Sclerosis-associated Interstitial Lung Disease Research Articles

Epigenetic Regulation of Profibrotic Macrophages in Systemic Sclerosis-Associated Interstitial Lung Disease.

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the leading cause of death in patients with SSc with unclear pathogenesis and limited treatment options. Evidence strongly supports an important role for profibrotic secreted phosphoprotein 1 (SPP1)-expressing macrophages in SSc-ILD. This study was undertaken to define the transcriptome and chromatin structural changes of SPP1 SSc-ILD macrophages in order to better understand their role in promoting fibrosis and to identify transcription factors associated with open chromatin driving their altered phenotype. We performed single-cell RNA sequencing (scRNA-Seq) on 11 explanted SSc-ILD and healthy control lung samples, as well as single-cell assay for transposase-accessible chromatin sequencing on 5 lung samples to define altered chromatin accessibility of SPP1 macrophages. We predicted transcription factors regulating SPP1 macrophages using single-cell regulatory network inference and clustering (SCENIC) and determined transcription factor binding sites associated with global alterations in SPP1 chromatin accessibility using Signac/Seurat. We identified distinct macrophage subpopulations using scRNA-Seq analysis in healthy and SSc-ILD lungs and assessed gene expression changes during the change of healthy control macrophages into SPP1 macrophages. Analysis of open chromatin validated SCENIC predictions, indicating that microphthalmia-associated transcription factor, transcription factor EB, activating transcription factor 6, sterol regulatory element binding transcription factor 1, basic helix-loop-helix family member E40, Kruppel-like factor 6, ETS variant transcription factor 5, and/or members of the activator protein 1 family of transcription factors regulate SPP1 macrophage differentiation. Our findings shed light on the underlying changes in chromatin structure and transcription factor regulation of profibrotic SPP1 macrophages in SSc-ILD. Similar alterations in SPP1 macrophages may underpin fibrosis in other organs involved in SSc and point to novel targets for the treatment of SSc-ILD, specifically targeting profibrotic macrophages.

Additional points to consider before incorporating the Food and Drug Administration–approved therapies for systemic sclerosis–associated interstitial lung disease: comment on the article by Khanna et al

We congratulate the authors for the excellent review, not only restricted to recently approved therapies, on the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD) (1). However, it is our opinion that some aspects that currently affect our medical practice merit further commentary. The pandemic of COVID-19 has generated unique challenges in the therapy of SSc-ILD, especially impacting the decision to start treatment. While there is no evidence suggesting that cyclophosphamide or rituximab can reduce mortality in SSc-ILD (2), these drugs have been associated with higher incidence of serious outcomes and mortality in COVID-19 patients (3, 4).

Nintedanib in Patients With Systemic Sclerosis-Associated Interstitial Lung Disease: Subgroup Analyses by Autoantibody Status and Modified Rodnan Skin Thickness Score.

