Interstitial Lung Disease In Systemic Sclerosis Research Articles

Biologic Correlates of Radiologic Features of Systemic Sclerosis Interstitial Lung Disease

Background and objectivesThe extent and pattern of radiological features (e.g., fibrosis, ground glass) can influence treatment approaches for systemic sclerosis-related interstitial lung disease (SSc-ILD). However, the pathobiology underlying these radiologic features is poorly understood and warrants further investigation.MethodsSixty-eight proteins were measured in bronchoalveolar lavage (BAL) fluid from 103 SSc-ILD participants in Scleroderma Lung Study I. Quantitative image analysis calculated the extent of fibrosis (QLF) and ground glass opacity (QGG) from concurrent high-resolution computerized tomography (HRCT) scans. The relationship between BAL proteins and quantitative HRCT scores was assessed by univariate and multivariate analyses.ResultsQLF scores correlated weakly with the extent of QGG, suggesting two distinct processes. In a univariate analysis, 25 proteins from several biologic pathways correlated with QLF scores, including pro-fibrotic factors, tissue remodeling proteins, proteins involved in monocyte/macrophage migration and activation, and proteins linked to inflammation and immune regulation. In contrast, QGG scores correlated with only 6 proteins of which four were unique and related to granulocyte activation, mobilization of bone marrow mesenchymal stem cells, and activation of T cells, B cells, macrophages and eosinophils. In the multivariate models, IL-4, CCL7, receptor activator of NF-κB, and tumor necrosis factor alpha were independently associated with QLF, whereas, IFN-γ was independently associated with QGG.InterpretationQLF and QGG represent distinct radiologic features of SSc-ILD, a conclusion reinforced by the presence of different biologic pathways present within BAL fluid that associate with each. The identified proteins and related biologic pathways may represent important therapeutic targets.

Efficacy of Rituximab Versus Cyclophosphamide and Mycophenolate for the Treatment of Interstitial Lung Disease in Systemic Sclerosis: A Systematic Review.

Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc), contributing to significant morbidity and mortality in affected individuals. The optimal treatment approach for SSc-associated ILD remains uncertain, with rituximab, cyclophosphamide, and mycophenolate among potential therapeutic options. This systematic review aims to evaluate and synthesize the existing evidence on the efficacy of rituximab compared to cyclophosphamide and mycophenolate for the treatment of ILD in patients with systemic sclerosis. A comprehensive search of the following electronic databases, PubMed, Science Direct, Google Scholar, and Cochrane Library, has been conducted to identify relevant studies, including randomized controlled trials, systematic review and meta-analysis, prospective cohort studies, and retrospective cohort studies. Data on study characteristics, participant demographics, interventions, outcomes, and key findings have been extracted and synthesized. The risk of bias in the included studies has been assessed using appropriate tools such as the Cochrane Bias assessment tool for randomized controlled trials, the New Castle Ottawa tool for cohort studies, and the AMSTAR checklist for systematic reviews and meta-analysis. The research team ultimately selected 15 high-quality studies for review. Rituximab demonstrated similar efficacy to cyclophosphamide and mycophenolate in improving lung function (forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO)), with fewer severe adverse events. Cyclophosphamide, while effective, had higher toxicity, leading to more frequent adverse events such as leukopenia and infections. Mycophenolate showed comparable efficacy to cyclophosphamide but with fewer side effects, making it a well-tolerated alternative. The findings of this systematic review will provide valuable insights into the comparative efficacy of rituximab, cyclophosphamide, and mycophenolate in the management of ILD in systemic sclerosis, informing clinical decision-making and guiding future research in this area.

Use of artificial intelligence algorithms to analyse systemic sclerosis-interstitial lung disease imaging features

