Dataset Information

Early Radiographic Progression of Scleroderma: Lung Disease Predicts Long-term Mortality.

ABSTRACT:

Background

Radiographic end points commonly are included in therapeutic trials for systemic sclerosis (SSc)-interstitial lung disease (ILD); however, the relationship between these outcomes and long-term mortality is unclear.

Research question

Do short-term changes in radiographic measures of ILD predict long-term survival in patients with SSc?

Study design and methods

The Scleroderma Lung Study (SLS) I and II evaluated the safety and efficacy of cyclophosphamide (in SLS I and II) and mycophenolate mofetil (in SLS II) for the treatment of SSc-ILD. Changes in the extent of ILD over time were assessed on high-resolution CT scans of the chest by quantitative image analysis, an approach that applies a computer-based algorithm to assess changes in the radiographic extent of ILD objectively. Participants subsequently were followed for up to 12 years (SLS I) and 8 years (SLS II). Cox proportional hazards models determined whether the change in the quantitative radiographic extent of ILD predicted survival, adjusting for other known predictors of survival.

Results

Among SLS I and II participants, 82 and 90 had follow-up imaging scans, respectively, and were included in the analysis. Participants in both trials who showed an increase in the total quantitative radiographic extent of ILD scores of ≥ 2% at 12 months (SLS I) or 24 months (SLS II) experienced significantly worse long-term survival than those with change scores of < 2% (P ≤ .01, log-rank test). In the multivariate Cox models, radiographic progression remained associated with worse long-term survival in SLS I (P = .089) and SLS II (P = .014).

Interpretation

Data from two independent clinical trial cohorts with extensive long-term follow-up demonstrated that radiographic progression of ILD over 12 to 24 months, in both treatment and placebo arms, can predict increased risk for long-term mortality in patients with SSc. These findings suggest that radiographic end points may serve as surrogates for mortality in SSc-ILD.

SUBMITTER: Volkmann ER

PROVIDER: S-EPMC9131045 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Early Radiographic Progression of Scleroderma: Lung Disease Predicts Long-term Mortality.

Volkmann Elizabeth R ER Tashkin Donald P DP Roth Michael D MD Goldin Jonathan J Kim Grace H J GHJ

Chest 20211208 5

<h4>Background</h4>Radiographic end points commonly are included in therapeutic trials for systemic sclerosis (SSc)-interstitial lung disease (ILD); however, the relationship between these outcomes and long-term mortality is unclear.<h4>Research question</h4>Do short-term changes in radiographic measures of ILD predict long-term survival in patients with SSc?<h4>Study design and methods</h4>The Scleroderma Lung Study (SLS) I and II evaluated the safety and efficacy of cyclophosphamide (in SLS I ...[more]

PMID: 34896093

Similar Datasets

Project description:ObjectiveSystemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterized by variable clinical outcomes, activation of innate immune pattern-recognition receptors (PRRs), and accumulation of α-smooth muscle actin (α-SMA)-expressing myofibroblasts. The aim of this study was to identify an association between these entities and mitochondrial DNA (mtDNA), an endogenous ligand for the intracellular DNA-sensing PRRs Toll-like receptor 9 (TLR-9) and cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING), which has yet to be determined.MethodsHuman lung fibroblasts (HLFs) from normal donors and SSc-ILD explants were treated with synthetic CpG DNA and assayed for α-SMA expression and extracellular mtDNA using quantitative polymerase chain reaction for the human MT-ATP6 gene. Plasma MT-ATP6 concentrations were evaluated in 2 independent SSc-ILD cohorts and demographically matched controls. The ability of SSc-ILD and control plasma to induce TLR-9 and cGAS/STING activation was evaluated with commercially available HEK 293 reporter cells. Plasma concentrations of type I interferons (IFNs), interleukin-6 (IL-6), and oxidized DNA were measured using electrochemiluminescence and enzyme-linked immunosorbent assay-based methods. Extracellular vesicles (EVs) precipitated from plasma were evaluated for MT-ATP6 concentrations and proteomics via liquid chromatography mass spectrometry.ResultsNormal HLFs and SSc-ILD fibroblasts developed increased α-SMA expression and MT-ATP6 release following CpG stimulation. Plasma mtDNA concentrations were increased in the 2 SSc-ILD cohorts, reflective of ventilatory decline, and were positively associated with both TLR-9 and cGAS/STING activation as well as type I IFN and IL-6 expression. Plasma mtDNA was not oxidized and was conveyed by EVs displaying a proteomics profile consistent with a multicellular origin.ConclusionThese findings demonstrate a previously unrecognized connection between EV-encapsulated mtDNA, clinical outcomes, and intracellular DNA-sensing PRR activation in SSc-ILD. Further study of these interactions could catalyze novel mechanistic and therapeutic insights into SSc-ILD and related disorders.

Dataset Information

Early Radiographic Progression of Scleroderma: Lung Disease Predicts Long-term Mortality.

Background

Research question

Study design and methods

Results

Interpretation

Publications

Early Radiographic Progression of Scleroderma: Lung Disease Predicts Long-term Mortality.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets