LUS in 75 patients presenting to the outpatient rheumatology clinic and describe the abnormalities (presence of B-lines (vertical comet-tail artefacts), pleural abnormalities, pleural effusions, and subpleural nodules) on lung ultrasound. We created a topological mapping of the number of B-lines per intercostal zone. RESULTS: We observed pleural effusions, pleural abnormalities, and pleural nodules in, respectively, 1.3%, 45.3%, and 14% of patients. There were 35 (46.7%) patients who had less than 5 B-lines, 15 (20%) patients who had between 5 and 10 B-lines, 11 (14.6%) between 10 and 20, 10 (13.3%) between 20 and 50, 1 (1.3%) between 50 and 100, and 3 (4%) of patients who had more than 100 B-lines. CONCLUSIONS: LUS in patients with RA shows an array of abnormalities ranging from interstitial syndromes to pleural abnormalities, subpleural nodules, and pleural effusions. Hotspots for the presence of B-lines are situated bilaterally in the posterior subscapular regions, as well as the anterior right mid-clavicular region.
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Introduction: Sarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures. Methods: After obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations. Results: In the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement. Discussion: The observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene-environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis.
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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19) which can lead to acute respiratory distress syndrome (ARDS) and evolve to pulmonary fibrosis. Computed tomography (CT) is used to study disease progression and describe radiological patterns in COVID-19 patients. This study aimed to assess disease progression regarding lung volume and density over time on follow-up in vivo chest CT and give a unique look at parenchymal and morphological airway changes in "end-stage" COVID-19 lungs using ex vivo microCT. Methods: Volumes and densities of the lung/lobes of three COVID-19 patients were assessed using follow-up in vivo CT and ex vivo whole lung microCT scans. Airways were quantified by airway segmentations on whole lung microCT and small-partition microCT. As controls, three discarded healthy donor lungs were used. Histology was performed in differently affected regions in the COVID-19 lungs. Results: In vivo, COVID-19 lung volumes decreased while density increased over time, mainly in lower lobes as previously shown. Ex vivo COVID-19 lung volumes decreased by 60% and all lobes were smaller compared to controls. Airways were more visible on ex vivo microCT in COVID-19, probably due to fibrosis and increased airway diameter. In addition, small-partition microCT showed more deformation of (small) airway morphology and fibrotic organization in severely affected regions with heterogeneous distributions within the same lung which was confirmed by histology. Conclusions: COVID-19-ARDS and subsequent pulmonary fibrosis alters lung architecture and airway morphology which is described using in vivo CT, ex vivo microCT, and histology.
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Millions of workers are exposed to substances known to cause occupational interstitial lung diseases (ILDs), particularly in developing countries. However, the burden of the disease is likely to be underestimated due to under-recognition, under-reporting or both. The diagnosis of occupational ILD requires a high level of suspicion and a thorough occupational history, as occupational and non-occupational ILDs may be clinically, functionally and radiologically indistinguishable, leading to delayed diagnosis and inappropriate management. A potential occupational aetiology should always be considered in the differential diagnosis of ILD, as removal from the workplace exposure, with or without treatment, is a key therapeutic intervention and may lead to significant improvement. In this article, we provide an overview of the 'traditional' inorganic dust-related ILDs but also address idiopathic pulmonary fibrosis and the immunologically mediated chronic beryllium disease, sarcoidosis and hypersensitivity pneumonitis, with emphasis on the importance of surveillance and prevention for reducing the burden of these conditions. To this end, health-care professionals should be specifically trained about the importance of occupational exposures as a potential cause of ILD.
