Autoantibody Profiling in Lupus Patients using Synthetic Nucleic Acids

Abstract Autoantibodies to nuclear components of cells (antinuclear antibodies, ANA), including DNA (a-DNA), are widely used in the diagnosis and subtyping of certain autoimmune diseases, including systemic lupus erythematosus (SLE). Despite clinical use over decades, precise, reproducible measurement of a-DNA titers remains difficult, likely due to the substantial sequence and length heterogeneity of DNA purified from natural sources. We designed and tested a panel of synthetic nucleic acid molecules composed of native deoxyribonucleotide units to measure a-DNA. ELISA assays using these antigens show specificity and reproducibility. Applying the ELISA tests to serological studies of pediatric and adult SLE, we identified novel clinical correlations. We also observed preferential recognition of a specific synthetic antigen by antibodies in SLE sera. We determined the probable basis for this finding using computational analyses, providing valuable structural information for future development of DNA antigens. Synthetic nucleic acid molecules offer the opportunity to standardize assays and to dissect antibody-antigen interactions

Cell lineage-specific mitochondrial resilience during mammalian organogenesis

Mitochondrial activity differs markedly between organs, but it is not known how and when this arises. Here we show that cell lineage-specific expression profiles involving essential mitochondrial genes emerge at an early stage in mouse development, including tissue-specific isoforms present before organ formation. However, the nuclear transcriptional signatures were not independent of organelle function. Genetically disrupting intra-mitochondrial protein synthesis with two different mtDNA mutations induced cell lineage-specific compensatory responses, including molecular pathways not previously implicated in organellar maintenance. We saw downregulation of genes whose expression is known to exacerbate the effects of exogenous mitochondrial toxins, indicating a transcriptional adaptation to mitochondrial dysfunction during embryonic development. The compensatory pathways were both tissue and mutation specific and under the control of transcription factors which promote organelle resilience. These are likely to contribute to the tissue specificity which characterizes human mitochondrial diseases and are potential targets for organ-directed treatments

Predictors of the first cardiovascular event in patients with systemic lupus erythematosus - a prospective cohort study

