scholarly journals Kinetic Changes in Serum KL-6 Levels Predict Disease Progression in Patients with Systemic Sclerosis-Associated Interstitial Lung Disease: A Retrospective Observational Study

2021 ◽  
Author(s):  
Satoshi Watanabe ◽  
Kazumasa Kase ◽  
Keigo Saeki ◽  
Noriyuki Ohkura ◽  
Akari Murata ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Disease Progression ◽  
Vital Capacity ◽  
Rapid Progression ◽  
Radiological Progression ◽  
Relative Decline ◽  
Predict Disease Progression

Abstract Background: The clinical course of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable. The Krebs von den Lungen-6 (KL-6) glycoprotein is a promising biomarker for reflectingepithelial injury. However, serum KL-6 and its association with the progression of SSc-ILD have been understudied. Methods: We reviewed 77 consecutive patients with SSc-ILD seen from 2004 to 2016. A longitudinal study of forced vital capacity (FVC), serum KL-6 levels, and the changes in KL-6 levels from baseline (ΔKL-6) was conducted. The progression of ILD was defined as ≥10% relative decline in FVC predicted or 5%–10% decline in FVC predicted along with radiological progression on chest computed tomography. The risk factors for ILD progression were assessed by univariate and multivariate regression.Results: The 77 study patients included 58 women (75%). The median age of the study patients was 56 years, and 59 (79%) patients had diffuse cutaneous SSc. During a 5-year follow-up period, 10 (13%) showed rapid progression of ILD within 2 years, 39 (51%) had overall progressionduring the 5 years, and 28 (36%) had stable disease. Most patients with progressive ILD showed elevationsin serum KL-6 levels over the initial 1-year follow-up period. The best cut-off value for ΔKL-6 that predicted progression of ILD was 193 U/mL (sensitivity 81.6%, specificity 92.9%). Multivariate analysis with adjustment revealed that diffuse cutaneous SSc(hazard ratio [HR] 3.1; 95% confidence interval [CI] 1.05-9.36]) and ΔKL-6 > 193 U/mL from baseline(HR, 4.7; 95% CI, 2.14-10.4)were independent predictors for progression of SSc-ILD.Conclusion: Changes in the KL-6 level can be useful for predicting disease progression in patients withSSc-ILD.

scholarly journals Natural history of systemic sclerosis–related interstitial lung disease: How to identify a progressive fibrosing phenotype

2019 ◽  
Vol 5 (2_suppl) ◽  
pp. 31-40 ◽  
Author(s):  
Elizabeth R Volkmann
Keyword(s):  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Lung Function ◽  
Natural History ◽  
Lung Disease ◽  
Disease Progression ◽  
Rapid Progression ◽  
History Of ◽  
Rate Of Decline ◽  
Patients Experience

The natural history of interstitial lung disease in patients with systemic sclerosis is highly variable. Historical observational studies have demonstrated that the greatest decline in lung function in systemic sclerosis occurs early in the course of the disease; however, not all patients experience a decline in lung function even in the absence of treatment. Furthermore, among patients who do experience a decline in lung function, the rate of decline can be either rapid or slow. The most common clinical phenotypes of systemic sclerosis–related interstitial lung disease are, therefore, as follows: (1) rapid progressors, (2) gradual progressors, (3) stabilizers, and (4) improvers. This review summarizes the features of systemic sclerosis–related interstitial lung disease patients who are more likely to experience rapid progression of interstitial lung disease, as well as those who are more likely not to experience interstitial lung disease progression. Understanding the clinical, biological, and radiographic factors that consistently predict interstitial lung disease–related outcomes in systemic sclerosis is central to our ability to recognize those patients who are at heightened risk for interstitial lung disease progression. With new options available for treating patients with systemic sclerosis–related interstitial lung disease, it is more important than ever to accurately identify patients who may derive the most benefit from aggressive systemic sclerosis–related interstitial lung disease therapy. Early therapeutic intervention in patients with this progressive fibrosing phenotype may ultimately improve morbidity and mortality outcomes in patients with systemic sclerosis–related interstitial lung disease.

