Severe Interstitial Lung Disease Research Articles

The Gut Microbial Metabolite Trimethylamine N-Oxide is Linked to Specific Complications of Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare immune-mediated connective tissue disease characterized by fibrosis of the skin and internal organs, whose pathogenesis is not fully understood. Recent studies have revealed dysbiosis in patients with systemic sclerosis and have indicated the possible role of the microbiota and its metabolites in the pathogenesis of the disease. Trimethylamine N-oxide (TMAO) is a compound produced by dysbiotic microbiota observed at higher concentrations in several autoimmune diseases. To determine concentrations of the bacteria-derived metabolite TMAO in patients with systemic sclerosis and to assess possible correlation between TMAO and a specific manifestation of the disease. The study included 63 patients with SSc and 47 matched control subjects. The concentration of TMAO was measured with high-performance liquid chromatography. Plasma TMAO level was significantly increased in patients with SSc (283.0 [188.5-367.5] ng/mL versus 205.5 [101.0-318.0] ng/mL; p < 0.01). An increased concentration of TMAO was observed in patients with concomitant interstitial lung disease (ILD) (302.0 ng/mL [212.0-385.5] ng/mL versus 204.0 [135.5-292.0] ng/mL; p < 0.01) and esophageal dysmotility (289.75 [213.75-387.5] ng/mL versus 209.5 ng/mL [141.5-315.0] ng/mL; p < 0.05) compared to patients without these complications. Furthermore, TMAO concentration exhibited significant correlation with markers of heart involvement (left ventricle ejection fraction, NT-proBNP), marker of ILD severity and Scleroderma Clinical Trials Consortium Damage Index. The concentration of TMAO, gut microbiota-associated metabolite, is increased in systemic sclerosis, particularly in patients with advanced organ involvement. This is the first study evaluating plasma TMAO in systemic sclerosis. Bacterial metabolites may be a link between dysbiosis and organ involvement in the course of the disease. Modulation of gut bacterial-derived metabolites may represent a new therapeutic approach in the management of systemic sclerosis.

Quantifying Functional Impairment of ABCA3 Variants Associated with Interstitial Lung Disease.

ATP-binding cassette subfamily A member 3 (ABCA3) is a lipid transporter within alveolar type II cells. Patients with bi-allelic variants in ABCA3 may suffer from a variable severity of interstitial lung disease. We characterized and quantified ABCA3 variants' overall lipid transport function by assessing the in vitro impairment of its intracellular trafficking and pumping activity. We expressed the results relative to the wild type, integrated the quantitative readouts from eight different assays and used newly generated data combined with previous results to correlate the variants' function and clinical phenotype. We differentiated normal (within 1 normalized standard deviation (nSD) of the wild-type mean), impaired (within 1 to 3 nSD) and defective (beyond 3 nSD) variants. The transport of phosphatidylcholine from the recycling pathway into ABCA3+ vesicles proved sensitive to the variants' dysfunction. The sum of the quantitated trafficking and pumping predicted a clinical outcome. More than an approximately 50% loss of function was associated with considerable morbidity and mortality. The in vitro quantification of ABCA3 function enables detailed variant characterization, substantially improves the phenotype prediction of genetic variants and possibly supports future treatment decisions.

NKX2.1 mutation revealed by a lymphoid interstitial pneumonia in an adult with rheumatoid arthritis.

This is the first case of a 37-year-old female patient carrier of a heterozygous NKX2.1 mutation associated with RA-ILD with a histological pattern of LIP. This case illustrates the wide panel of ILD subtypes associated with NKX2.1 mutations. https://bit.ly/3F49OTS.

A novel corpus of molecular to higher-order events that facilitates the understanding of the pathogenic mechanisms of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive chronic fibrosing interstitial lung disease with causes that have remained unclear to date. Development of effective treatments will require elucidation of the detailed pathogenetic mechanisms of IPF at both the molecular and cellular levels. With a biomedical corpus that includes IPF-related entities and events, text-mining systems can efficiently extract such mechanism-related information from huge amounts of literature on the disease. A novel corpus consisting of 150 abstracts with 9297 entities intended for training a text-mining system was constructed to clarify IPF-related pathogenetic mechanisms. For this corpus, entity information was annotated, as were relation and event information. To construct IPF-related networks, we also conducted entity normalization with IDs assigned to entities. Thereby, we extracted the same entities, which are expressed differently. Moreover, IPF-related events have been defined in this corpus, in contrast to existing corpora. This corpus will be useful to extract IPF-related information from scientific texts. Because many entities and events are related to lung diseases, this freely available corpus can also be used to extract information related to other lung diseases such as lung cancer and interstitial pneumonia caused by COVID-19.

