Anticentromere antibody levels and isotypes and the development of systemic sclerosis

Objective Little is known on the disease course of very early systemic sclerosis (SSc). Among the information yet to be elucidated is whether anticentromere antibody (ACA) isotype levels can serve as biomarkers for future SSc development and for organ involvement. This study was undertaken to evaluate whether IgG, IgM, and IgA ACA levels in IgG ACA-positive patients are associated with disease severity and/or progression from very early SSc to definite SSc. Methods IgG ACA-positive patients from 5 different cohorts who had very early SSc or SSc fulfilling the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 criteria were included. A diagnosis of very early SSc was based on the presence of IgG ACAs and Raynaud's phenomenon, and/or puffy fingers and/or abnormal nailfold capillaroscopy, but not fulfilling the ACR/EULAR 2013 criteria for SSc. Multivariable regression analyses were performed to determine the association between baseline ACA isotype levels and progression to definite SSc with organ involvement. Results Six hundred twenty-five IgG ACA-positive patients were included, of whom 138 (22%) fulfilled the criteria for very early SSc and 487 (78%) had definite SSc. Levels of IgG ACAs (odds ratio 2.5 [95% confidence interval 1.8-3.7]) and IgM ACAs (odds ratio 1.8 [95% confidence interval 1.3-2.3]) were significantly higher in patients with definite SSc. Of 115 patients with very early SSc with follow-up, progression to definite SSc occurred within 5 years in 48 (42%). Progression to definite SSc was associated with higher IgG ACA levels at baseline (odds ratio 4.3 [95% confidence interval 1.7-10.7]). Conclusion ACA isotype levels may serve as biomarkers to identify patients with very early SSc who are at risk for disease progression to definite SSc.Pathophysiology and treatment of rheumatic disease

Does the impact of COVID-19 on patients with systemic sclerosis change over time?

ObjectiveThe outcome of patients with COVID-19 improved over the pandemic, including patients with systemic rheumatic diseases. However, data on patients with systemic sclerosis (SSc) are lacking. This study aimed to assess the outcome of patients with both SSc and COVID-19 over several waves.MethodsPatients with both SSc and COVID-19 who were registered in the European Scleroderma Trials and Research group (EUSTAR) were collected between April 2020 and April 2021. Patients were assigned to waves 1, 2, or 3 depending on the date of their COVID-19 diagnosis. Primary endpoints were death, intensive care unit stay, or ventilatory support (severe outcome). Subgroup analyses of patients who were hospitalized or died were conducted. General and SSc-specific characteristics and treatment were compared over the waves. Descriptive statistics and multivariate logistic regression were applied.ResultsA total of 333 patients were included; 57 patients (17%) had a severe outcome, and 30 patients (9%) died. Compared to wave 1, significantly fewer patients with SSc suffered from severe COVID-19 in waves 2 and 3 (28.2% vs 9.8% and 12.7%; P P P = 0.001), and fewer patients died (15.7% vs 5.0% and 7.5%; P = 0.011). Patients were significantly younger, more often men, had less frequent arterial hypertension, and less SSc cardiac involvement over waves 1 to 3. Patients received significantly less medium to high doses of corticosteroids as they did SSc treatment.ConclusionThe outcome of patients with both SSc and COVID-19 improved significantly over time because of intrinsic and extrinsic factors.Pathophysiology and treatment of rheumatic disease

Scleroderma Skin: How Is Treatment Best Guided by Data and Implemented in Clinical Practice?

As skin involvement is the hall mark of systemic sclerosis (SSc) and changes of skin involvement have shown to correlate with internal organ involvement, assessing the extend of skin involvement is key. Although the modified Rodnan skin score is a validated tool used to evaluate the skin in SSc, it has its drawbacks. Novel imagine methods are promising but should be further evaluated. As for molecule markers for skin progression there are conflicting data on the predictive significance of baseline SSc skin gene expression profiles, but immune cell type signature in SSc skin correlates with progression