The use of artificial intelligence (AI) in high-resolution computed tomography (HRCT) for diagnosing systemic sclerosis-associated interstitial lung disease (SSc-ILD) is relatively limited. This study aimed to analyse lung HRCT images of patients with systemic sclerosis with interstitial lung disease (SSc-ILD) using artificial intelligence (AI), conduct correlation analysis with clinical manifestations and prognosis, and explore the features and prognosis of SSc-ILD. Overall, 72 lung HRCT images and clinical data of 58 patients with SSC-ILD were collected. ILD lesion type, location, and volume on HRCT images were identified and evaluated using AI. The imaging characteristics of diffuse SSC (dSSc)-ILD and limited SSc-ILD (lSSc-ILD) were statistically analysed. Furthermore, the correlations between lesion type, clinical indicators, and prognosis were investigated. dSSc and lSSc were more prevalent in patients with a disease duration of < 1 and ≥ 5 years, respectively. SSc-ILD mainly comprises non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), and unclassifiable idiopathic interstitial pneumonia. HRCT reveals various lesion types in the early stages of the disease, with an increase in the number of lesion types as the disease progresses. Lesions appearing as grid, ground-glass, and nodular shadows were dispersed throughout both lungs, while those appearing as consolidation shadows and honeycomb were distributed across the lungs. Ground-glass opacity lesion type was absent on HRCT images of patients with SSc-ILD and pulmonary hypertension. This study showed that AI can efficiently analyse imaging characteristics of SSc-ILD, demonstrating its potential to learn from complex images with high generalisation ability.

Transcriptomic analyses of lung tissues reveal key genes associated with progression of systemic sclerosis-interstitial lung disease (SSc-ILD)

Systemic sclerosis-interstitial lung disease (SSc-ILD) is the leading cause of death in SSc, affecting around 50% of the patients. Lung tissue of patients with early-stage SSc-ILD is characterized by a predominant inflammatory response with inconspicuous fibrosis, which may progress to honeycombing fibrosis. Hence, a better understanding of the molecular mechanisms underpinning SSc-ILD pathogenesis is needed to improve treatment options and progression prediction. This transcriptomic study aims to reveal the differential gene expression between control (ctrl) lung tissue and inflammatory, prefibrotic and fibrotic lung tissue to capture progression of early to late phase SSc-ILD. Twelve explanted lungs from patients with SSc-ILD were used to analyze gene expression from formalin-fixed paraffin-embedded lung tissues with varying stages of ILD (n=18) and control lung tissue (n=6). The SSc-ILD tissues were stratified into three ROIs: inflammatory, prefibrotic, and fibrotic using histological assessments to define a longitudinal simulation of early to late phases of SSc-ILD. The nanoString (nS) nCounter Human Fibrosis Panel was used to profile the transcriptome in the regions of interest. Validation of potential targetswas performed with immunohistochemistry in the same tissues that were used for transcriptome analysis. To validate our simulation model, we performed subgroup analysis that showed an incremental increase in pathway scores related to the severity of fibrosis. Ctrl vs SSc-ILD comparison demonstrated 24 differentially expressed genes, two of which had the most pronounced p-values. Cyclin-dependent kinase inhibitor (cdkn2c) was overexpressed (P=0.00052) in SSc-ILD compared to ctrl, while expression of Pellino E3 ubiquitin-protein ligase 1 (peli1) showed lower expression (P=0.0012). Additionally, in all four groups, cdkn2c and peli1 gene expression showed an incremental increase and decrease, respectively. Immunohistochemistry of cdkn2c showed consistent results with the nS analysis. More cdkn2c and less peli1 expression were associated with more advanced stages of SSc-ILD on histologic assessment. We report the potential of the cell cycle inhibitor and senescence marker, cdkn2c (p18) to be associated with fibrosis progression.

Update on systemic sclerosis

The updates to the European recommendations and the German guidelines for the treatment of systemic sclerosis are expected shortly, which are very good evidence-based guidelines for all those treating the disease; however, there are still disease manifestations with insufficient studies and current study results that were published after the review of the literature for the guidelines and might be of interest to the reader. The aim of this work is to provide an overview of the publications in the last year that are interesting from the authors' point of view. The aim is to provide practically relevant information on the current state of knowledge that can supplement the guidelines. The pathogenesis of systemic sclerosis (SSc) is becoming better understood in its interplay between environmental factors and the development of autoantibodies. There have also been overviews of the manifestation and prognosis of cardiac involvement in the last year. The American Thoracic Society issued the first guidelines for the treatment of interstitial lung disease in SSc. There are an increasing number of studies that suggest that disease-modulating combination therapies, such as rituximab and mycophenolate mofetil (MMF) are beneficial. Work addressing the involvement of joints suggests that inflammatory changes are common. Current options for the treatment of gastrointestinal involvement are presented. The diagnosis and treatment of systemic sclerosis is making progress and many symptoms and complications are treatable. Nevertheless, much remains to be done to improve the quality of life of the patients.

Concordance and Prognostic Relevance of Different Definitions of Systemic Sclerosis Interstitial Lung Disease Progression.