Abstract 2660: HMBD-501 - a novel Fc engineered, exatecan-based next generation HER3 targeting antibody drug conjugate shows robust efficacy and tolerability in pre-clinical solid tumor models

Abstract HER3 is a member of the epidermal growth factor receptor (ERBB) family of tyrosine kinase receptors overexpressed in a broad range of tumors and is associated with disease progression and poor survival. For example, more than 50% of melanoma, cervical, lung, gastric, colorectal, and ovarian cancers show overexpression of HER3, while in breast, pancreatic and prostate cancers the overexpression ranges between 25-40%. In addition, recent studies show that HER3 expression is significantly induced in tumors during metastasis (in colorectal) and during acquired resistance to tyrosine kinase inhibitors (TKI) in lung cancers. This widespread overexpression of HER3 makes it an ideal target for antibody drug conjugates (ADCs). ADCs are a therapeutic modality that harness an antibody’s target specificity to selectively deliver cytotoxic payloads to tumors. Patritumab-Deruxtecan (U3-1402), a HER3-targeting ADC, showed clinical response in a subset of EGFR mutant and TKI resistant lung cancers in a Phase 1 study, albeit with toxicities including severe interstitial lung disease (ILD) and high grade cytopenias. Mechanistic studies show that these ADC-related toxicities are likely driven by Fc- or micropinocytosis-mediated uptake of ADCs by normal cells. We have developed HMBD-501, a novel anti-HER3 ADC with (i) a high-affinity Fab, which can bind to HER3 in the presence or absence of its ligand NRG1, (ii) an engineered Fc-domain to avoid FcgR binding and potential toxicities, and (iii) site-specific conjugation to a next generation cleavable linker and exatecan-based payload. In our preclinical studies, HMBD-501 demonstrates superior inhibition of tumor growth compared to other exatecan-based anti-HER3 ADCs, in a variety of in vitro and in vivo cancer models with a range of HER3 expression. Additionally, the optimized Fc engineering of HMBD-501 shows enhanced tolerability in vivo indicating a potential reduction in Fc mediated toxicities. Finally, the next generation site-specific conjugation-linker-payload technology of HMBD-501 allows optimal plasma stability and pharmacokinetic profile. In conclusion, HMBD-501 represents a next generation HER3 targeting ADC that has a potentially best-in-class efficacy and tolerability profile. Our findings strongly support the development of HMBD-501 as a promising candidate in the treatment of HER3 expressing solid tumors. Citation Format: Suhail Ahmed Kabeer Rasheed, Dipti Thakkar, Shalini Paliwal, Wen Jie Chin, Akshaya Bansal, Ben Ayers, Che Theng ng, Brendon Hanson, Piers Ingram, Jerome Boyd-Kirkup. HMBD-501 - a novel Fc engineered, exatecan-based next generation HER3 targeting antibody drug conjugate shows robust efficacy and tolerability in pre-clinical solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2660.

The relationship between perceived and performance fatigability in severe fibrotic interstitial lung disease: a prospective, cross-sectional study.

This study suggests that interventions geared to improve peripheral factors of performance fatigability during exercise in interstitial lung disease may prove valuable to decrease patients' perceived fatigability, since both seem closely related https://bit.ly/3lpIUPs.

Pregnancy Outcomes in Patients With Interstitial Lung Disease.

Women with interstitial lung disease (ILD) are recommended to avoid pregnancy based on limited data. This study seeks to determine maternal and pregnancy outcomes in the largest-to-date cohort of patients with ILD. Medical records in the Duke University Health System were reviewed for pregnancies in patients with a diagnosis of ILD with underlying autoimmune disease. Pregnancies were classified as having very severe, severe, mild-moderate, or normal lung function based on pulmonary function tests (PFTs). Adverse pregnancy outcomes (APOs) were defined using the Predictors of Pregnancy Outcome in Systemic Lupus Erythematosus and Antiphospholipid Syndrome APO (PROMISSE-APO) and Severe PROMISSE-APO criteria. Among 86 pregnancies in 60 women, 85% women were Black, 71% had sarcoidosis, and 29% had connective tissue disease (CTD)-associated ILD (CTD-ILD). Of the pregnancies with available PFTs (n = 59), 12% had very severe ILD, 25% had severe ILD, 51% had mild-moderate ILD, and 12% had normal lung function. PROMISSE-APOs occurred in 32% of pregnancies, including all pregnancies with very severe ILD (P= 0.02 across severity groups), 56% of pregnancies with CTD-ILD, and 23% with sarcoidosis (P= 0.02). Severe PROMISSE-APOs occurred in 15% of pregnancies, including 60% with very severe ILD and 28% with CTD-ILD. There were no maternal deaths. One woman required an intensive care hospital stay during pregnancy. Three women had volume overload after delivery that resolved with medical management. Seven women received oxygen during delivery, although none were intubated. Although APOs were common in women with very severe ILD and underlying CTD, overall maternal morbidity and mortality were low. These data suggest women with ILD may be able to safely attempt pregnancy.

