Jump to content

Search the Community

Showing results for tags 'Lupus'.

  • Search By Tags

    Type tags separated by commas.
  • Search By Author

Content Type


  • The LuPUS Message Board
    • Announcements
    • What is the LuPUS Message Board?
    • A Welcome to New Members
    • User Problems
    • Links
  • Medical
    • Medical News 2003
    • Medical News 2004
    • Medical News 2005
    • Medical News 2006
    • Medical News 2007
    • Medical News 2008
    • Medical News 2009
    • Medical News 2010
    • Medical News 2011
    • Medical News 2012
    • Medical News 2013
    • Medical News 2014
    • Medical News 2015
    • Medical News 2016
    • Medical News 2017
    • Medical News 2018
    • Medical News 2019
    • Medical News 2020
    • Medical News 2021
    • Coronavirus: COVID-19
    • Medication & Therapy
    • Lupus and Pregnancy
    • Sjögren’s syndrome
    • Lymphoedema
    • Marginal Zone Lymphoma
  • Non-Medical
    • LuPUS Message Board
  • Public
    • Guest & Test Messages
    • Free Offers
    • Contributors


  • Admin
  • Admin
  • Changes To My Diet For Health Reasons


There are no results to display.

There are no results to display.

Find results in...

Find results that contain...

Date Created

  • Start


Last Updated

  • Start


Filter by number of...


  • Start





Website URL





Surname (Last or Family name)