Systemic sclerosis in the time of COVID-19

The COVID-19 pandemic represents one of the biggest challenges of the 21st century. In addition to the general effect on society and health-care systems, patients with systemic sclerosis and their physicians face specific challenges related to the chronic nature of their disease, the involvement of multiple organs, and the use of immunosuppressive treatments. Data from registries and single centre cohorts indicate that the risk of contracting SARS-CoV-2 does not seem to increase substantially in people with systemic sclerosis; conversely, severe COVID-19 outcomes are seen more frequently in these patients than in the general population. Vaccination against SARS-CoV-2 is therefore highly recommended for patients with systemic sclerosis; however, no specific recommendations are available regarding the different vaccine platforms. Both patients and physicians should be aware that the effectiveness of vaccines might be reduced in patients taking immunosuppressive therapy, because antibody responses might be blunted, specifically in patients treated with rituximab and mycophenolate mofetil.Pathophysiology and treatment of rheumatic disease

Systemic sclerosis in the time of COVID-19

The COVID-19 pandemic represents one of the biggest challenges of the 21st century. In addition to the general effect on society and health-care systems, patients with systemic sclerosis and their physicians face specific challenges related to the chronic nature of their disease, the involvement of multiple organs, and the use of immunosuppressive treatments. Data from registries and single centre cohorts indicate that the risk of contracting SARS-CoV-2 does not seem to increase substantially in people with systemic sclerosis; conversely, severe COVID-19 outcomes are seen more frequently in these patients than in the general population. Vaccination against SARS-CoV-2 is therefore highly recommended for patients with systemic sclerosis; however, no specific recommendations are available regarding the different vaccine platforms. Both patients and physicians should be aware that the effectiveness of vaccines might be reduced in patients taking immunosuppressive therapy, because antibody responses might be blunted, specifically in patients treated with rituximab and mycophenolate mofetil

Safety and tolerability of nintedanib in patients with interstitial lung diseases in subgroups by sex: a post-hoc analysis of pooled data from four randomised controlled trials

Background Nintedanib is a tyrosine kinase inhibitor used in the treatment of progressive fibrosing interstitial lung diseases (ILDs). We assessed the safety and tolerability of nintedanib in patients with autoimmune disease-related ILDs and with other ILDs in subgroups by sex.Methods In this post-hoc analysis, we pooled data from the two INPULSIS trials in patients with idiopathic pulmonary fibrosis (IPF), the SENSCIS trial in patients with fibrosing ILDs associated with systemic sclerosis, and the INBUILD trial in patients with progressive fibrosing ILDs other than IPF. In each trial, patients were randomly assigned to receive oral nintedanib 150 mg twice daily or matched placebo. We assessed adverse events reported over 52 weeks in patients with autoimmune disease-related ILDs and other ILDs in subgroups by sex.Findings In these analyses, we included 746 patients with autoimmune disease-related ILDs (523 [70%] were female, 223 [30%] were male; 615 [82%] had systemic sclerosis), of whom 370 (50%) received nintedanib (268 [72%] female and 102 [28%] male patients) and 376 (50%) received placebo (255 [68%] female and 121 (32%] male patients); and 1554 patients with other ILDs (437 [28%J female, 1117 [72%] male; 1061 [68%] with IPF), of whom 888 (57%) received nintedanib (237 [27%] female and 651 [73%] male patients) and 666 (43%) received placebo (200 [30%]female and 466 [70%] male patients). Of 102 male and 268 female patients with autoimmune disease-related ILDs treated with nintedanib, nausea was reported in 21 (21%) male and 92 (34%) female patients, vomiting in 12 (12%) male and 73 (27%) female patients, alanine aminotransferase increase in four (4%) male and 31(12%) female patients, aspartate aminotransferase increase in three (3%) male and 23 (9%) female patients, and adverse events leading to dose reduction in 18 (18%) male and 101 (38%) female patients; 28 (27%) male and 107 (40%) female patients had at least one treatment interruption. Of 651 male and 237 female nintedanib-treated patients with other ILDs, nausea was reported in 135 (21%) male and 95 (40%) female patients, vomiting in 51 (8%) male and 70 (30%) female patients, alanine aminotransferase increase in 19 (3%) male and 31 (13%) female patients, aspartate aminotransferase increase in 17 (3%) male and 26 (11%) female patients, and adverse events leading to dose reduction in 106 (16%) male and 84 (35%) female patients; 155 (24%) male and 82 (35%) female patients had at least one treatment interruption. The proportions of patients with adverse events leading to discontinuation of nintedanib were similar between female and male patients with autoimmune disease-related ILDs (44 [16%] of 268 vs 17 [17%] of 102), but were greater among female than male patients with other ILDs (62 [26%] of 237 vs 112 [17%] of 651). Across subgroups by diagnosis and sex, diarrhoea was the most frequent adverse event associated with nintedanib (autoimmune-related ILDs: 198 [74%] of 268 female and 73 [72%] of 102 male patients; other ILDs: 155 [65%] of 237 female and 408 [63%] of 651 male patients), and was the event that most frequently led to treatment discontinuation (autoimmune-related ILDs: 20 [7%] female and five [5%] male patients; other ILDs: 16 [7%] female and 27 [4%] male patients).Interpretation The adverse event profile of nintedanib was generally similar between male and female patients with autoimmune disease-related ILDs, and between male and female patients with other ILDs, but nausea, vomiting, liver enzyme elevations, dose reductions, and treatment interruptions were more frequent in female patients than in male patients. Sex should be considered in the monitoring and management of adverse events that might be associated with nintedanib. Copyright (C) 2022 Elsevier Ltd. All rights reserved