Systemic Lupus Erythematosus (SLE) is an autoimmune, inflammatory disease that mainly affects women. The prognosis of SLE has improved dramatically, but mortality rates are still higher than in the general population. With the improved general prognosis, cardiovascular disease (CVD) has emerged as a major cause of morbidity and mortality among SLE patients. Previous studies have demonstrated that the development of atherosclerosis is accelerated in SLE, and have identified a set of traditional and nontraditional risk factors that characterize SLE patients with CVD. Nevertheless, many unsolved issues with respect to SLE related CVD remain. The general aim of this thesis was to investigate risk factors for manifest CVD and for cardiovascular mortality (CVM) in SLE, with special focus on traditional risk factors, lupus phenotype, inflammatory and endothelial biomarkers, autoantibodies and genetic predisposition. In the first paper, we prospectively studied traditional and non-traditional risk factors for the development of the first cardiovascular event (CVE) in 182 SLE patients with a follow-up time of 8 years. 24(13%) patients had a first event. We demonstrated that of the traditional risk factors, only age and smoking predicted the first CVE. Additionally, antiphospholipid antibodies (aPL), endothelial biomarkers, represented by soluble vascular cell adhesion molecule 1(sVCAM-1), and absence of thrombocytopenia were independent predictors of CVE. Thus, activation of the endothelium and the coagulation system are important features in SLE-related CVD and the importance to advocate smoking cessation among SLE patients is underscored In the second paper, we prospectively investigated causes of mortality and risk factors for overall mortality and CVM in a cohort of 208 SLE patients, with a follow-up time of 12 years. We also evaluated Systematic coronary risk evaluation (SCORE, tool for evaluating the 10 year risk for cardiovascular death in the age span 40-65 years, based on traditional risk factors) in this population. Cystatin C, a sensitive measure of renal function, in addition to traditional and non-traditional risk factors, were evaluated as risk factors. 42 patients died, 48 % of which were due to CVM. Age, previous arterial events and high cystatin C levels were the strongest predictors for overall mortality and for CVM. After adjusting for these three variables, smoking, sVCAM-1 and high sensitiviy C-reactive protein (hsCRP) predicted CVM. SCORE estimated 4 but we observed 9 cases of CVM, a non-significant difference. We conclude that except for smoking, traditional risk factors are less important than cystatin C, endothelial and inflammatory biomarkers as predictors of CVM in SLE patients. In the third paper, we investigated whether a risk allele for SLE in the signal transducer and activator of transcription factor 4 gene (STAT4) was associated with vascular events or presence of antiphospholipid antibodies (aPL). A total of 578 unrelated SLE patients (424 from mid-Sweden and 154 from southern-Sweden) were included in a cross-sectional design. Occurrence of previous cardiovascular events and aPL were tabulated. Matched controls (N=651) were genotyped as a comparison. The results demonstrate that the STAT4 risk allele was associated with ischemic cerebrovascular disease (ICVD), with a dose-dependent relationship between ICVD and number of risk alleles. The risk allele was furthermore associated with the presence of two or more aPLs, also in a dose-dependent manner. The association remained after adjustment for known traditional risk factors. We conclude that patients with the STAT4 risk allele have an increased risk of ICVD. Our results imply that genetic predisposition is an important risk factor for ICVD in SLE patients, and that aPL may be one underlying mechanism. In the fourth paper, we evaluated the potential association between smoking and aPL. 367 SLE patients were investigated in a cross-sectional study. Occurrence of aPL (anticardiolipin (aCL) IgG and IgM, anti-β2 glycoprotein-1 IgG (aβ2GP1 IgG), lupus anticoagulant (LAC)) and smoking habits (never, ever, former, current) were tabulated. Never smoking was used as reference in all calculations. In multivariable models, adjusted for age, sex and age at disease onset, aCL and aβ2GP1 of the IgG isotype and LAC were associated with ever smoking, this association seemed to be driven mainly by the former smoking group. Our results demonstrate that smoking is associated with pro-thrombotic aPL in SLE patients, though we can not from this study draw firm conclusions about the temporal relationship between exposure to smoking and occurrence of aPL. Further studies are warranted to investigate the mechanisms behind these observations. In prospective studies we have demonstrated that in particular smoking, systemic inflammation, endothelial activation and aPL are major risk factors for SLE related CVD and CVM. Furthermore, genetic predisposition, in our studies represented by a STAT4 SLE risk allele, contributes to the high risk of ICVD and to the occurrence of aPL, a possible underlying pathogenic mechanism. Finally we demonstrate that smoking, known to have unfavorable effects on the immune system and to significantly increase cardiovascular risk in SLE patients, is also associated with pro-thrombotic aPL in patients with SLE. Thus in SLE smoking stands out as the most important of the traditional risk factors with potential influence also on lupus related risk factors such as aPL

Crowdsourcing the Perception of Machine Teaching

Teachable interfaces can empower end-users to attune machine learning systems to their idiosyncratic characteristics and environment by explicitly providing pertinent training examples. While facilitating control, their effectiveness can be hindered by the lack of expertise or misconceptions. We investigate how users may conceptualize, experience, and reflect on their engagement in machine teaching by deploying a mobile teachable testbed in Amazon Mechanical Turk. Using a performance-based payment scheme, Mechanical Turkers (N = 100) are called to train, test, and re-train a robust recognition model in real-time with a few snapshots taken in their environment. We find that participants incorporate diversity in their examples drawing from parallels to how humans recognize objects independent of size, viewpoint, location, and illumination. Many of their misconceptions relate to consistency and model capabilities for reasoning. With limited variation and edge cases in testing, the majority of them do not change strategies on a second training attempt.Comment: 10 pages, 8 figures, 5 tables, CHI2020 conferenc

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154675/1/art41191.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154675/2/art41191_am.pd