First name

Date of Birth




  1. The Flu Vaccine, Inflammatory Arthritis, and COVID-19: What You Need to Know This year, the flu vaccine is more important than ever. Here’s what you need to know about getting vaccinated safely when you have inflammatory arthritis like rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis. Learn more about our FREE COVID-19 Patient Support Program for chronic illness patients and their loved ones. Getting a flu vaccine is important every single flu season, especially if you have a form of inflammatory arthritis such a rheumatoid arthritis (RA), psoriatic arthritis (PsA), or axial spondyloarthritis (axSpA) — but in the midst of the COVID-19 pandemic, it’s even more critical. While experts are hoping that COVID-related prevention practices like mask wearing, social distancing, and ramped-up hygiene will translate into less influenza spread this season, rheumatology experts are still urging patients to get vaccinated. The good news is that many people with chronic illness don’t need convincing. According to a recent survey of members of the CreakyJoints and Global Healthy Living Foundation’s COVID-19 Patient Support Program (a free program that provides information, advice, and support to help people with underlying health issues navigate the pandemic), 85 percent of 780 respondents said they were planning to get a flu vaccine this fall. About 10 percent said they did not plan to, and 5 percent did not know if they would get the flu vaccine this fall. “As we are getting ready to enter flu season, and with COVID-19 continuing to spread throughout our communities, I think it is extremely important for people to get the flu vaccine this year,” says Justin Owensby, PharmD, PhD, a research pharmacist in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham (UAB). “As the novel coronavirus has severely stressed our health care system/resources, having even a mild flu season will further tax the system,” which may lead to even more strain on the hospitals and health care workers who will help you if you end up needing emergency care because of flu complications such as pneumonia. Here’s more about why, when, and how to get your flu vaccine safely this year. Why You Need the Flu Vaccine, Period First, simply having inflammatory arthritis increases your chances of getting the flu — and, if you do catch it, your risk of serious infection and severe complications is greater. “Compared to the general population, people living with inflammatory arthritis are at substantially higher risk of getting a vaccine-preventable infection, such as the flu or pneumonia, and consequently more complications and hospitalizations from those infections,” explains Dr. Owensby. For example, RA patients have nearly a three times greater risk of getting the flu than healthy patients in the same age group, according to a 2012 analysis of 46,030 RA patients and an equal number of healthy controls, published in the journal BMC Musculoskeletal Diseases. Yet another study, presented as an abstract at the American College of Rheumatology conference in 2018, found that RA patients who get influenza experience increased hospital stays as well as higher costs compared to healthy controls. Inflammatory arthritis decreases your body’s natural immune defenses and some disease-modifying medications used to manage your condition can also weaken your immune response. “The flu shot is designed to strengthen your immune system by allowing it to recognize and fight off an influenza infection,” says Owensby. “Flu vaccines have been shown to reduce the risk of flu illness, hospitalization, and death.” COVID-19 and Flu Coinfection As if that’s not convincing enough, here’s yet another reason to roll up your sleeve: “People can get coinfected with influenza and COVID-19, says Jeffrey Curtis, MD, MS, MPH, professor of Medicine in the Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham (UAB). “You can have both infections at the same time, and if that happens, the severity will be much worse.” While the flu shot won’t protect you from getting COVID-19, it may help reduce the risk of spreading COVID. “If you have the flu, and you’re coughing and sneezing, common sense says you’re more likely to transmit COVID,” says Dr. Curtis, “so if you can decrease the incidence and transmission of influenza, then you it’s possible that you can decrease the transmission to COVID.” More research is needed to confirm this effect, however. When Should I Get the Flu Vaccine? The CDC recommends getting your flu shot before influenza spreads within your area; ideally by the end of October. However, getting vaccinated anytime during the flu season, even in January or later, can protect you. Dr. Curtis says it’s important to remember that it takes about two weeks after vaccination for antibodies that protect against flu to develop in the body — and that immunity doesn’t always last the entire season. “There is some temporariness to the duration of protection of the flu vaccinations, so if you get the flu shot in September, it might not offer the same protection in March,” he says. Yet if putting it off until November means you might just put it off forever, Dr. Curtis urges patients to get it done and over with it when it’s top of mind. If you suspect you may have been exposed to COVID-19 or have a confirmed diagnosis of COVID-19, the CDC suggests delaying the flu shot until you’re no longer showing signs and symptoms, adds Owensby. This isn’t because there’s evidence that having COVID affects the effectiveness of the flu vaccination, but rather because you don’t want to unnecessarily expose others to COVID-19. What’s the Best Place to Get the Flu Vaccine? For people with inflammatory arthritis who have been staying at home as much as possible and limiting their outings to minimize exposure to COVID-19, the idea of heading to a doctor or pharmacy to get a flu shot may seem scary. You can find reassurance in the fact that the CDC has given guidance to local pharmacies, grocery stores, and doctor’s offices for safe vaccination practice during the COVID-19 pandemic, including: Screening patients for COVID-19 symptoms or exposure to COVID-19 prior to arrival Limiting the overall number of patients at any given time Providing specific appointment times to manage patient flow and avoid crowding Ensuring staff wear medical face masks and use eye protection Limiting and monitoring points of entry to the facility and installing barriers, such as clear plastic sneeze guards, to limit physical contact with patients Implementing policies for wearing cloth face coverings and practicing respiratory hygiene, cough etiquette, and hand hygiene Setting up a one-way flow through the site and using measures to direct patient traffic and ensure physical distancing Arranging a separate vaccination area or separate hours for persons at increased risk for severe illness from COVID-19, when feasible Ensuring a minimum distance of 6 feet between patients in line, in waiting areas for vaccination, between vaccination stations, and in postvaccination monitoring areas Other safe places to get your flu shot this year may include: Drive-through immunization services Curbside clinics Mobile outreach units Home visits “It doesn’t matter where as long as you get one,” says Dr. Owensby. He recommends using VaccineFinder.org to find where flu vaccines are available near you. “[And] when going to get a flu vaccine, be sure to practice everyday preventive actions.” If you’re not sure whether a local pharmacy or clinic is following COVID-19-related precautions, ask around and get feedback and recommendations from family and friends. You can also call ahead to ask about how crowded the facility is and find out the times of day when it’s likely to be emptiest. What Type of Flu Shot Is Best? Dr. Curtis says there are three considerations for people with inflammatory arthritis: Is it a live vaccine? A live vaccine, such as the nasal spray, can cause side effects in people with inflammatory arthritis who have weakened immune systems. Instead, opt for the flu shot, which is made from inactivated (or killed) influenza virus, which cannot cause illness. Is it quadrivalent? This means that it’s a four-component vaccine, which this year protect against the following four flu strains: A/Hawaii/70/2019 (H1N1) pdm09-like virus; A/Hong Kong/45/2019 (H3N2)-like virus (updated); B/Washington/02/2019; (B/Victoria lineage)-like virus (updated), plus B/Phuket/3073/2013-like (Yamagata lineage) virus. The trivalent vaccine, which offers protection against three strains, does not include the fourth virus, B/Phuket/3073/2013-like (Yamagata lineage) virus. Is it high-dose? This is a more potent type of flu vaccine, and while it’s generally reserved for adults 65 and older, it is beneficial for people with inflammatory arthritis who may have a weaker response to the flu vaccine than people without these health conditions. In fact, research published in The Lancet Rheumatology reported that the high-dose flu shot (Fluzone) substantially improved the immune response in seropositive RA patients compared to the standard-dose flu shot. However, many high-dose vaccines are trivalent, and don’t protect against B/Phuket/3073/2013-like (Yamagata lineage) virus. Talk with your rheumatologist about the best type of flu vaccine for you, and be sure to check with your insurance to see if it’s covered, says Dr. Curtis. If you’re under 65, the high-dose shot may not be covered. Do I Need to Adjust My Arthritis Medications? While the decision to adjust your medications should be between you and your rheumatologist, there are studies showing that some medications, including high doses of steroids, methotrexate, and the biologic rituximab, reduce the body’s immune response to flu vaccine, says Dr. Owensby. Rituximab Treatment with the infused drug rituximab has been shown to decrease the response to the flu shot, says Dr. Owensby, so your doctor may recommend delaying the time between vaccine and your next infusion. Methotrexate Recent studies have shown that a brief, two-week discontinuation of methotrexate after receiving the flu shot can boost your immune response to it, says Dr. Owensby. Although researchers have also found that people taking methotrexate or TNF inhibitor biologics — like etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade) — do have an acceptable response to the flu vaccine, the response isn’t as strong as it is in healthy individuals who are not taking immunosuppressants. Your best bet is talk to your doctor about the the pros and cons of skipping a dose of your medication around the time you get your flu shot. Dr. Curtis emphasizes that people should not “stop taking medication prematurely,” without consulting their doctors. Can the Flu Shot Increase My Risk of Getting Sick? “To my knowledge, there is no evidence suggesting getting a flu shot will make you more susceptible to COVID-19,” says Owensby. “Although they are both contagious respiratory illnesses, they are caused by different viruses.” COVID-19 is caused by SARS-CoV-2 and flu is caused by different strains of influenza viruses. Similarly, getting the flu shot will not give you the flu, says Dr. Curtis. In fact, those mild flu-like symptoms you may experience after the shot — headache, achiness, malaise, low-grade fever — are all signs of your immune system revving up to protect against the flu, he explains. Keep Practicing Mask Wearing, Social Distancing, and Good Hygiene While experts agree that you need to get a flu shot, it doesn’t mean you should stop taking other precautions to stay healthy this flu season. “Even after receiving the flu shot, it’s still important to take all the steps you can to avoid getting the flu,” says Owensby. So, get vaccinated, amp up your efforts to eat well and exercise, prioritize sleep, manage stress, and of course, practice a whole lot of hand washing and sanitizing. https://creakyjoints.org/living-with-arthritis/coronavirus/daily-living/flu-vaccine-inflammatory-arthritis-covid-19/?utm_source=CreakyJoints&utm_campaign=d589052654-cj-list_september-2020-newsletter_non-psp&utm_medium=email&utm_term=0_2a31b3d2f0-d589052654-232962794
  2. CBD may improve steroid therapy in autoimmune, Covid-19 patients Israeli startup Stero Therapeutics says cannabis component could enhance steroid treatment or enable reduced steroid dosage to avoid negative effects. By Brian Blum JUNE 18, 2020, 8:30 AM Cannabis component CBD may enhance effects of steroids. Image by HQuality via Shutterstock.com Can cannabis help treat Covid-19? Israeli canna-tech startup Stero Therapeutics wanted to find out. But unexpectedly good news threw a hitch in those plans. At the height of the corona crisis, the Bnei Brak-based company was set to launch a clinical trial with 10 Covid-19 patients at Rabin Medical Center in Petah Tikva when the hospital ran out of patients. Rabin and several other Israeli medical centers closed their coronavirus wards as the number of new cases slowed to a trickle. Stero is now turning its attention toward Europe, where there is, unfortunately, still no shortage of people suffering from the virus. With cases spiking again in Israel, though, a clinical trial closer to home is no longer out of the question. While Covid-19 has occupied Stero’s interest for the past two months, it was never the company’s main focus. The overlap was steroids. Stero aims to determine if CBD, the non-psychoactive component in cannabis, can enhance the effect of corticosteroids — the first line of treatment for autoimmune illnesses like inflammatory bowel disease and lupus — or enable reducing steroid dosage while maintaining or improving its therapeutic effects. Stero founder and CEO David Bassa. Photo: courtesy Stero founder and CEO David Bassa’s previous company, Talent Biotech, had developed expertise in using CBD to prevent and treat graft vs. host disease (GvHD), a life-threatening immune condition that can occur following an organ transplant. In GvHD, immune cells from the donor attack the recipient’s tissues. The primary therapy for GvHD is also steroids. Talent had reached Phase 2b trials when Canadian cannabis company Kalytera bought the company for $10 million in 2017 — the Israeli cannabis industry’s first major “exit.” Kalytera has taken Talent’s technology toward Phase 3 trials with an eye on FDA and European CE approval as early as the end of this year. Now no longer with Kalytera, Bassa set his sights on an even bigger medical goal: whether CBD could reduce, improve and possibly even replace steroids as a first line of treatment in just about any kind of immune system overreaction. Crohn’s, hives… and Covid? Bassa established Stero after receiving a broad US patent covering 130 autoimmune and inflammatory diseases, including Crohn’s disease, hepatitis, arthritis and chronic urticaria (hives). “The patent covers botanic and synthetically produced CBD, at any dosage and in combination with other drugs,” Bassa tells ISRAEL21c. Stero chose two indications to start with – Crohn’s and urticaria. They had enrolled Crohn’s disease patients in a clinical trial and were just starting with urticaria when Covid-19 upended everything. Steroids are also used to fight off Covid-19’s most deadly effect in acute infections: an immune system over-response known as a cytokine storm. Cytokines are a signalling molecule released in response to a virus. They activate inflammation as a way of containing and eradicating the pathogen. In a cytokine storm, the immune system releases too many of these molecules. The result is often more collateral damage than the virus itself would have caused. In a landmark UK trial, researchers found that use of dexamethasone, a type of steroid, reduced deaths for COVID-19 patients on ventilators by a third and cut deaths for those receiving just oxygen by 20%. The researchers say that if the drug had been used at the beginning of the pandemic, up to 5,000 British lives could have been saved. Stero had proposed to investigate whether CBD can boost the therapeutic effectiveness of steroids in Covid-19 patients. For its trials with Crohn’s and urticaria research, the aim is to see if CBD can reduce the need for high dosages of steroids with all the negative side effects they cause. Meanwhile, the Medical Cannabis Research and Innovation Center at Rambam Health Care Campus in Haifa has proposed a trial of its own to determine if certain strains of cannabis can save severely ill Covid-19 patients from cytokine storms. Four-month trial Stero’s first focus is the approximately 30 percent of Crohn’s disease patients who are steroid dependent, Bassa explains. In the four-month randomized, double-blind trial, half the patients will get CBD oil and half will get a lookalike placebo. In the first month, the steroid dosage will be reduced while the CBD (or placebo) is introduced. If a patient has a major Crohn’s flareup and is receiving the placebo, he or she will be dropped from that arm of the trial and given CBD instead. Patients who flare up while receiving CBD will be put back on their regular dose of steroids. Bassa cautions readers with inflammatory conditions against experimenting at home. The amount of CBD in the trial is 300 mg a day – about 10 times the amount usually used by consumers of CBD as a wellness product where it’s legal. Stero’s CBD is synthetically produced, making it more expensive than CBD from plants, but Bassa says synthetic CBD “assures us a clearer eventual path with the FDA.” Serendipity and a promise The CBD-steroid connection was discovered by accident. Dr. Moshe Yeshurun, Stero’s senior medical adviser, directs the bone marrow transplantation unit at Rabin Medical Center. He had GvHD patients “who were suffering very much and he wanted to ease their pain by giving them medical cannabis,” Bassa tells ISRAEL21c. But the patients also started to get better and show less signs of disease. Bassa’s story has a similar unexpected twist. He was a successful software entrepreneur when his mother was diagnosed with multiple myeloma, a deadly blood cancer. In looking for a drug that could help her, he discovered that Prof. Moshe Mittleman, from Tel Aviv Sourasky Medical Center, was investigating whether off-label use of erythropoietin, a molecule generally used to boost blood hemoglobin, could ease multiple myeloma. Bassa’s mother began taking erythropoietin. “She lived another 11 years instead of the three that was predicted,” Bassa says. Bassa’s mother made him promise to “take the solution that worked for her to the world,” he recalls. He raised $2 million to build a company to commercialize erythropoietin for blood cancer, but he was ultimately not successful. “Luckily for patients, there are newer treatments today that have already replaced erythropoietin,” he explains. What he couldn’t do for erythropoietin he is trying to do in the cannabis space. Cannabis Innovation Center Stero, which has raised $1 million, is one of a half-dozen companies Bassa operates out of his Cannabis Innovation Center in Bnei Brak. He has a partnership with Clalit, Israel’s largest HMO. Indeed, most of Bassa’s team of 20 works in Clalit hospitals and clinics. Mor Research Applications, the technology-transfer office of Clalit, is Stero Biotech’s main shareholder. Bassa’s other companies include CannaLean Biotechs, which is exploring whether CBD can help lower cholesterol; CannaMore, which is studying CBD’s potential role in treating bronchiolitis obliterans, a pulmonary disease; and BioSeedXL, a tech incubator for cannabis companies. For more information on Stero Biotechs, click here. https://www.israel21c.org/cbd-may-improve-steroid-therapy-in-autoimmune-covid-19-patients/ https://www.israel21c.org/13-promising-covid-treatments-emerging-from-israel/