Abstract P1-11-13: DE-REAL: ITALIAN MULTICENTER EXPERIENCE OF TRASTUZUMAB DERUXTECAN IN A REAL WORLD SETTING

Abstract INTRODUCTION: Trastuzumab Deruxtecan (TDxd) is an innovative antibody drug conjugate (ADC) comprising an anti-HER2 antibody, a cleavable tetrapeptide-based linker and a potent topoisomerase I inhibitor. TDxd has demonstrated promising clinical efficacy in previously treated HER2-positive metastatic breast cancer patients (pts). Drug-drug interactions (DDIs) can influence drug activity and potentially affect treatment efficacy or determine increased toxicity. Drug-PIN® (Personalized Interactions Network) is a tool able to identify interactions between drugs and combine them with demographic, clinical and biochemical patient data. In this multicentric retrospective study, we aim to describe clinical outcomes, toxicities and drug-drug interactions (DDIs) of TDxd in a real-world population. METHODS: Pts with histological and radiological confirmed HER2+ mBC (defined as HER2 3+ or HER2 2+ with an amplification detected in SISH/FISH) who received TDxd were included in the study. The availability of complete data about clinical outcomes, toxicities and concurrent medications was needed. Pts who received at least one month of treatment were eligible. Radiological response and toxicities were evaluated following RECIST 1.1 and CTCAE v5 criteria. Drug-PIN® was used to define DDis, Drug-PIN® score and Drug-PIN® tier (green for no significant DDis and yellow, dark yellow, orange, red for increasing DDIs) for each pts. Clinical and pathological features were collected from the referral hospital in an anonymous database and analyzed with R-package. Univariate analysis was conducted calculating the AUC of ROC or the PFS using the Kaplan and Meier curves and log- rank test as appropriate. Multivariate analysis was conducted using logistic or Cox proportional hazard regression model as appropriate. RESULTS: One hundred forty-three pts were enrolled from 11 Italian oncological hospitals. Median age was 56 years (33-84). Estrogen receptor (HR) status was positive in 108 (75%) pts and negative in 35 (25%) pts. TDxd was administered as the first, second, third or subsequent line in 4 (3%), 17 (12%), 41 (29%) and 81 (56%) pts, respectively, with an average of 4 treatments received (range 1-11). Among 114 pts with measurable disease, the ORR was 68% (6% of complete response). Eight (7%) pts had a primary resistance to TDxd. Median PFS was not reached and the milestone-1 year PFS was 56.7% in the overall population. PFS at 12 months was 100% vs 54.1 % in pts receiving upfront or second versus subsequent lines (p=0.094). A toxicity of any grade was registered in 80 pts (56%). Most common toxicities were nausea (43, 30%), neutropenia (28, 19%) and asthenia (19, 13%). Severe tox was reported in 21 (15%) pts. Most common severe tox were neutropenia, nausea/vomiting and interstitial lung disease (ILD) observed in 14, 2 and 2 pts, respectively. Concomitant medications were taken by 63 pts, with 8 pts receiving more than 5 drugs. Among pts taking any medications, median Drug-PIN® score was 6.3 (range 1.7-190). 127, 11, 3 and 2 pts were in the green, yellow, dark yellow and red Drug-PIN® tier, respectively. Sixteen pts (11%) had a relevant DDI. The median PFS was not reached vs 12 months in pts with green Drug-PIN® tier compared to yellow or more, however the difference did not reach statistical significance and a longer follow up is needed. Asthenia of any grade was associated with an elevated Drug-PIN® score (AUC 0,681; P= 0.011). Severe ILD was reported in 2/16 pts with DDIs while no cases (0/124) occurred in pts with no DDIs (threshold Drug-PIN® score: 19.4/Drug-PIN® tier: &amp;gt;yellow, P=0.0061). CONCLUSIONS: TDxd demonstrated to be effective and safe in our unselected real world population, even in heavily pretreated pts. No new safety concerns were reported. DDIs seems to be associated with specific toxicities such as asthenia and ILD. Citation Format: Andrea Botticelli, Simone Scagnoli, Simona Pisegna, Daniele Santini, Antonella Palazzo, Roberta Scafetta, Luigi Rossi, Michelino de Laurentiis, Roberta Caputo, Annarita Verrazzo, Rossana Berardi, Vittoria Barberi, Domenico Bilancia, Giuliana D’auria, Daniele Alesini, Michela Palleschi, Agnese Fabbri, Lidia Strigari, Robert Preissner, Paolo Marchetti, Alessandra Fabi. DE-REAL: ITALIAN MULTICENTER EXPERIENCE OF TRASTUZUMAB DERUXTECAN IN A REAL WORLD SETTING [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-13.