Interstitial lung disease (ILD) in systemic sclerosis (SSc) is a common complication that has varied progression rate and prognosis. Different progression definitions are available: include minimal clinically important worsening of forced vital capacity (FVC MCIW), EUSTAR (EUropean Scleroderma Trials and Research group) progression, OMERACT (Outcome Measures in Rheumatology Clinical Trials) progression, and Erice ILD working group progression. Pulmonary function and symptoms changes may act as specific confounding factors applying these definitions in SSc. To assess the concordance and prognostic value of four different definitions in SSc-ILD patients overall and specific clinical groups. Progression status in consecutive SSc-ILD patients was assessed over 24 months, 60-month disease-related mortality risk was compared between progressors and non-progressors using the four definitions. Among 245 patients, 26 SSc-related deaths were reported. Mortality was linked to progression for FVC MCIW (HR 2.27, 95% CI 1.03-4.97), OMERACT (HR 2.90, 95% CI 1.28-6.57), and Erice definitions (HR 11.02, 95% CI 2.38-51.08). The association between progression and mortality was poor in patients with disease duration ≥3 years, mild functional impairment, and pulmonary artery systolic pressure (PASP)≥40 mmHg. Erice criteria appeared superior in patients with duration ≥3 years, limited cutaneous variant, and PASP<40 mmHg. OMERACT criteria performed better in diffuse cutaneous variant patients with severe functional impairment. The four evaluated definitions of progression in SSc-ILD are not interchangeable, resulting in up to a third of cases being classified differently based on the adopted criteria, and presenting different prognostic values, particularly within specific clinical groups.

Real-World Clinical Profile and Safety of Nintedanib in Systemic Sclerosis-Associated Interstitial Lung Disease: A Subgroup Analysis of Interstitial Lung Disease Data From an Interstitial Lung Disease (ILD) Specialty Clinic in India.

Systemic sclerosis (SSc) is a multisystem autoimmune disorder characterized by dysregulated innate and adaptive immunity. Interstitial lung disease (ILD) is a common and serious complication of SSc, often leading to significant morbidity and mortality. Consistent demographic characteristics that aid in the early diagnosis of ILD in SSc are lacking. This study aims to identify clinical and demographic parameters associated with ILD in SSc patients and assess the safety and tolerability of nintedanibwith other immunosuppressants. This study is a subgroup analysis of data from the ILD clinic at All India Institute of Medical Sciences Raipur, collected between January 2022 and January 2024. We assessed the clinical and demographic profiles, high-resolution computed tomography thorax patterns, autoantibody profiles, lung function, and treatments used in the patients. We enrolled 57 patients with SSc-associated ILD. The mean age of the participants was 39.0 ± 11.1 years, with 53 (92.9%) being women. The mean body mass index was 20.4 ± 4.32 kg/m². Dyspnea was the most common symptom, followed by skin tightening and cough. Antinuclear antibody tests were positive in 92.9% of patients, and anti-Scl-70 antibodies were positive in 57.9%. Rheumatoid arthritis-SSc overlap was observed in 15.8% of patients. The mean predicted forced vital capacity was 46.5 ± 19.9%, the mean predicted total lung capacity was 64.5 ± 20.4%, and the mean predicted diffusing capacity for carbon monoxide was 46.2 ± 15.7%. The mean six-minute walk distance was 360.3 ± 81.2 meters, and the mean King's Brief Interstitial Lung Disease score was 63.9 ± 10.7. Common radiological abnormalities included ground-glass opacities in 57.8%, traction bronchiectasis in 43.8%, and honeycombing in 28.07%. The predominant ILD pattern was nonspecific interstitial pneumonia. Patients received a combination of prednisolone (5 mg/day) with mycophenolate mofetil (63.2%), hydroxychloroquine (17.5%), cyclophosphamide (12.3%), and methotrexate (7.02%). Nintedanib, the only antifibrotic used, was administered to 17 (29.8%) patients. ILD is relatively common in SSc, particularly in patients with diffuse cutaneous SSc and those with anti-topoisomerase antibodies. Female patients comprised the predominant population in this study. Patients tolerated mycophenolate mofetil and cyclophosphamide well. Nintedanib was the only antifibrotic used, and all patients tolerated the combination of antifibrotics and immunosuppressants well. Early diagnosis is crucial to slow disease progression and preserve lung function. Our results highlight the need for vigilant screening in high-risk groups and suggest that MMF, cyclophosphamide, and nintedanib can be safely incorporated into treatment regimens, offering a potential strategy to improve patient outcomes.