  3. Benlysta Treatment Lowers Disease Activity for SLE Patients, Real-world Data Shows MAY 29, 2020 BY INES MARTINS, PHD Treatment with Benlysta (belimumab) induces meaningful and long-lasting reductions in systemic lupus erythematosus (SLE) disease activity, helping a significant proportion of patients achieve durable remission or a status of low disease activity, a study in a real-world Italian population shows. Patients diagnosed in the prior two years, with low damage accrual and lower disease activity scores, were the ones who benefited the most from this treatment, the research revealed. The study, “Early disease and low baseline damage predict response to belimumab in patients with systemic lupus erythematosus,” was published in the journal Arthritis and Rheumatology. Benlysta, developed by GlaxoSmithKline, is approved in the U.S., the European Union and Japan as an add-on biologic treatment for people 5 years and older with active SLE. The therapy has shown consistent safety and effectiveness in clinical practice, leading the European League Against Rheumatism (EULAR) to recommend its use for people who failed standard care treatments. As with most other SLE therapies, the ultimate goal of Benlysta is to help patients achieve remission or a state of low disease activity, both associated with a lower risk of flares, reduced organ damage, and a better prognosis overall. Researchers in Italy set out to investigate the factors that predict responses, remission, low disease activity, damage, and treatment discontinuation in SLE patients receiving Benlysta in a real-world setting. According to the investigators, they studied the largest nationwide group of European patients aimed at investigating Benlysta in SLE. The team retrospectively examined patients treated from January 2013 to March 2019, and included in the Belimumab in Real Life Setting Study (BeRLiSS). Physicians prescribing Benlysta at Italian reference centers were invited to participate and to provide data regarding specific outcome measures at pre-determined time intervals. For their study, the team of scientists included 466 participants with active SLE, 77 of whom had been diagnosed within the prior two years (classified as early lupus). All patients received Benlysta via an into-the-vein infusion at 24 centers. Patients were followed for a median of 18 months. During that time, researchers assessed the proportion of patients who achieved remission and low disease activity — based on the SLE Disease Activity Index (SLEDAI) scores and medication use — and those who experienced clinically meaningful responses to treatment, defined as an improvement of four or more points in the SLEDAI score (a measure called SLE Responder Index 4 (SRI4). The team also examined changes in disease flares, organ damage, and treatment discontinuation, and conducted statistical analyses to predict which factors were associated with better outcomes. Results demonstrated that nearly half of patients (49.2%) achieved SRI4 after six months on treatment, a proportion that kept increasing for the first two years — 61.3% at one year, 69.7% at two years — and remained constant in the next two years (69.6% at three years and 66.7% at four years on Benlysta). Predictors of response varied at each time point, but those with greater disease activity always were significantly more likely to respond to treatment. Patients with early disease were nearly two times more likely to respond to Benlysta at six months and almost four times more likely at two years, while those without organ damage at treatment initiation (baseline) also were more likely to respond within the first year. Notably, smoking significantly reduced the likelihood of a late response. A significant proportion of patients (66.1%) spent at least half of their follow-up time in a low disease activity state and 44.3% were in remission at least 25% of the time. The team found that having lower disease activity and no organ damage at baseline were significant predictors of being on remission and low disease activity for these long periods. Patients with high numbers of flares and kidney involvement at baseline were less likely to achieve remission. Benlysta treatment significantly reduced the incidence of flares, and only 9.4% of patients experienced new damage events while on treatment. The team found that being at least half of follow-up time on low disease activity was protective from further damage, while having increased damage at baseline was predictive of further damage accrual. Regarding safety, there were no deaths or severe infusion reactions among more than 10,000 Benlysta infusions. A total of 271 patients reported adverse side effects, with the most common being infections. Also, 165 patients discontinued treatment within the first year, either due to an adverse event, inadequate response, pregnancy or remission. The researchers noted that discontinuation due to lack of effectiveness was associated significantly with a higher rate of flares before treatment. “Our study provided novel evidence of a remarkable achievement of remission or LDA [low disease activity] during treatment, which were also likely to persist over time, and confirmed previous results on real-life use of belimumab [Benlysta],” the researchers wrote. “At present, belimumab is frequently used as the last option in SLE treatment. Based on our data, we suggest that an earlier use of belimumab in patients with active SLE may maximize its efficacy,” they concluded. Ines Martins, PhD Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência. Inês currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner. Fact Checked By: Jose Marques Lopes, PhD José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease. https://lupusnewstoday.com/benlysta-lowers-disease-activity-organ-damage-sle-patients-real-world-data?utm_source=LUP+NEws+E-mail+List&utm_campaign=5d7643d560-RSS_WEEKLY_EMAIL_CAMPAIGN_US&utm_medium=email&utm_term=0_50dac6e56f-5d7643d560-71887989
  4. Lupus Patients Receiving More Quality Clinical Care Report Better Health Outcomes, Study Finds FEBRUARY 12, 2020 BY STEVE BRYSON PHD https://lupusnewstoday.com/2020/02/12/patient-receiving-more-quality-clinical-care-report-lower-disease-activity-damage-study/?utm_source=LUP+NEws+E-mail+List&utm_campaign=17fbd096f4-RSS_WEEKLY_EMAIL_CAMPAIGN_US&utm_medium=email&utm_term=0_50dac6e56f-17fbd096f4-71887989 People with systemic lupus erythematosus (SLE) who received more quality clinical care report lower disease activity, slower accumulation of disease-related damage, and a higher physical health-related quality of life, a study finds. The analysis identified parameters that led to improved self-reported health outcomes, including taking antimalarial medications (such as hydroxychloroquine), blood pressure counseling, and osteoporosis protection. The study, “Quality of care predicts outcome in systemic lupus erythematosus: a cross-sectional analysis of a German long-term study (LuLa cohort),” was published in the journal Lupus. SLE affects people differently, sometimes requiring them to make frequent visits to healthcare providers due to the disease’s chronic nature. Also, because SLE can affect a variety of organs, patients may need to consult with specialists in different medical fields. Rheumatology organizations in the U.S., Great Britain, and Europe have developed recommendations to manage this complex disease, but these recommendations haven’t been properly assessed. Studies on the impact of the quality of healthcare on SLE outcomes are also insufficient. As such, researchers at the Heinrich-Heine-University Düsseldorf, in Germany, in collaboration with the German Lupus Self-Help Community, evaluated the quality of SLE care in the country to identify gaps in healthcare and find links between healthcare management practices and long-term patient outcomes. Participants were taking part in the LuLa Study, a nationwide survey of SLE patients started in 2001, in which patients receive an annual questionnaire on multiple aspects of life with this disease. In 2013, a total of 580 patients were included in this study after completing and returning their questionnaires. Of these, most were women (93.8%), with a mean age of 54 years, and a mean disease duration of 20 years. The primary outcomes were patient-reported disease activity, disease-related damage, and health-related quality of life (HRQoL), as assessed by questionnaires. Disease activity was measured using the Systemic Lupus Activity Questionnaire, disease-related damage with the Brief Index of Lupus Damage Questionnaire, and HRQoL with the Short Form 12 Health Survey. Twenty-one factors that predict good clinical care in SLE were selected for the analysis, including urine and blood tests in the previous year; taking antimalarials, vitamin D, and calcium; counseling on vaccinations and blood pressure; and treatment for co-existing conditions such as hypertension, osteoporosis, and lipid (fat) metabolism disorder. These parameters were then statistically compared with the patient-reported disease outcomes after adjusting for age, sex, and disease duration. Results showed that at least six of 10 parameters — taking antimalarials, urine and blood testing, blood pressure and vaccination counseling, treatment of osteoporosis, hypertension and lipid metabolism disorder, and taking vitamin D and calcium if prednisolone dose is higher than 7.5 mg per day — were important in the healthcare of people with SLE. Receiving more clinical care was significantly associated with both low disease activity and slower disease-related damage. Also, while it did not have a significant impact on mental health, receiving more care was linked to a better physical HRQoL score. Taking antimalarials and protecting against osteoporosis had the greatest impact on disease damage, while osteoporosis protection and blood-pressure counseling had the highest impact on reducing disease activity. In addition, blood-pressure counseling was important in improving mental and physical HRQoL. “Our study illustrates a strong link between quality of care and important SLE outcome parameters including quality of life, disease-related damage and disease activity,” the scientists wrote. “Improvement of healthcare provided on an individual level could therefore be a good approach to improve the outcome of patients with lupus erythematosus,” they added. “The 10 parameters identified in our analysis should be of particular importance in the care of patients with lupus erythematosus.” Steve Bryson PhD Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone. Fact Checked By: Jose Marques Lopes, PhD José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
  5. Turning Points in Research for Systemic Lupus in 2019 December 24, 2019 2019's Top Treatmen Advances in Lupus: 2019 was a significant year for new developments in the treatment of systemic lupus. These include new treatment options for systemic lupus and updated treatment guidelines for established treatments. In this slideshow, we highlight a few of the achievements made throughout the year. https://www.rheumatologynetwork.com/lupus/turning-points-research-systemic-lupus-2019
  6. Biomarkers associating endothelial Dysregulation in pediatric-onset systemic lupus erythematous Wan-Fang Lee1 , Chao-Yi Wu1,2, Huang-Yu Yang2,3, Wen-I Lee1 , Li-Chen Chen1 , Liang-Shiou Ou1 and Jing-Long Huang1,2* Abstract Background/purpose: Endothelium is a key element in the regulation of vascular homeostasis and its alteration can lead to the development of vascular diseases. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with potential extensive vascular lesions, involving skin vessels, renal glomeruli, cardiovascular system, brain, lung alveoli, gastrointestinal tract vessels and more. We aimed to assess endothelial dysregulation related biomarkers in pediatric-onset SLE (pSLE) patient serum and elucidate its correlation with their clinical features, laboratory parameters, and the overall disease activity. Methods: Disease activities were evaluated by SLE disease activity index (SLEDAI). Patient characteristics were obtained by retrospective chart review. Six biomarkers associated with endothelial dysregulation, including Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Tie2, Vascular endothelial growth factor (VEGF), thrombomodulin, and a disintegrin-like and metalloprotease with thrombospondin type 1 motif (ADAMTS13) were tested through enzyme-linked immunosorbent assay (ELISA) measurement. Results: This study comprised 118 pSLE patients. Data from 40 age-matched healthy controls were also obtained. The mean diagnostic age was 13 ± 4.12 years-old and 90.7% are females. Serum levels of VEGF, Tie2, thrombomodulin were significantly higher while serum ADAMTS13 was lower in active pSLE patients when compared to those with inactive diseases (all p < 0.05). In organ specific association, serum thrombomodulin level was higher in pSLE patient with renal involvement, and serum ADAMTS13 levels was negatively associated with neurological involvement (p < 0.05). A cutoff of thrombomodulin at 3333.6 pg/ml best correlated renal involvement. (AUC = 0.752, p < 0.01). Conclusion: Endothelial dysregulation associating proteins seems to be potent biomarkers for pSLE activity as well as organ involvement in pSLE patients. These biomarkers may be beneficial in understanding of the vascular pathogenesis and disease monitoring. Keywords: Systemic lupus erythematosus, Biomarkers, Endothelial cell. https://ped-rheum.biomedcentral.com/track/pdf/10.1186/s12969-019-0369-7
  7. 10 Challenges in Treating Lupus 10 most important challenges in treating patients with SLE. (©Blueringmedia,AdobeStock) Gregory M. Weiss, M.D. June 13, 2019 We have come a long way since the introduction of glucocorticoids for the treatment of systemic lupus erythematosus (SLE). A one-year survival rate of 50 percent has become a 10-year survival of 90 percent due to advances in treatment. Even with improved treatment and prognosis several challenges remain in the management of SLE. In this article, we highlight the 10 most important challenges in treating patients with SLE as outlined by Laurent Arnaud, M.D., Ph.D., of Strasbourg, France, in a review published in Lupus Science & Medicine earlier this year. 1) Treat to target favoring disease remission (or low disease activity) In 2016, a large international panel sought to define remission in systemic lupus erythematosus (SLE). The panel was able to agree on three principles: Remission should be a durable state. A validated index should be used. Distinction should be made between remission on and off therapy. While at the same time the Asia Pacific Lupus Collaboration developed a Low Disease Activity State index, the challenge remains to validate whether these definitions are predictive of outcomes and ultimately used as targets in treat-to-target management of SLE. 2) Limiting the use of glucocorticoids While glucocorticoids have played a major role in the improvement of systemic lupus erythematosus (SLE) prognosis, a large number of patients never discontinue glucocorticoids. Glucocorticoid dose predicts its overall exposure which can increase the risk of damage accrual even at low doses. Several challenges exist with regards to glucocorticoid treatment in SLE: Using a low dose glucocorticoid or a glucocorticoid free regimen should be discussed as a major target. Glucocorticoid management should be addressed as an important concern in future research with glucocorticoid tapering schemes, glucocorticoid-related adverse events, damage accrual and cumulative glucocorticoid doses being examined. Glucocorticoid doses should be managed using more objective tools such as the glucocorticoid cumulative dose, follow-up of disease activity and damage, and recording of glucocorticoid-related adverse events. 3) Deriving more comprehensive tools for the evaluation of disease activity Do to multiple organs being involved in systemic lupus erythematosus (SLE), it is difficult to define disease activity as a whole. While several tools have been developed to assess the overall activity of the disease, in most cases the clinician has to form a judgment with regard to whether each manifestation is due to SLE or some other cause. The authors believe that a more objective and reproducible measure of disease activity is needed and may include biomarkers and utilization of modern technology such as deep machine learning. 4) Developing more effective and better tolerated drugs While drug therapy in systemic lupus erythematosus (SLE) has improved, several gaps remain in the care of SLE patients such as the progression of lupus nephritis to end-stage kidney disease. For example, in lupus nephritis, a significant proportion of patients still progress towards end-stage kidney disease. “Our group has recently published a systematic review (in the Annals of Rheumatic Diseases) of 74 targeted therapies for SLE, showing that we may expect great changes in the therapeutic tools available for SLE treatment,” the authors wrote. “We believe that current challenges are shifting from whether some new drugs will be available to the identification of the best strategy for the selection of the most adequate drug (or drug combination) at the patient level, to warrant a positive balance between efficacy and side effects. The need to investigate biomarkers that would allow adequate prediction of response to therapy remains high, but when solved will allow a more rational selection of the optimal pharmacological agent within the broad pipeline of targeted therapies for SLE.” These current challenges are shifting from whether new drugs will be available to identifying the best strategy for the selection of the most adequate drug, or drug combination, at the patient level. Identifying strong biomarkers will allow a more rational selection of the optimal pharmacological agent. 5) Dissecting the heterogeneity of the disease at the molecular and genetic level Both environmental and genetic factors play roles in the development and exacerbation of systemic lupus erythematosus (SLE). To date, a large number of nucleotide polymorphisms have been implicated in SLE however none of them have utility on their own in the diagnosis or treatment of patients. An important challenge will be to develop an optimal genetic model for patients’ sub-stratification using multiomics to better personalize medicine for patients with SLE 6) Identifying relevant biomarkers for individualized treatment Matching the right treatment to the individual patient remains a challenge in SLE. Traditional markers such as anti-double-stranded-DNA fall short and should give way to multiomics, which utilize high-throughput tools such as next-generation sequencing and computerization of data, to open the door for an integrated and personalized treatment approach. Non-coding RNAs, owing to being tissue-specific regulators of gene expression, may emerge as important makers of flares in SLE. It remains a challenge to develop a holistic approach to SLE, a challenge that will require a specialized interface between all providers. 7) Managing fertility and pregnancy Pregnancy remains a significant challenge in women with systemic lupus erythematosus (SLE). We as clinicians have to improve the outcomes of pregnancy in patients with aPL and/or anti-SSA/B antibodies. The overall prognosis of pregnancy in SLE is better when the disease has been in remission for at least six months, or one year for nephritis with a low organ damage score. Strong predictors of complications during pregnancy with SLE include: Active SLE at the time of conception and/or positivity for lupus anticoagulant or triple positivity, use of antihypertensive treatments, and low platelet count. Finally, clinicians should be aware that pregnancy complications can mimic SLE flares and anti-phospholipid antibodies can lead to both maternal and fetal adverse events. Managing comorbidities Late cardiovascular morbidity and mortality have increased along with overall systemic lupus erythematosus (SLE) patient survival. One challenge here is that measures validated for determining cardiovascular disease risk are based on North American populations and may not be adapted from the general population to patients with SLE. Infections remain an serious comorbidity with SLE. Vaccines should be used provided immunosuppressive therapy does not contraindicate use. Osteoporosis can be significant in SLE patients especially with glucocorticoid treatment. Anti-osteoporotic treatment should be considered. 9) Improving the network of care More light should be shed on rare diseases like systemic lupus erythematosus (SLE). We need to improve early diagnosis while limiting diagnosis uncertainty. Training of new clinicians should included recognition of rare diseases and education should be provided to practicing caregivers, patients, and their families alike. Global awareness should be the goal. 10) Favoring a holistic approach All aspects of the patient with SLE should be addressed. Patient reported outcome measures can facilitate holistic treatment and lead to better quality of life. Just as organ damage is a concern, so should fatigue, depression, pain, sleep disturbance and obesity be. Better trials are needed in an effort to find non-pharmacological interventions aimed at treating the whole patient. Finally, individual factors such as race, smoking, and socioeconomic background should be taken into consideration when developing a plan for patients with SLE. REFERENCE Renaud Felten, Flora Sagez, Pierre-Edouard Gavand, et al. “10 most important contemporary challenges in the management of SLE.” Lupus Science & Medicine 2019;6:e000303. DOI:10.1136/ lupus-2018-000303 https://www.rheumatologynetwork.com/lupus/10-challenges-treating-lupus
