Large‐Scale Characterization of Systemic Sclerosis Serum Protein Profile: Comparison to Peripheral Blood Cell Transcriptome and Correlations With Skin/Lung Fibrosis

OBJECTIVE: To provide a large-scale assessment of serum protein dysregulations in diffuse cutaneous systemic sclerosis (dcSSc) and to investigate serum protein correlates of SSc fibrotic features. METHODS: Baseline serum protein profile of 66 participants with dcSSc enrolled in the Scleroderma: Cyclophosphamide Or Transplant trial and 66 healthy, age- and gender-matched controls was investigated. A panel of 230 proteins, including several cytokines and chemokines was determined. Whole blood gene expression profiling in concomitantly collected samples was performed. RESULTS: Mean disease duration was 2.3 years, all had interstitial lung disease (ILD), and none were treated with immunosuppressive agents at baseline visit. Ninety proteins were differentially expressed compared to controls. Similar to previous global skin transcript results, hepatic fibrosis, granulocyte and agranulocyte adhesion and diapedesis were the top over-represented pathways. Eighteen proteins correlated with modified Rodnan Skin Score (mRSS). Soluble EGFR was significantly down-regulated in dcSSc and showed the strongest negative correlation with mRSS and predicted its course, whereas Alpha 1 Antichymotrypsin was significantly up-regulated in dcSSc and showed the strongest positive correlation with mRSS. Furthermore, higher CA15.3 correlated with more severe ILD, based on lower forced vital capacity and higher high-resolution CT scores. Only 14 genes showed significant differential expression in the same direction in serum protein and whole blood RNA gene expression analyses. CONCLUSIONS: dcSSc has a distinct serum protein profile with prominent dysregulation of proteins related to fibrosis and immune cell adhesion/diapedesis. The differential expression for most serum proteins in SSc is likely to originate outside the peripheral blood cells

Randomized, Double‐Blind, Placebo‐Controlled Trial of the Effect of Vitamin D3 on the Interferon Signature in Patients With Systemic Lupus Erythematosus

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

Clinical and Molecular Findings After Autologous Stem Cell Transplantation or Cyclophosphamide for Scleroderma: Handling Missing Longitudinal Data

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/175915/1/acr24785_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175915/2/acr24785.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175915/3/acr24785-sup-0001-Disclosureform.pd

Mycophenolate mofetil withdrawal in patients with systemic lupus erythematosus: a multicentre, open-label, randomised controlled trial

Mycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy. This multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed. Between Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 [90%] of 50 participants) and the withdrawal group (46 [88%] of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 [64%]) compared with the withdrawal group (24 [46%]). Mycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE. The National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma

BackgroundDespite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma.MethodsWe randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score.ResultsIn the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group.ConclusionsMyeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .)

morton_2023_oi_221502_1674145740.31597.pdf

   Importance: Neurodevelopmental disabilities are commonly associated with congenital heart disease (CHD) but medical and sociodemographic factors explain only one third of variance in outcome.  Objective: To determine whether predicted damaging de novo variants (dDNV) in genes not previously linked to neurodevelopmental disability are associated with neurologic outcomes in CHD. A post-hoc aim sought to determine whether some dDNV or rare predicted loss-of-function (pLOF) variants in specific gene categories are associated with outcomes.  Design: Prospective observational study from September 2017-June 2020.  Setting: Multicenter Participants: Participants were drawn from the Pediatric Cardiac Genomics Consortium (n=197) or Single Ventricle Reconstruction trial (n=24). Inclusion criteria were CHD, ≥ age 8 years, and available exome sequencing data. Individuals with pathogenic variants in known CHD- or neurodevelopmental-related genes were excluded. Cases and controls were frequency-matched for CHD class, age group, and sex. All 221 participants were included in post-hoc analyses, and 219 in case/control analysis.  Exposure: Participants were heterozygous for (cases) or lacked (controls) predicted dDNV in genes not previously associated with neurodevelopmental disability. Participants were separately stratified as heterozygous or not heterozygous for dDNV or pLOF variants in four gene categories: chromatin-modifying, constrained, high-brain-expressed, and neurodevelopmental risk.  Main Outcomes and Measures: Neurodevelopmental and brain MRI metrics.  Results: Participants were median 15.0 years, interquartile range [IQR] 10.0-21.2; 50% (110/219) were male. Case and control participants had similar outcomes. dDNV/pLOF variants in chromatin-modifying genes were associated with worse verbal comprehension (n=16 vs. 200 participants, mean±SD: 91.4±20.4 vs. 103.4±17.8, p=0.01), social responsiveness (n=15 vs. 183, 57.3±17.2 vs. 49.4±11.2, p=0.03), and working memory (n=5 vs. 87, 73.8±16.4 vs. 97.3±15.7, p=0.03), as well as higher likelihood of autism spectrum disorder (4/14 vs. 8/153, 28.6% vs. 5.2%, p = 0.01). dDNV/pLOF variants in constrained genes were associated with impaired memory (immediated story memory: n=95 vs. 122, 9.7±3.7 vs. 10.7±3.0, p=0.03; immediate picture memory: n= 93 vs 116, 7.8±3.1 vs. 9.0±2.9, p=0.01). Adults with dDNV/pLOF variants in high-brain-expressed genes had greater hyperactivity symptoms (n=42 vs 33, 55.5±15.4 vs. 46.6±12.3, p=0.01).  Conclusions and Relevance: Neurodevelopmental outcomes are not associated with dDNV as a group, but may be worse in those with dDNV/pLOF variants in some gene sets, such as chromatin-modifying genes. Future studies should confirm the importance of specific variants to brain function and structure.</p