Mortality surrogates in combined pulmonary fibrosis and emphysema.

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.

Decreased serpin C1 in extracellular vesicles predicts response to methotrexate treatment in patients with pulmonary sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic granulomatous disease of unknown etiology primarily affecting the lungs. Treatment is needed when disease symptoms worsen and organ function deteriorates. In pulmonary sarcoidosis, prednisone and methotrexate (MTX) are the most common anti-inflammatory therapies. However, there is large inter-patient variability in response to treatment, and predictive response markers are currently lacking. OBJECTIVE: In this study, we investigated the predictive potential of biomarkers in extracellular vesicles (EVs) isolated from biobanked serum of patients with pulmonary sarcoidosis stored prior to start of therapy. METHODS: Protein concentrations of a four-protein test panel of inflammatory proteins were measured in a discovery (n = 16) and replication (n = 129) cohort of patients with sarcoidosis and 47 healthy controls. Response to therapy was defined as an improvement of the absolute score of > 5% forced vital capacity (FVC) and/or > 10% diffusion lung of carbon monoxide (DLCO) after 24 weeks compared to baseline (before treatment). RESULTS: Serum protein levels differed between EV fractions and serum, and between sarcoidosis cases and controls. Serpin C1 concentrations in the low density lipid particle EV fraction were lower at baseline in the group of patients with a good response to MTX treatment in both the discovery cohort (p = 0.059) and in the replication cohort (p = 0.032). EV Serpin C1 showed to be a significant predictor for response to treatment with MTX (OR 0.4; p = 0.032). CONCLUSION: This study shows that proteins isolated from EVs harbor a distinct signal and have potential as new predictive therapy response biomarkers in sarcoidosis.

Long-term expanding human airway organoids for disease modeling.

Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here, we describe a method to establish long-term-expanding human airway organoids from broncho-alveolar resections or lavage material. The pseudostratified airway organoids consist of basal cells, functional multi-ciliated cells, mucus-producing secretory cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoids established from lung cancer resections and metastasis biopsies retain tumor histopathology as well as cancer gene mutations and are amenable to drug screening. Respiratory syncytial virus (RSV) infection recapitulates central disease features, dramatically increases organoid cell motility via the non-structural viral NS2 protein, and preferentially recruits neutrophils upon co-culturing. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.

European Respiratory Society statement on familial pulmonary fibrosis.

Genetic predisposition to pulmonary fibrosis has been confirmed by the discovery of several gene mutations that cause pulmonary fibrosis. Although genetic sequencing of familial pulmonary fibrosis (FPF) cases is embedded in routine clinical practice in several countries, many centres have yet to incorporate genetic sequencing within interstitial lung disease (ILD) services and proper international consensus has not yet been established. An international and multidisciplinary expert Task Force (pulmonologists, geneticists, paediatrician, pathologist, genetic counsellor, patient representative and librarian) reviewed the literature between 1945 and 2022, and reached consensus for all of the following questions: 1) Which patients may benefit from genetic sequencing and clinical counselling? 2) What is known of the natural history of FPF? 3) Which genes are usually tested? 4) What is the evidence for telomere length measurement? 5) What is the role of common genetic variants (polymorphisms) in the diagnostic workup? 6) What are the optimal treatment options for FPF? 7) Which family members are eligible for genetic sequencing? 8) Which clinical screening and follow-up parameters may be considered in family members? Through a robust review of the literature, the Task Force offers a statement on genetic sequencing, clinical management and screening of patients with FPF and their relatives. This proposal may serve as a basis for a prospective evaluation and future international recommendations.