A stability indicating method development and validation of a rapid and sensitive RP-HPLC method for Nintedanib and its application in quantification of nanostructured lipid carriers.

Nintedanib (NTB) is a multiple tyrosine kinase inhibitor, been investigated for many disease conditions like idiopathic pulmonary fibrosis (IPF), systemic sclerosis interstitial lung disease (SSc-ILD) and non-small cell lung cancer (NSCLC). NTB is available as oral capsule formulation, but its ability to detect degradants formed through oxidative, photolytic and hydrolytic processes makes it difficult to quantify. In the current work, a novel reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated. The developed method is simple, precise, reproducible, stable and accurate. The inherent stability of NTB was evaluated using the proposed analytical method approach and force degradation studies were carried out. NTB was separated chromatographically on the Shimadzu C 18 column as stationary phase (250 ×4.6 mm, 5 µm) using an isocratic elution method with 0.1% v/v triethyl amine (TEA) in HPLC grade water and acetonitrile (ACN) in the ratio 35:65% v/v. The mobile phase was pumped at a constant flow rate of 1.0 ml/min, and the eluent was detected at 390 nm wavelength. NTB was eluted at 6.77±0.00 min of retention time (t R) with a correlation coefficient of 0.999, the developed method was linear in the concentration range of 0.5 µg/ml to 4.5 µg/ml. The recovery rate was found to be in the range of 99.391±0.468% for 1.5 µg/ml concentration. Six replicate standards were determined to have an % RSD of 0.04. The formulation excipients didn't interfere with the determination of NTB, demonstrating the specificity of the developed method. The proposed approach of the analytical method developed can be used to quantify the amount of NTB present in bulk drugs and pharmaceutical formulations.

A Comparison of Nailfold Video Capillaroscopy Findings in Mixed Connective Tissue Disease Interstitial Lung Disease vs Systemic Sclerosis Interstitial Lung Disease: A Single-Centre Study.

To differentiate the nailfold capillaroscopy (NFC) findings in patients with MCTD-ILD and SSc-ILD and correlate the NFC changes and lung functions among them. In this observational study from Oct 2020 to Oct 2022, 27 patients with MCTD-ILD and 27 patients with SSc-ILD were included. NFC was performed using Jiangsu Jiahua, JH 1004, China. Statistical analysis was conducted using IBM SPSS software, version 26, and tests including Mann-Whitney U-test, student t-test, chi-square test, or Fisher's exact test were used to compare between groups. In this study, major capillaroscopic changes were more frequent in SSc-ILD group (92%) than in MCTD-ILD group (72.3%), with normal capillaries seen in 7.4% of MCTD-ILD cases. The mean FVC was higher in SSc-ILD group compared to MCTD-ILD group, and patients with capillary loss had a lower mean FVC. Loss of capillaries was more frequent in SSc-ILD group, while dilated capillaries were predominantly observed in MCTD-ILD group. A significant association was found between the severity of restriction in spirometry and NFC. There is an important role for NFC in detecting the severity of lung involvement, as the grading of restrictive severity in spirometry is strongly associated with capillaroscopic abnormalities.

The Value of Ultrasound for Detecting and Following Subclinical Interstitial Lung Disease in Systemic Sclerosis.

Interstitial lung disease (ILD) is a complication in patients with systemic sclerosis (SSc). Accurate strategies to identify its presence in early phases are essential. We conducted the study aiming to determine the validity of ultrasound (US) in detecting subclinical ILD in SSc, and to ascertain its potential in determining the disease progression. 133 patients without respiratory symptoms and 133 healthy controls were included. Borg scale, Rodnan skin score (RSS), auscultation, chest radiographs, and respiratory function tests (RFT) were performed. A rheumatologist performed the lung US. High-resolution CT (HRCT) was also performed. The patients were followed every 12 weeks for 48 weeks. A total of 79 of 133 patients (59.4%) showed US signs of ILD in contrast to healthy controls (4.8%) (p = 0.0001). Anti-centromere antibodies (p = 0.005) and RSS (p = 0.004) showed an association with ILD. A positive correlation was demonstrated between the US and HRCT findings (p = 0.001). The sensitivity and specificity of US in detecting ILD were 91.2% and 88.6%, respectively. In the follow-up, a total of 30 patients out of 79 (37.9%) who demonstrated US signs of ILD at baseline, showed changes in the ILD score by US. US showed a high prevalence of subclinical ILD in SSc patients. It proved to be a valid, reliable, and feasible tool to detect ILD in SSc and to monitor disease progression.

