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ObjectiveVitamin D modulates the immune response and blocks induction of an interferon (IFN) signature by systemic lupus erythematosus (SLE) sera. This study was undertaken to investigate the effects of vitamin D supplementation on the IFN signature in patients with SLE.MethodsSLE patients (n = 57) with stable, inactive disease, a serum 25-hydroxyvitamin D (25[OH]D) level ≤20 ng/ml, an elevated anti-double-stranded DNA antibody level, and an IFN signature (as determined by measuring the expression levels of 3 IFN response genes) were randomized into a 12-week double-blind, placebo-controlled trial of vitamin D3 at doses of 2,000 IU or 4,000 IU. An IFN signature response was defined as a 50% reduction in the expression of 1 of the 3 genes or a 25% reduction in the expression of 2 of the 3 genes. Disease activity, adverse events, and endocrine effects were assessed.ResultsBaseline characteristics of the patients in the 3 treatment groups (placebo, low-dose vitamin D3 , or high-dose vitamin D3 ) were similar. Repletion of 25(OH)D (i.e., levels ≥30 ng/ml) was not observed in any of the patients who were receiving placebo, while repletion was observed in 16 of 33 patients receiving vitamin D3 . The percentage of patients with an IFN signature response did not differ among the treatment groups. Moreover, there was no difference in the percentage of patients with an IFN signature response between those who remained vitamin D deficient and those who demonstrated repletion of vitamin D. Modular microarray analysis of a subset of patients (n = 40) did not reveal changes from baseline in any modules (including the IFN-inducible module) in any of the treatment groups, and no differences in expression were found between patients who demonstrated vitamin D repletion and patients who were persistently vitamin D deficient. Vitamin D3 was well tolerated, and there were no safety concerns.ConclusionVitamin D3 supplementation up to 4,000 IU daily was safe and well-tolerated but failed to diminish the IFN signature in vitamin D-deficient SLE patients. Higher 25(OH)D levels sustained for a longer duration may be required to affect immunologic outcomes.

Objective Vitamin D modulates the immune response and blocks induction of an interferon (IFN) signature by systemic lupus erythematosus (SLE) sera. This study was undertaken to investigate the effects of vitamin D supplementation on the IFN signature in patients with SLE. Methods SLE patients (n = 57) with stable, inactive disease, a serum 25-hydroxyvitamin D (25[OH]D) level ≤20 ng/ml, an elevated anti-double-stranded DNA antibody level, and an IFN signature (as determined by measuring the expression levels of 3 IFN response genes) were randomized into a 12-week double-blind, placebo-controlled trial of vitamin D3 at doses of 2,000 IU or 4,000 IU. An IFN signature response was defined as a 50% reduction in the expression of 1 of the 3 genes or a 25% reduction in the expression of 2 of the 3 genes. Disease activity, adverse events, and endocrine effects were assessed. Results Baseline characteristics of the patients in the 3 treatment groups (placebo, low-dose vitamin D3, or high-dose vitamin D3) were similar. Repletion of 25(OH)D (i.e., levels ≥30 ng/ml) was not observed in any of the patients who were receiving placebo, while repletion was observed in 16 of 33 patients receiving vitamin D3. The percentage of patients with an IFN signature response did not differ among the treatment groups. Moreover, there was no difference in the percentage of patients with an IFN signature response between those who remained vitamin D deficient and those who demonstrated repletion of vitamin D. Modular microarray analysis of a subset of patients (n = 40) did not reveal changes from baseline in any modules (including the IFN-inducible module) in any of the treatment groups, and no differences in expression were found between patients who demonstrated vitamin D repletion and patients who were persistently vitamin D deficient. Vitamin D3 was well tolerated, and there were no safety concerns. Conclusion Vitamin D3 supplementation up to 4,000 IU daily was safe and well-tolerated but failed to diminish the IFN signature in vitamin D-deficient SLE patients. Higher 25(OH)D levels sustained for a longer duration may be required to affect immunologic outcomes. [ABSTRACT FROM AUTHOR]