Early experience of COVID-19 vaccination in adults with systemic rheumatic diseases : Results from the COVID-19 Global Rheumatology Alliance Vaccine Survey

Funding Information: Competing interests SES has received funding from the Vasculitis Foundation and the Vasculitis Clinical Research Consortium unrelated to this work. JL has received research grant funding from Pfizer unrelated to this work. ES is a Board Member of the Canadian Arthritis Patient Alliance, a patient run, volunteer-based organisation whose activities are primarily supported by independent grants from pharmaceutical companies. MP was supported by a Rheumatology Research Foundation Scientist Development grant. DA-R is a Scientific Advisor for GlaxoSmithKilne unrelated to this work. FB reports personal fees from Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, TRB Chemedica and 4P Pharma outside of the submitted work. No funding relevant to this manuscript. RC: speakers bureau for Janssen, Roche, Sanofi, AbbVie. KD reports no COI-unpaid volunteer president of the Autoinflammatory Alliance. Any grants or funding from pharma is received by the non-profit organisation only. CLH received funding under a sponsored research agreement unrelated to the data in the paper from Vifor Pharmaceuticals. LeK has received a research grant from Lilly unrelated to this work. AHJK participated in consulting, advisory board or speaker's bureau for Alexion Pharmaceuticals, Aurinia Pharmaceuticals, Annexon Biosciences, Exagen Diagnostics and GlaxoSmithKilne and received funding under a sponsored research agreement unrelated to the data in the paper from GlaxoSmithKline. JSingh has received consultant fees from Crealta/ Horizon, Medisys, Fidia, PK Med, Two Labs, Adept Field Solutions, Clinical Care Options, Clearview Healthcare Partners, Putnam Associates, Focus Forward, Navigant Consulting, Spherix, MedIQ, Jupiter Life Science, UBM, Trio Health, Medscape, WebMD and Practice Point Communications; and the National Institutes of Health and the American College of Rheumatology. JSingh owns stock options in TPT Global Tech, Vaxart Pharmaceuticals and Charlotte’s Web Holdings. JSingh previously owned stock options in Amarin, Viking and Moderna Pharmaceuticals. JSingh is on the speaker’s bureau of Simply Speaking. JSingh is a member of the executive of Outcomes Measures in Rheumatology (OMERACT), an organisation that develops outcome measures in rheumatology and receives arms-length funding from eight companies. JSingh serves on the FDA Arthritis Advisory Committee. JSingh is the chair of the Veterans Affairs Rheumatology Field Advisory Committee. JSingh is the editor and the Director of the University of Alabama at Birmingham (UAB) Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis. NSingh is supported by funding from the Rheumatology Research Foundation Investigator Award and the American Heart Association. MFU-G has received research support from Pfizer and Janssen, unrelated to this work. SB reports personal fees from Novartis, AbbVie, Pfizer and Horizon Pharma, outside the submitted work. RG reports personal fees from AbbVie New Zealand, Cornerstones, Janssen New Zealand and personal fees and non-financial support Pfizer New Zealand (all <US$10 000) outside the submitted work. PMM reports personal fees from AbbVie, Eli Lilly, Janssen, Novartis, Pfizer and UCB, grants and personal fees from Orphazyme, outside the submitted work. PCR reports personal fees from AbbVie, Gilead, Lilly and Roche, grants and personal fees from Novartis, UCB Pharma, Janssen and Pfizer and non-financial support from BMS, outside the submitted work. PS reports honoraria from Social media editor for @ACR_Journals, outside the submitted work. ZSW reports grants from NIH, BMS and Principia/ Sanofi and personal fees from Viela Bio and MedPace, outside the submitted work. JY reports personal fees from Pfizer and Eli Lilly, and grants and personal fees from AstraZeneca, outside the submitted work. MJL reports grants from American College of Rheumatology, during the conduct of the study and consulting fees from AbbVie, Amgen, Actelion, Boehringer Ingelheim, BMS, Celgene, Gilead, J&J, Mallinckrodt, Novartis, Pfizer, Roche, Sandoz, Sanofi, Sobi and UCB, outside the submitted work. LGR was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS; ZIAES101074) of the National Institutes of Health. JH reports grants from Childhood Arthritis and Rheumatology Research Alliance (CARRA) and Rheumatology Research Alliance, and personal fees from Novartis, Pfizer and Biogen, outside the submitted work. JSimard received research grant funding from the National Institutes of Health unrelated to this work (NIAMS: R01 AR077103 and NIAID R01 AI154533). JSparks has performed consultancy for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Inova Diagnostics, Optum and Pfizer unrelated to this work. Funding Information: Funding This study was supported by the European Alliance of Associations for Rheumatology and American College of Rheumatology Research and Education Foundation. Dr. Lisa Rider's involvement was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. Publisher Copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Background. We describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine. Methods From 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination. Results We analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), Janssen/Johnson & Johnson (1.7%) and others (1.2%). The most common rheumatic disease was rheumatoid arthritis (42.3%), and 81.2% of respondents were on a DMARD. The majority (81.9%) reported communicating with clinicians about vaccination. Most (66.9%) were willing to temporarily discontinue DMARDs to improve vaccine efficacy, although many (44.3%) were concerned about rheumatic disease flares. After vaccination, the most reported patient-reported adverse events were fatigue/somnolence (33.4%), headache (27.7%), muscle/joint pains (22.8%) and fever/chills (19.9%). Rheumatic disease flares that required medication changes occurred in 4.6%. Conclusion. Among adults with systemic rheumatic disease who received COVID-19 vaccination, patient-reported adverse events were typical of those reported in the general population. Most patients were willing to temporarily discontinue DMARDs to improve vaccine efficacy. The relatively low frequency of rheumatic disease flare requiring medications was reassuring.publishersversionPeer reviewe