ObjectiveUsing data from the SENSCIS trial, these analyses were undertaken to assess the effects of nintedanib versus placebo in subgroups of patients with systemic sclerosis–associated interstitial lung disease (SSc‐ILD), based on characteristics previously identified as being associated with the progression of SSc‐ILD.MethodsPatients with SSc‐ILD were randomized to receive either nintedanib or placebo, stratified by anti–topoisomerase I antibody (ATA) status. We assessed the rate of decline in forced vital capacity (FVC) (expressed in ml/year) over 52 weeks in subgroups based on baseline ATA status, modified Rodnan skin thickness score (MRSS) (<18 versus ≥18), and SSc subtype (limited cutaneous SSc [lcSSc] versus diffuse cutaneous SSc [dcSSc]).ResultsAt baseline, 60.8% of 576 patients who received treatment with either nintedanib or placebo were positive for ATA, 51.9% had dcSSc, and 77.5% of 574 patients with MRSS data available had an MRSS of <18. The effect of nintedanib versus placebo on reducing the rate of decline in FVC (ml/year) was numerically more pronounced in ATA‐negative patients compared to ATA‐positive patients (adjusted difference in the rate of FVC decline, 57.2 ml/year [95% confidence interval (95% CI) –3.5, 118.0] versus 29.9 ml/year [95% CI –19.1, 78.8]), in patients with a baseline MRSS ≥18 compared to those with a baseline MRSS of <18 (adjusted difference in the rate of FVC decline, 88.7 ml/year [95% CI 7.7, 169.8] versus 26.4 ml/year [95% CI –16.8, 69.6]), and in patients with dcSSc compared to those with lcSSc (adjusted difference in the rate of FVC decline, 56.6 ml/year [95% CI 3.2, 110.0] versus 25.3 ml/year [95% CI –28.9, 79.6]). However, all exploratory interaction P values were nonsignificant (all P > 0.05), indicating that there was no heterogeneity in the effect of nintedanib versus placebo between these subgroups of patients.ConclusionIn patients with SSc‐ILD, reduction in the annual rate of decline in FVC among patients receiving nintedanib compared to those receiving placebo was not found to be heterogenous across subgroups based on ATA status, MRSS, or SSc subtype.

Diagnosis and monitoring of systemic sclerosis-associated interstitial lung disease using high-resolution computed tomography.

Patients with systemic sclerosis are at high risk of developing systemic sclerosis–associated interstitial lung disease. Symptoms and outcomes of systemic sclerosis–associated interstitial lung disease range from subclinical lung involvement to respiratory failure and death. Early and accurate diagnosis of systemic sclerosis–associated interstitial lung disease is therefore important to enable appropriate intervention. The most sensitive and specific way to diagnose systemic sclerosis–associated interstitial lung disease is by high-resolution computed tomography, and experts recommend that high-resolution computed tomography should be performed in all patients with systemic sclerosis at the time of initial diagnosis. In addition to being an important screening and diagnostic tool, high-resolution computed tomography can be used to evaluate disease extent in systemic sclerosis–associated interstitial lung disease and may be helpful in assessing prognosis in some patients. Currently, there is no consensus with regards to frequency and scanning intervals in patients at risk of interstitial lung disease development and/or progression. However, expert guidance does suggest that frequency of screening using high-resolution computed tomography should be guided by risk of developing interstitial lung disease. Most experienced clinicians would not repeat high-resolution computed tomography more than once a year or every other year for the first few years unless symptoms arose. Several computed tomography techniques have been developed in recent years that are suitable for regular monitoring, including low-radiation protocols, which, together with other technologies, such as lung ultrasound and magnetic resonance imaging, may further assist in the evaluation and monitoring of patients with systemic sclerosis–associated interstitial lung disease. A video abstract to accompany this article is available at: https://www.globalmedcomms.com/respiratory/Khanna/HRCTinSScILD

Systemic Sclerosis Associated Interstitial Lung Disease and Nintedanib: A Rare Disease and a Promising Drug.

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is a rare disease with a progressive nature, eventually leading to lung fibrosis. Nintedanib, a tyrosine kinase inhibitor, is a widely accepted drug for treating idiopathic pulmonary fibrosis (IPF), a disease that shares some similarities with SSc-ILD regarding pathological disease processes. In this review, we aim to discuss the pathogenesis of SSc-ILD and the overall role of nintedanib in the management of SSc-ILD. SSc-ILD involves multiple pathological mediators contributing to various pathways that ultimately cause lung fibrosis. The pathogenesis of SSc-ILD is a complex phenomenon and still needs further study. Nintedanib has demonstrated its efficacy in the treatment of SSc-ILD by reducing the progression of the pathological process. It has also proven its clinical significance in the management of SSc-ILD. However, the currently available literature does not have any evidence to compare the effectiveness of nintedanib with the already available treatment modalities such as cyclophosphamide (CYC), mycophenolate mofetil (MMF), and azathioprine (AZT). The current literature also lacks information about nintedanib's long-term consequences on patients with SSc-ILD. Therefore, to create better evidence-based treatment guidelines, we recommend that researchers conduct randomized clinical trials comparing nintedanib to MMF, CYC, AZT, etc., and continue surveillance to explore the long-term consequences of nintedanib.