MUC5B rs35705950 minor allele associates with older age and better survival in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: The minor T-allele of the MUC5B promoter polymorphism rs35705950 is strongly associated with idiopathic pulmonary fibrosis (IPF). However, conflicting results have been reported on the relationship between the MUC5B minor allele and survival and it is unknown whether a specific subgroup of IPF patients might benefit from MUC5B minor allele carriage. We investigated the association between MUC5B rs35705950, survival and patient characteristics in a real-world population of European IPF patients. METHODS: In this retrospective study, 1751 patients with IPF from 8 European centres were included. MUC5B rs35705950 genotype, demographics, clinical characteristics at diagnosis and survival data were analysed. RESULTS: In a multi-variate Cox proportional hazard model the MUC5B minor allele was a significant independent predictor of survival when adjusted for age, sex, high resolution computed tomography pattern, smoking behaviour and pulmonary function tests in IPF. MUC5B minor allele carriers were significantly older at diagnosis (p = 0.001). The percentage of MUC5B minor allele carriers increased significantly with age from 44% in patients aged <56 year, to 63% in patients aged >75. In IPF patients aged <56, the MUC5B minor allele was not associated with survival. In IPF patients aged ≥56, survival was significantly better for MUC5B minor allele carriers (45 months [CI: 42-49]) compared to non-carriers (29 months [CI: 26-33]; p = 4 × 10-12 ). CONCLUSION: MUC5B minor allele carriage associates with a better median transplant-free survival of 16 months in the European IPF population aged over 56 years. MUC5B genotype status might aid disease prognostication in clinical management of IPF patients.

Improved Survival of IPF patients Treated With Antifibrotic Drugs Compared With Untreated Patients.

PURPOSE: Pirfenidone and nintedanib unequivocally inhibit FVC decline, but have been inconsistently linked to reduced mortality in phase III studies. On the contrary, real-world data show a survival benefit of antifibrotic drugs. However, it is unknown what this benefit is across different Gender, Age, and Physiology (GAP) stages. RESEARCH QUESTIONS: Is there a difference in transplant-free (TPF) survival of IPF patients receiving antifibrotic drugs (IPFAF) compared with an untreated cohort (IPFnon-AF)? Is this different for patients with GAP stage I, II, or III. METHODS: This is a single-center observational cohort study using prospectively included patients diagnosed with IPF between 2008-2018. Primary outcomes were TPF survival difference and 1-, 2-, and 3-year cumulative mortality for IPFAF and IPFnon-AF. This was repeated after stratification for GAP stage. RESULTS: In total, 457 patients were included. The median transplant-free survival was 3.4 years in IPFAF (n = 313) and 2.2 years in IPFnon-AF (n = 144, p = 0.005). For GAP stage II, a median survival of 3.1 and 1.7 years was noted for IPFAF (n = 143) and IPFnon-AF (n = 59, p < 0.001), respectively. A significantly lower 1-, 2-, and 3- year cumulative mortality was found for IPFAF with GAP stage II (1 yr: 7.0% vs 35.6%, 2 yr: 26.6% vs 55.9%, and 3 yr: 46.9% vs 69.5%). The 1-year cumulative mortality of IPFAF with GAP III was also significantly lower (19.0% vs 65.0%). CONCLUSION: This large real-world study showed a survival benefit in IPFAF compared with IPFnon-AF. This especially holds true for patients with GAP stage II and III.

New Insights via RNA Profiling of Formalin-Fixed Paraffin-Embedded Lung Tissue of Pulmonary Fibrosis Patients.

In sporadic idiopathic pulmonary fibrosis (sIPF) and pulmonary fibrosis caused by a mutation in telomere (TRG-PF) or surfactant related genes (SRG-PF), there are a number of aberrant cellular processes known that can lead to fibrogenesis. We investigated whether RNA expression of genes involved in these processes differed between sIPF, TRG-PF, and SRG-PF and whether expression levels were associated with survival. RNA expression of 28 genes was measured in lung biopsies of 26 sIPF, 17 TRG-PF, and 6 SRG-PF patients. Significant differences in RNA expression of TGFBR2 (p = 0.02) and SFTPA2 (p = 0.02) were found between sIPF, TRG-PF, and SRG-PF. Patients with low (

Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary Fibrosis.