  8. SLE Breakthrough Finds a Link Between Microbial Translocation and Autoantibodies (©AysezgicmeliShutterstock.com) Gregory M. Weiss, M.D. August 7, 2019 Lupus, Modern Medicine News, News, Rheumatology A previously unknown direct relationship has been found between microbial translocation from the gastrointestinal tract and autoantibody levels in patients with systemic lupus erythematosus. The findings by, Gary Gilkeson, M.D., and Wei Jiang, M.D., of the Medical University of South Carolina in Charleston, appear in the May 20 online issue of Arthritis and Rheumatology. The authors state, “An understanding of the mechanism of autoantibody induction in systemic lupus erythematosus (SLE) can lead to the development of therapeutic targets that prevent autoantibody production thereby slowing disease onset, mitigating downstream inflammation and reducing tissue damages.” Systemic lupus erythematosus is a chronic autoimmune mediated inflammatory disease that results from a loss of tolerance to the patient’s own antigens leading to autoantibody production. It is known that genetic factors influence the development of lupus leading to clustering of the disease within families. The source of autoantibody production in systemic lupus erythematosus remains elusive and is likely multifactorial with genetic, environmental, immunologic, and hormonal factors contributing to development of the disease. Recent research has implicated increased intestinal permeability in the pathogenesis of autoimmune disease. While under normal conditions the gastrointestinal tract serves as a barrier to environmental antigens, however, in certain disease states, this barrier may be compromised allowing translocation of gut microbes into the bloodstream. The authors sought to determine the role of microbial translocation in systemic lupus erythematosus. They examined lupus patients and their first-degree relatives comparing them to healthy controls. Two cohorts were included in the study. The first group consisted of 18 unrelated healthy control subjects and 18 first-degree relatives of systemic lupus erythematosus patients. The second included 19 healthy controls and 21 lupus patients. Plasma autoantibodies and lipopolysaccharide levels were measured and DNA bacterial DNA was extracted from plasma to determine if translocation had occurred. From the bacterial DNA microbiome species was determined. Auto-antigen array demonstrated higher plasma levels of a large spectrum of autoantibodies in systemic lupus erythematosus patients and first-degree relatives of lupus patients compared to healthy controls. Four representative lupus-related IgG autoantibodies including anti-double stranded DNA, anti-nucleosome, anti-single stranded DNA and anti-chromatin were increased in lupus patients and first-degree relatives compared to healthy control subjects. Compared to unrelated healthy control subjects, systemic lupus erythematosus patients and parents or children who were first-degree relatives had increased microbial translocation as evidenced by plasma lipopolysaccharide levels. First-degree relatives of lupus patients but not lupus patients themselves had decreased intestinal species diversity when compared to healthy controls. Take-home points and final thoughts First-degree relatives of systemic lupus erythematosus patients also have significantly elevated levels of lupus related autoantibodies. Increased levels of lipopolysaccharide in these patients are consistent with prior research linking infection, bacterial translocation and autoimmunity. The authors state, “The increased translocation of bacterial products into the systemic circulation from the permeable mucosa suggests that insights into autoimmune pathology can be gained from studying the circulating microbiome as opposed to other sites.” In a letter to the editor the authors discuss why they believe bacterial diversity was decreased in relatives but not in lupus patients themselves. They found after reanalyzing the data that diversity differences did not occur within a specific racial group but did between different races. They point out that, “while race may play a role in differences in circulating microbiome diversity, additional studies are needed to confirm this hypothesis.” Systemic lupus erythematosus is a very complex disease with an etiology that has remained elusive. The authors have discovered a possible infectious cause of lupus that could lead to focus on intestinal integrity and possibly uncover medications that we are using that compromise gut barrier. While the discovery of bacterial translocation in lupus opens the door for future investigation into preventing this from happening, the sheer number of different possible causes for systemic lupus erythematosus remains daunting. With continued efforts like those of the authors, we take important steps toward understanding lupus in the hopes of improving the quality of life of those who suffer from it. REFERENCE Elizabeth Ogunrinde, Zejun Zhou, Zhenwu Luo, et al. "A link between plasma microbial translocation, microbiome, and autoantibody development in first-degree relatives of systemic lupus erythematosus patients." Arthritis and Rheumatology. 2019 May 20. doi: 10.1002/art.40935 https://www.rheumatologynetwork.com/lupus/sle-breakthrough-finds-link-between-microbial-translocation-and-autoantibodies?rememberme=1&elq_mid=8392&elq_cid=1830808&GUID=9D824BFE-EF27-47A3-BAE0-900DC34C90C7
  9. Take the Right Shots for Lupus! August 15, 2019 While August is when we savor the last weeks of summer, it is also the time to look ahead and prepare for fall. In recognition of National Immunization Month, our Chief Scientific Officer Dr. Teodora Staeva provides background on vaccines and relays government recommendations for which are safe for people with lupus. “Vaccines help to develop immunity, in other words protect against disease, by imitating an infection,” notes Dr. Staeva. “Most vaccines contain small amounts of the germs (or parts of them) that cause disease but are either killed or weakened. The vaccine prompts the immune system to produce T cells and antibodies against these germs, and thus allows the body to learn how to fight these microbes in the future. However, several rounds of vaccination are often required to achieve optimal protection.” Currently there are four main types of vaccines. Live-attenuated vaccines use the weakened (attenuated) form of the virus so that it does not cause serious illness in individuals with healthy immune systems. Vaccines with live viruses are generally NOT recommended for people with lupus. Inactivated vaccines are made by killing the germ while making the vaccine. These are considered safe and effective for people with lupus. Subunit or purified antigen vaccines use only specific pieces of the germ. Thus, they give a very robust immune response targeted to key portions of the microbe. Generally, these vaccines can be used widely, including on people with weakened immune systems. Toxoid vaccines use a toxin (harmful product) made by the germ that causes a disease. They create immunity to the parts of the germ that cause a disease instead of the germ itself. That means the immune response is targeted to the toxin instead of the whole germ. “People with lupus are at greater risk for infections due to immunosuppression, so vaccines are very important,” noted Dr. Staeva. “But speak to your doctor before getting any vaccine to determine which are right for you and when.” _________________________________________________________________________ Recommendations from the U.S. Department of Health & Human Services (HHS), Office of Women’s Health: People with lupus typically can get the following vaccines that do not contain live viruses: The flu shot (not nasal spray which contains a live form of the flu virus) Pneumonia vaccine Human papillomavirus (HPV) vaccine Tetanus, diphtheria, and acellular pertussis (Td/Tdap) vaccine Vaccines with live viruses that may not be safe for people with lupus, include: Nasal spray vaccine for the flu Varicella (chickenpox) vaccine Herpes Zoster (Shingles) vaccine Measles, Mumps, Rubella (MMR) vaccine Live typhoid vaccine (oral) Sources: U.S. Department of Health & Human Services, Office of Women’s Health https://www.lupusresearch.org/take-the-right-shots-for-lupus/
  10. Fatigue in Patients with Lupus is Real Fatigue in patients with systemic lupus erythematosus (SLE) has been linked to anti-NR2 antibodies, which responds to treatment with belimumab, a study shows. (©ArtemidaPsy,Shutterstock.com) Whitney J. Palmer June 24, 2019 Lupus, Rheumatology, Women's Health Patients with systemic lupus erythematosus (SLE) who have higher levels of antibodies to the receptor in the brain associated with memory and learning also experience more severe levels of fatigue, new research shows. The results, published in a recent issue of Annals of Rheumat ic Diseases, identifies a link between fatigue—one of the most challenging symptoms patients with systemic lupus erythematosus face—and the presence of anti-NR2, a brain-reacting antibody. “The presence of anti-NR2 antibodies in patients with lupus with fatigue is a helpful diagnostic tool and may offer a major approach in the therapeutic management of this important disabling symptom in patients with lupus,” said Andreas Schwarting, M.D., a rheumatologist, immunologist, and medical director at the University Medical Center of the Johannesburg-Gutenberg University Mainz in Germany. Elevated levels of anti-NR2 have been reported in 25 percent to 38 percent of patients with lupus, they said, so these findings could affect a substantial number of patients. To determine the impact of these autoantibodies, researchers analyzed blood samples from 426 patients with lupus. They also assessed fatigue severity using a self-reporting questionnaire. The findings found that patients with higher anti-NR2 levels experienced the more significant impacts of fatigue, including motoric and cognitive fatigue. Researchers found no correlation between anti-NR2 levels and renal function, erythrocyte sedimentation rate, or C-reactive protein. Study results also showed belimumab effectively relieved fatigue. Patients receiving belimumab for six months to 36 months saw a significant decline in their levels of anti-NR2 antibodies, as well as a clinically significant drop in their fatigue scores. Overall, investigators said, the findings could directly impact patient care. “The results of our study offer a sustained clinical advantage: to add an objective measurement of fatigue in lupus patients to a subjective questionnaire,” they said. “Anti-NMDAR antibodies should be identified routinely for patients with lupus suffering from fatigue.” REFERENCE Schwarting A, Mockel T, Lutgendorf F, et al. "Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies." Annals of Rheumatic Diseases(2019), doi: 10.1136/annrheumdis-2019-215098. https://www.rheumatologynetwork.com/lupus/fatigue-patients-lupus-real?rememberme=1&elq_mid=7437&elq_cid=1830808&GUID=9D824BFE-EF27-47A3-BAE0-900DC34C90C7
  11. Fracture Risk is High in Lupus Patients with systemic lupus erythematosus (SLE) are at an increased risk for fractures, new research shows. The risk is particularly high among patients with lupus nephritis. (©PollapatChirawongShutterstock.com) Whitney J. Palmer June 24, 2019 Lupus, Joint/Bone Health, News, Rheumatology Patients with systemic lupus erythematosus (SLE) are at an increased risk for fractures, new research shows. The risk is particularly high among patients with lupus nephritis. In a study published in a recent issue of Arthritis & Rheumatology, investigators foiund that patients with lupus nephritis were far more likely to break a bone than patients who do not have lupus. “Patients with lupus nephritis may be at particularly high risk of fracture due to secondary or tertiary hyperparathyroidism and vitamin D deficiency,” said study author Sara Tedeschi, M.D., MPH, a rheumatology fellow at Brigham and Women’s Hospital. To assess fracture risk, researchers examined medical records for 47,709 lupus patients, including 9,449 patients who also had lupus nephritis. They identified pelvic, wrist, hip, and humeral fractures and compared these records to those of 190,836 patients without lupus. According to results, all lupus patients had a two-fold higher risk for any fracture compared to patients without lupus. Lupus nephritis patients have a three-fold risk over non-lupus patients and a 1.6-fold increase over lupus patients. However, findings did indicate that African American patients with lupus experienced a lower fracture risk than other study participants. When examining risk for specific types of fractures, investigators found lupus patients were at high risk for hip and pelvic fracture compared to patients without lupus. The risk was also elevated, though not as much, for humerus and wrist fractures. Researchers also discovered younger lupus patients had a 2.3-times higher fracture risk than younger patients who didn’t have lupus. Lupus patients over age 50 had a two-fold fracture risk increase. Less than half of patients with lupus received glucocorticoid treatment, indicating use of this medication was only responsible for some increased fracture risk. Ultimately, investigators said, these results reinforce the importance of identifying high-risk patients who have lupus and lupus nephritis to monitor them and provide for fracture prevention. REFERENCE Tedeschi S, Kim S, Guan H, Grossman J, Costenbader K. "Comparative Fracture Risks Among United States Medicaid Enrollees With and Those Without Systemic Lupus Erythematosus." Arthritis & Rheumatology (2019), doi: 10.1002/art.40818 https://www.rheumatologynetwork.com/lupus/fracture-risk-high-lupus?rememberme=1&elq_mid=7437&elq_cid=1830808&GUID=9D824BFE-EF27-47A3-BAE0-900DC34C90C7
  12. Treatment with Tofacitinib Helps Relieve Arthritis and Rash Symptoms in Lupus Patients, Study Shows lupusnewstoday.com/2019/05/31/tofacitinib-relieve-arthritis-skin-rash-symptoms-sle/ Ana PenaMay 31, 2019 Tofacitinib tablets, a medicine approved to treat rheumatoid and psoriatic arthritis, may work for lessening signs and symptoms of arthritis and skin rash in people with systemic lupus erythematosus (SLE), a small study has found. These findings were reported in the letter “Successful treatment of arthritis and rash with tofacitinib in systemic lupus erythematosus: the experience from a single centre” that was published in the journal Annals of Rheumatic Diseases. Tofacitinib is marketed by Pfizer with the brand name Xeljanz for treating rheumatoid and psoriatic arthritis in adults who have failed treatment with methotrexate or other disease-modifying anti-rheumatic drugs (DMARDs). The medicine also has been approved to help manage inflammation in adults with ulcerative colitis, another chronic inflammatory condition. It blocks the activity of certain janus kinases (JAK) enzymes, which are critical for the activity of the immune system. By targeting JAKs, tofacitinib inhibits the activity of several signaling molecules, including interferons and interleukins known to have a role in SLE development and progression. Clinical data collected from rheumatoid arthritis patients indicates that tofacitinib can act quickly to reduce inflammation, as corticosteroids do, but without the side effects of steroids. Tofacitinib has been used off-label to treat SLE in some patients, but there is still very little data about the effectiveness and safety of this treatment for lupus. That’s why a group of researchers at the Peking Union Medical College Hospital in China evaluated tofacitinib’s effectiveness in a group of 10 lupus patients seen at the center. Nine women and one man received 5 mg of tofacitinib two times a day, and were followed by the team for at least four weeks and up to one year. At each follow-up visit, patients were monitored for disease activity with laboratory tests, such as measurement of anti-dsDNA antibodies and complement C3 levels, and by using scoring systems commonly used in clinics — SLE Disease Activity Index-2000 (SLEDAI-2K) and physician’s global assessment (PGA). Within one year, tofacitinib yielded a quick resolution of arthritis in all four patients who had such symptoms, and promoted significant relief in skin rash in six of nine participants. All those patients who experienced improvements achieved clinical remission of arthritis or skin rash. Tofacitinib’s effectiveness for rash, however, was more uncertain. In two patients, the medicine improved symptoms only partially or not at all. And another patient even experienced a flare during the follow-up period. Despite the rapid benefit seen for disease activity, SLE blood markers remained unchanged during the study. This agrees with prior tests reported for a different JAK inhibitor, baricitinib (sold in the U.S as Olumiant), in lupus patients and animal models. Two patients experienced treatment-related adverse events. One had herpes varicella zoster (shingles) and the other had alopecia (spot baldness). Both continued on tofacitinib, but their dosage was tapered and they ended up achieving disease remission. Based on these findings the team believes that “tofacitinib can rapidly improve the symptoms and signs of arthritis and partially improve skin rash in patients with SLE, sparing steroid to reach [clinical remission].” In view of the small number of patients studied and the variable periods of follow-up for each of them, researchers stress that more studies are needed to confirm tofacitinib’s effectiveness and define its specific indication in patients with SLE.
  13. Gene Changes Key to Successful Pregnancy in Lupus April 29, 2019 Pregnant women with lupus are more likely to suffer complications than those who don’t. Lupus Research Alliance Scientific Advisory Board members Dr. Virginia Pascual, Professor at Weill Cornell Medicine; and Dr. Jane Salmon, Collette Kean Research Professor at Hospital for Special Surgery, and their colleagues asked if testing the blood, of pregnant women with lupus, using advanced technologies could identify, early in pregnancy, lupus patients at high risk for complications. Their new paper in the Journal of Experimental Medicine shows that during uncomplicated pregnancy in both healthy and lupus women some genes that incite the immune system become less active. These changes may make the immune system less aggressive and reduce the odds that it will attack the fetus. However, women with lupus who had pregnancy complications, including preeclampsia, did not show the desirable decrease in these immune signatures. Doctors came up with the term “lupus” because they thought the disease’s skin inflammation looked liked a wolf’s bite. The study “supports the idea that in some cases, pregnancy can ‘tame the wolf.’” Drs. Timothy Niewold and Shilpi Mehta-Lee wrote in a commentary on the paper. They note that the findings may enable doctors to identify patients with lupus who are susceptible to pregnancy complications and need careful monitoring To the immune system, a fetus developing in the womb resembles a foreign invader. Normally during pregnancy, the mother’s immune system develops what researchers call tolerance and avoids attacking the fetus. But when patients with lupus become pregnant, their immune system may be less likely to develop tolerance to the fetus, leading to complications such as preeclampsia, premature birth, and even death of the fetus. In the new study, Dr. Pascual and colleagues compared 92 pregnant women with lupus to 43 pregnant women who didn’t have the disease. The researchers obtained blood samples from the women during and shortly after their pregnancies. To detect the earliest changes associated with pregnancy onset, the scientists also analyzed blood from patients undergoing assisted reproductive technology. The researchers evaluated the patients’ immune system by measuring the activity of different genes that help determine how strongly it responds to potential threats. For a subset of these study participants, the investigators also examined the types of cells that are producing the specific immune responses. Early in pregnancy, the activity of key genes decreased in women who didn’t have lupus, probably increasing their tolerance to the developing baby. The researchers saw similar changes in women with lupus who had successful pregnancies. However, the immune system of women with lupus who went on to develop complications was not turned down. Their immune system might be more likely to attack the fetus or prevent its proper development. This inability to turn down the immune activity appears to be a risk factor for adverse pregnancy outcomes in lupus. Testing for these changes in gene activity might pinpoint patients with lupus who are more likely to develop pregnancy complications and who needs careful monitoring and specific therapeutic intervention to improve the outcome. https://www.lupusresearch.org/gene-changes-key-to-successful-pregnancy-in-lupus/