Evaluation of mean platelet volume before and after cyclophosphamide treatment in systemic sclerosis associated interstitial lung disease

Aim: Studies carried out in patients with systemic sclerosis (SSc) have shown that mean platelet volume (MPV) is associated with more advanced stage of SSc. However, the effect of cyclophosphamide (CP) on MPV in systemic sclerosis-associated interstitial lung disease (SSc-ILD) is less clear. In this study, we aimed to investigate the MPV response to CP treatment in SSc-ILD. Methods: Thirty-eight SSc-ILD patients who responded positively to CP were included in this retrospective cohort study. MPV values before the treatment were compared with third, sixth, and ninth months’ values during treatment. Results: Over the nine-year period, 82 patients were diagnosed with SSc in the rheumatology clinic of our hospital. Forty-three of them had SSc-ILD and all were administered CP treatment for 9 months. Thirty-eight clinically benefited from CP, among which 32 were females (84%) and 6 (16%) were males. The MPV levels in SSc-ILD patients after CP (9.44 fL) were significantly higher than those before CP (7.89 fL) (P=0.001). Conclusion: Cyclophosphamide treatment causes an increase in MPV in SSc-ILD. MPV, a negative acute phase reactant, is considered an independent risk factor for coronary and peripheral artery diseases. Patients receiving CP should be followed more closely for such diseases.

SAT0198 Rituximab for the Treatment of Systemic Sclerosis Associated Interstitial Lung Disease: a Case Series

BackgroundRituximab (RTX) is a chimeric mAb against human CD20 that depletes peripheral B cells and introduced for systemic rheumatic diseases. Basic research and clinical studies have provided preliminary data pointing...

FRI0254 Prognosis factors for survival and progression-free survival in systemic sclerosis–associated interstitial lung disease

BackgroundSystemic sclerosis-associated interstitial lung disease (SSc-ILD) is one of the leading cause of morbi-moratlity in SSc. Progression of ILD is variable among patients and some prognosis factors of mortality and...

Bronchoalveolar lavage cellular profiles in patients with systemic sclerosis–associated interstitial lung disease are not predictive of disease progression

To evaluate the prognostic value of bronchoalveolar lavage (BAL) cellular profiles in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). BAL cellularity was examined in relation to mortality (n = 141), serial pulmonary function findings (n = 134), and "progression-free survival" (n = 134), by proportional hazards analysis. Baseline severity was quantified according to the extent of disease on high-resolution computed tomography, the diffusing capacity for carbon monoxide, and the presence or absence of pulmonary hypertension. Mortality was subclassified into overall mortality (during 10 years of followup), early mortality (occurring within 2 years of presentation), and late mortality (occurring 2-10 years after presentation). Overall mortality was associated with neutrophilia on BAL (hazard ratio 2.23 [95% confidence interval 1.20-4.14], P = 0.01), but this effect was lost when disease severity was taken into account. Early mortality was associated with neutrophilia on BAL (hazard ratio 8.40 [95% confidence interval 1.91-36.95], P = 0.005), independent of disease severity. Late mortality was not associated with neutrophilia on BAL. The presence of neutrophilia on BAL was not associated with time to decline in pulmonary function or progression-free survival. Neither eosinophilia nor lymphocytosis on BAL was associated with mortality, rapidity of functional deterioration, or progression-free survival. These findings were unaltered when treatment status was taken into account. BAL findings provide only limited prognostic information in SSc-ILD. Neutrophilia on BAL is linked to early mortality, but BAL findings are not linked to long-term survival or the rapidity of progression of lung disease. The usefulness of BAL to define alveolitis in SSc is questionable.