The Performance of Pulmonary Function Tests in Predicting Systemic Sclerosis—Interstitial Lung Disease in the European Scleroderma Trial and Research Database

Background and Objectives: In SSc, ILD is a major cause of morbidity and mortality. We aimed to investigate the performance of DLCO (diffusing capacity of lung carbon monoxide) and FVC (forced vital capacity) delta change (Δ) and baseline values in predicting the development of SSc-ILD. Methods: Longitudinal data of DLCO, FVC, and ILD on the HRCT of SSc patients from the EUSTAR database were evaluated at baseline (t0) and after 12 (±4) (t1) and 24 (±4) (t2) months. Results: 474/17805 patients were eligible for the study (403 females); 46 (9.7%) developed ILD at t2. Positivity for anti-topoisomerase antibodies (117 patients) showed an association with ILD development at t2 (p = 0.0031). Neither the mean t0 to t1 change (Δ) of DLCO nor the mean t0 to t1 FVCΔ predicted the appearance of ILD at t2. Investigating the possible role of baseline DLCO and FVC values in predicting ILD appearance after 24 (±4) months, we observed a moderate predictive capability of t0 DLCO &lt; 80%, stronger than that of FVC &lt; 80%. Conclusions: We suggest that an impaired baseline DLCO may be predictive of the appearance of ILD after 2 years of follow-up. This result advances the hypothesis that a reduction in gas exchange may be considered an early sign of lung involvement. However, further rigorous studies are warranted to understand the predictive role of DLCO evaluation in the course of SSc.

Contribution of Left Ventricular Diastolic Dysfunction to Survival and Breathlessness in Systemic Sclerosis-Associated Interstitial Lung Disease.

To explore the effect of left ventricular (LV) diastolic dysfunction (LVDD) in systemic sclerosis (SSc)-associated interstitial lung disease (ILD), and to investigate SSc-specific associations and clinical correlates of LVDD. There were 102 Australian Scleroderma Cohort Study participants with definite SSc and radiographic ILD included. Diastolic function was classified as normal, indeterminate, or abnormal according to 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines for assessment of LV diastolic function. Associations between clinical features and patient- and physician-reported dyspnea were evaluated using logistic regression. Survival analyses were performed using Kaplan-Meier survival estimates and Cox regression modeling. LVDD was identified in 26% of participants, whereas 19% had indeterminate and 55% had normal diastolic function. Those with ILD and LVDD had increased mortality (hazard ratio 2.4, 95% CI 1.0-5.7; P = 0.05). After adjusting for age and sex, those with ILD and LVDD were more likely to have severe dyspnea on the Borg Dyspnoea Scale (odds ratio [OR] 2.6, 95% CI 1.0-6.6; P = 0.05) and numerically more likely to record World Health Organization Function Class II or higher dyspnea (OR 4.2, 95% CI 0.9-20.0; P = 0.08). Older age (95% CI 1.0-6.4; P = 0.05), hypertension (OR 5.0, 95% CI 1.8-13.8; P < 0.01), and ischemic heart disease (OR 4.8, 95% CI 1.5-15.7; P < 0.01) were all associated with LVDD, as was proximal muscle atrophy (OR 5.0, 95% CI 1.9-13.6; P < 0.01) and multimorbidity (Charlson Comorbidity Index scores ≥ 4, OR 3.0, 95% CI 1.1-8.7; P = 0.04). LVDD in SSc-ILD is more strongly associated with traditional LVDD risk factors than SSc-specific factors. LVDD is associated with worse dyspnea and survival in those with SSc-ILD.