Prolonged COVID-19 symptom duration in people with systemic autoimmune rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance Vaccine Survey

OBJECTIVE: We investigated prolonged COVID-19 symptom duration, defined as lasting 28 days or longer, among people with systemic autoimmune rheumatic diseases (SARDs). METHODS: We analysed data from the COVID-19 Global Rheumatology Alliance Vaccine Survey (2 April 2021-15 October 2021) to identify people with SARDs reporting test-confirmed COVID-19. Participants reported COVID-19 severity and symptom duration, sociodemographics and clinical characteristics. We reported the proportion experiencing prolonged symptom duration and investigated associations with baseline characteristics using logistic regression. RESULTS: We identified 441 respondents with SARDs and COVID-19 (mean age 48.2 years, 83.7% female, 39.5% rheumatoid arthritis). The median COVID-19 symptom duration was 15 days (IQR 7, 25). Overall, 107 (24.2%) respondents had prolonged symptom duration (≥28 days); 42/429 (9.8%) reported symptoms lasting ≥90 days. Factors associated with higher odds of prolonged symptom duration included: hospitalisation for COVID-19 vs not hospitalised and mild acute symptoms (age-adjusted OR (aOR) 6.49, 95% CI 3.03 to 14.1), comorbidity count (aOR 1.11 per comorbidity, 95% CI 1.02 to 1.21) and osteoarthritis (aOR 2.11, 95% CI 1.01 to 4.27). COVID-19 onset in 2021 vs June 2020 or earlier was associated with lower odds of prolonged symptom duration (aOR 0.42, 95% CI 0.21 to 0.81). CONCLUSION: Most people with SARDs had complete symptom resolution by day 15 after COVID-19 onset. However, about 1 in 4 experienced COVID-19 symptom duration 28 days or longer; 1 in 10 experienced symptoms 90 days or longer. Future studies are needed to investigate the possible relationships between immunomodulating medications, SARD type/flare, vaccine doses and novel viral variants with prolonged COVID-19 symptoms and other postacute sequelae of COVID-19 among people with SARDs