scholarly journals OP0272 68GA-FAPI-04 PET/CT STUDY EXTENSION FOR THE ASSESSMENT OF FIBROBLAST ACTIVATION AND RISK EVALUATION IN SYSTEMIC SCLEROSIS-RELATED INTERSTITIAL LUNG DISEASE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 165.1-166
Author(s):  
C. Bergmann ◽  
J. H. W. Distler ◽  
C. Treutlein ◽  
K. Tascilar ◽  
A. T. Mueller ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Disease Progression ◽  
Forced Vital Capacity ◽  
Vital Capacity ◽  
Control Group ◽  
Research Support ◽  
Fibroblast Activation ◽  
Pet Ct

Background:Interstitial lung disease (ILD) is the most common cause of death in systemic sclerosis (SSc). To date, the progression of SSc-ILD is judged by the accrual of lung damage on computed tomography (CT) and functional decline (forced vital capacity). However, this approach does not directly assess the activity of tissue remodeling. Moreover, prediction of the course of ILD in individual SSc patients remains challenging. Fibroblast Activation Protein (FAP) is a specific, ex vivo validated marker for activated fibroblasts.Objectives:The aims of this study were: 1. To assess differences in the uptake of 68GA-FAPI 04 in SSc-ILD patients compared to controls, to analyze 2. whether 68GA-FAPI 04 uptake at baseline correlates with other risk factors of disease progression and 3. Whether 68GA-FAPI 04 uptake is associated with the course of SSc-ILD.Methods:Between September 2018 and April 2020, 21 patients with SSc-ILD confirmed by HRCT and onset of SSc-ILD within ≤ 5 years or signs of progressive ILD and 21 controls without ILD were consecutively enrolled. All participants underwent 68Ga-FAPI-04 PET/CT imaging and standard-of-care procedures including HRCT and lung function testing (PFT) at baseline. Patients with SSc-ILD patients were followed-up for 6 months with HRCT and PFT. Follow-up 68Ga-FAPI-04 PET/CT scans were obtained in a subset of patients treated with nintedanib. We compared baseline 68Ga-FAPI-04 PET/CT uptake to standard diagnostic tools and currently used predictors of ILD progression. The association of 68Ga-FAPI-04 uptake with changes in FVC was analyzed using mixed-effects models.Results:68Ga-FAPI-04 accumulated in fibrotic areas of the lungs in SSc-ILD compared to controls with a median (q1-q3 interval) wlSUVmean of 0.8 (0.6 to 2.1) in the SSc-ILD group and 0.5 (0.4 to 0.5) in the control group (p<0.0001 with Mann-Whitney test) and a median whole lung maximal standardized uptake value (wlSUVmax) of 4.4 (3.05 to 5.2) in the SSc-ILD group compared to 0.7 (0.65 to 0.7) in the control group (p<0.0001). wlFAPI-MAV and wlTL-FAPI were not measurable in control subjects, as no 68Ga-FAPI-04 uptake above background level was observed. In the SSc-ILD group the median wlFAPI-MAV was 254cm3 (163.4 to 442.3) and the median wlTL-FAPI was 183.6 cm3 (98.04 to 960.7). 68Ga-FAPI-04 uptake was higher in patients with extensive disease, with previous ILD progression or high EUSTAR activity scores. Increased 68Ga-FAPI-04 uptake at baseline was associated with progression of ILD independently of extent of involvement on HRCT scan and the forced vital capacity at baseline. In consecutive 68Ga-FAPI-04-PET/CTs, changes in 68Ga-FAPI-04 uptake was concordant with the observed response to the fibroblast-targeting antifibrotic agent nintedanib.Conclusion:Our study presents first in human evidence that 68Ga-FAPI-04-fibroblast uptake correlates with fibrotic activity and disease progression in the lungs of SSc-ILD patients and that 68Ga-FAPI-04-PET/CT may be of potential to improve risk assessment of SSc-ILD.Figure 1.A and B:68Ga-FAPI-04 PET/CT scan from a patient with SSc-ILD with selective 68Ga-FAPI-04 uptake in fibrotic areas of the left- and right lower lung lobes (red arrows), but not in non-fibrotic areas such as the middle lobe (green arrow). B Corresponding CT component.Acknowledgements:We gratefully acknowledge Prof. Uwe Haberkorn (University Hospital Heidelberg and DKFZ, Heidelberg, Germany) and iTheranostics Inc. (Dulles, VA, USA) for providing the precursor FAPI-04.Disclosure of Interests:Christina Bergmann: None declared, Jörg H.W. Distler Speakers bureau: Actelion, Anamar, ARXX, Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, and UCB, Grant/research support from: Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB, Christoph Treutlein: None declared, Koray Tascilar Speakers bureau: Gilead sciences GmbH, Pfizer Turkey, UCB Turkey, Anna-Theresa Mueller: None declared, Armin Atzinger: None declared, Alexandru-Emil Matei: None declared, Johannes Knitza: None declared, Andrea-Hermina Györfi: None declared, Anja Lueck: None declared, Clara Dees: None declared, Alina Soare: None declared, Andreas Ramming: None declared, Verena Schönau: None declared, Oliver Distler Speakers bureau: Arxx Therapeutics, Baecon Discovery, Blade Therapeutics,Bayer, Böhringer Ingelheim, Catenion,Competitive Drug Development International Ltd, Corbuspharma, CSL Behring, ChemomAb, Horizon Pharmaceuticals, Ergonex, Galaapagos NV, Glenmark Pharmaceuticals,GSK, Inventiva, Italfarmaco, IQvia, Kymera, Lilly, Medac, Medscape, MSD, Novartis, Pfizer, Roche, Sanofi, Taget Bio Sciencec, UCB, Grant/research support from: Bayer,Böhringer Ingelheim, Mitsubishi Tanabe Pharma, Olaf Prante: None declared, Philipp Ritt: None declared, Theresa Ida Goetz: None declared, Markus Koehner: None declared, Michael Cordes: None declared, Tobias Baeuerle: None declared, Torsten Kuwert Speakers bureau: Honoraria for occasional lectures by Siemens Healthineers, Grant/research support from: Research grant to the Clinic of Nuclear Medicine by this entity covering projects in the field of SPECT/CT, Georg Schett: None declared, Christian Schmidkonz: None declared