Serum Rcn3 level is a potential diagnostic biomarker for connective tissue disease-associated interstitial lung disease and reflects the severity of pulmonary function

BackgroundAlthough reticulocalbin 3 (Rcn3) has a critical role in alveolar epithelial function as well as in pathogenesis of pulmonary fibrosis, no study has yet examined its diagnostic and prognostic values for interstitial lung disease (ILD). This study aimed to evaluate Rcn3 as a potential marker in differential diagnosis of idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated interstitial lung disease (CTD-ILD) and in reflecting the severity of disease.MethodsThis was a retrospective observational pilot study included 71 ILD patients and 39 healthy controls. These patients were stratified into IPF group (39) and CTD-ILD group (32). The severity of ILD was evaluated through pulmonary function test.ResultsSerum Rcn3 level was statistically higher in CTD-ILD patients than that in IPF patients (p = 0.017) and healthy controls (p = 0.010). Serum Rcn3 further showed statistically negative correlation with pulmonary function indexes (TLC% pred and DLCO% pred) and positive correlation with inflammatory indexes (CRP and ESR) (r = − 0.367, p = 0.039; r = − 0.370, p = 0.037; r = 0.355, p = 0.046; r = 0.392, p = 0.026, respectively) in CTD-ILD patients rather than IPF patients. ROC analysis demonstrated that serum Rcn3 had superior diagnostic value for CTD-ILD and a cutoff value of 2.73 ng/mL had a sensitivity of 69%, a specificity of 69% and an accuracy of 45% for diagnose of CTD-ILD.ConclusionsSerum Rcn3 levels might be a clinically useful biomarker in screening and evaluating CTD-ILD.

Human epididymis protein 4 as a clinical biomarker in identifying interstitial lung disease in patients with idiopathic inflammatory myopathies.

Human epididymis protein 4 (HE4) can differentiate interstitial lung disease from patients with some rheumatic diseases. However, the clinical utility of HE4 in idiopathic inflammatory myopathies (IIM) remains unclear. 80 IIM patients and 91 age and gender-matched healthy controls (HCs) were recruited. Clinical and laboratory data were recorded at baseline and 12weeks. HE4 was tested by the method of electrochemical luminescence. Compared to HCs, the levels of HE4 significantly elevated in IIM patients. Patients with elevated HE4 had a higher interstitial lung disease (ILD) prevalence. Among patients with ILD, histological patterns of organizing pneumonia had higher HE4 levels than non-specific interstitial pneumonia. Further, there was a positive correlation between HE4 and the semi-quantitative CT grade (r=0.778, p<0.001) and a negative relation between HE4 and the percentage of forced vital capacity (p<0.001) and diffusing capacity of the lung for carbon monoxide (DLco) (p=0.001). An optimal cut-off value of HE4 (79.6pmol/L) for distinguishing IIM-ILD was analyzed by ROC analysis with an AUC of 0.733 (p=0.002). Regression analysis revealed that elevated HE4 independently identified IIM-related ILD (OR 34.8, 95%CI, 3.58-338.14, p=0.002). With the improvement after treatment, serum HE4 levels were significantly decreased (p=0.006), accompanied by improved DLco% (p=0.012). Serum HE4 was significantly elevated in patients with IIM and may be utilized as a serum biomarker to evaluate the disease severity and prognosis of IIM-related ILD.

Endothelin-1 as a Biomarker of Idiopathic Pulmonary Fibrosis and Interstitial Lung Disease Associated with Autoimmune Diseases.

The aim of this study was to determine the role of endothelin-1 (ET-1), a molecule involved in multiple vascular and fibrosing abnormalities, as a biomarker of interstitial lung disease (ILD), as well as its use for the differential diagnosis between idiopathic pulmonary fibrosis (IPF) and ILD associated with autoimmune diseases (AD-ILD), using a large and well-defined cohort of patients with ILD. A total of 112 patients with IPF, 91 patients with AD-ILD (28 rheumatoid arthritis (RA), 26 systemic sclerosis, 20 idiopathic inflammatory myositis and 17 interstitial pneumonia with autoimmune features) and 44 healthy controls were included. ET-1 serum levels were determined by enzyme-linked immunosorbent assay. A significant increase in ET-1 levels was found in patients with IPF compared to controls. Likewise, AD-ILD patients also showed higher ET-1 levels than controls when the whole cohort was stratified by the type of AD. Similar ET-1 levels were found in IPF and AD-ILD patients, regardless of the underlying AD. Interestingly, increased ET-1 levels were correlated with worse lung function in IPF and RA-ILD patients. Our study supports that serum ET-1 may be useful as a biomarker of ILD, although it could not help in the differential diagnosis between IPF and AD-ILD. Moreover, ET-1 levels may be associated with ILD severity.