High serum C-X-C motif chemokine ligand 10 (CXCL10) levels may be associated with new onset interstitial lung disease in patients with systemic sclerosis: evidence from observational, clinical, transcriptomic and in vitro studies

Systemic sclerosis-interstitial lung disease (SSc-ILD) is the leading cause of death in patients with SSc. There is an unmet need for predictive biomarkers to identify patients with SSc at risk of ILD. Previous studies have shown that interferon (IFN) pathways may play a role in SSc. We assessed the use of C-X-C motif chemokine ligand 10 (CXCL10) as a predictive biomarker for new onset of ILD in patients with SSc. One-hundred-sixty-five (Female, N=130) patients with SSc (SSc-ILD, N=41) and 13 (Female, N=8) healthy controls were investigated retrospectively. CXCL10 protein levels were measured by ELISA. We performed log rank analysis with baseline CXCL10 serum levels. CXCL10 nanoString data from lung tissues obtained from transplanted patients with SSc-ILD were extracted. Fifteen (Female, N=10) patients with SSc (SSc-ILD, N=7) were recruited for bronchoalveolar lavage (BAL) procedure. Lung fibroblasts were treated with BAL-fluid or serum from patients with SSc with or without ILD. Inflammatory/fibrotic genes were assessed. Serum CXCL10 levels were higher in patients with SSc-ILD compared to SSc patients without ILD [Median (IQR):126pg/ml (66-282.5) vs. 78.5pg/ml (50-122), P=0.029, 95% CI: 1.5×10-6 to 0.4284]. Survival analysis showed that baseline CXCL10 levels >78.5pg/ml have a 2.74-fold increased risk of developing new onset of ILD (Log-rank: P=0.119) on follow-up. CXCL10 levels in BAL supernatant were not different in patients with SSc-ILD compared to SSc without ILD [76.1pg/ml (7.2-120.8) vs. 22.3pg/ml (12.1-43.7), P=0.24, 95% CI:-19.5 to 100]. NanoString showed that CXCL10 mRNA expression was higher in inflammatory compared to fibrotic lung tissues [4.7 (4.2-5.6) vs. 4.3 (3.6-4.7), P=0.029]. Fibroblasts treated with SSc-ILD serum or BAL fluids overexpressed CXCL10. Clinical, transcriptomic, and invitro data showed that CXCL10 is potentially involved in early SSc-ILD. More research is needed to confirm whether CXCL10 can be classified as a prospective biomarker to detect patients with SSc at higher risk of developing new onset ILD. This collaborative project is co-financed by the Ministry of Economic Affairs and Climate Policy of the Netherlands utilizing the PPP-allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships (PPP-2019_007). Part of this study is financially supported by Sanofi Genzyme (NL8921).

Systemic sclerosis interstitial lung disease: unmet needs and potential solutions.

Systemic sclerosis (SSc), or scleroderma, is a rare, complex, systemic autoimmune disease of unknown aetiology, characterized by high morbidity and mortality often resulting from cardiopulmonary complications such as interstitial lung disease and pulmonary arterial hypertension. Despite substantial progress in unravelling the pathways involved in the pathogenesis of SSc and the increasing number of therapeutic targets tested in clinical trials, there is still no cure for this disease, although several proposed treatments might limit the involvement of specific organs, thereby slowing the natural history of the disease. A specific focus of recent research has been to address the plethora of unmet needs regarding the global management of SSc-related interstitial lung disease, including its pathogenesis, early diagnosis, risk stratification of patients, appropriate treatment regimens and monitoring of treatment response, as well as the definition of progression and predictors of progression and mortality. More refined stratification of patients on the basis of clinical features, molecular signatures, identification of subpopulations with distinct clinical trajectories and implementation of outcome measures for future clinical trials could also improve therapeutic management strategies, helping to avoid poor outcomes related to lung involvement.

A stability indicating method development and validation of a rapid and sensitive RP-HPLC method for Nintedanib and its application in quantification of nanostructured lipid carriers

Background: Nintedanib (NTB) is a multiple tyrosine kinase inhibitor, been investigated for many disease conditions like idiopathic pulmonary fibrosis (IPF), systemic sclerosis interstitial lung disease (SSc-ILD) and non-small cell lung cancer (NSCLC). NTB is available as oral capsule formulation, but its ability to detect degradants formed through oxidative, photolytic and hydrolytic processes makes it difficult to quantify. In the current work, a novel reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated. Methods: The developed method is simple, precise, reproducible, stable and accurate. The inherent stability of NTB was evaluated using the proposed analytical method approach and force degradation studies were carried out. NTB was separated chromatographically on the Shimadzu C18 column as stationary phase (250 ×4.6 mm, 5 µm) using an isocratic elution method with 0.1% v/v triethyl amine (TEA) in HPLC grade water and acetonitrile (ACN) in the ratio 35:65% v/v. The mobile phase was pumped at a constant flow rate of 1.0 ml/min, and the eluent was detected at 390 nm wavelength. Results: NTB was eluted at 6.77±0.00 min of retention time (tR) with a correlation coefficient of 0.999, the developed method was linear in the concentration range of 0.5 µg/ml to 4.5 µg/ml. The recovery rate was found to be in the range of 99.391±0.468% for 1.5 µg/ml concentration. Six replicate standards were determined to have an % RSD of 0.04. Conclusion: The formulation excipients didn't interfere with the determination of NTB, demonstrating the specificity of the developed method. The proposed approach of the analytical method developed can be used to quantify the amount of NTB present in bulk drugs and pharmaceutical formulations.