Mycophenolate in scleroderma-associated interstitial lung disease: Real-world data from rheumatology and pulmonology clinics in South Asia

2021 ◽  
pp. 239719832110244
Author(s):  
Ramya Janardana ◽  
Aparna Irodi ◽  
Pramod P Chebbi ◽  
Ruchika Goel ◽  
Leena R Vimala ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Mycophenolate Mofetil ◽  
Systemic Sclerosis ◽  
High Resolution ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Forced Vital Capacity ◽  
Vital Capacity ◽  
High Resolution Computed Tomography

Introduction: There is a paucity of real-world data on mycophenolate mofetil/mycophenolate sodium in systemic sclerosis-related interstitial lung disease. Aim: To study the efficacy of mycophenolate mofetil/ mycophenolate sodium in systemic sclerosis-related interstitial lung disease. Methods: In this single-centre study, clinical, laboratory and imaging details of consecutive patients with systemic sclerosis-related interstitial lung disease receiving mycophenolate mofetil/mycophenolate sodium from rheumatology and pulmonology clinics between January 2008 and March 2017 were retrospectively retrieved. The change in percentage of predicted normal forced vital capacity at last follow-up visit as compared with baseline was studied. In addition, high-resolution computed tomography scans at baseline and 2-year follow-up visit were scored as either stable/improved or worsened by experienced thoracic radiologists blinded to the clinical details of patients. Results: Altogether, 88 patients (85.2% females) with mean age (SD) of 33.8 years (± 11.3) and median (interquartile range) duration of disease since non-Raynaud’s symptoms of 36 months (13.5–60) were studied. Diffuse systemic sclerosis comprised 85.2% of them. The mean baseline forced vital capacity was 61.2 ± 17.9% and median scores for ground glass opacities and fibrosis in high-resolution computed tomography were 0.5 (0–1.3) and 1 (0–1.3), respectively. At a median follow-up duration of 30 months (interquartile range = 16.5–49), the percentage of forced vital capacity improved by 1.8% (–3.82 to 9.07) as compared with baseline visit ( p = 0.02). In the 2-year follow-up, the ground glass opacity and fibrosis scores in high-resolution computed tomography improved in 17.3% and 7.7% of patients and stabilized in 63.5% and 78.8% patients, respectively. Conclusion: Mycophenolate mofetil/mycophenolate sodium was efficacious in improving /stabilizing forced vital capacity irrespective of the baseline high-resolution computed tomography lung scores in our patients with systemic sclerosis-related interstitial lung disease during the ⩾ 2-year follow-up period.

scholarly journals Serum Krebs von den Lungen-6 level predicts disease progression in interstitial lung disease