  14. Discovery may help explain why women get autoimmune diseases far more often than men April 19, 2019 , University of Michigan Stark differences in the presence of autoimmune antibodies and immune factors in the blood (top) and kidneys (bottom) of mice that produced excess VGLL3 (left column) compared with healthy mice (right column). Credit: University of Michigan It's one of the great mysteries of medicine, and one that affects the lives of millions of people: Why do women's immune systems gang up on them far more than men's do, causing nine times more women to develop autoimmune diseases such as lupus? Part of the answer, it turns out, may lie in the skin. New evidence points to a key role for a molecular switch called VGLL3. Three years ago, a team of University of Michigan researchers showed that women have more VGLL3 in their skin cells than men. Now, working in mice, they've discovered that having too much VGLL3 in skin cells pushes the immune system into overdrive, leading to a "self-attacking" autoimmune response. Surprisingly, this response extends beyond the skin, attacking internal organs too. Writing in JCI Insight, the team describes how VGLL3 appears to set off a series of events in skin that trigger the immune system to come running—even when there's nothing to defend against. "VGLL3 appears to regulate immune response genes that have been implicated as important to autoimmune diseases that are more common in women, but that don't appear to be regulated by sex hormones," says Johann Gudjonsson, M.D., Ph.D., who led the research team and is a professor of dermatology at the U-M Medical School. "Now, we have shown that over-expression of VGLL3 in the skin of transgenic mice is by itself sufficient to drive a phenotype that has striking similarities to systemic lupus erythematosus, including skin rash, and kidney injury." Effects of excess VGLL3 Gudjonsson worked with co-first authors Allison Billi, M.D., Ph.D., and Mehrnaz Gharaee-Kermani, Ph.D., and colleagues from several U-M departments, to trace VGLL3's effects. They found that extra VGLL3 in skin cells changed expression levels of a number of genes important to the immune system. Expression of many of the same genes is altered in autoimmune diseases like lupus. The gene expression changes caused by excess VGLL3 wreaked havoc in the mice. Their skin becomes scaly and raw. Immune cells abound, filling the skin and lymph nodes. The mice also produce antibodies against their own tissues, including the same antibodies that can destroy the kidneys of lupus patients. The researchers don't yet know what causes female skin cells to have more VGLL3 to begin with. It may be that over evolutionary time females have developed stronger immune systems to fight off infections—but at the cost of increased risk for autoimmune disease if the body mistakes itself for an invader. The researchers also don't know what triggers might set off extra VGLL3 activity. But they do know that in men with lupus, the same VGLL3 pathway seen in women with lupus is activated. Many of the current therapies for lupus, like steroids, come with unwanted side effects, from increased infection risk to cancer. Finding the key factors downstream of VGLL3 may identify targets for new, and potentially safer, therapies that could benefit patients of both sexes. Lupus, which affects 1.5 million Americans, can cause debilitating symptoms, and current broad-based treatment with steroids can make patients far more vulnerable to infections and cancer. Patients' role in future research Their colleague and senior coauthor Michelle Kahlenberg, M.D., of the U-M Division of Rheumatology, is now recruiting patients with lupus for a study sponsored by U-M's A. Alfred Taubman Medical Research Institute that could provide answers to these questions and more. Billi, a resident in dermatology, notes that when she speaks with patients who come to Michigan Medicine's dermatology clinics for treatment of the skin problems lupus can cause, she has to acknowledge the limits of current treatment. Even so, she says, patients are eager to take part in studies by contributing skin and DNA samples that could lead to new discoveries about their condition. "Many patients are frustrated that they've had to try multiple therapies, and still nothing is working well," she says. "To be able to tell them that we're working on a mouse that has the same disease as them, and that we need their help, brings out their motivation and interest in research. They know that it's a long game, and they're in for it." More information: Allison C. Billi et al, The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity, JCI Insight (2019). DOI: 10.1172/jci.insight.127291 Provided by University of Michigan The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity Allison C. Billi,1 Mehrnaz Gharaee-Kermani,2 Joseph Fullmer,1 Lam C. Tsoi,1,3,4,5 Brett D. Hill,6 Dennis Gruszka,7 Jessica Ludwig,7 Xianying Xing,1 Shannon Estadt,2,8 Sonya J. Wolf,2,8 Syed Monem Rizvi,6 Celine C. Berthier,9 Jeffrey B. Hodgin,10 Maria A. Beamer,1Mrinal K. Sarkar,1 Yun Liang,1 Ranjitha Uppala,1,8 Shuai Shao,1,11 Chang Zeng,1 Paul W. Harms,1,10 Monique E. Verhaegen,1 John J. Voorhees,1 Fei Wen,6 Nicole L. Ward,7 Andrzej A. Dlugosz,1,12 J. Michelle Kahlenberg,2,3 and Johann E. Gudjonsson1,3 First published April 18, 2019 - More info Abstract Autoimmune disease is 4 times more common in women than men. This bias is largely unexplained. Female skin is “autoimmunity prone,” showing upregulation of many proinflammatory genes, even in healthy women. We previously identified VGLL3 as a putative transcription cofactor enriched in female skin. Here, we demonstrate that skin-directed overexpression of murine VGLL3 causes a severe lupus-like rash and systemic autoimmune disease that involves B cell expansion, autoantibody production, immune complex deposition, and end-organ damage. Excess epidermal VGLL3 drives a proinflammatory gene expression program that overlaps with both female skin and cutaneous lupus. This includes increased B cell–activating factor (BAFF), the only current biologic target in systemic lupus erythematosus (SLE); IFN-κ, a key inflammatory mediator in cutaneous lupus; and CXCL13, a biomarker of early-onset SLE and renal involvement. Our results demonstrate that skin-targeted overexpression of the female-biased factor VGLL3 is sufficient to drive cutaneous and systemic autoimmune disease that is strikingly similar to SLE. This work strongly implicates VGLL3 as a pivotal orchestrator of sex-biased autoimmunity. Introduction Autoimmune disease is common, can be deadly, and affects women disproportionately. The prevalence of systemic lupus erythematosus (SLE) is 9 times higher among women than men, and many other autoimmune diseases show similar profound female skewing (1). However, the cause of this female bias remains elusive. Previous work has focused primarily on the influence of sex hormones, yet female bias in autoimmunity is observed even prior to puberty and following menopause (2), indicating alternative mechanisms at play. As most autoimmune diseases remain incurable, investigating the causes of autoimmunity is critical, and the drivers of female-biased autoimmunity are logical targets. We previously identified the conserved putative transcription cofactor vestigial like family member 3 (VGLL3) as a candidate female-biased immune regulator (3). VGLL3 is more abundant in the epidermis of women than men and shows female-specific nuclear localization, suggesting a role in sex-biased transcriptional regulation. In cell culture, VGLL3 knockdown decreased expression of select female-biased immune transcripts, including B cell–activating factor (BAFF, also known as TNFSF13B), the target of the only currently approved biologic therapy for SLE. Intriguingly, men who have SLE showed loss of sex-specific regulation of VGLL3, demonstrating upregulation and nuclear localization of VGLL3 in inflamed skin (3). This suggested that VGLL3 may govern a key upstream regulatory program promoting autoimmunity, but this hypothesis had yet to be explored. Results Human and murine VGLL3 share 87% sequence homology, including an identical putative transcription cofactor domain (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.127291DS1). Similar to human women, female mice showed 2.8-fold higher Vgll3 expression than male mice in the skin (P = 0.053) (Supplemental Figure 1B), suggesting conserved sex-biased dynamics. To test for a causative role for cutaneous VGLL3 in promoting autoimmune disease, we generated transgenic mice overexpressing Vgll3 under the control of the bovine keratin 5 (K5) promoter (Figure 1A), which drives gene expression primarily in the epidermis but also in some other stratified squamous epithelia (4). Levels of Vgll3, as shown by quantitative reverse transcription PCR (qRT-PCR), in transgenic skin varied both across and within founder lines, with transgenic mice generally showing 5- to 50-fold expression relative to WT mice, and no consistent variation by sex (data not shown). Compared with WT mice, these K5-Vgll3–transgenic mice showed increased epidermal VGLL3 staining, with conspicuous nuclear localization (Figure 1B) analogous to human VGLL3 distribution in affected skin of patients with SLE (3). Transgenic pups were indistinguishable from WT pups at birth. Within 6–12 weeks of life, they began developing progressive skin thickening and scaling prominently involving the face and ears, common sites for human discoid lupus erythematosus (DLE) lesions (Figure 1C and Supplemental Figure 1C). No consistent skin phenotypic variation by sex was noted among transgenic littermates (data not shown). Figure 1 Overexpression of VGLL3 in the epidermis produces a skin phenotype with gross and histologic features of cutaneous lupus. (A) Transgenic (TG) cassette. The bovine keratin 5 (K5) promoter drives polycistronic expression of the full-length mouse VGLL3 and mCherry red fluorescent protein linked by an internal ribosome entry site (IRES). β-glob, rabbit β-globin intronic sequence; pA, polyadenylation signal. (B) Detection of VGLL3 protein (red) by immunofluorescence (IF) in skin of female WT and TG mice. Scale bar: 20 μm. Images are representative of sections from 3 WT and 3 TG animals examined. (C) Left: WT mouse compared with age-matched TG mouse with lupus-like skin rash. Right: Bright-field and fluorescence images of WT and lesional TG tail skin. Scale bar: 2 mm. (D) H&E staining of WT and TG volar skin sections, demonstrating epidermal hyperplasia, basal cell vacuolization, apoptotic keratinocytes (arrowhead, magnified on inset), and dermal inflammatory infiltrate. Scale bar: 20 μm. (E) TUNEL (red) staining of WT and TG tail skin sections. Scale bar: 50 μm. (F) Periodic acid–Schiff staining of WT and TG dorsal skin sections. Arrowheads indicate subtle basement membrane thickening. Scale bar: 20 μm. (G) Detection of IgG and complement factor C3 by IF in WT and TG nonlesional neck skin. Scale bar: 50 μm. In E–G, images are representative of sections from 3 WT and 3 TG animals examined. Histologically, early skin lesions showed epidermal thickening and focal interface dermatitis, an inflammatory reaction pattern seen in cutaneous lupus (Figure 1D and Supplemental Figure 1, D and E). TUNEL staining confirmed increased keratinocyte apoptosis (Figure 1E), subtle basement membrane thickening was evident on periodic acid–Schiff (PAS) staining (Figure 1F), and direct immunofluorescence (IF) revealed IgG and C3 deposition at the dermal-epidermal junction (Figure 1G all are characteristic features of cutaneous lupus in humans. To examine the effects of VGLL3 that were driving this lupus-like cutaneous phenotype, we evaluated WT mice and robustly expressing transgenic mice by qRT-PCR for transcript levels of a panel of proinflammatory and lupus-related factors. Many of these transcripts showed significant elevation in transgenic mice (Figure 2A and Supplemental Figure 2A), including Tnfsf13b (encoding BAFF); IFN-κ (Ifnk), the predominant type I IFN in cutaneous lupus (5); and Cxcl13, a biomarker of early-onset SLE, heightened disease activity, and renal involvement (6). IF studies of key VGLL3-regulated factors (Figure 2B) corroborated our qRT-PCR findings. Thus, epidermal VGLL3 overexpression drives immunological gene dysregulation, similar to what we previously observed in the skin of healthy women (3). Figure 2 Overexpression of VGLL3 in the epidermis recapitulates the autoimmunity-prone genetic signature of human female skin. (A) Detection of Vgll3 and enriched immune transcripts versus example nonenriched transcript Ifnb (IFN-β) by quantitative reverse transcription PCR (qRT-PCR) in skin of WT (n = 3) and TG mice (n = 2) with high Vgll3 expression (more than tenfold WT average). Horizontal bars represent the mean. *P < 0.05 by 2-tailed Student’s t test. (B) Detection of VGLL3 targets CXCL13 (top, red) and IFN-κ (bottom, green) by IF in WT and TG skin. Blue, DNA. Scale bar: 20 μm. Images are representative of sections from 3 WT and 3 TG animals examined. (C) Literature-based network analysis of genes differentially expressed in nonlesional, normal-appearing TG skin relative to WT skin by RNA-seq. (D) Expression in nonlesional TG versus WT skin of genes dysregulated (dysreg) in discoid lupus erythematosus (DLE; P = 4.0 × 10–10) or subacute cutaneous lupus erythematosus (SCLE; P = 2.3 × 10–8) versus all genes. x axis, log2 fold change (FC) in TG versus WT. See Methods for additional statistical details. For a broader examination of VGLL3 effects, we performed RNA-seq of normal-appearing dorsal skin from WT and transgenic mice to identify differentially expressed genes (transgenic DEGs) (Supplemental Table 1). Results largely affirmed our qRT-PCR data (Supplemental Figure 2B) and revealed that the panel of transcripts examined in Supplemental Figure 2B represent only a fraction of the VGLL3-regulated transcripts identified in transgenic mice. Of the 120 gene ontology terms significantly enriched (FDR ≤ 10%) among transgenic DEGs, nearly half were related to immunological processes (Supplemental Figure 2C). Importantly, these included multiple key pathways involved in SLE pathogenesis, such as IFN responses. Literature-based network analysis of transgenic DEGs revealed additional nodes of autoimmune pathogenesis (Figure 2C). To further explore our hypothesis that female-biased VGLL3 expression in human skin drives gene changes that may predispose women to autoimmunity, we compared transgenic DEGs with the set of genes upregulated in healthy human female skin relative to male skin (3) and found a significant overlap (P = 0.032). To evaluate for a direct effect of VGLL3 overexpression in keratinocytes of our mouse model, we cultured primary keratinocytes from WT and transgenic mouse tails and performed RNA-seq. Genes differentially expressed in transgenic keratinocytes also demonstrated enrichment for immunological gene ontology terms, such as immune response (P = 6.8 × 10–9) and cytokine activity (P = 1.2 × 10–8), and showed even more significant overlap with female-biased genes (P = 4.0 × 10–7). Thus, epidermal overexpression of VGLL3 is a prominent driver of immunological dysregulation and sex-biased gene expression in keratinocytes. We then compared our mouse skin RNA-seq results to transcriptomic data from skin of cutaneous lupus patients (7). Genes dysregulated in lesional skin of patients with DLE or subacute cutaneous lupus erythematosus (SCLE) were overrepresented among transgenic DEGs (DLE, P = 1.1 × 10–13; SCLE, P = 5.0 × 10–9) and showed widespread upregulation in transgenic mice (Figure 2D), revealing a shared pattern of gene dysregulation in skin of K5-Vgll3–transgenic mice and lupus patients. Together, these in vivo data demonstrate that VGLL3 overexpression in the epidermis is sufficient to drive a female-biased gene expression signature with dysregulation of pathways implicated in human autoimmune disease. Immunohistochemistry of K5-Vgll3–transgenic skin revealed a mixed inflammatory infiltrate (Figure 3). T and B cells were increased, as were DCs, which promote lymphocyte expansion, autoantibody production by B cells, and tissue damage in SLE (8). Flow cytometry of cells isolated from skin corroborated these findings, demonstrating increased plasmacytoid DCs, as well as IgM+ and IgG+ cells, consistent with B cell expansion (Supplemental Figure 3). Neutrophils were also elevated, consistent with the neutrophilic inflammation noted on some lesional sections (Supplemental Figure 1F) and observed in a significant subset of cutaneous lupus manifestations (9). These results illustrate that epidermal overexpression of VGLL3 results in a cutaneous phenotype with gross, histologic, and inflammatory features of cutaneous lupus. Figure 3 Overexpression of VGLL3 in the epidermis causes skin inflammation with features of cutaneous lupus. Detection of the indicated cell markers by immunohistochemistry in WT and TG ear sections. Ki67, cell proliferation marker; MECA, mouse endothelial cell antigen. Scale bar: 50 μm. Images are representative of sections from 4 WT and 4 TG animals examined. To further interrogate the inflammatory response in the K5-Vgll3–transgenic mouse, we analyzed skin-draining lymph nodes, spleen, and ear tissue from WT and transgenic mice with mass cytometry (CyTOF) using a 37-marker panel (Supplemental Figure 4 and Supplemental Table 2). Transgenic mice showed significant lymphadenopathy and splenomegaly (Figure 4A), features common in SLE and some lupus mouse models (10, 11). CyTOF data visualized using the dimensional reduction tool viSNE (12) showed expansion of B cell populations that were most prominent in skin-draining lymph nodes (Figure 4B and Supplemental Figure 4). Key populations emerging from CyTOF are highlighted in a SPADE tree (13) (Figure 4, C–E, and Supplemental Figure 5). B cells were significantly overrepresented in transgenic lymph nodes (q = 6.2 × 10–4; blue circles in Figure 4D) and spleen (q = 0.024). Together, these findings suggest that skin-directed VGLL3 overexpression drives a systemic inflammatory response with B cell expansion. Figure 4 Skin-directed VGLL3 overexpression drives a systemic inflammatory response with B cell expansion. (A) Left: Representative images of WT and TG skin-draining lymph nodes (LN) and spleens. Right: LN and spleen weights represented as a percentage of total body weight. Error bars represent mean ± SEM. **P < 0.01 by 2‑tailed Student’s t test (LN, n = 6 WT and 3 TG; spleen, n = 8 WT and 8 TG). (B) CyTOF data derived from a single experiment consisting of 3 age- and sex-matched WT and TG mice visualized by viSNE. Left: viSNE maps depicting expression of select markers. Each dot is a cell. Color reflects the level of expression of marker from low (blue) to high (red). Right: Contour plot of viSNE maps colored by density of cells isolated from the specified tissues in WT and TG mice. Here, color reflects cell density from low (blue) to high (red). Data shown correspond to 1 WT and 1 TG mouse that are representative of the experiment. LN and spleen data represent approximately 20,000 CD45+ live singlets per sample. Ear skin samples represent all recorded CD45+ live singlets (WT, 262 and TG, 264) for each sample. The complete viSNE analysis for all markers and samples for the experiment can be found in Supplemental Figure 4. Data are representative of 2 independent CyTOF experiments. (C) SPADE tree of LN samples depicted in B. Node size represents the number of cells in the population derived from the experiment represented in B and Supplemental Figure 4B. Mϕ, macrophage; Neut, neutrophil; Tγδ, γ δ T cell. (D) Percentage dot plot showing the proportion of each cell type in aggregated WT and TG lymph node samples for the CyTOF experiment. Colors correspond to the populations indicated in C and E. (E) Heatmap showing marker expression of the SPADE populations specified in Cacross aggregated LN, spleen, and skin samples included in the CyTOF experiment. Q val, q values for differential detection in WT versus TG LN. †q = 6.2 × 10–4, significantly upregulated in TG LN. Peripheral blood mononuclear cells (PBMCs) of patients with SLE show altered gene expression, with prominent dysregulation of genes in IFN and cytokine signaling pathways that likely contributes to systemic inflammation (14). Evaluating gene expression in blood of WT versus K5-Vgll3–transgenic mice, we observed a significantly higher effect size for genes whose human orthologs are dysregulated in blood of SLE patients (P = 1.6 × 10–22) (Figure 5A and Supplemental Table 3), indicating a shared pattern of gene dysregulation in circulating immune cells of K5-Vgll3–transgenic mice and patients with SLE. Figure 5 Mice with skin-directed VGLL3 overexpression develop manifestations of systemic autoimmune disease. (A) Differential expression in WT (n = 4) and TG (n = 4) mouse blood of genes dysregulated in SLE peripheral blood mononuclear cells (aqua) versus all genes (peach). (B) Detection at 1:50 dilution of circulating antinuclear antibodies (Ig) by indirect IF in HEp-2 cells in WT, TG, and positive control (+ control, aged NZM2328) serum. In total, 7 TG and 3 WT animals were evaluated; all TG mouse sera showed positive autoantibody staining at a dilution of 1:25 or higher, whereas all WT mouse sera were negative. (C) Detection of circulating anti–double-stranded DNA antibodies (α-dsDNA) by ELISA. Error bars represent mean ± SEM. ***P = 0.0005 by 2-tailed Student’s t test. n = 6 WT and 6 TG. (D) Detection of IgG (red) and complement factor C3 (green) by IF in WT and TG glomeruli. Blue, DNA. Scale bar: 20 μm. Images are representative of glomeruli visualized on sections from 6 WT and 6 TG animals examined. 