Safety and tolerability of nintedanib in patients with interstitial lung diseases in subgroups by sex: a post-hoc analysis of pooled data from four randomised controlled trials

Background Nintedanib is a tyrosine kinase inhibitor used in the treatment of progressive fibrosing interstitial lung diseases (ILDs). We assessed the safety and tolerability of nintedanib in patients with autoimmune disease-related ILDs and with other ILDs in subgroups by sex.Methods In this post-hoc analysis, we pooled data from the two INPULSIS trials in patients with idiopathic pulmonary fibrosis (IPF), the SENSCIS trial in patients with fibrosing ILDs associated with systemic sclerosis, and the INBUILD trial in patients with progressive fibrosing ILDs other than IPF. In each trial, patients were randomly assigned to receive oral nintedanib 150 mg twice daily or matched placebo. We assessed adverse events reported over 52 weeks in patients with autoimmune disease-related ILDs and other ILDs in subgroups by sex.Findings In these analyses, we included 746 patients with autoimmune disease-related ILDs (523 [70%] were female, 223 [30%] were male; 615 [82%] had systemic sclerosis), of whom 370 (50%) received nintedanib (268 [72%] female and 102 [28%] male patients) and 376 (50%) received placebo (255 [68%] female and 121 (32%] male patients); and 1554 patients with other ILDs (437 [28%J female, 1117 [72%] male; 1061 [68%] with IPF), of whom 888 (57%) received nintedanib (237 [27%] female and 651 [73%] male patients) and 666 (43%) received placebo (200 [30%]female and 466 [70%] male patients). Of 102 male and 268 female patients with autoimmune disease-related ILDs treated with nintedanib, nausea was reported in 21 (21%) male and 92 (34%) female patients, vomiting in 12 (12%) male and 73 (27%) female patients, alanine aminotransferase increase in four (4%) male and 31(12%) female patients, aspartate aminotransferase increase in three (3%) male and 23 (9%) female patients, and adverse events leading to dose reduction in 18 (18%) male and 101 (38%) female patients; 28 (27%) male and 107 (40%) female patients had at least one treatment interruption. Of 651 male and 237 female nintedanib-treated patients with other ILDs, nausea was reported in 135 (21%) male and 95 (40%) female patients, vomiting in 51 (8%) male and 70 (30%) female patients, alanine aminotransferase increase in 19 (3%) male and 31 (13%) female patients, aspartate aminotransferase increase in 17 (3%) male and 26 (11%) female patients, and adverse events leading to dose reduction in 106 (16%) male and 84 (35%) female patients; 155 (24%) male and 82 (35%) female patients had at least one treatment interruption. The proportions of patients with adverse events leading to discontinuation of nintedanib were similar between female and male patients with autoimmune disease-related ILDs (44 [16%] of 268 vs 17 [17%] of 102), but were greater among female than male patients with other ILDs (62 [26%] of 237 vs 112 [17%] of 651). Across subgroups by diagnosis and sex, diarrhoea was the most frequent adverse event associated with nintedanib (autoimmune-related ILDs: 198 [74%] of 268 female and 73 [72%] of 102 male patients; other ILDs: 155 [65%] of 237 female and 408 [63%] of 651 male patients), and was the event that most frequently led to treatment discontinuation (autoimmune-related ILDs: 20 [7%] female and five [5%] male patients; other ILDs: 16 [7%] female and 27 [4%] male patients).Interpretation The adverse event profile of nintedanib was generally similar between male and female patients with autoimmune disease-related ILDs, and between male and female patients with other ILDs, but nausea, vomiting, liver enzyme elevations, dose reductions, and treatment interruptions were more frequent in female patients than in male patients. Sex should be considered in the monitoring and management of adverse events that might be associated with nintedanib. Copyright (C) 2022 Elsevier Ltd. All rights reserved.Pathophysiology and treatment of rheumatic disease