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244114
Author(s):  
Ui Won Ko ◽  
Eun Jung Cho ◽  
Heung-Bum Oh ◽  
Hyun Jung Koo ◽  
Kyung-Hyun Do ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Disease Progression ◽  
Characteristic Curve ◽  
Area Under The Curve ◽  
High Serum ◽  
High Resolution Computed Tomography ◽  
Relative Decline ◽  
Cox Analysis

Disease progression (DP) in interstitial lung disease (ILD) is variable and difficult to predict. In previous reports, serum Krebs von den Lungen-6 (KL-6) was suggested to be useful in diagnosing and predicting survival in ILD. The aim of our study was to investigate the usefulness of serum KL-6 as a predictor of DP in ILD. Clinical data of 199 patients with ILD (idiopathic pulmonary fibrosis: 22.8%) were prospectively collected and serum KL-6 levels were measured. DP was defined as a relative decline in forced vital capacity (FVC) ≥ 10%, acute exacerbation, or death during follow-up. The median follow-up period was 11.1 months. The mean age of the subjects was 62.2 years, and 59.8% were male. DP occurred in 21.6% of patients. The progressed group showed lower FVC, lower diffusing capacity for carbon monoxide, lower the minimum oxygen saturation during the 6-minute walk test, higher fibrosis scores on high-resolution computed tomography, and higher KL-6 levels (826.3 vs. 629.0 U/mL; p < 0.001) than those of the non-progressed group. In receiver operating characteristic curve analysis, serum KL-6 levels were a significant predictor of DP in ILD (area under the curve = 0.629, p = 0.009, and the optimal cut-off level was 811 U/mL). In multivariable Cox analysis, high serum KL-6 levels (≥ 800 U/mL) were only independently associated with DP in ILD (HR 2.689, 95% CI 1.445–5.004, P = 0.002). Serum KL-6 levels might be useful to predict DP in patients with ILD.

scholarly journals POS0866 TWO-DIMENSIONAL HRCT-BASED RADIOMIC FEATURES IN SSC-ILD DISTINGUISH DRUG RESPONDERS FROM NON-RESPONDERS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 688-689
Author(s):  
C. Meier ◽  
M. Maciukiewicz ◽  
M. Brunner ◽  
J. Schniering ◽  
H. Gabrys ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Linear Regression ◽  
Lung Disease ◽  
Treatment Response ◽  
Two Dimensional ◽  
Research Support ◽  
Pre Treatment