0 of 6 WT and 6 of 6 transgenic mice scored positive for renal immune complex deposition. Finally, we investigated whether the B cell expansion of the K5-Vgll3 mouse was associated with autoantibody production. Autoantibodies are integral to pathogenesis of SLE and associated with increased risk of progression from cutaneous to systemic lupus (15). Commonly used SLE classification systems include their detection as a diagnostic criterion. By indirect IF of HEp-2 cells, antinuclear antibodies were detected in sera of transgenic mice with developed phenotypes (Figure 5B). A homogeneous pattern of nuclear staining was observed, which is commonly found in SLE patients. Anti–double-stranded DNA (anti-dsDNA) antibodies, which are a specific marker for SLE and fluctuate with disease activity (16), were abundant in sera of transgenic mice (Figure 5C). As anti-dsDNA antibodies are pathogenic to the kidney (17), we examined kidneys of transgenic mice and found IgG and C3 deposition in glomeruli (Figure 5D). Most transgenic mice were harvested by 4–5 months of age due to the severity of the skin phenotype, limiting time for evolution of fulminant nephritis; nonetheless, examination of the transgenic kidneys revealed a subtle trend toward increased inflammation relative to WT kidneys (P = 0.20; Supplemental Figure 6, A and B). As expected based on the mild histology, significant proteinuria was not detected (P = 0.19; Supplemental Figure 6C). Thus, skin-directed VGLL3 overexpression stimulates development of lupus-specific anti-dsDNA autoantibodies that results in immune complex deposition in the kidney, the purported initiating event in development of lupus nephritis (17). Discussion Female sex alone carries a greater risk for developing SLE than any genetic or environmental factor identified to date (18). Previously, we determined that women express an autoimmunity-prone genetic signature in their skin. We hypothesized that this program was driven by the putative transcription cofactor VGLL3, which is upregulated and nuclear localized in the skin of healthy women and SLE patients of both sexes (3). Here, we establish that skin-directed overexpression of murine VGLL3 is sufficient to drive an autoimmunity-prone transcriptional signature similar to that observed in female skin, causing inflammation and activation of type I IFN signaling that mimics cutaneous lupus. Intriguingly, although VGLL3 overexpression in our model was restricted by the bovine K5 promoter to keratinocytes and some other squamous epithelia (4), K5-Vgll3–transgenic mice developed systemic inflammation, with B cell activation and autoantibody production that culminated in renal immune complex deposition analogous to that seen in lupus nephritis. Thus, overexpression of a single female-biased gene is sufficient to trigger cutaneous autoimmune disease accompanied by a systemic autoimmune response with striking similarities to SLE. This includes development of anti-dsDNA antibodies, whose presence constitutes an independent risk factor for lupus nephritis (19), and detection of immune complexes in the skin and kidneys. A growing body of evidence suggests that, in autoimmune disease pathogenesis, the initial break in self-tolerance — the inciting “first hit” — occurs at epithelial surfaces. In rheumatoid arthritis, localized mucosal tissue damage may lead to posttranslational modification of peptides, resulting in formation of anti-citrullinated peptide antibodies (20), autoantibodies that often precede the onset of disease and in susceptible individuals may incite it (21). In antinuclear antibody–associated diseases, such as SLE and other connective tissue diseases, the first hit may occur in the skin. In patients with SLE, clearance of apoptotic cells is impaired (22). Insults, such as ultraviolet light, which induces immunological activation and apoptosis of keratinocytes, cause release of endogenous nuclear antigens. Presence of these autoantigens results in elaboration of cytokines and immune cell recruitment, and cytotoxic inflammation perpetuates their release, with resulting accumulation and possible entry into circulation as proinflammatory microparticles. Inflammation in the skin may therefore prime or exacerbate antinuclear antigen-focused autoimmunity. There are sparse data suggesting that treatment of cutaneous lupus may prevent progression to SLE (23). The results herein demonstrate that cutaneous disease may be sufficient to trigger a break in self-tolerance with evolution of systemic autoimmune disease. These findings are complemented by reports in mice describing evolution of SLE-like disease with development of anti-dsDNA antibodies and immune complex nephritis in response to epidermal IFN-γ overexpression (24, 25). Further study of the IFN-γ epidermal overexpression and K5-Vgll3 lupus mouse models may reveal that treatment of cutaneous lupus is sufficient to ameliorate or even prevent progression to systemic disease. If so, this could prompt a paradigm shift in our understanding of the pathogenesis of SLE. Our results do not distinguish a principal pathway promoting autoimmunity in the K5-Vgll3–transgenic mouse. As the VGLL3-regulated factor IFN-κ is the predominant type I IFN in cutaneous lupus (5), this presents a parsimonious explanation; however, VGLL3 alters the expression of genes that act in multiple independent inflammatory pathways, and the lupus-like phenotype of the K5-Vgll3–transgenic mouse may represent the cumulative manifestation of widespread immunological VGLL3-induced dysregulation. This is reflected in the diverse inflammatory pathways activated in the skin of transgenic mice (Figure 2C), many of which have key roles in autoimmunity: MHC class I, antigen binding, cytokine activation, humoral immune responses, cellular response to IFN, and regulation of T cell–mediated cytotoxicity (26). The significant overlap of VGLL3 targets with genes dysregulated in female skin suggests that the transgenic mouse phenotype represents a fully developed autoimmune disease of which female-biased autoimmunity is the forme fruste. Additional studies of the component inflammatory pathways in the K5-Vgll3 lupus model are required to dissect the pathogenesis further. Finally, one of the principal challenges of treating lupus is disease heterogeneity. Broad immunosuppressants address disease in a majority of patients but carry serious risks of infection and malignancy that contribute substantially to morbidity and mortality. In contrast, narrower agents, such as belimumab, the biologic therapy that targets BAFF, are effective only in a subset of patients where presumably the disease is driven more heavily by the targeted autoimmune pathway. As VGLL3 appears to be not only constitutively active in women but also turned on in men with SLE (3), targeting VGLL3 may prove beneficial in patients of both sexes. Additionally, the low levels of VGLL3 in healthy men suggest that it may be amenable to depletion without adverse effects. Given stimulation of diverse inflammatory pathways — including those involving type I IFN and BAFF — observed in the K5-Vgll3–transgenic mouse, VGLL3 depletion may successfully treat more subgroups within this heterogeneous patient population. In conclusion, our data support the assertion that enrichment of VGLL3 in female skin primes women for autoimmunity. This positions VGLL3 as a master orchestrator of sex bias in autoimmune disease, providing potentially novel avenues for future research and therapeutic development. Methods Mice, primary keratinocyte isolation, and culture The K5-Vgll3-IRES-tdTomato–transgenic (K5-Vgll3–transgenic) cassette was generated as follows. The Vgll3-IRES-mCherry insert was synthesized de novo by GenScript and subcloned into the pBK5 vector, in which the bovine K5 promoter drives expression primarily in epidermis but also in some other stratified squamous epithelia (4). Of note, expression of this specific promoter has been reported to be absent in thymus and spleen (4, 27), indicating no significant expression in the immune cells therein. The Vgll3 coding sequence was taken from NCBI reference sequence NM_028572.1. The mCherry coding sequence was taken from GenBank (accession AY678264, nt 1–711) (28). Following sequence verification, the transgenic cassette was isolated by restriction enzyme digest, purified, and injected into C57BL/6 mouse oocytes at the University of Michigan Transgenic Core. Founders were identified by PCR using the following PCR primers: forward, 5′-ATCGTGCCAAGTGTGGGCTTCGATACA-3′ (located in the Vgll3 coding sequence), reverse, 5′-CACATTGCCAAAAGACGGCAATATGG-3′ (located in the IRES) and were crossed with C57BL/6J breeders (The Jackson Laboratory) to establish transgenic lines. Transgene-positive offspring were screened for cutaneous phenotypes. Nine independent founder lines were generated that demonstrated spontaneous development of cutaneous phenotypes; progeny of 6 additional independent founders either failed to develop phenotypes or were harvested for experimental purposes prior to development of phenotypes. Phenotypes observed were overall fairly uniform and typically involved alopecia and ulceration that progressed with age, often necessitating euthanasia; transgenic animals from 6 independent founder lines are pictured at time of euthanasia in Supplemental Figure 1C. Transgenic mice were observed scratching and excessively barbering, and some transgenic animals were noted to be excessively barbering nontransgenic littermates. K5-Vgll3–transgenic mouse skin harvested from multiple sites was evaluated by fluorescent microscopy of transgenic mCherry to verify epidermal transgene expression (tail, Figure 1C). For RNA-seq analysis of nonlesional (posterior dorsal) skin and blood, 4 transgenic animals representing 3 independent founder lines were included (see below for associated methods). For RNA-seq analysis of transgenic and WT primary keratinocytes, all animals were from a single litter representing 1 founder line to enable simultaneous isolation, culture, and harvest. RNA‑seq analysis of transgenic nonlesional skin and primary keratinocytes confirmed significant Vgll3 mRNA overexpression relative to WT skin and primary keratinocytes, respectively. qRT-PCR also confirmed significant Vgll3 mRNA overexpression, although the variation and upper limit of Vgll3overexpression was greater (generally 5- to 50-fold), possibly due to increase in epidermal thickness. Consistent with prior reports of absent expression in lymphoreticular organs (4, 27), RNA-seq analysis of K5-Vgll3–transgenic blood showed no Vgll3 upregulation that would be suggestive of leakage of transgene expression in immune cells (data not shown). Given the overall similarity in phenotype and gene expression changes noted by RNA-seq analysis of nonlesional skin of 3 different founder lines, multiple founder lines were included throughout the manuscript, including in qRT-PCR analyses. Primary keratinocytes were isolated as previously described from tails of 3 WT and 3 transgenic 23-day-old weanlings from a single litter (29) with the following change: skin was incubated for 1.5 hours at 37°C rather than overnight at 4°C. Cells were expanded in culture for 3 days and harvested for RNA using Buffer RLT (Qiagen) per the manufacturer’s protocol. Tissue collection For harvest of tissues for generating RNA and frozen or paraffin sectioning, transgenic mice and WT controls were euthanized at 8 weeks of age or older. Whole blood was obtained by cardiac stick and RNA was isolated using the Mouse RiboPure-Blood RNA Isolation Kit (Thermo Fisher Scientific) or TriPure Isolation Reagent (MilliporeSigma) per the manufacturer’s protocols. Nonlesional posterior dorsal skin was removed by punch biopsy. Ears were removed in entirety. Skin from the indicated sites was otherwise harvested and processed as previously described (30). For harvest of tissues for mass cytometry (CyTOF) and flow cytometry, sex-matched transgenic and WT littermates were sacrificed at 8 weeks of age or older. Ears, spleen, and skin-draining (cervical and inguinal) lymph nodes were removed in entirety. The ear and dorsal skin samples were minced with a sterile razor and transferred to 18 ml RPMI (Gibco) containing 10% fetal calf serum (Atlanta Biologicals) and 1% Penicillin-Streptomycin (Gibco) (hereafter, RPMI complete media). To each sample, 2 ml of a skin digestion solution consisting of Hanks’ Balanced Salt Solution (Gibco) with 1 mg/ml DNAse I (MilliporeSigma), 1 mg/ml Hyaluronidase type V (MilliporeSigma), and 5 mg/ml Collagenase type IV (MilliporeSigma) was added. Samples were rotated for 2 hours at 37°C to digest. Following digestion, samples were filtered through a 40-μm cell strainer, washed with fresh RPMI complete media, and incubated on ice. Spleens and lymph nodes (4 lymph nodes combined for each animal) were weighed before being ground through a 70-μm cell strainer and suspended in RPMI complete media. For spleen samples, media were removed, and cells were incubated in RBC lysis buffer (Invitrogen) for 2 minutes. Lysis buffer was removed, and spleen samples were resuspended in fresh RPMI complete media. qRT-PCR RNA was converted to cDNA using a High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems). qRT-PCR was performed in technical duplicates for the biological replicate numbers indicated in the figure legends using TaqMan Universal PCR Master Mix (Applied Biosystems). TaqMan primer sets and probes were purchased from Applied Biosystems by Life Technologies and are listed in Supplemental Table 4. All values were normalized to the housekeeping gene 18S. All qRT-PCR data are presented with y axis log2-scaled and autolog numbered. RNA-seq and gene expression analyses Stranded mRNA libraries were prepared from nonlesional (posterior dorsal) skin, cultured keratinocytes, and whole blood from age- and sex-matched WT and transgenic mice (2 male and 2 female each) using the TruSeq RNA library prep kit (Illumina) and sequenced on the Illumina HiSeq 4000 sequencer at the University of Michigan DNA Sequencing Core. Data were quality controlled and analyzed using the pipeline described previously for RNA-seq analysis, including adapter trimming (31), read mapping, and quantification of gene expression (32). We used the GENCODE release m18 (GRCm38) from mouse. We filtered for average abundance of ≥1 read per gene across all samples. DESeq was used for expression normalization. Generalized linear regression was used for differential expression analysis using negative binomial distribution to model the count data (33). FDR was used to control the multiple testing. DEGs were defined as having FDR ≤ 10% and with |log2fold change| ≥ 1 (Supplemental Tables 1 and 3). For Supplemental Figure 2B, data are presented with y axis after log2 scaling and autologing of numbers for ease of comparison to qPCR data. Software‑extracted literature‑based network analysis was performed using Genomatix Pathway System Software. For identification of genes dysregulated in DLE and SCLE, microarray data from 26 DLE and 23 SCLE lesional skin biopsies and 7 normal skin biopsies (GEO GSE81071) were utilized to identify genes that are differentially expressed in DLE and SCLE skin (termed dysregulated in text to avoid confusion with transgenic DEGs) at the FDR ≤ 10% and with |log2fold change| ≥ 1 threshold. For identification of genes dysregulated in blood of SLE patients, RNA-seq data from whole blood of 99 SLE and 18 healthy control patients were analyzed as above and used to identify genes that were differentially expressed in blood of SLE patients (termed dysregulated in text to avoid confusion with transgenic DEGs). We performed analysis only for genes expressed in at least 20% of the normal samples. For investigation of target overlap with DLE and SCLE skin and SLE blood, only genes with identical names in mouse and human were included. Histology and immunostaining Hematoxylin (Surgipath, 3801540) and eosin (Surgipath, 3801600) staining was performed per standard protocols. Epidermal thickness was quantified on the H&E-stained sections using Adobe Photoshop. For each animal, approximately 100 measurements were taken from 8 different fields of view for each section analyzed. Epidermal thickness was measured from the stratum basale to stratum granulosum, excluding the stratum corneum and hair follicles for each animal. IF to detect VGLL3 and target proteins was performed as follows. For CXCL13 detection, formalin-fixed, paraffin-embedded tissue sections were deparaffinized, rehydrated, and heated at 95°C for 20 minutes in pH 6 antigen retrieval buffer. Slides were blocked and incubated with goat anti-mouse CXCL13 antibody (R&D System, AF470-SP) overnight at 4°C. For VGLL3 and IFN-κ detection, cryosections were subjected to acetone fixation. Slides were blocked and incubated with rabbit anti-mouse VGLL3 antibody (St. John’s Laboratory, STJ115228) or sheep anti-mouse IFN-κ antibody (R&D System, AF5206), respectively. All slides were then incubated with biotinylated secondary antibodies (Vector Laboratories) as appropriate, incubated with fluorochrome-conjugated streptavidin (Streptavidin, Alexa Fluor 488 conjugate [Thermo Fisher Scientific, S32354] or Streptavidin, Alexa Fluor 594 conjugate [Life Technologies, S32356]) as appropriate and mounted. Images were acquired using Zeiss Axioskop 2 microscope and analyzed by SPOT software V.5.1. PAS staining of paraffin sections was performed using the Periodic acid–Schiff (PAS) staining system (MilliporeSigma) per the manufacturer’s instructions (see procedure 395). TUNEL staining of paraffin sections was performed using the In Situ Cell Death Detection Kit, TMR red (Roche). Slides were mounted with ProLong Gold Antifade Mountant with DAPI (Thermo Fisher Scientific). IF of immune complex components was performed as follows. Slides with tissue cryosections were dried for 1 hour at 37°C, incubated in 4% paraformaldehyde for 20 minutes, and blocked. C3-FITC (ICL, GC3-90F-Z) and IgG-Texas Red-X (Thermo Fisher Scientific, T-862) goat anti-mouse antibodies were then added, and slides were incubated at 4°C for 1 hour. Hoechst stain (BD Biosciences, 561906) was added. Slides were dried and mounted using ProLong Gold Antifade Mountant (Thermo Fisher Scientific). Images were captured as above. For renal immune complex deposition, 10 glomeruli were assessed for each mouse, and mice were considered positive if more than one glomerulus demonstrated deposition of C3 and IgG. Immunohistochemistry of frozen sections was performed as previously described (30) using antibodies specific for CD4 (BD Biosciences, 550280), CD8a (BD Biosciences, 550281), CD11c (BD Biosciences, 550283), CD19 (BD Biosciences, 550284), F4/80 (eBioscience, 14-4801-82), Ki-67 (DAKO, M7249), and MECA-32 (Developmental Studies Hybridoma Bank, MECA-32-s). Antibodies were detected using either rabbit anti-rat IgG biotinylated (Vector Laboratories), goat anti-rabbit IgG biotinylated (Vector Laboratories), or rabbit anti-hamster IgG biotinylated (Southern Biotech) secondary antibodies, amplified with Avidin/Biotinylated Enzyme Complex (Vector Laboratories), and visualized using the enzyme substrate diaminobenzidine (Vector Laboratories). Slides were counterstained with hematoxylin. Images were captured using a Leica DM L82 microscope with an attached QImaging MicroPublisher 3.3 Mega Pixel camera and Q-capture Pro software. For detection of antinuclear antibodies, serum was taken undiluted, diluted 1:25, or diluted 1:50 and used for indirect IF on Kallestad HEp-2 Slides (Bio-Rad) with FITC goat anti-mouse Ig antibody (BD Biosciences) as the detection reagent. Imaging was performed as for IF above. Mass cytometry (CyTOF) Stimulation. Tissue was harvested and cell suspensions were prepared as above. All samples were then stimulated for 3 hours at 37°C in RPMI complete media with 5 ng/ml phorbol 12-myristate 13-acetate (MilliporeSigma), 1 μg/ml ionomycin (MilliporeSigma), 3 μg/ml Golgistop with Brefeldin A (BioLegend), and 0.67 μl/ml BD GolgiStop Protein Transport Inhibitor with Monensin (Thermo Fisher Scientific), and then incubated on ice until staining. Antibody conjugation with lanthanide metal. The lanthanide metals (Fluidigm) were conjugated to the antibodies using the Maxpar Antibody Labeling Kit (Fluidigm) per the manufacturer’s instructions. Briefly, 2.5 mM Maxpar polymer was preloaded with lanthanide metal at 37°C for 1 hour and buffer exchanged to conjugation buffer using a 3 K Nanosep Centrifugal Device (Pall Life Sciences). The antibody was partially reduced using TCEP at 37°C for 30 minutes and buffer exchanged to conjugation buffer using an Amicon Ultra 0.5-ml 50-kDa Centrifugal Filter Concentrator (MilliporeSigma). The lanthanide-loaded polymer was conjugated to partially reduced antibody following overnight incubation at room temperature. The unbound metal was removed from the metal-tagged antibody by washing with wash buffer in a 50-kDa concentrator. The final concentration of metal-tagged antibody was determined by measuring the absorbance at 280 nm against the wash buffer. See Supplemental Table 2 for the antibodies. Staining of cells with metal-tagged antibodies. Cell-ID Cisplatin-195Pt and Cell-ID Intercalator Iridium-191/193 (Fluidigm) were used to identify live cells. The cells were washed once with prewarmed serum-free media by pelleting at 300 g for 5 minutes at room temperature and stained with 1.25 μM live/dead stain (Cell-ID Cisplatin-195Pt diluted in serum-free media from 500 mM stock) at room temperature for 5 minutes. Free cisplatin was quenched by washing the cells with serum-containing media. CyPBS (1× PBS without heavy metal contaminants, prepared from 10 × PBS stock [Invitrogen] in deionized distilled Milli-Q water [MilliporeSigma]) was used to prepare CyFACS buffer (CyPBS containing 0.1% BSA, 2 mM EDTA and 0.05% sodium azide). The cells were then washed with CyFACS buffer and incubated with TruStain FcX (anti-mouse CD16/32, Biolegends) for 10 minutes at room temperature to block the Fc receptors. For cells surface marker staining, the metal-tagged antibody cocktail was made in CyFACS buffer and added to the cells in the presence of TruStain FcX (BioLegend) and incubated on ice for 60 minutes. Following cell surface marker staining, the cells were washed twice with CyFACS buffer and fixed with 1.6% paraformaldehyde in CyPBS for 20 minutes at room temperature. The cells were then washed and stored overnight at 4°C in CyFACS buffer. The following day, the cells were pelleted at 800 g for 5 minutes and permeabilized with eBioscience permeabilization buffer (Thermo Fisher Scientific) for 30 minutes at room temperature. The cells were then stained with intracellular staining metal-tagged antibody cocktail (made in eBioscience permeabilization buffer) at room temperature for 60 minutes. Following intracellular staining, the cells were washed once with permeabilization buffer and twice with CyFACS buffer and stained with 62.5 nM Cell-ID Intercalator Iridium-191/193 (diluted in 1.6% paraformaldehyde in PBS from 500 μM stock) at room temperature for 40 minutes or left at 4°C until ready for acquisition on CyTOF. CyTOF analysis of samples stained with metal-tagged antibodies. The samples were acquired using CyTOF Helios system (Fluidigm). The system was maintained and tuned according to the manufacturer’s instructions. In addition, internal vendor-set calibration was performed before acquiring samples. The fixed cells were washed twice with CyPBS and deionized distilled Milli-Q water and filtered through a 40-μM cell strainer. EQ Four Element Calibration Beads (Fluidigm) were added at the recommended concentration to the samples before acquisition on CyTOF. The samples were acquired on CyTOF at approximately 50–300 events/s. After acquisition, the instrument software applied a signal correction algorithm based on the calibration bead signal to correct for any temporal variation in detector sensitivity. CyTOF data analysis Total events were gated to remove noncellular events (negative for DNA intercalator), dead cells (uptake of cisplatin), and doublets (event length greater than 25). A viSNE was performed using combined lymph node (~20,000 events/sample), spleen (~20,000 events/sample), and ear (between 262 and 1234 events/sample) samples using Cytobank (34). All antibody channels were included in the viSNE analysis except for IL-17f, as it was suspected this marker was staining nonspecifically (37 included markers). The viSNE run was performed with 2000 iterations, a perplexity of 30, and a θ of 0.5. A spanning-tree progression analysis of density-normalized events (SPADE) clustering algorithm was performed on the same events used in the viSNE analysis using the Cytobank platform (13). As with the viSNE analysis, all antibody channels were included except for IL-17f, as we suspected this marker was staining nonspecifically (37 included markers). After some experimentation, it was found that 50 nodes with 100% event downsampling gave an adequate resolution of cellular subsets. SPADE nodes were manually bubbled based on defined phenotypic markers of major cellular populations (summarized in Figure 4E). Samples were compared based on the percentage of total cells from that sample contained within a bubble or individual node. Flow cytometry WT and transgenic ear tissue was harvested and cell suspensions were prepared as above. Cells were resuspended in blocking reagent of 1% BSA (Fisher Bioreagents) and 1% Horse Serum (Corning) in PBS. Antibody master mixes were prepared using antibodies specific for IgG-PerCP (BioLegend, 405334), IgM-APC (BioLegend, 406509), PDCA-1-APC (BioLegend, 127016), Cd11c-Pacific Blue (BioLegend, 117322), F4/80-Pacific Blue (BioLegend, 123124), and Ly-6G-PE (BioLegend, 127606) and added to each sample. Samples were incubated at room temperature in a dark environment for 45 minutes, washed with PBS, and resuspended in 4% paraformaldehyde in PBS (Affymetrix). Flow cytometry was performed with a BD LSR II (BD Biosciences). After manual gating to exclude dead cells and debris, data corresponding to all remaining cells were analyzed and visualized using FlowJo software (Tree Star). Detection of autoantibodies Anti–dsDNA antibodies were detected in serum using the Mouse anti-dsDNA IgG2a ELISA Kit (Alpha Diagnostic International) according to manufacturer’s instructions. Renal pathology scoring Kidneys from 4 WT and 4 transgenic animals were analyzed. A semiquantitative scoring system (0, no involvement; 0.5, minimal involvement of <10% per section; 1, mild involvement of 10%–30% of section; 2, moderate involvement of 31%–60% of section; and 3, severe involvement >60% of section) was used to assess 13 different parameters of activity and chronicity: mesangial hypercellularity, mesangial deposits, mesangial sclerosis, endocapillary cellular infiltrate, subepithelial deposits, subendothelial deposits, capillary thrombi, capillary sclerosis, cellular crescents, organized crescents, synechiae, tubular atrophy, and interstitial fibrosis. An activity and chronicity index was generated by compiling scores from groups of related parameters. For activity, mesangial hypercellularity, mesangial deposits, endocapillary cellular infiltrate, and cellular crescents were considered; for chronicity, interstitial fibrosis, tubular atrophy, organized crescents, and capillary sclerosis were considered. Analysis of urine albumin/creatinine ratio Urine from 8 WT and 5 transgenic animals was analyzed. Urine was collected from animals within 1 week of euthanasia. Technical duplicates were performed for every sample. To calculate albumin-to-creatinine ratios, urinary albumin was measured using the Albuwell M Kit (Exocell) and urinary creatinine using the QuantiChrom Creatinine Assay Kit (BioAssay Systems), both according to the manufacturer’s protocol. Data availability RNA-seq data have been deposited in GEO (GSE128453). CyTOF data have been made publically available in FlowReposity under repository ID FR‑FCM‑Z2Y6 (35). Statistics qRT-PCR data were tested for statistical significance using 2-tailed Student’s t test assuming homoscedasticity. Significance was defined as P ≤ 0.05. RNA-seq data were tested for normality, and statistical significance was calculated using a 2-tailed Student’s t test, Mann-Whitney U test, or Friedman’s test, as appropriate. For CyTOF data, statistical analysis on the bubbled SPADE populations was performed using Prism 8.0 (GraphPad). P values were computed using unpaired Student’s t tests assuming homoscedasticity. P values were considered discoveries if they fell below an FDR of 10% using the 2-stage step-up method of Benjamini, Krieger, and Yekutieli (36). Study approval Procedures involving the care and the use of mice in this study were reviewed and approved by the University of Michigan Institutional Animal Care and Use Committee (protocol PRO00006657). Author contributions ACB, MGK, MEV, AAD, JMK, and JEG conceived the study and designed experiments; LCT, BDH, and CCB developed computational methods and analyzed the data; MGK, JF, DG, JL, XX, SE, SJW, SMR, JBH, YL, PWH, and MEV conducted the experiments; and ACB, JMK, and JEG wrote the paper with input from all authors, including MAB, MKS, RU, SS, CZ, JJV, FW, and NLW. Supplemental material View Supplemental data View Supplemental Table 1 View Supplemental Table 3 Acknowledgments This work was supported by the A. Alfred Taubman Medical Research Institute’s Taubman Institute Innovation Projects program (to JEG, JMK, LCT, and FW), the Parfet Emerging Scholar Award (to JMK), and the Frances and Kenneth Eisenberg Emerging Scholar Award (to JEG); the University of Michigan Babcock Endowment Fund (to LCT and JEG); the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH (5T32AR007197-40 to ACB; K01AR072129 to LCT; R01-AR071384 to JMK; R01-AR069071 to JEG; and P50-AR070590, R01-AR062546, R01-AR063437, and R01-AR073196 to NLW); the Office of the Director of the NIH (S10-OD020053 to FW); a Rogel Cancer Center Support Grant (NIH P30-CA046592 to BDH, SMR, and FW); the National Science Foundation (1511720, 1645229, and 1653611 to FW); a Rheumatology Research Foundation Innovative Research Award (to JMK); the Dermatology Foundation (to LCT); the Arthritis National Research Foundation (to LCT); and the National Psoriasis Foundation (to LCT and NLW). Footnotes Conflict of interest: The authors have declared that no conflict of interest exists. Copyright: © 2019 American Society for Clinical Investigation Reference information: JCI Insight. 2019;4(8):e127291. https://doi.org/10.1172/jci.insight.127291. References Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol. 2008;8(9):737–744. View this article via: PubMed CrossRef Google Scholar Tedeschi SK, Bermas B, Costenbader KH. Sexual disparities in the incidence and course of SLE and RA. Clin Immunol. 2013;149(2):211–218. View this article via: PubMed CrossRef Google Scholar Liang Y, et al. A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases. Nat Immunol. 2017;18(2):152–160. View this article via: PubMed Google Scholar Ramírez A, Bravo A, Jorcano JL, Vidal M. Sequences 5’ of the bovine keratin 5 gene direct tissue- and cell-type-specific expression of a lacZ gene in the adult and during development. Differentiation. 1994;58(1):53–64. View this article via: PubMed Google Scholar Sarkar MK, et al. Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa. Ann Rheum Dis. 2018;77(11):1653–1664. View this article via: PubMed CrossRef Google Scholar Ezzat M, El-Gammasy T, Shaheen K, Shokr E. Elevated production of serum B-cell-attracting chemokine-1 (BCA-1/CXCL13) is correlated with childhood-onset lupus disease activity, severity, and renal involvement. Lupus. 2011;20(8):845–854. View this article via: PubMed CrossRef Google Scholar Liu J, Berthier CC, Kahlenberg JM. Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon-Induced Up-Regulation of Interferon Regulatory Factor 1. Arthritis Rheumatol. 2017;69(9):1840–1849. View this article via: PubMed CrossRef Google Scholar Teichmann LL, Ols ML, Kashgarian M, Reizis B, Kaplan DH, Shlomchik MJ. Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity. 2010;33(6):967–978. View this article via: PubMed CrossRef Google Scholar Ribero S, Sciascia S, Borradori L, Lipsker D. The Cutaneous Spectrum of Lupus Erythematosus. Clin Rev Allergy Immunol. 2017;53(3):291–305. View this article via: PubMed CrossRef Google Scholar Cohen PL, Eisenberg RA. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991;9:243–269. View this article via: PubMed CrossRef Google Scholar Andrews BS, et al. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med. 1978;148(5):1198–1215. View this article via: PubMed CrossRef Google Scholar Amir el-AD , et al. viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. Nat Biotechnol. 2013;31(6):545–552. View this article via: PubMed CrossRef Google Scholar Qiu P, et al. Extracting a cellular hierarchy from high-dimensional cytometry data with SPADE. Nat Biotechnol. 2011;29(10):886–891. View this article via: PubMed CrossRef Google Scholar Rai R, Chauhan SK, Singh VV, Rai M, Rai G. RNA-seq Analysis Reveals Unique Transcriptome Signatures in Systemic Lupus Erythematosus Patients with Distinct Autoantibody Specificities. PLoS One. 2016;11(11):e0166312. View this article via: PubMed CrossRef Google Scholar Wieczorek IT, Propert KJ, Okawa J, Werth VP. Systemic symptoms in the progression of cutaneous to systemic lupus erythematosus. JAMA Dermatol. 2014;150(3):291–296. View this article via: PubMed CrossRef Google Scholar ter Borg EJ, Horst G, Hummel EJ, Limburg PC, Kallenberg CG. Measurement of increases in anti-double-stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus. A long-term, prospective study. Arthritis Rheum. 1990;33(5):634–643. View this article via: PubMed CrossRef Google Scholar Raz E, Brezis M, Rosenmann E, Eilat D. Anti-DNA antibodies bind directly to renal antigens and induce kidney dysfunction in the isolated perfused rat kidney. J Immunol. 1989;142(9):3076–3082. View this article via: PubMed Google Scholar Voskuhl R. Sex differences in autoimmune diseases. Biol Sex Differ. 2011;2(1):1. View this article via: PubMed CrossRef Google Scholar Moroni G, et al. The value of a panel of autoantibodies for predicting the activity of lupus nephritis at time of renal biopsy. J Immunol Res. 2015;2015:106904. View this article via: PubMed Google Scholar Catrina AI, Deane KD, Scher JU. Gene, environment, microbiome and mucosal immune tolerance in rheumatoid arthritis. Rheumatology (Oxford). 2016;55(3):391–402. View this article via: PubMed Google Scholar England BR, Thiele GM, Mikuls TR. Anticitrullinated protein antibodies: origin and role in the pathogenesis of rheumatoid arthritis. Curr Opin Rheumatol. 2017;29(1):57–64. View this article via: PubMed CrossRef Google Scholar Kuhn A, et al. Accumulation of apoptotic cells in the epidermis of patients with cutaneous lupus erythematosus after ultraviolet irradiation. Arthritis Rheum. 2006;54(3):939–950. View this article via: PubMed CrossRef Google Scholar James JA, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus. 2007;16(6):401–409. View this article via: PubMed CrossRef Google Scholar Carroll JM, Crompton T, Seery JP, Watt FM. Transgenic mice expressing IFN-gamma in the epidermis have eczema, hair hypopigmentation, and hair loss. J Invest Dermatol. 1997;108(4):412–422. View this article via: PubMed CrossRef Google Scholar Seery JP, Carroll JM, Cattell V, Watt FM. Antinuclear autoantibodies and lupus nephritis in transgenic mice expressing interferon gamma in the epidermis. J Exp Med. 1997;186(9):1451–1459. View this article via: PubMed CrossRef Google Scholar Tsokos GC, Lo MS, Costa Reis P, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol. 2016;12(12):716–730. View this article via: PubMed CrossRef Google Scholar Wang Y, et al. Chronic skin-specific inflammation promotes vascular inflammation and thrombosis. J Invest Dermatol. 2012;132(8):2067–2075. View this article via: PubMed CrossRef Google Scholar Shaner NC, Campbell RE, Steinbach PA, Giepmans BN, Palmer AE, Tsien RY. Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nat Biotechnol. 2004;22(12):1567–1572. View this article via: PubMed CrossRef Google Scholar Lichti U, Anders J, Yuspa SH. Isolation and short-term culture of primary keratinocytes, hair follicle populations and dermal cells from newborn mice and keratinocytes from adult mice for in vitro analysis and for grafting to immunodeficient mice. Nat Protoc. 2008;3(5):799–810. View this article via: PubMed CrossRef Google Scholar Johnston A, et al. Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation. J Immunol. 2013;190(5):2252–2262. View this article via: PubMed CrossRef Google Scholar Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30(15):2114–2120. View this article via: PubMed CrossRef Google Scholar Anders S, Pyl PT, Huber W. HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31(2):166–169. View this article via: PubMed CrossRef Google Scholar Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. View this article via: PubMed CrossRef Google Scholar Kotecha N, Krutzik PO, Irish JM. Web-based analysis and publication of flow cytometry experiments. Curr Protoc Cytom. 2010;Chapter 10:Unit10.17. View this article via: PubMed Google Scholar Spidlen J, Breuer K, Rosenberg C, Kotecha N, Brinkman RR. FlowRepository ‑ A Resource of Annotated Flow Cytometry Datasets Associated with Peer‑reviewed Publications. Cytometry A. 2012;81(9):727–731. Benjamini Y, Krieger AM, Yekutieli D. Adaptive linear step-up procedures that control the false discovery rate. Biometrika. 2006;93(3):491–507. View this article via: CrossRef Google Scholar