Genomic Fingerprint Associated with Familial Idiopathic Pulmonary Fibrosis: A Review.

Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease; although the recent introduction of two anti-fibrosis drugs, pirfenidone and Nidanib, have resulted in a significant reduction in lung function decline, IPF is still not curable. Approximately 2-20% of patients with IPF have a family history of the disease, which is considered the strongest risk factor for idiopathic interstitial pneumonia. However, the genetic predispositions of familial IPF (f-IPF), a particular type of IPF, remain largely unknown. Genetics affect the susceptibility and progression of f-IPF. Genomic markers are increasingly being recognized for their contribution to disease prognosis and drug therapy outcomes. Existing data suggest that genomics may help identify individuals at risk for f-IPF, accurately classify patients, elucidate key pathways involved in disease pathogenesis, and ultimately develop more effective targeted therapies. Since several genetic variants associated with the disease have been found in f-IPF, this review systematically summarizes the latest progress in the gene spectrum of the f-IPF population and the underlying mechanisms of f-IPF. The genetic susceptibility variation related to the disease phenotype is also illustrated. This review aims to improve the understanding of the IPF pathogenesis and facilitate his early detection.

Role of computed tomography findings, complete blood count parameters and systemic inflammatory markers for predicting the severity in interstitial lung diseases.

The present study aimed to find quantitative and semiquantitative methods to detect the development of fibroproliferative processes at an early stage and predict the severity and prognosis of the disease in interstitial lung diseases (ILDs) using High-Resolution Computed Tomography (HRCT), Pulmonary Function Tests (PFTs) and Complete Blood Count (CBC) parameters. A total of 63 patients (26 female and 37 male) who were admitted to our hospital between January 2014 and January 2018, whose follow-ups were regular and who underwent HRCT, PFT, and CBC examinations on the same day, were included in our study. The median age of the patients included was 65 years (range: 47-79). There were significant differences among the mild, moderate, and severe form ILD groups created using the Warrick scoring system for NLR, neutrophil count, and PNR values (p = 0.025, 0.035, 0.006, respectively). Also, there were significant differences among the groups for FVC, FEV1/FVC, PAD, RAA, RV/LV ratio, MLnMD, and MLnC values. Correlation analyses between the parameters revealed significant relationships between Warrick Score, and NLR and neutrophil count, PNR, FVC, FEV1/FVC, PAD, RAA, RV/LV ratio, MLnMD, and MLnC . The results of the present study suggested that NLR, neutrophil count, and PNR values could be used as objective evaluation criteria to determine the severity and prognosis in interstitial lung diseases. Also, usage of Warrick Score, FVC, FEV1/FVC, PAD, RAA, RV/LV ratio, MLnMD, and MLnC values could provide quantitative and semiquantitative data for an objective evaluation. Carrying out multicenter studies and creating a scoring system using these parameters could create standardization in determining the prognosis of patients with ILD.

Clinical Images: Severe interstitial lung disease in Sjögren disease - What happens in the lungs? Inflammation or fibrosis?

Clinical Images: Severe interstitial lung disease in Sjögren disease - What happens in the lungs? Inflammation or fibrosis?

Retrospective analysis and a cross-sectional questionnaire survey of lung cancer concomitant with interstitial lung disease

