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Background: The American Thoracic Society convened an international multidisciplinary panel to develop clinical practice guidelines for the treatment of systemic sclerosis–associated interstitial lung disease (SSc-ILD). Objective: To conduct a systematic review and evaluate the literature to determine whether patients with SSc-ILD should be treated with nintedanib alone or with the combination of nintedanib plus mycophenolate. Data Sources: Literature searches were conducted across MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases through June 2022 for studies using nintedanib or nintedanib plus mycophenolate to treat patients with SSc-ILD. Data Extraction: Mortality, disease progression, quality of life, and adverse event data were extracted, and meta-analysis was performed when possible. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group method was used to assess the quality of evidence. Synthesis: For nintedanib therapy alone, the systematic review included three total studies and revealed that disease progression was less in the nintedanib arm (the annual rate of decline in forced vital capacity [FVC] was 44.5 ml less, the absolute change from baseline was 46.4 ml less, and FVC% predicted was 1.2% less in the nintedanib arm) compared with placebo. However, gastrointestinal side effects and treatment discontinuation were double in the nintedanib arm compared with placebo. For combination therapy, the systematic review also included three total studies and revealed that changes in the annual rate of decline in FVC favored combination therapy over placebo (mean difference, 79.1 ml). Combination therapy was, however, associated with increased gastrointestinal adverse effects compared with placebo. The quality of evidence for all outcomes was very low as per GRADE. Conclusions: The use of nintedanib alone and in combination with mycophenolate in patients with SSc-ILD is associated with a significant reduction in disease progression compared with placebo but at the cost of increased gastrointestinal side effects and treatment discontinuation. The quality of evidence is very low. [ABSTRACT FROM AUTHOR]

P+ monolayers in Si are of great scientific and technological interest, both intrinsically as a material in the "ideal vacuum" of crystalline Si and because they are showing great promise as qubits of electron and nuclear spin. The GHz complex conductivity σ(ω) can allow one to elucidate basic physical properties and is also important for fast devices, but measuring σ(ω) in 2D materials has not been easy. We report on such measurements, including showing (i) qualitatively a lack of any resonances up to 5 GHz (indicating no energy splittings below about 0.02 meV); and (ii) the quantitatively ideal Drude behavior of this novel material up to 5 GHz, showing a lower bound on the scattering rate of about 2 × 1010 s−1. We also discuss deconvolving the confounding effect of the distributed resistance and capacitance of the monolayer. [ABSTRACT FROM AUTHOR]

Background: The American Thoracic Society (ATS) convened an international, multidisciplinary panel to develop clinical practice guidelines for the treatment of systemic sclerosis--associated interstitial lung disease (SSc-ILD). Objective: To conduct a systematic review and evaluate the literature to determine the impact of treating patients with SSc-ILD with tocilizumab on prespecified critical and important outcomes determined by the ATS guideline panel. Data Sources: A literature search was conducted across MEDLINE, EMBASE, and Cochrane databases through June 2022 for studies using tocilizumab to treat patients with SSc-ILD. Data Extraction: Mortality and disease progression were determined to be critical outcomes of focus, with quality of life and adverse events important outcomes. Data on these outcomes were extracted and meta-analyses performed using the generic inverse variance method when possible. The Grading of Recommendations, Assessment, Development, and Evaluation Working Group method was used to assess the quality of evidence. Synthesis: The literature review resulted in five studies for inclusion. The absolute decrease from baseline in forced vital capacity (FVC) for the tocilizumab arm was 118ml, 241ml, and 129ml less than the placebo arm at 24, 48, and 96weeks, respectively, favoring tocilizumab. The mean decrease in FVC% predicted at 48weeks was 6.50% less and the risk of decrease .10% was 66% less in the tocilizumab arm, whereas patients were 1.97 times more likely to have any increase in FVC% predicted if they received tocilizumab in place of placebo. When the placebo arm was given tocilizumab from 48 to 96weeks, the mean change in absolute FVC was 54.90ml less and the mean change in FVC% predicted was 1.30% less. For diffusing capacity of the lung for carbon monoxide (DLCO)% predicted, at 48weeks there was 1.50% less change and from 48 to 96weeks there was 5.40% less change in the tocilizumab arm. Quantitative Interstitial Lung Disease scores and Quantitative Lung Fibrosis scores at 48weeks and modified Rodnan skin scores at 72weeks all favored the tocilizumab arm, as did several adverse event parameters, including serious adverse events (mean difference, 227.40; 95% confidence interval, 230.10 to 224.70). The quality of evidence was very low grade. Conclusions: Tocilizumab use in patients with SSc-ILD is associated with less disease progression and a better toxicity profile than placebo. However, the quality of evidence is very low, and large prospective studies dedicated to assessing tocilizumab specifically for SSc-ILD are needed. [ABSTRACT FROM AUTHOR]