In only around 40% of families with pulmonary fibrosis (PF) a suspected genetic cause can be found. Genetic overlap analysis of Whole Exome Sequencing (WES) data may be a powerful tool to discover new shared variants in novel genes for PF. As a proof of principle, we first selected unrelated PF patients for whom a genetic variant was detected (n = 125) in established PF genes and searched for overlapping variants. Second, we performed WES (n = 149) and identified novel potentially deleterious variants shared by at least two unrelated PF patients. These variants were genotyped in validation cohorts (n = 2748). In 125 unrelated patients, a potentially deleterious variant was detected in known PF genes of which 15 variants in six genes overlapped, involving 51 patients. Overlap analysis of WES data identified two novel variants of interest: TOM1L2 c.421T > C p.(Y141H) and TDP1c.1373dupG p.(S459fs*5), neither gene had been related to pulmonary fibrosis before. Both proteins were present in the alveolar epithelium. No apparent characteristics of telomere disease were observed. This study underlines the potential of searching for overlapping rare potentially deleterious variants to identify disease-associated variants and genes. A previously unreported variant was found in two putative new PF genes, but further research is needed to determine causality.

Simultaneous Assessment of mTORC1, JAK/STAT, and NLRP3 Inflammasome Activation Pathways in Patients with Sarcoidosis.

The unknown etiology of sarcoidosis, along with the variability in organ involvement and disease course, complicates the effective treatment of this disease. Based on recent studies, the cellular inflammatory pathways involved in granuloma formation are of interest regarding possible new treatment options, such as the mechanistic (formerly mammalian) target of rapamycin complex 1 (mTORC1) pathway, the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, and the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome pathway. The aim of this study was to explore the potential coexpression of these three inflammatory pathways in patients with sarcoidosis and see whether possible differences were related to disease outcome. The tissue of 60 patients with sarcoidosis was used to determine the activity of these three signaling pathways using immunohistochemistry. The activation of NLRP3 was present in 85% of all patients, and the activation of mTORC1 and JAK/STAT was present in 49% and 50% of patients, respectively. Furthermore, the presence of NLRP3 activation at diagnosis was associated with a chronic disease course of sarcoidosis. Our finding of different new conceptual inflammatory tissue phenotypes in sarcoidosis could possibly guide future treatment studies using the available inhibitors of either NLRP3, JAK-STAT, and mTORC1 inhibitors in a more personalized medicine approach.

Decreased Survival and Lung Function in Progressive Pulmonary Fibrosis.

Background and Objectives: Progressive pulmonary fibrosis (PPF) is a recently described term reserved for patients with fibrotic ILD other than idiopathic pulmonary fibrosis (IPF) with fast clinical deterioration. Here, survival and prognostic biomarkers at the time of diagnosis for PPF are investigated in a fibrotic ILD other than IPF cohort (non-IPF). Materials and Methods: Patients diagnosed during the period of 2012-2018 at the ILD Center of Excellence (St. Antonius Hospital, Nieuwegein, The Netherlands) with a fibrotic ILD were included in this study. The presence of PPF was investigated using the criteria from the updated IPF/PPF guideline during the first year after diagnosis. Logistic regression analysis was used to determine risk factors for PPF. A Kaplan-Meier survival analysis with log-rank test was conducted to analyze survival in patients with and without PPF. Results: This study included 304 non-IPF patients and, for comparison, 379 IPF patients. In non-IPF patients, 146 (46%) fulfilled ≥2 criteria for PPF. These patients had a median transplant-free survival rate of 2.9 ± 0.4 years, which was worse than non-IPF patients without PPF (10.1 ± 1.8 years, p < 0.001). The risk for PPF was increased in patients with FVC < 50% (odds ratio (OR) of 2.50, 95% CI = 1.01-6.17, p = 0.047) or DLCOc ≤ 35% (OR = 2.57, 95% CI = 1.24-5.35, p = 0.011). In the first 3 years after diagnosis, survival in PPF and IPF is the same, while in the following years IPF has a significantly worse survival. Conclusions: The non-IPF cohort with PPF had a significantly worse transplant-free survival compared with the non-IPF cohort without PPF. Independent risk factors for PPF in non-IPF were FVC < 50% and DLCOc ≤ 35%.