Objective: To describe the clinical characteristics and prognosis of lung cancer concomitant with interstitial lung disease (LC-ILD), and to understand the current status of knowledge of LC-ILD by physicians in the departments related to the treatment of the disease. Methods: We conducted a retrospective analysis of in-hospitalized pathology identified lung cancer (LC) patients who were admitted to our hospital between January 2014 and December 2018. After reviewing their chest CT imagings and pathological reports, 70 patients who were concomitant with interstitial lung disease (ILD) were enrolled in our study. On the other hand, a cross-sectional survey using an online questionnaire was conducted in LC-ILD management doctors who came from 29 provincial hospitals. The perceptions of demographic features, LC characteristics and management, ILD characteristics and management, and the prognosis of LC-ILD were investigated. Results: Among the 70 enrolled LC-ILD cases, there were 52 males, and the mean age was (64.3±7.63) years (ranged from 49 years to 84 years). There were 51 patients who were older than 59 years. The most common pathological pattern of LC was adenocarcinoma. Most of them were diagnosed with LC and ILD simultaneously, and they were usually treated with chemotherapy while unresectable. There were 11 patients (15.7%) with positive EGFR or ALK mutation. Forty-five patients (64.3%) died during the follow-up, and 33 were died from LC progression. There were no significant differences between the surgical group and non-surgical group on age, pathological patterns, EGFR or ALK mutation. However, LC-ILD patients in the surgical group were diagnosed with earlier TNM classification and with better prognosis. A total of 1 014 doctors answered the questionnaire completely. In the feedback, patients aged 60 years and older (785 doctors/77.4%), and male patients (720 doctors/71%) were the predominant LC-ILD patients. Adenocarcinoma (390 doctors/38.5%), adenocarcinoma or squamous-cell cancer (SCC) (182 doctors/17.9%), and SCC (151 doctors/14.9%) were considered as the common pathological patterns of LC-ILD patients. In most doctors' feedback, the EGFR or ALK mutation was not common for LC-ILD: low (646 doctors/63.7%) or hardly (306 doctors/30.5%) positive mutation. The diagnosis of ILD was earlier than LC (506 doctors/49.9%) or there was no identified precedence of LC and ILD diagnosis (208 doctors/20.5%). Most of the doctors (693 doctors/68.3%) agreed that the vital factor for surgery or not was the severity of ILD for LC-ILD patients. There were great divergences on the treatment protocol both for the advanced LC and ILD. The patients with LC-ILD were died mostly from LC progression and ILD exacerbation (542 doctors/53.5%), followed by ILD exacerbation (237 doctors/23.4%) or LC progression (226 doctors/22.3%). Conclusions: The elderly male patients were predisposed to LC-ILD, and adenocarcinoma was the common pathological pattern. The LC-ILD patients with non-advanced LC who were performed with surgery had better prognosis. However, it is recommended to consider whether to perform surgery in combination with the severity of the ILD.

Beneficial effects of nintedanib on cardiomyopathy in patients with systemic sclerosis: a pilot study.

Nintedanib is an inhibitor of tyrosine kinases that has been shown to slow the progression of interstitial lung disease (ILD), including ILD associated with SSc. The aim of this study was to explore the effect of nintedanib on cardiomyopathy associated with systemic sclerosis (SSc). Twenty consecutively hospitalized patients with SSc-ILD were enrolled and prospectively followed. The rate of change at 6 months in cardiac magnetic resonance (CMR) parametric mapping, including myocardial extracellular volume, was primarily evaluated. Other endpoints included changes in CMR functional parameters, echocardiographic parameters, modified Rodnan skin score, serum biomarkers and pulmonary function test. Nintedanib was administered in 10 patients, whereas the other 10 were treated without nintedanib or watched, according to ILD severity and progression. Baseline values of CMR parametric mapping were not different between the two groups. The rate of change at 6 months in myocardial extracellular volume was highly different, almost divergent, between the nintedanib group and the control group (-1.62% vs +2.00%, P = 0.0001). Among other endpoints, the change in right ventricular ejection fraction was significantly different between the two groups (P = 0.02), with a preferential change in the nintedanib group. Our data indicate beneficial signals of nintedanib on cardiomyopathy associated with SSc. The anti-fibrotic effect of nintedanib might not be limited to the lung.

Assessment of idiopathic inflammatory myopathy using a deep learning method for muscle T2 mapping segmentation

ObjectiveTo investigate the utility of an automatic deep learning (DL) method for segmentation of T2 maps in patients with idiopathic inflammatory myopathy (IIM) against healthy controls, and also the association of quantitative T2 values in patients with laboratory and pulmonary findings.MethodsStructural MRI and T2 mapping of bilateral thigh muscles from patients with IIM and healthy volunteers were segmented using dedicated software based on a pre-trained convolutional neural network. Incremental and federated learning were implemented for continuous adaptation and improvement. Muscle T2 values derived from DL segmentation were compared between patients and healthy controls, and T2 values of patients were further analyzed with serum muscle enzymes, and interstitial lung disease (ILD) which was diagnosed and graded based on chest HRCT.ResultsOverall, 64 patients (27 patients with dermatomyositis, 29 with polymyositis, and 8 with antisynthetase syndrome (ASS)) and 10 healthy controls were included. By using DL-based muscle segmentation, T2 values generated from T2 maps accurately differentiated patients from those of controls (p < 0.001) with a cutoff value of 36.4 ms (sensitivity 96.9%, and specificity 100%). In patients with IIM, muscle T2 values positively correlated with all the serum muscle enzymes (all p < 0.05). ILD score of patients with ASS was markedly higher than that of those without ASS (p = 0.011), while dissociation between the severity of muscular involvement and ILD was observed (p = 0.080).ConclusionAutomatic DL could be used to segment thigh muscles and help quantitatively assess muscular inflammation of IIM through T2 mapping.Key Points• Muscle T2 mapping automatically segmented by deep learning can differentiate IIM from healthy controls.• T2 value, an indicator of active muscle inflammation, positively correlates with serum muscle enzymes.• T2 mapping can detect muscle disease in patients with normal muscle enzyme levels.

