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ObjectiveTo investigate the prevalence of the MUC5B promoter variant rs35705950 in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) and whether its presence predicts response to immunosuppression with cyclophosphamide (CYC) and mycophenolate (MMF).MethodsSSc-ILD patients who participated in Scleroderma Lung Study (SLS) II (MMF versus CYC) were included in this study (N = 142). TaqMan Genotyping Assays were used to determine the MUC5B rs35705950 single nucleotide polymorphism. Joint models were created to examine how the presence of this variant affected the course of the forced vital capacity (FVC) over 2 years. Linear regression models were used to investigate the relationship between the presence of this variant and the change in quantitative radiographic fibrosis.ResultsAmong 128 participants who were tested for this variant, 18% possessed at least one copy of the MUC5B minor allele. Patients with at least one copy of this allele were similar to those without the allele with respect to age, sex, SSc subtype, ILD disease severity; however, this variant was rare among African Americans (3.7%). The presence of the MUC5B variant did not affect the course of the FVC, nor the change in quantitative radiographic fibrosis, ground glass or ILD scores in either treatment arm.ConclusionIn the context of a randomized controlled trial for SSc-ILD, the presence of the MUC5B variant did not predict disease severity, nor affect treatment response to MMF or CYC. Future studies are needed to determine whether this variant affects ILD progression in other SSc cohorts and in patients receiving anti-fibrotic therapy.

ObjectiveTo investigate the relationship between Krebs von den Lungen 6 (KL-6) and CCL18 levels and the severity and progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD).MethodsPatients enrolled in the Scleroderma Lung Study II (cyclophosphamide [CYC] versus mycophenolate mofetil [MMF]) were included. Baseline and 12-month plasma samples were analyzed by enzyme-linked immunosorbent assay to assess CCL18 and KL-6 levels. The forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLco) were measured every 3 months. Joint models were created to investigate the relationship between baseline CCL18 and KL-6 levels and the course of the FVC and DLco over 1 year according to treatment arm.ResultsBaseline KL-6 and CCL18 levels each correlated with the extent of radiographic fibrosis. Levels of both CCL18 and KL-6 declined significantly at 1 year. In both treatment arms (n = 71 for CYC, n = 62 for MMF), a higher baseline KL-6 level predicted progression of ILD based on the course of FVC (P = 0.024 for CYC; P = 0.005 for MMF) and DLco (P < 0.001 for CYC; P = 0.004 for MMF) over 1 year. A higher baseline CCL18 level predicted progression of ILD based on the course of the FVC (P < 0.001 for CYC; P = 0.007 for MMF) and DLco (P = 0.001 for CYC; P < 0.001 for MMF) over 1 year, as well as mortality (P = 0.0008 for CYC arm only).ConclusionIn a rigorously conducted clinical trial for SSc-related ILD, KL-6 and CCL18 levels correlated with ILD severity and declined with immunosuppression. Patients with higher baseline KL-6 and CCL18 levels were more likely to experience disease progression despite treatment. KL-6 and CCL18 levels could be used to identify patients with a progressive ILD phenotype who may benefit from a more aggressive initial treatment approach.

BackgroundIncreased circulatory levels of the chemokine CXCL4 have been associated with the presence of interstitial lung disease (ILD) in an observational study of patients with systemic sclerosis (SSc). The purpose of the present study was to evaluate the relationship between baseline CXCL4 level and extent of ILD in the context of a randomized controlled trial and to determine whether changes in CXCL4 levels in response to immunosuppression are associated with future progression of SSc-ILD.MethodsA total of 142 SSc-ILD patients from Scleroderma Lung Study (SLS) II were randomized in a double-blind, parallel-arm trial, to receive mycophenolate (MMF) for 2 years or oral cyclophosphamide (CYC) for 1 year followed by 1 year of placebo. Plasma CXCL4 levels were measured at baseline, 12 months, and 24 months in SLS II participants (N = 136) and at a single time point in healthy controls (N = 67). A mixed-effects model evaluated the relationship between change in CXCL4 levels and SSc-ILD progression. The primary outcome was the course of the forced vital capacity.ResultsBaseline CXCL4 levels were significantly higher in SSc-ILD patients compared with healthy controls (2699 ± 1489 ng/ml vs 2233 ± 1351 ng/ml (mean ± SD); P = 0.019). However, no significant correlations were identified between CXCL4 levels and extent of ILD at baseline, as measured by the forced vital capacity, diffusing capacity of carbon monoxide, or radiographic extent of ILD. Plasma CXCL4 decreased significantly from baseline to 12 months in all patients (CYC: P