Extrapulmonary manifestations of a telomere syndrome in patients with idiopathic pulmonary fibrosis are associated with decreased survival.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a heterogenous disease with a median survival of 3-4 years. Patients with mutations in telomere-related genes exhibit extrapulmonary signs and symptoms. These patients represent a distinct phenotype of IPF with worse survival. As genetic analyses are not available for most patients with IPF, we sought to determine the predictive value of extrapulmonary signs and symptoms of a telomere syndrome in patients with IPF. METHODS: We retrospectively studied 409 patients with IPF. Clinical characteristics, laboratory results and family history suggestive of a telomere syndrome were related to leukocyte telomere length measured by quantitative PCR and patient outcomes. RESULTS: The cohort included 293 patients with sporadic IPF and 116 patients with a background of familial pulmonary fibrosis. Any or a combination of a clinical history (haematological disease, liver disease, early greying of hair, nail dystrophy, skin abnormalities), a family history or haematological laboratory abnormalities (macrocytosis, anaemia, thrombopenia or leukopenia) suggestive of a telomere syndrome was present in 27% of IPF patients and associated with shorter leukocyte telomere length and shorter survival (p = 0.002 in a multivariate model). In sporadic IPF, having either a clinical history, family history or haematological laboratory abnormalities was not significantly associated with decreased survival (p = 0.07 in a multivariate model). CONCLUSION: Taking a careful clinical and family history focused on extrapulmonary manifestations of a telomere syndrome can provide important prognostic information in patients with IPF, as this is associated with shorter survival.

Genetic testing in interstitial lung disease: An international survey.

BACKGROUND AND OBJECTIVE: Genetic analysis is emerging for interstitial lung diseases (ILDs); however, ILD practices are not yet standardized. We surveyed patients', relatives' and pulmonologists' experiences and needs on genetic testing in ILD to evaluate the current situation and identify future needs. METHODS: A clinical epidemiologist (MT) together with members of the ERS taskforce and representatives of the European Idiopathic Pulmonary Fibrosis and related disorders Federation (EU-IPFF) patient organisation developed a survey for patients, relatives and pulmonologists. Online surveys consisted of questions on five main topics: awareness of hereditary ILD, the provision of information, genetic testing, screening of asymptomatic relatives and clinical impact of genetic analysis in ILD. RESULTS: Survey respondents consisted of 458 patients with ILD, 181 patients' relatives and 352 pulmonologists. Most respondents think genetic testing can be useful, particularly for explaining the cause of disease, predicting its course, determining risk for developing disease and the need to test relatives. Informing patients and relatives on genetic analysis is primarily performed by the pulmonologist, but 88% (218) of pulmonologists identify a need for more information and 96% (240) ask for guidelines on genetic testing in ILD. A third of the pulmonologists who would offer genetic testing currently do not offer a genetic test, primarily because they have limited access to genetic tests. Following genetic testing, 72% (171) of pulmonologists may change the diagnostic work-up and 57% (137) may change the therapeutic approach. CONCLUSION: This survey shows that there is wide support for implementation of genetic testing in ILD and a high need for information, guidelines and access to testing among patients, their relatives and pulmonologists.

Clustering of lung diseases in the family of interstitial lung disease patients.

BACKGROUND: The presence of familial interstitial lung disease (ILD) has been found to predict development of progressive pulmonary fibrosis. However, the role of non-ILD lung diseases in ILD patients' families has not yet been investigated. We aimed to identify associations between ILDs and non-ILD lung diseases from ILD patients' self-reported family health history. METHODS: We analysed questionnaires on family health history of 1164 ILD patients for the occurrence of ILD and non-ILD lung disease in relatives. Logistic regression analysis was used to study associations with diagnosis groups. RESULTS: Familial pulmonary fibrosis was reported by 20% of patients with idiopathic pulmonary fibrosis (IPF; OR 9.2, 95% CI 4.7-17.9), and 15% of patients with unclassifiable pulmonary fibrosis (OR 4.1, 95% CI 2.0-8.2). Familial occurrence was reported by 14% of patients with sarcoidosis (OR 3.3, 95% CI 1.9-5.8). Regarding non-ILD lung disease, significantly more patients with IPF (36%) reported lung cancer in their family (OR 2.3, 95% CI 1.4-3.5), and patients with hypersensitivity pneumonitis (18%) mostly reported COPD (OR 2.3, 95% CI 1.3-4.2). Comparison of sporadic and familial ILD patients' reports showed that emphysema (OR 4.6, 95% CI 1.8-11.6), and lung cancer (OR 2.4, 95% CI 1.2-4.9) were predictive for familial pulmonary fibrosis, particularly when reported both in a family (OR 16.7, 95% CI 3.2-86.6; p < 0.001). CONCLUSIONS: Our findings provide evidence for clustering of ILD and non-ILD lung diseases in families and show that self-reported emphysema and lung cancer of relatives in this population predicts familial pulmonary fibrosis.