An interleukin 6 responsive plasma cell signature is associated with disease progression in systemic sclerosis interstitial lung disease

Systemic sclerosis (SSc) interstitial lung disease (ILD) is among the leading causes of SSc-related morbidity and mortality. Tocilizumab (TCZ, anti-IL6RA) has demonstrated a reduced rate of pulmonary function decline in two phase 2/3 trials (faSScinate and focuSSced) in SSc-ILD patients. We performed transcriptome analysis of skin biopsy samples collected in the studies to decipher gene networks that were potentially associated with clinical responses to TCZ treatment. One module correlated with disease progression showed pharmacodynamic changes with TCZ treatment, and was characterized by plasma cell (PC) genes. PC signature gene expression levels were also significantly increased in both fibrotic SSc and IPF lungs compared to controls. scRNAseq analyses confirmed that PC signature genes were co-expressed in CD38 and CD138 expressing PC subsets in SSc lungs. These data provide insights into the potential role of PC in disease progression and mechanisms of action of TCZ in fibrotic interstitial lung diseases.

Real life data on nintedanib safety: idiopathic pulmonary fibrosis versus systemic sclerosis-interstitial lung disease and strategies adopted to manage adverse effects

ObjectiveNintedanib (NIN) is an antifibrotic drug approved to slow the progression of idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-related interstitial lung disease (SSc-ILD). NIN can frequently cause gastrointestinal adverse effects. We aimed to investigate the NIN safety profile in a real life setting, comparing IPF and SSc-ILD patients and evaluating the strategies adopted to manage NIN adverse effects.MethodsPatients taking NIN for IPF or SSc-ILD were enrolled. Alongside epidemiological and disease-specific data, the period of NIN use and the need for dosage reduction and/or interruption were investigated. Particular attention was paid to possible adverse effects and strategies adopted to manage them.ResultsTwenty-seven SSc-ILD and 82 IPF patients were enrolled. No significant differences emerged between the two cohorts regarding the frequency of any possible adverse effect. Although the rates of NIN dosage reduction or interruption were similar between the two subgroups, SSc-ILD presented a mean period before NIN dosage reduction and NIN interruption significantly shorter than IPF (3 ± 2.6 vs 10.5 ± 8.9 months—p < 0.001 and 2.3 ± 0.5 vs 10.3 ± 9.9 months—p = 0.008, respectively). Several different strategies were tried to manage NIN adverse effects: especially in SSc-ILD, the variable combination of diet adjustment set by a nutritionist, probiotics and diosmectite was ultimately successful in maintaining patients on an adequate dose of NIN.ConclusionWe presented data on the NIN safety profile in a real life setting, which was similar between SSc-ILD and IPF. A combination of multiple managing strategies and dose adjustment appears essential to cope optimally with NIN adverse effects.

Elevated interleukin-11 in systemic sclerosis and role in disease pathogenesis.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease in which there is elevated inflammation, aberrant cytokine expression, and subsequent fibrosis. Interleukin-11 (IL-11) is a recently described profibrotic cytokine that can mediate fibrosis in the heart, lungs, and skin and is upregulated by transforming Growth Factor-β (TGF-β1). The objective of this study was to quantify the serum levels of IL-11 in early diffuse SSc patients. Also, if IL-11 could regulate the alarmin IL-33 in dermal fibroblasts was quantified. Early diffuse SSc patient sera was isolated and IL-11 was quantified by specific commercial ELISA compared to healthy control (n = 17). Healthy dermal fibroblasts were cultured in vitro and then serum starved and incubated with or without recombinant IL-11. At specific early and late time points the supernatant was quantified for the alarmin IL-33 by specific ELISA. In early diffuse SSc patients it was demonstrated that they have elevated IL-11 in their sera. In a subgroup of SSc patients with interstitial lung disease (ILD) this elevation was particularly pronounced compared to those devoid of fibrotic lung disease. In vitro incubation of healthy dermal fibroblasts led to a significant induction of IL-33 cytokine release into the cell media. IL-11 is a profibrotic cytokine that is elevated in early diffuse SSc and is particularly elevated in those with ILD. This suggests that IL-11 could be a possible biomarker of ILD in SSc. It was also found that IL-11 led to release of the cytokine alarmin IL-33 in fibroblasts at earlier time points but not late time points, suggesting early stimulation elicits an inflammatory response in the local microenvironment but prolonged stimulation leads to fibrosis.