Methotrexate, leflunomide and tacrolimus use and the progression of rheumatoid arthritis-associated interstitial lung disease.

To examine the association between MTX, LEF and tacrolimus use and the progression of RA-associated interstitial lung disease (ILD). The Korean RA-ILD cohort prospectively enrolled patients with RA-associated ILD at multiple centres from 2015 to 2018 and followed up with them for 3 years. ILD progression was defined by any of the followings: a decrease of ≥10% in forced vital capacity, a decrease of ≥15% in the diffusing capacity of the lung for carbon monoxide, or death from respiratory failure. Of 143 patients, 64 patients experienced ILD progression during a median follow-up period of 33 months. The use of MTX [adjusted hazard ratio (aHR), 1.06; 95% CI, 0.59, 1.89], LEF (aHR, 1.75; 95% CI, 0.88, 3.46) and tacrolimus (aHR, 0.94; 95% CI, 0.52, 1.72) did not increase the risk of ILD progression. However, the association between LEF use and the risk of ILD progression was significant in subgroups with poor lung function (aHR, 8.42; 95% CI, 2.61, 27.15). Older age, male sex, a shorter RA duration, higher RA disease activity and extensive disease at baseline were independently associated with ILD progression. None of the three treatments increased the risk of RA-associated ILD progression, except for LEF, which increased the risk of ILD progression in patients with severe ILD. The appropriate use of conventional synthetic disease-modifying antirheumatic drugs considering RA disease activity and ILD severity would be important for the management of RA-associated ILD.

Autologous Stem Cell Transplantation (ASCT) for Refractory Juvenile-Onset Systemic Sclerosis (jSSc) Is Safe and Well Tolerated and Improves Clinical and Patient-Reported Outcomes

Introduction: jSSc is a rare autoimmune disease that leads to inflammation, fibrosis, and dysfunction of multiple organ systems which can cause skin sclerosis, interstitial lung disease (ILD), myositis, fasciitis, gastrointestinal and vascular disease. Severe SSc is often refractory to immunomodulatory medications including newer targeted agents. ASCT has demonstrated success in adults with SSc, but experience and data in pediatric patients is limited. Methods: We report our first four consecutive adolescent and young adult ASCT patients. All patients were referred to our scleroderma center at UPMC Children's Hospital of Pittsburgh where they were evaluated by our multidisciplinary team. Baseline patient characteristics are summarized in Table 1. Patients met criteria for ASCT by severity of lung or skin disease, or both. The first 3 patients had severe ILD or musculoskeletal chest wall weakness resulting in pulmonary function tests (PFTs) below traditional cut offs for adult SSc ASCT trials. All four patients had refractory disease and had previously received 3-8 immunomodulatory medications. Autologous stem cells were mobilized with cyclophosphamide and filgrastim and collected via pheresis. Following this, conditioning chemoradiation was administered per an IRB-approved individual treatment plan (Patients 1-3) or on our clinical trial NCT03630211 (Patient 4) with rituximab, anti-thymocyte globulin (ATG), TBI 600 cGy with lung and kidney shielding, and cyclophosphamide or thiotepa +/- alemtuzumab. A CD34+ selected cryopreserved autologous peripheral blood stem cell graft was infused on day 0. Antimicrobial prophylaxis was given per institutional standard and PCRs for EBV, CMV and adenovirus were closely monitored. Steroids were weaned off by 5 weeks post-ASCT. Results: The median cell dose was 5.9 e6 CD34/kg. All patients engrafted, with median neutrophil engraftment on day 11 (range 11-15), and median platelet engraftment (>50K) on day 18.5 (range 16-20). There were infusion-related side effects with equine ATG, but none with rabbit ATG. There were no cases of sinusoidal obstructive syndrome, thrombotic microangiopathy or clinically significant bleeding. No patients required a PCA for pain and received minimal (median=3) doses of narcotics. Patients were discharged from the hospital a median of 19 days after transplant (range 17-21). Only one patient was readmitted, and had a negative 48 hour infectious rule out. Two patients acquired COVID-19 infections at 5 and 19.5 months post-ASCT; both remained outpatient with quick improvement after treatment with best available therapy. There were no viral reactivations, bacterial or fungal infections. There has been no evidence of organ toxicity and there are objective improvements in clinical parameters as well as patient reported outcomes (PROs) over the follow-up visits (Table 2). All patients demonstrated an improvement in their skin involvement, as measured by the modified Rodnan Skin Score (mRSS). There was an improvement in clinical symptoms and exam findings of Raynaud's. The lower esophageal sphincter became less hypotensive; objective measures and symptoms of gastroesophageal reflux were much improved. Despite severely reduced values of forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) prior to ASCT, all subjects regained pre-ASCT values. All patients demonstrated an improvement in their PROs and report improvement in fatigue, pain, and the ability to participate in activities of daily living. All patients are off immunomodulatory medications. Tandem serial skin biopsies of the forearm support decreased collagen burden and disappearance of a myofibroblasts population with single cell RNA sequencing (n=3, timepoints 0, 6, 12 mos; data not shown), which correlates with an improvement in the skin score. Conclusions: In refractory jSSc patients, ASCT is well tolerated, even in patients with severe disease who would otherwise not be eligible for clinical trials based on exclusion criteria that were developed for adults with SSc. ASCT can serve as a hard reset to the immune system for patients with this refractory autoimmune disease, with improvements in clinical parameters that reflect disease modification involving the skin, musculoskeletal, vascular, and gastrointestinal systems. Further clinical research treating patients with this rare disease is of great need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial