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease.

BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).

Pulmonary fibrosis in non-mutation carriers of families with short telomere syndrome gene mutations.

BACKGROUND AND OBJECTIVE: Diagnostic and predictive genetic testing for disease cause and risk estimation is common in many countries. For genetic diseases, predictive test results are commonly straightforward: presence of the mutation involves increased risk for disease and absence of the mutation involves no inherit risk for disease. Germline mutations in telomere-related genes (TRGs) can lead to telomere shortening and are associated with short telomere syndrome (STS). Telomere length is heritable, and in families with STS due to a TRG mutation, progeny with and without the TRG mutation is known to have shorter than average telomeres. We hypothesize that progeny of TRG mutation carriers who did not inherit the TRG mutation may still develop pulmonary fibrosis. METHODS: A genetic screen of 99 unrelated families with familial pulmonary fibrosis revealed five patients with features of pulmonary fibrosis but without carrying the familial disease-causing TRG mutation. RESULTS: Features of STS were present in each family, including short telomeres in blood and tissue of the non-mutation carrying patients. Additional genetic, clinical or environmental risk factors for pulmonary fibrosis were present in each non-mutation carrying patient. CONCLUSION: Our study shows that non-mutation carrying first-degree relatives in families with STS are at increased risk for pulmonary fibrosis. Disease development may be triggered by inherited short telomeres and additional risk factors for disease. This observation has profound consequences for genetic counselling. Unlike any other genetic syndrome, absence of the mutation does not imply absence of disease risk. Therefore, clinical follow-up is still urged for non-mutation carrying first-degree family members.

Connective Tissue Growth Factor Single Nucleotide Polymorphisms in (Familial) Pulmonary Fibrosis and Connective Tissue Disease Associated Interstitial Lung Disease.

PURPOSE: Connective tissue growth factor (CTGF) is an important mediator in fibrotic disease. Single nucleotide polymorphisms (SNPs) in CTGF have been found to be associated with different fibrotic diseases and CTGF protein was found to be upregulated in lung tissue, bronchoalveolar lavage cells, and plasma of idiopathic pulmonary fibrosis (IPF) patients. We investigated whether genetic variants predispose to sporadic IPF (spIPF), familial pulmonary fibrosis (FPF), and connective tissue disease associated ILD (CTD-ILD). METHODS: In total, 294 patients with spIPF and 294 healthy individuals were genotyped for CTGF rs12526196, rs9402373, rs6918698, and rs9399005. For replication of CTGF rs6918698 findings in pulmonary fibrosis, 128 patients with FPF, 125 with CTD-ILD, and an independent control cohort of 130 individuals were included. Lung tissue of 6 IPF patients was stained for CTGF to assess pulmonary localization. RESULTS: Of the four SNPs, only the minor allele frequency (MAF) of CTGF rs6918698 deviated between spIPF (MAF 0.41) and controls (MAF 0.47; OR 0.774 (0.615-0.975); p = 0.030). Further comparison of CTGF rs6918698G showed a difference between FPF (MAF 0.33) and controls (MAF 0.48; OR 0.545 (0.382-0.778); p = 0.001), but not with CTD-ILD. CTGF was localized in alveolar and bronchiolar epithelium, alveolar macrophages, myofibroblasts and endothelium and highly expressed in the basal cell layer of sandwich foci. CONCLUSION: CTGF rs6918698G associates with spIPF and with FPF, but not with CTD-ILD in a Dutch cohort. CTGF is localized in lung tissue involved in IPF pathogenesis. Further research into the role of this SNP on CTGF expression and fibrogenesis is warranted.

Serial CT analysis in idiopathic pulmonary fibrosis: comparison of visual features that determine patient outcome.