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Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Sarcoidose , Humanos , Diagnóstico Diferencial , Fibrose Pulmonar Idiopática/diagnóstico , Pulmão , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Sarcoidose/diagnósticoRESUMO
INTRODUCTION: In the European Union (EU), the indication for the antifibrotic pirfenidone prior to April 2023 did not include patients with advanced idiopathic pulmonary fibrosis (IPF). This analysis compared the efficacy and safety of pirfenidone in advanced IPF versus non-advanced IPF. METHODS: Data were included from the following studies of pirfenidone: ASCEND (NCT01366209); CAPACITY (004 [NCT00287716] and 006 [NCT00287729]); RECAP (NCT00662038; advanced IPF defined as percent predicted forced vital capacity [%FVC] < 50% and/or percent predicted carbon monoxide diffusing capacity [%DLco] < 35% at baseline); PASSPORT (NCT02699879; advanced IPF defined as baseline %FVC < 50%); and SP-IPF (NCT02951429; patients with advanced IPF [defined as %DLco ≤ 40% at screening] at risk of group 3 pulmonary hypertension). RESULTS: In the pooled ASCEND/CAPACITY studies, the annual mean rate of FVC decline from baseline to Week 52 was significantly lower for pirfenidone versus placebo in advanced (p = 0.0035) and non-advanced IPF (p = 0.0001). Rate of all-cause mortality over 52 weeks was numerically lower for pirfenidone versus placebo in advanced and non-advanced IPF. In RECAP, the mean annual rate of FVC decline from baseline to Week 180 of pirfenidone treatment was similar in patients with advanced (- 141.5 mL) and non-advanced IPF (- 153.5 mL). In SP-IPF, the mean annual rate of FVC decline and rate of all-cause mortality from baseline to Week 52 in patients treated with placebo + pirfenidone were - 93.0 mL and 20.2%, respectively. No new safety signals were identified, and the safety profile of pirfenidone in patients with advanced IPF was generally consistent with that of non-advanced IPF. CONCLUSIONS: These results highlight the benefit of pirfenidone treatment in patients with advanced and non-advanced IPF. As such, the indication for pirfenidone in the EU has now been updated to include the treatment of adult patients with advanced IPF. TRIAL REGISTRATIONS: ASCEND (NCT01366209), CAPACITY 004 (NCT00287716), CAPACITY 006 (NCT00287729), RECAP (NCT00662038), PASSPORT (NCT02699879), and SP-IPF (NCT02951429).
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Anti-Inflamatórios não Esteroides , Fibrose Pulmonar Idiopática , Adulto , Humanos , Anti-Inflamatórios não Esteroides/efeitos adversos , Fibrose Pulmonar Idiopática/diagnóstico , Piridonas/efeitos adversos , Resultado do Tratamento , Capacidade VitalRESUMO
ObjectiveMultiple spliceosome components are known autoantigens in systemic sclerosis (SSc). Here we aim to identify new and characterize rare anti-spliceosomal autoantibodies in patients with SSc without known autoantibody specificity. MethodsSera that precipitated spliceosome subcomplexes, as detected by immunoprecipitation-mass spectrometry (IP-MS), were identified from a database of 106 patients with SSc without known autoantibody specificity. New autoantibody specificities were confirmed with immunoprecipitation-western blot. The IP-MS pattern of new anti-spliceosomal autoantibodies was compared with anti-U1 RNP-positive sera of patients with different systemic autoimmune rheumatic diseases and anti-SmD-positive sera of patients with systemic lupus erythematosus (n = 24). ResultsThe NineTeen Complex (NTC) was identified and confirmed as new spliceosomal autoantigen in one patient with SSc. U5 RNP, as well as additional splicing factors, were precipitated by the serum of another patient with SSc. The IP-MS patterns of anti-NTC and anti-U5 RNP autoantibodies were distinct from those of anti-U1 RNP- and anti-SmD-positive sera. Furthermore, there was no difference in IP-MS patterns between a limited number of anti-U1 RNP-positive sera of patients with different systemic autoimmune rheumatic diseases. ConclusionAnti-NTC autoantibodies are a new anti-spliceosomal autoantibody specificity, here first identified in a patient with SSc. Anti-U5 RNP autoantibodies are a distinct but rare anti-spliceosomal autoantibody specificity. All major spliceosomal subcomplexes have now been described as target of autoantibodies in systemic autoimmune diseases.