Serum cold-inducible RNA-binding protein levels as a potential biomarker for systemic sclerosis-associated interstitial lung disease

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by fibrotic, inflammatory, and vascular dysfunction. Danger-associated molecular patterns (DAMPs)-mediated inflammasome activation has been reported to be involved in the pathogenesis of SSc. Cold-inducible RNA-binding protein (CIRP) is newly identified as a DAMP. Here we examined the clinical significance of serum levels of CIRP in 60 patients with SSc and 20 healthy control patients (HCs) using an enzyme-linked immunosorbent assay. Serum CIRP levels in diffuse cutaneous SSc (dcSSc) patients were significantly increased compared with limited cutaneous SSc (lcSSc) patients or HCs. When examining the relationship with SSc-specific parameters, serum CIRP levels with the presence of interstitial lung disease (ILD) were higher than those without ILD. In detail, serum CIRP levels correlated negatively with the percent predicted diffusing capacity for carbon monoxide and positively with levels of Krebs von den Lungen-6. In addition, elevated serum CIRP levels declined along with decreased SSc-ILD activity in patients who received immunosuppressive therapy. These results suggest that CIRP may play a role in the development of ILD in SSc. Moreover, CIRP could serve as a useful serological marker of SSc-ILD in terms of disease activity and therapeutic effects.

Characteristics and risk factors of mortality in patients with systemic sclerosis-associated interstitial lung disease

Background Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterized by dysregulation of fibroblast function, which often involves the lungs. Interstitial lung disease (ILD) associated with SSc (SSc-ILD) is a major cause of death among patients with SSc. Our study aimed to identify risk factors for mortality and compare the clinical characteristics of patients with SSc-ILD. Patients and methods Patients were retrospectively enrolled between 2010 and 2018 in a tertiary hospital in Korea. Patients with SSc-ILD were classified depending on the first pulmonary function test or radiologic findings: extensive (n = 46, >20% disease extent on computed tomography (CT) or forced vital capacity [FVC] < 70% in indeterminate cases) and limited (n = 60, <20% disease extent on CT or FVC ≥70% in indeterminate cases). Results Patients in the extensive group were younger (mean age ± SD 49.3 ± 11.5) than those in the limited group (53.9 ± 12.5, p = .067) at diagnosis. The extensive group showed frequent pulmonary hypertension (43.5% vs. 16.7%, p = .009) and higher erythrocyte sedimentation rate (61.3 ± 33.7 vs. 42.1 ± 26.0, p = .003) and mortality (32.6%, mean duration of follow-up, 100.0 ± 44.7 months vs. 10.0%, 86.0 ± 53.4 months, p = .011). ILD was detected within five years from the first visit (median years 3.5 (1.0, 6.0) vs. 4.5 (0.6, 9.0), survivors vs. non-survivors), and mortality occurred in 19.8% of all patients during a 15-year follow-up. Older age, lower FVC, and initial disease stage (limited or extensive) were associated with mortality, but FVC decline was similar in the limited and extensive groups, such as 15–20% in the first year and 8–10% in the next year, regardless of the initial extent of the disease. Conclusions Approximately 10% of patients with SSc-ILD in the limited and extensive group showed progression. ILD was detected at a median of less than five years from the first visit; therefore, it is necessary to carefully monitor patients’ symptoms and signs from an early stage. Long-term surveillance is also required. Key messages Patients with systemic sclerosis-interstitial lung disease manifested a heterogeneous disease course. Approximately 10% of the patients in the limited group showed progression, which was similar to the proportion of patients in the extensive group. Interstitial lung disease was detected at a median of less than five years from the first visit.