AIMS: Patients with idiopathic pulmonary fibrosis (IPF) receiving antifibrotic medication and patients with non-IPF fibrosing lung disease often demonstrate rates of annualised forced vital capacity (FVC) decline within the range of measurement variation (5.0%-9.9%). We examined whether change in visual CT variables could help confirm whether marginal FVC declines represented genuine clinical deterioration rather than measurement noise. METHODS: In two IPF cohorts (cohort 1: n=103, cohort 2: n=108), separate pairs of radiologists scored paired volumetric CTs (acquired between 6 and 24 months from baseline). Change in interstitial lung disease, honeycombing, reticulation, ground-glass opacity extents and traction bronchiectasis severity was evaluated using a 5-point scale, with mortality prediction analysed using univariable and multivariable Cox regression analyses. Both IPF populations were then combined to determine whether change in CT variables could predict mortality in patients with marginal FVC declines. RESULTS: On univariate analysis, change in all CT variables except ground-glass opacity predicted mortality in both cohorts. On multivariate analysis adjusted for patient age, gender, antifibrotic use and baseline disease severity (diffusing capacity for carbon monoxide), change in traction bronchiectasis severity predicted mortality independent of FVC decline. Change in traction bronchiectasis severity demonstrated good interobserver agreement among both scorer pairs. Across all study patients with marginal FVC declines, change in traction bronchiectasis severity independently predicted mortality and identified more patients with deterioration than change in honeycombing extent. CONCLUSIONS: Change in traction bronchiectasis severity is a measure of disease progression that could be used to help resolve the clinical importance of marginal FVC declines.

Pharmacogenetics of antitumor necrosis factor therapy in severe sarcoidosis.

PURPOSE OF REVIEW: Antitumor necrosis factor (TNF) treatment is an effective third-line treatment option in severe sarcoidosis. But not all patients respond to treatment. Pharmacogenetics studies the influence of genetic variations on treatment response. RECENT FINDINGS: In sarcoidosis, only one study reported on a relationship between genetic variation in TNF and response to anti-TNF therapy. In immune-mediated inflammatory diseases (IMIDs) other than sarcoidosis, several genetic variants were associated with response to anti-TNF therapy. Genes related to TNF, the target of this group of drugs, and the pathway by which TNF exerts its effect, TNF receptor, were studied most extensively. Recent findings related genetic variations in the human leukocyte antigen region to development of antidrug antibodies.We also included new original data on genetic variations and response to anti-TNF therapy in severe sarcoidosis. We found that TNFRSF1A rs1800693 AA genotype, TNFRSF1B 196T and absence of HLA-DRB103 associate with better response after infliximab treatment in severe sarcoidosis. SUMMARY: Data on pharmacogenetics of anti-TNF therapy in severe sarcoidosis are scarce. Findings in other IMIDs indicate there may be a role for pharmacogenetics in predicting response and adverse events in anti-TNF therapy, also in sarcoidosis. Future studies are needed to evaluate pharmacogenetics as a predicting marker in anti-TNF therapy in sarcoidosis.

ABCA3 mutations in adult pulmonary fibrosis patients: a case series and review of literature.

PURPOSE OF REVIEW: The current review aims to recognize the variability in clinical presentation of adult patients with bi-allelic ABCA3 mutations, create more depth in ABCA3 mutations reported and highlight the influence of environmental factors on disease course. RECENT FINDINGS: Mutations in ABCA3 are predominantly linked to neonatal and pediatric interstitial lung disease (ILD) with a minority surviving beyond puberty. Here, we present three patients with ABCA3 mutations who present with disease at the age of 19, 61 and 77. Moreover, we identified c.4451G>C (p.R1484P), c.1675G>A (p.G559R) and c.4745C>G (p.T1582S) as three novel ABCA3 mutations. In addition, we identified six additional patients with ABCA3 mutations in literature who reached an age above 18. Furthermore, we discuss the influence of infections, drugs and smoking on disease course. SUMMARY: Although extremely rare, patients with bi-allelic mutations in ABCA3 may present at adulthood. Late onset of disease may be influenced by type of mutation or environmental factors.