Background: The American Thoracic Society convened an international, multidisciplinary panel to develop clinical practice guidelines for the treatment of systemic sclerosis--associated interstitial lung disease (SSc-ILD). Objective: To conduct a systematic review and evaluate the literature to determine whether patients with SSc-ILD should be treated with rituximab. Data Sources: A literature search was conducted across MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases through June 2022 for studies using rituximab to treat patients with SSc-ILD. Data Extraction: Disease progression, quality of life, mortality, and adverse event data were extracted. The intervention was rituximab. The standard-of-care comparator group was decided a priori by consensus of the panel as either placebo or mycophenolate. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group approach was used to assess the quality of evidence. Synthesis: Three relevant studies were selected. Rituximab significantly improved the forced vital capacity % predicted (mean difference, 3.13; 95% confidence interval [CI], 0.37 to 5.90) and the modified Rodnan Skin Score (mean difference, 27.01; 95% CI, 11.46 to 22.56) at 24--48 weeks. Conclusions: Rituximab use in patients with SSc-ILD is associated with stabilization of lung function. The quality of evidence for study outcomes was considered to be very low, as defined by the GRADE approach. Additional research on treatment with rituximab is imperative. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung disease (ILD) is a significant cause of morbidity and mortality in patients with systemic sclerosis (SSc). To date, clinical practice guidelines regarding treatment for patients with SSc-ILD are primarily consensus based. Methods: An international expert guideline committee composed of 24 individuals with expertise in rheumatology, SSc, pulmonology, ILD, or methodology, and with personal experience with SSc-ILD, discussed systematic reviews of the published evidence assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Predetermined conflict-of-interest management strategies were applied, and recommendations were made for or against specific treatment interventions exclusively by the nonconflicted panelists. The confidence in effect estimates, importance of outcomes studied, balance of desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention, and implications for health equity were all considered in making the recommendations. This was in accordance with the American Thoracic Society guideline development process, which is in compliance with the Institute of Medicine standards for trustworthy guidelines. Results: For treatment of patients with SSc-ILD, the committee: 1) recommends the use of mycophenolate; 2) recommends further research into the safety and efficacy of (a) pirfenidone and (b) the combination of pirfenidone plus mycophenolate; and 3) suggests the use of (a) cyclophosphamide, (b) rituximab, (c) tocilizumab, (d) nintedanib, and (e) the combination of nintedanib plus mycophenolate. Conclusions: The recommendations herein provide an evidence-based clinical practice guideline for the treatment of patients with SSc-ILD and are intended to serve as the basis for informed and shared decision making by clinicians and patients. [ABSTRACT FROM AUTHOR]

The article reports a systematic review and meta-analysis on the use of cyclophosphamide in patients with systemic sclerosis-associated interstitial lung disease. Key topics include risk of bias in randomized controlled trials, summary of evidence for cyclophosphamide versus placebo, and important outcomes such as adverse events and changes in pulmonary function.

The article reports on the creation of an evidence-based clinical practice guideline for the treatment of systemic sclerosis–associated interstitial lung disease in 2023 Topics include recommendations for therapies such as cyclophosphamide, mycophenolate, rituximab, tocilizumab, nintedanib, and pirfenidone, with an emphasis on patient preferences, and the conclusions underscore the need for further research to determine optimal treatment combinations and initiation timing.

Advances in pulmonary arterial hypertension therapies have led to improvements in the quality of life and survival for patients with idiopathic pulmonary arterial hypertension, but these trends have not uniformly translated to patients with systemic sclerosis-associated pulmonary arterial hypertension. In order to better understand the heterogeneity in treatment response and survival, we aimed to examine the histological and immunophenotypic differences between the systemic sclerosis-associated pulmonary arterial hypertension and idiopathic pulmonary arterial hypertension pulmonary vasculopathies. We performed a semi-quantitative lung morphometry-based analysis comparing sections obtained from systemic sclerosis-associated pulmonary arterial hypertension (n = 24), idiopathic pulmonary arterial hypertension (n = 9), and control (n = 13) bio-banked lung tissue specimens. H&E (Hematoxylin and Eosin) and VVG (Verhoeff-Van Gieson)-stained lung sections were analyzed for interstitial and vascular pathology. Immunohistochemistry was used to stain for an array of inflammatory and fibrosis mediators. Baseline demographic and hemodynamic data for each patient were collected via chart review at the time of lung explantation. Plexiform lesions were present in 5/9 (55%) of idiopathic pulmonary arterial hypertension samples, but absent in all systemic sclerosis-associated pulmonary arterial hypertension samples (0/24). Systemic sclerosis-associated pulmonary arterial hypertension lungs demonstrated significantly worse interstitial fibrosis (p = 0.0001) and interstitial cellularity (p = 0.0002) compared to idiopathic pulmonary arterial hypertension lungs. The degree of smooth muscle hypertrophy and pulmonary artery intimal proliferation were not different between systemic sclerosis-associated pulmonary arterial hypertension and idiopathic pulmonary arterial hypertension lungs. Immunohistochemistry analysis revealed that systemic sclerosis-associated pulmonary arterial hypertension lungs exhibited increased interstitial infiltration of CD3 T-cells (p = 0.009), CD20 B-cells (p = 0.01), and CD163 macrophages (p = 0.048) when compared to idiopathic pulmonary arterial hypertension and control lungs. Systemic sclerosis-associated pulmonary arterial hypertension lungs display a distinct pulmonary vascular pathology as well as significant interstitial fibrosis when compared to idiopathic pulmonary arterial hypertension lungs., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Objective: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment., Methods: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. α-Smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay., Results: By week 14, cGMP increased by 94 (78)% with riociguat and 10 (39)% with placebo (P < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (P = 0.004 and P = 0.008, respectively). There were no differences in skin collagen markers between the two groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies was associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively)., Conclusion: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis., Trial Registration: Clinicaltrials.gov, NCT02283762., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)