Anti‐centromere antibody levels and isotypes and the development of systemic sclerosis

Objective Little is known on the disease course of very early systemic sclerosis (SSc). Among the information yet to be elucidated is whether anticentromere antibody (ACA) isotype levels can serve as biomarkers for future SSc development and for organ involvement. This study was undertaken to evaluate whether IgG, IgM, and IgA ACA levels in IgG ACA-positive patients are associated with disease severity and/or progression from very early SSc to definite SSc. Methods IgG ACA-positive patients from 5 different cohorts who had very early SSc or SSc fulfilling the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 criteria were included. A diagnosis of very early SSc was based on the presence of IgG ACAs and Raynaud's phenomenon, and/or puffy fingers and/or abnormal nailfold capillaroscopy, but not fulfilling the ACR/EULAR 2013 criteria for SSc. Multivariable regression analyses were performed to determine the association between baseline ACA isotype levels and progression to definite SSc with organ involvement. Results Six hundred twenty-five IgG ACA-positive patients were included, of whom 138 (22%) fulfilled the criteria for very early SSc and 487 (78%) had definite SSc. Levels of IgG ACAs (odds ratio 2.5 [95% confidence interval 1.8-3.7]) and IgM ACAs (odds ratio 1.8 [95% confidence interval 1.3-2.3]) were significantly higher in patients with definite SSc. Of 115 patients with very early SSc with follow-up, progression to definite SSc occurred within 5 years in 48 (42%). Progression to definite SSc was associated with higher IgG ACA levels at baseline (odds ratio 4.3 [95% confidence interval 1.7-10.7]). Conclusion ACA isotype levels may serve as biomarkers to identify patients with very early SSc who are at risk for disease progression to definite SSc.Pathophysiology and treatment of rheumatic disease

A multicenter study confirms CD226 gene association with systemic sclerosis-related pulmonary fibrosis

Contains fulltext : 110852.pdf (publisher's version ) (Open Access)INTRODUCTION: CD226 genetic variants have been associated with a number of autoimmune diseases and recently with systemic sclerosis (SSc). The aim of this study was to test the influence of CD226 loci in SSc susceptibility, clinical phenotypes and autoantibody status in a large multicenter European population. METHODS: A total of seven European populations of Caucasian ancestry were included, comprising 2,131 patients with SSc and 3,966 healthy controls. Three CD226 single nucleotide polymorphisms (SNPs), rs763361, rs3479968 and rs727088, were genotyped using Taqman 5'allelic discrimination assays. RESULTS: Pooled analyses showed no evidence of association of the three SNPs, neither with the global disease nor with the analyzed subphenotypes. However, haplotype block analysis revealed a significant association for the TCG haplotype (SNP order: rs763361, rs34794968, rs727088) with lung fibrosis positive patients (PBonf = 3.18E-02 OR 1.27 (1.05 to 1.54)). CONCLUSION: Our data suggest that the tested genetic variants do not individually influence SSc susceptibility but a CD226 three-variant haplotype is related with genetic predisposition to SSc-related pulmonary fibrosis