Background: Total shoulder arthroplasty (TSA) is a common procedure that may be considered for patients with glenohumeral osteoarthritis. Patients undergoing this procedure may be afflicted by comorbid conditions, such as systemic lupus erythematosus (SLE), which may impact odds of various postoperative complications., Methods: Adult patients with and without SLE who underwent TSA (anatomic or reverse) were queried from the Jan 2010 to Oct 2022 PearlDiver M165 database. Patients with and without SLE were matched (1:4) based on age, sex, and Elixhauser Comorbidity Index. Ninety-day adverse events and five-year implant survival were assessed and compared with multivariable analysis. Sub-analyses were done for SLE patients with and without a prescription of immunomodulatory therapy (IMT - corticosteroids, hydroxychloroquine, and/or biologics) within 90 days prior to surgery and compared to non-SLE patients with multivariable analyses. Lastly, SLE patients with and without a 90-day history of IMT were directly compared with multivariate logistic regression. A Bonferroni correction was applied to univariable analyses and multivariable regressions., Results: Of 211,832 TSA patients identified, SLE was noted for 2,228 (1.1%). After matching, 8,261 patients without SLE and 2,085 patients with SLE were selected. SLE patients were at an increased odds of 90-day aggregated events including severe (OR=3.50), minor (OR=3.13), all (OR=2.35), and orthopedic-related (OR=1.41) adverse events (p<0.0030 for all). There was no difference in 5-year implant survival. Of those with SLE, IMT medications were being received by 1,267 (60.8%). Any, severe, minor, and orthopedic 90-day adverse events were significantly elevated for both those with and without IMT relative to those without SLE (p<0.0030 for all except for orthopedic-related adverse events for those not on IMT which were not significant). Relative to those not on IMT medications, those on IMT medications were at significantly higher odds of any, severe, minor, and orthopedic-related adverse events., Conclusion: Following TSA, patients with SLE were found to be at an increased odds of 90-day adverse events but not of 5-year revisions. Furthermore, those on IMT medications were at higher risk of any, severe, minor, and orthopedic-related adverse events compared to those who were not on these medications. These findings may help with patient counselling and surgical planning when those with SLE are considered for TSA., (Copyright © 2024. Published by Elsevier Inc.)

A defining feature of systemic lupus erythematosus (SLE) is loss of tolerance to self-DNA, and deficiency of DNASE1L3, the main enzyme responsible for chromatin degradation in blood, is also associated with SLE. This association can be found in an ultrarare population of pediatric patients with DNASE1L3 deficiency who develop SLE, adult patients with loss-of-function variants of DNASE1L3 who are at a higher risk for SLE, and patients with sporadic SLE who have neutralizing autoantibodies against DNASE1L3. To mitigate the pathogenic effects of inherited and acquired DNASE1L3 deficiencies, we engineered a long-acting enzyme biologic with dual DNASE1/DNASE1L3 activity that is resistant to DNASE1 and DNASE1L3 inhibitors. Notably, we found that the biologic prevented the development of lupus in Dnase1-/-Dnase1L3-/- double-knockout mice and rescued animals from death in pristane-induced lupus. Finally, we confirmed that the human isoform of the enzyme biologic was not recognized by autoantibodies in SLE and efficiently degraded genomic and mitochondrial cell-free DNA, as well as microparticle DNA, in SLE plasma. Our findings suggest that autoimmune diseases characterized by aberrant DNA accumulation, such as SLE, can be effectively treated with a replacement DNASE tailored to bypass pathogenic mechanisms, both genetic and acquired, that restrict DNASE1L3 activity.

The IL-7 receptor alpha chain (IL-7Rα or CD127) can be differentially expressed in memory CD8 + T cells. Here we investigated whether IL-7Rα could serve as a key molecule in defining a comprehensive landscape of heterogeneity in human effector memory (EM) CD8 + T cells using high-dimensional Cytometry by Time-Of-Flight (CyTOF) and single-cell RNA-seq (scRNA-seq). IL-7Rα had diverse, but organized, expressional relationship in EM CD8 + T cells with molecules related to cell function and gene regulation, which rendered an immune landscape defining heterogeneous cell subsets. The differential expression of these molecules likely has biological implications as we found in vivo signatures of transcription factors and homeostasis cytokine receptors, including T-bet and IL-7Rα. Our findings indicate the existence of heterogeneity in human EM CD8 + T cells as defined by distinct but organized expression patterns of multiple molecules in relationship to IL-7Rα and its possible biological significance in modulating downstream events., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)