Rituximab is often used as rescue therapy in interstitial lung disease (ILD) associated with connective tissue disease (CTD), but has not been studied in clinical trials. This study aimed to assess whether rituximab is superior to cyclophosphamide as a treatment for severe or progressive CTD associated ILD. We conducted a randomised, double-blind, double-dummy, phase 2b trial to assess the superiority of rituximab compared with cyclophosphamide. Patients aged 18-80 years with severe or progressive ILD related to scleroderma, idiopathic inflammatory myositis, or mixed CTD, recruited across 11 specialist ILD or rheumatology centres in the UK, were randomly assigned (1:1) to receive rituximab (1000 mg at weeks 0 and 2 intravenously) or cyclophosphamide (600 mg/m2 body surface area every 4 weeks intravenously for six doses). The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks compared with baseline, analysed using a mixed-effects model with random intercepts, adjusted for baseline FVC and CTD type. Prespecified secondary endpoints reported in this Article were change in FVC at 48 weeks versus baseline; changes from baseline in 6 min walk distance, diffusing capacity of the lung for carbon monoxide (DLCO), physician-assessed global disease activity (GDA) score, and quality-of-life scores on the St George's Respiratory Questionnaire (SGRQ), King's Brief Interstitial Lung Disease (KBILD) questionnaire, and European Quality of Life Five-Dimension (EQ-5D) questionnaire at 24 and 48 weeks; overall survival, progression-free survival, and time to treatment failure; and corticosteroid use. All endpoints were analysed in the modified intention-to-treat population, which comprised all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT01862926). Between Dec 1, 2014, and March 31, 2020, we screened 145 participants, of whom 101 participants were randomly allocated: 50 (50%) to receive cyclophosphamide and 51 (50%) to receive rituximab. 48 (96%) participants in the cyclophosphamide group and 49 (96%) in the rituximab group received at least one dose of treatment and were included in analyses; 43 (86%) participants in the cyclophosphamide group and 42 (82%) participants in the rituximab group completed 24 weeks of treatment and follow-up. At 24 weeks, FVC was improved from baseline in both the cyclophosphamide group (unadjusted mean increase 99 mL [SD 329]) and the rituximab group (97 mL [234]); in the adjusted mixed-effects model, the difference in the primary endpoint at 24 weeks was -40 mL (95% CI -153 to 74; p=0·49) between the rituximab group and the cyclophosphamide group. KBILD quality-of-life scores were improved at 24 weeks by a mean 9·4 points (SD 20·8) in the cyclophosphamide group and 8·8 points (17·0) in the rituximab group. No significant differences in secondary endpoints were identified between the treatment groups, with the exception of change in GDA score at week 48, which favoured cyclophosphamide (difference 0·90 [95% CI 0·11 to 1·68]). Improvements in lung function and respiratory-related quality-of-life measures were observed in both treatment groups. Lower corticosteroid exposure over 48 weeks of follow-up was recorded in the rituximab group. Two (4%) of 48 participants who received cyclophosphamide and three (6%) of 49 who received rituximab died during the study, all due to complications of CTD or ILD. Overall survival, progression-free survival, and time to treatment failure did not significantly differ between the two groups. All participants reported at least one adverse event during the study. Numerically fewer adverse events were reported by participants receiving rituximab (445 events) than those receiving cyclophosphamide (646 events). Gastrointestinal and respiratory disorders were the most commonly reported adverse events in both groups. There were 62 serious adverse events of which 33 occurred in the cyclophosphamide group and 29 in the rituximab group. Rituximab was not superior to cyclophosphamide to treat patients with CTD-ILD, although participants in both treatment groups had increased FVC at 24 weeks, in addition to clinically important improvements in patient-reported quality of life. Rituximab was associated with fewer adverse events. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with CTD-ILD requiring intravenous therapy. Efficacy and Mechanism Evaluation Programme (Medical Research Council and National Institute for Health Research, UK).