Objectives: Determine relationships between skin gene expression and systemic sclerosis (SSc) clinical disease features, and changes in skin gene expression over time.Methods: A total of 339 forearm skin biopsies were obtained from 113 SSc patients and 44 matched healthy controls. 105 SSc patients had a second biopsy, and 76 had a third biopsy. Global gene expression profiling was performed, and differentially expressed genes and cell type-specific signatures in SSc were evaluated for relationships to modified Rodnan Skin Score (mRSS) and other clinical variables. Changes in skin gene expression over time were analysed by mixed effects models and principal component analysis. Immunohistochemical staining was performed to validate conclusions.Results: Gene expression dysregulation was greater in SSc patients with affected skin than in those with unaffected skin. Immune cell and fibroblast signatures positively correlated with mRSS. High baseline immune cell and fibroblast signatures predicted higher mRSS over time, but were not independently predictive of longitudinal mRSS after adjustment for baseline mRSS. In early diffuse cutaneous SSc, immune cell and fibroblast signatures declined over time, and overall skin gene expression trended towards normalisation. On immunohistochemical staining, most early diffuse cutaneous SSc patients with high baseline T cell and macrophage numbers had declines in these numbers at follow-up.Conclusions: Skin thickness in SSc is related to dysregulated immune cell and fibroblast gene expression. Skin gene expression changes over time in early diffuse SSc, with a tendency towards normalisation. These observations are relevant for understanding SSc pathogenesis and could inform treatment strategies and clinical trial design. [ABSTRACT FROM AUTHOR]

Objectives: Determine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease., Methods: Skin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated., Results: SSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression., Conclusions: Skin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design., Competing Interests: Competing interests: DK reports consultancy fees from Acceleron, Actelion, Bayer, Blade Therapeutics, BMS, Galapagos, Genentech/Roche, GSK, Mitsubishi Tanabi, Sanofi-A ventis/Genzyme, and UCB Pharma, and reports grants from Bayer, BMS, and Genentech/Roche outside the submitted work, and reports ownership interest in Eicos Sciences, Inc. WRS reports consulting fees from UT Health Science Center at Houston. JKG reports grants from Corbus Pharmaceuticals, Cumberland Pharmaceuticals and Eicos Pharmaceuticals outside the submitted work. AAS reports support from Sanofi outside the submitted work. MLW reports grants and personal fees from Celdara Medical, LLC and personal fees from Abbvie, Acceleron, BMS, Corbus Pharmaceuticals and Boehringer Ingelheim outside the submitted work. JLB reports grants from Hoffman La Roche and the Scleroderma Foundation outside the submitted work. SB and PB are employees of Boehringer Ingelheim. FVC reports personal fees from Boehringer Ingelheim outside the submitted work. EJB reports a grant from Pfizer and support from Bohringer Ingelheim, Corbus Pharmaceuticals and Eicos outside the submitted work. MDM reports personal fees from Medtelligence, Actelion Pharma, Astellas, Mitsubishi-Tanabe, and Boehringer Ingelheim and grants from Bayer, Reata, Sanofi, Corbus, Eicos and Boehringer Ingelheim outside the submitted work. SA reports personal fees from Boehringer Ingelheim and grants from Boehringer Ingelheim, Bayer and Momenta outside the submitted work., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)