Background:Management of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) is complicated by high inter-patient variability. To date, no validated predictors of treatment response are available for routine use. High resolution computed tomography (HRCT)-based radiomics, i.e. the high-dimensional, quantitative analysis of imaging metadata, have previously been shown to be successful in discriminating (SSc-)ILD phenotypes in preclinical and clinical studies1. Since HRCT is an integral part of the routine work-up in SSc, HRCT-based radiomic features may hold potential as non-invasive biomarkers.Objectives:To predict treatment response using two-dimensional (2D) HRCT-based radiomics in SSc-ILD patients from a prospectively followed cohort.Methods:Inclusion criteria were diagnosis of SSc-ILD in HRCT, availability of a suitable chest HRCT scan within 12 months prior to initiation of a new treatment, and availability of clinical baseline and follow-up information. Treatment response was defined as the absence of all of the following over a follow-up period of 12-24 months: relative decrease in forced vital capacity (FVC) ≥5%, increase of ILD in HRCT as assessed by a radiologist, change in treatment regimen due to insufficient response, ILD-related death or lung transplantation. Of each pre-treatment HRCT, 6 slices (15±5 mm apart, starting from the basal lung margin) were manually segmented and 1513 2D radiomic features were extracted using the in-house software Z-Rad (Python 2.7). Features were Z-score transformed and pre-filtered for inter- and intra-reader robustness (intraclass correlation coefficient >0.85) and inter-feature correlation (Spearman’s rho <0.9). A categorical linear regression model was created using 3-fold cross-validated elastic nets for feature selection. Features were then summarized and divided by their number. For generation of a score cut-off, Youden’s score was used. For two-group analyses of continuous variables, Wilcoxon’s test was performed, whereas categorical data was assessed using Fisher’s exact test.Results:A total of 64 pre-treatment HRCTs from 54 patients were analyzed. In 9 patients, >1 asynchronous treatments were assessed, while 45 patients had only 1 eligible treatment approach. The response rate within the assessed follow-up period was 45.3% (n=29). For score generation, 13 radiomic features were selected and an optimal cut-off value of -0.1589 was determined. Univariate linear regression showed significant association between our categorical radiomics-based score and treatment response (p=0.007, area under the curve = 0.65 (0.51-0.79), sensitivity=0.90, specificity=0.43), whereby a high score was predictive for treatment response.No differences between patients with high (n=46) or low (n=18) scores were detected for baseline age (mean±SD=55.5±12.0 and 55.5±13.6 years, p=0.84), duration of SSc (mean±SD=6.2±8.4 and 4.7±4.4 years, p=0.79), time since ILD diagnosis (2.7±2.9 and 2.4±3.1 years, p=0.59), FVC (77.6±20.6 and 80.1±17.9, p=0.41) or DLco (54.4±21.0 and 57.6±18.9, p=0.40). Distribution of anti-Scl-70 positivity (45.7% vs. 55.6%, p=0.58) and diffuse cutaneous disease (47.7% vs. 61.1%, p=0.41) was not significantly different between patients with high and low scores, respectively, although a trend towards higher percentages in the high score group was observed.Conclusion:Our results indicate that, following validation in external cohorts, radiomics may be a promising tool for future pre-treatment patient stratification. Moreover, our radiomics-based score seems not to be associated with commonly studied clinical predictors such as anti-Scl-70 positivity or lung function, underlining a possible additive value to ‘traditional’ clinical parameters.References:[1]Schniering, J., et al. Resolving phenotypic and prognostic differences in interstitial lung disease related to systemic sclerosis by computed tomography-based radiomics. medRxiv [Preprint] doi:10.1101/2020.06.09.20124800 (2020).Disclosure of Interests:Chantal Meier: None declared, Malgorzata Maciukiewicz: None declared, Matthias Brunner: None declared, Janine Schniering: None declared, Hubert Gabrys: None declared, Anja Kühnis: None declared, Oliver Distler Speakers bureau: Speaker fee on Scleroderma and related complications: Bayer, Boehringer Ingelheim, Medscape, Novartis, Roche. Speaker fee on rheumatology topic other than Scleroderma: MSD, iQone, Novartis, Pfizer, Roche, Consultant of: Consultancy fee for Scleroderma and its complications: Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Bayer, Baecon Discovery, Boehringer, CSL Behring, ChemomAb, Corbus Pharmaceuticals, Horizon Pharmaceuticals, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, Kymera, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Roivant Sciences, Sanofi, UCB. Consultancy fee for rheumatology topic other than Scleroderma: Abbvie, Amgen, Lilly, Pfizer, Grant/research support from: Research Grants to investigate the pathophysiology and potential treatment of Scleroderma and its complications: Kymera Therapeutics, Mitsubishi Tanabe, Thomas Frauenfelder: None declared, Stephanie Tanadini-Lang: None declared, Britta Maurer Speakers bureau: Speaker fees from Boehringer-Ingelheim, Grant/research support from: Grant/research support from AbbVie, Protagen, Novartis Biomedical Research, congress support from Pfizer, Roche, Actelion, mepha, and MSD

scholarly journals Diagnosis and management of interstitial lung disease of systemic sclerosis in challenging health conditions

2019 ◽  
pp. 18-20
Author(s):  
Daniel Rivas-Vargas
Keyword(s):  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Vital Capacity ◽  
Screening Method ◽  
Skin Fibrosis ◽  
Number Of Patients ◽  
History Of ◽  
Salt And Pepper

A 51-year-old woman presented with swelling in both hands and a 3-months history of triphasic Raynaud phenomenon. She denied cough and dyspnea. The physical examination was notable for swollen hands, facial telangiectasia and salt and pepper lesions. She had no skin fibrosis. The determination of antinuclear antibodies and antitopoisomerase were positive. A spirometry demonstrated a forced vital capacity of 86% of the predicted. High resolution chest computed tomography revealed bilateral, basal and subpleural ground glass opacities. These findings were consistent with the diagnosis of Scleroderma-Related Interstitial Lung Disease. Moreover, due to the absence of skin fibrosis, a diagnosis of systemic sclerosis sine scleroderma was made. Infusions of endovenous cyclophosphamide were indicated at 4-week intervals, followed by oral azathioprine. This case showed that using PFT as the single screening method for SSc-ILD may cause clinicians to miss a significant number of patients and that the absence of pulmonary symptoms does not exclude lung disease in patients with normal FVC.

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