  15. APRIL 2019 11 April 2019 by Professor Graham R V Hughes MD FRCP Easter comes late this year. Frenetic Brexit politics – the Westminster establishment fighting to overturn the ‘popular vote’. So sad. Last week I gave a lecture at an ‘immuno-therapy’ meeting in Madrid. Three hundred attendees, including representatives of the Spanish patients’ APS Society. The atmosphere was fantastic. So many doctors (and patients’) wanting to learn more about our syndrome. Talking about ‘learning more’, we now have a date for our own Patients’ Meeting – Friday, 13th September 2019. (For details of the programme and admission, please visit our website: www.ghic.world). This year we are opening up the meeting to include topics on Sjogren’s and lupus, as well as antiphospholipid syndrome. I will also send this blog, as well as details or our annual Patients’ Meeting, to our colleagues in Spain. Patient of the Month “I still feel tired all the time”. Mrs J.S. aged 55, was referred by her G.P. complaining of a variety of symptoms, including aches and pains, headaches, constipation, pins and needles and mental sluggishness. Above all else, she felt constantly fatigued. Despite this very full set of symptoms, the diagnosis remained uncertain. The pins and needles in both hands were put down to carpal tunnel syndrome. But there was little else to find. In view of the frequent headaches, Mrs J.S. was referred to a neurologist who arranged for further tests, including a brain MRI (which showed two small ‘dot’ lesions – reported as probably not significant. To her credit, the neurologist considered lupus and arranged lupus blood tests among the more routine ones. The tests came back showing a normal blood count. However, the ESR (the guide to inflammation) came back ‘borderline positive’ at 35 (normal under 20). The tests for lupus were essentially negative (anti-DNA negative, ANA ‘weak’ (1 in 80). What is the diagnosis (1)? The penny dropped. Could this be thyroid? Bilateral carpal tunnel syndrome is certainly seen in ‘low thyroid’, and significantly Mrs J.S. had a sister with ‘Hashimotos thyroiditis’ – and underactive thyroid with auto-immune features. As with all her other tests the thyroid blood tests were ‘borderline’. Nevertheless, the fatigue, the constipation, the aches and pains, could all be down to ‘low thyroid’. Following a *‘kerbside consult’, with her endocrinology colleague, she instituted thyroxine treatment. Within 2 months the pins and needles were gone and the mental sluggishness, as well as the constipation, were improving. BUT – the aches and pains and the fatigue remained – as bad as ever. What is the diagnosis (2)? It turned out that Mrs J.S. had suffered a series of miscarriages in her early 20’s and she and her husband remained childless. Could the problems – especially the frequent headaches – be due to Hughes Syndrome? Sure enough the antiphospholipid antibody (aPL) tests were strongly positive – not even ‘borderline’. She was started on clopidogrel (‘Plavix’) – an anti-clotting drug similar to aspirin (Mrs J.S. had previously tried aspirin but found it caused indigestion. Result? An almost immediate lessening of the headaches. And, if anything, a further improvement in her memory problems. BUT: no improvement in the fatigue or the aches and pains. What is the diagnosis (3)? Mrs J.S. was referred to a lupus clinic. Again, the results were similar (‘borderline’ ANA and negative anti-DNA). The lupus clinic doctor had seen this before – possible ‘Sjogren’s syndrome’. And, sure enough, the Shirmer’s test – a simple ‘blotting paper’ eye test was completely dry – a useful and very inexpensive screening test for the dry eyes of Sjogren’s Syndrome. Low dose hydroxychloroquine (Plaquenil) (one a day) was started. Three months later at follow-up clinic, ‘fatigue gone. Aches gone. Back to normal life”. What is this patient teaching us? I often talk of ‘The Big Three’ diseases – Lupus, Sjogren’s and Hughes Syndrome, which can overlap clinically However, the world of auto-immune diseases in which I practice includes another ‘big three’, which frequently go together : Hughes Syndrome, Sjogren’s Syndrome and low thyroid (often, specifically, Hashimoto’s thyroiditis) – three ‘named’ syndromes. Clearly, to miss one or even two of the triad would be an ‘under-treatment’. The three conditions can have similar features. And fortunately, potentially very successful treatment – thyroid, aspirin (or Plavix) and hydroxychloroquine. I call the combination of aspirin and hydroxychloroquine (derived from quinine) my ‘two trees’ – treatment –willow and cinchona. Perhaps the biggest lesson from this patient is that there may be more than one diagnosis causing the problems. PROFESSOR GRAHAM R V HUGHES MD FRCP Head of The London Lupus Centre London Bridge Hospital http://www.ghic.world/blog/april-2019
  16. An Increased Risk of Dementia Possible in Lupus Stephanie Pappas Jul 13, 2016 Neuropsychiatric symptoms have long been known to affect some patients with systemic lupus erythematosus. But now, emerging evidence suggests that lupus patients may be at increased risk of dementia, as well. A retrospective study published in April in the journal Arthritis Care and Research used the Taiwan Longitudinal Health Insurance Database 2005, a random sampling of the 99.9 percent of Taiwanese citizens covered by the country's national health insurance, to compare dementia rates in people with systemic lupus erythematosus to age- and sex-matched patients without the autoimmune disease. The analysis revealed a doubled rate of dementia in SLE patients. There were 357 cases per 100,00 person-years in the lupus cohort, compared with 180 cases per 100,000 person-years in the non-SLE cohort. {Crude hazard ratio 1.92, 95 percent CI, 1.14−3.23, P< 0.001.) Dementia is a condition of gradual decline, while neuropsychiatric SLE usually manifests early in the diagnosis, wrote study author Dr. Yu-Ru Lin of Taipei Medical Hospital and colleagues. Antiphospholipid antibodies might put patients at risk of micro-stroke, they hypothesized. Alternatively, anatomical changes in the brain attributable to the disease or corticosteroid treatments may contribute to cognitive decline. Rheumatology Network spoke with Dr. Yehuda Shoenfeld, an autoimmunity researcher at Tel Aviv University in Israel, for a deeper look at the dementia-lupus connection. Though not involved with the Taiwanese study, Dr. Shoenfeld has conducted research on lupus autoantibodies and has written about neuropsychiatric lupus in the clinic. He provided his perspective on the need to better understand how lupus might affect the brain. RN: Obviously, neurologic symptoms are well-known in systemic lupus erythematosus. What is the difference between central nervous system lupus and dementia? Shoenfeld: There are neurological, physical findings and also X-ray findings in which you see defects in neurological functions, mainly nerves which can be motor or sensory or so forth. It can be represented by conversions. It can be represented by paralysis. It can be presented as paresthesia, which means it feels like ants are going on your body. So it's more in the domain of physical examination. Dementia is more that you lose your capacity for cognition, memory or so forth. You cannot detect it by X-rays, but you can detect it by talking to the patient and listening to him and you can see that he's not finding himself, I would say, in space. So this is a big difference. What is new about this study by Lin and colleagues? So far we knew that CNS lupus is quite common, 20 percent of the patients can suffer from that. There are many manifestations of CNS lupus from paralysis to conversion, from deafness to blindness, from paresthesia to pains and so forth. Dementia up until now was not part of the story of lupus - neither in regular lupus nor in CNS lupus. We did have psychotic attack in CNS lupus, which could be completely resolved upon proper therapy, for instance with corticosteroids or immunosuppressive drugs. Suddenly, there is dementia. Now, I want to remind you that lupus is a disease of young females, so it's not elderly females with dementia at this age. So the people who published the paper came with the idea that in those patients with CNS lupus, you can find, eventually, more dementia, which is a new revelation, not known so far. With my colleague, Professor Howard Amital [of Sheba Medical Center], an expert on Big Data — we asked the computer to cross the word dementia with SLE in a health database, but we did something else in this respect. We compared it to two other autoimmune diseases. I have to say that, to my great surprise, we have found also that patients with SLE have a threefold increase in dementia. We were not able so far to segregate it to the different factor that we would like to, but we found also with rheumatoid, there was an increase. There was no increase, for instance, in Behcet's syndrome. So most probably, these results are correct, and they should raise a red light. We will analyze our results and we will publish it very soon. But I think it's interesting, even though I had not believed this when I had received the paper from you. What kind of mechanisms might explain why there could be this link? When you have an organic damage to the brain, being autoimmune in nature, being the position of autoantibodies, being the position of other factors it causes chronic damage to the brain and eventually, there is some kind expression that above this threshold it can cause the psychological defects which are expressed as dementia. It's like accumulating damage. Given what is known right now, what is the message for practicing rheumatologists? Before we do anything with patients, we should confirm the results and indeed analyze what could be the mechanism and then eventually work on this to see how we could prevent this. Maybe, for instance, a very quick recovery should be installed whenever there are any signs of CNS lupus. We have to see if, indeed, it's limited only to patients with CNS lupus. There is a lot to analyze now, to learn, to study and to draw conclusions for the future. References: Lin Y-R, Chou L-C, Chen H-C, Liou T-H, Huang S-W, Lin H-W. "Increased risk of dementia in patients with systemic lupus erythematosus: A nationwide population-based cohort study." Arthritis Care & Research. 2016. doi:10.1002/acr.22914. Kivity S, Agmon-Levin N, Zandman-Goddard G, Chapman J, Shoenfeld Y. "Neuropsychiatric lupus: a mosaic of clinical presentations." BMC Medicine BMC Med. 2015;13(1):43. doi:10.1186/s12916-015-0269-8. https://www.rheumatologynetwork.com/lupus/increased-risk-dementia-possible-lupus
  17. SLE Patients at Higher Risk for Some Blood Cancers, Study Says FEBRUARY 18, 2019 BY JOANA CARVALHO IN NEWS. Click Here to receive Lupus News via e-mail Systemic lupus erythematosus (SLE) patients have a higher risk for certain cancers — including cervical, thyroid, ovarian, and oral cancer, as well as lymphoma, multiple myeloma, and leukemia — than the general population, emphasizing the importance of cancer screening programs as part of SLE management. The findings of the study, “Systemic lupus erythematosus is a risk factor for cancer: a nationwide population-based study in Korea,” were published in Lupus. SLE, the most prevalent form of lupus, is a chronic autoimmune disease characterized by behavioral and psychological symptoms including pain, fatigue, depression, and impaired cognition. Previous studies have suggested that SLE patients are more likely to be affected by certain types of cancers, including non-Hodgkin’s lymphoma, lung, liver, and vaginal cancer. “However, some studies have found a decreased risk of some hormone-sensitive cancers, such as breast, ovarian, and endometrial cancer, in SLE patients. However, whether patients with SLE have increased or decreased risk of breast cancer remains unclear,” the researchers said. In this study, investigators set out to characterize the relationship between SLE and cancer in the entire Korean population. The nationwide, retrospective, cohort study involved 21,016 SLE patients and 105,080 age- and sex-matched controls without SLE. The cohort was selected from the Korean National Health Insurance Service (NHIS) database between 2008 and 2014. Over a follow-up period of seven years, 763 (3.36%) SLE patients and 2,667 (2.54%) controls developed cancer. The incidence risk of cancer was higher in SLE patients compared to controls (6.427 vs 4.466). Incidence risk refers to the chance of a disease happening over a defined period of time. After accounting for age and sex, SLE patients showed a 44% higher risk of developing cancer. No differences in cancer risk were found between female and male SLE patients. SLE patients at higher risk for cancer were younger (under 40) and male, being 12 and 29 times more likely of developing lymphoma than control subjects. Looking at different cancer types, researchers found that SLE patients were more likely to develop cervical, thryoid, ovarian, and oral cancer, as well as lymphoma, leukemia, and multiple myeloma than controls. On the other hand, no significant differences in the risk of stomach, colorectal, liver, pancreatic, lung, breast, prostate, biliary, laryngeal, renal, bladder, nerve, and skin cancer were found between SLE patients and controls. While the mechanisms leading to increased risk of cancer in SLE patients are yet to be fully understood, the findings highlight the need for cancer screening programs among this patient population. “In conclusion, SLE is an independent risk factor for malignancy, especially cervical, thyroid, ovarian, oral … as well as lymphoma, multiple myeloma, and leukemia. The importance of cancer screening programs should be emphasized in SLE patients,” the scientists concluded. https://lupusnewstoday.com/2019/02/18/sle-patients-may-be-at-higher-risk-of-developing-certain-types-of-cancer/?utm_source=LUP+NEws+E-mail+List&amp;utm_campaign=1e70fc3e85-RSS_WEEKLY_EMAIL_CAMPAIGN_US&amp;utm_medium=email&amp;utm_term=0_50dac6e56f-1e70fc3e85-71887989
  18. Congratulations and Many Thanks to Lady Gaga! To the entire world, Lady Gaga is a winner. But to the lupus community she’s a hero. Last night at the 2019 Grammy’s, she won an award for Best Pop Solo in honor of her aunt Joanne who lost her battle with lupus at 19. Afterwards she tweeted: Lady Gaga has shared the song’s significance on social media. “I have carried a deep grief in my heart over my family’s tragedy. The loss of Joanne affected my father so deeply that it affected me. When he cried, I cried. When he was angry, I was angry. When he was hurt, I hurt. Today I transform this grief to hope and healing. After 10 years with you I still get nervous before the Grammys, but I know I have an angel with me.” Hear about lupus research from Lady Gaga's dad And watch this video to hear directly from Lady Gaga’s dad, Joe Germanotta, about why he has honoured his sister by actively supporting the Lupus Research Alliance. As a member of our Board of Directors, Joe believes that the research funded by the Lupus Research Alliance is where hope begins. Where our funded research discoveries are breaking through to deliver better treatments and a cure!
  19. Lupus: 3 Things to Know Mark L. Fuerst Dec 3, 2018 Lupus Three new studies in systemic lupus erythematosus (SLE) reveal that a gut bacterium may be linked to autoimmune diseases, including SLE; pregnancy complications in women with lupus have decreased over the past 2 decades; and physical or emotional abuse in childhood raises the risk of lupus.1-3Scroll through the slides for the latest findings and their clinical implications. http://www.rheumatologynetwork.com/lupus/lupus-3-things-know
  20. Sex Differences in Lupus Mortality Mariah Zebrowski Leach, JD, MS Monday, December 4, 2017 Lupus A comprehensive US population-based study identified an average 22-year and 12-year deficit in life expectancy among females and males with systemic lupus erythematosus (SLE), respectively, compared with the general population. Background In the United States, SLE is a source of significantly decreased life expectancy. While marked differences have been observed between the sexes in terms of the incidence, prevalence, and clinical manifestations of SLE, this area is still poorly understood. Falasinnu and colleagues1 at Stanford School of Medicine identified sex-based differences in the causes of death among SLE decedents in the United States and recognized clinically relevant comorbidities that may warrant careful consideration in patients’ clinical management. The study This study examined SLE-related deaths using the 2014 National Center for Health Statistics multiple cause of death (MCOD) database, a population-based electronic medical recording of all death certificates issued in the United States. The analysis considered not only the number of death certificates listing SLE as the underlying cause of death, but also those listing SLE in general. Demographic information considered included age, race/ethnicity, sex, educational attainment, foreign-born status, marital status, and pregnancy status. SLE decedents were compared with non-SLE decedents in the general population belonging to the same age group. The findings In 2014, there were 2,660,497 deaths in the United States, of which 2036 (0.1%) listed SLE among the causes of death. Approximately 86.2% of SLE deaths occurred among females, with a median age at death of 59 years and the highest proportion of deaths occurring between 45 and 64 years of age. In comparison, the overall median age at death for females in the general population was 81 years, and the majority of deaths occurred among females over 65 years of age. Black females experienced the greatest burden of SLE mortality. Approximately 32% of all female SLE decedents were black, compared with only 11% of non–SLE-related deaths in the general population. Female decedents with SLE had a slightly higher proportion of foreign-born individuals than the general population, but there were no other significant demographic differences. The most frequently listed comorbidities among female decedents with SLE were septicemia (4.32%) and hypertension (3.04%). Among male decedents with SLE, the median age at death was 61 years, compared with 73 years in the general population. Of male decedents with SLE, 23.5% were black, compared with only 12% in the general population. The age-standardized mortality was highest among American Indian males. There were no other demographic differences related to SLE among male decedents. The most frequently listed comorbidities among male decedents with SLE were heart disease (3.70%) and diabetes mellitus with complications (3.61%). Implications for physicians and future research This study offers an opportunity to better describe the association between SLE and related comorbidities in the context of mortality, although the MCOD data have a number of limitations. Inaccuracy on death certificates can lead to the underestimation of the SLE mortality burden, and researchers were unable to differentiate between causes of death that were related to the natural age process, disease activity, and drug therapy. Still, the MCOD data provide a comprehensive understanding of the population-based burden of SLE mortality. While female SLE patients tend to have more frequent disease exacerbations, male patients appear to have significantly greater multisystemic damage accrual and disease severity. Greater disease severity among male SLE patients may be related to under diagnosis due to selective attention given to females by physicians during clinical decision-making. This potential for gender bias needs to be carefully considered. Racial minorities generally have a disproportionately higher burden of mortality. The scope and degree of these differences in SLE are particularly pronounced, with mortality rates among black females nearly four times as high as those in white females. “Our findings reinforce the urgent need for interventions that reduce morbidity and mortality in patients with SLE to improve health outcomes and ultimately reduce health disparities,” the researchers write. They note that novel translational research programs are currently underway to attempt to address these disparities. Clinically relevant comorbidities also need to be considered more carefully in the course of patients’ clinical management and the natural history of SLE. This study revealed future targets for the investigation of sex-based differences and directions for epidemiological research. “A comprehensive understanding of causes of death and the related comorbidities can improve clinical diagnostic and therapeutic strategies, impact survival outcomes in patients living with SLE, and enhance population-based disease surveillance estimates,” the researchers conclude. References: 1. Falasinnu T, Chaichian Y, Simard JF. Impact of sex on systemic lupus erythematosus-related causes of premature mortality in the United States. J Womens Health (Larchmt). 2017;26:1214-1221. doi: 10.1089/jwh.2017.6334.
  21. Environmental Factors Tied to Lupus Gregory M. Weiss, M.D. Tuesday, December 5, 2017 Lupus Key points • Ultraviolet light may cause flare-ups in systemic lupus erythematosus (SLE). • The chemicals found in cigarette smoke can worsen the symptoms of SLE. • Estrogen analogues such as oral contraceptives and bisphenol A (BPA), a substance used to make plastic bottles, may increase the risk of SLE. Background SLE affects women and African Americans disproportionately. Dr. Gaurav Gulati at the University of Cincinnati in Ohio points out that even though we have treatments for lupus, a complete understanding of its etiology and progression is lacking. Although genetics clearly plays a role in SLE, it appears that environmental factors may act as triggers in those who are susceptible. Dr. Gulati conducted a review of the literature related to SLE and environmental versus genetic factors; he presented his findings recently in Seminars in Arthritis and Rheumatism. The study A systematic review was conducted that looked at over 100 studies focused on SLE. The results • A triad of factors was found in one study that linked a patient’s genetics, how the patient’s DNA changes over time, and exposure to environmental factors to the development and course of SLE. • Twin studies reveal only a 24% concordance of SLE in identical siblings; this points to a conclusion that a combination of genetic predisposition and environmental factors is involved in the development of lupus. • Heavy metals and other trace elements may be triggers for SLE; uranium, lead, and cadmium are linked to autoimmunity. • Elements such as mercury, nickel, and gold have been implicated in delayed hypersensitivity and inflammation, and a higher rate of lupus has been noted among dental workers. • An increase in SLE has been found in women who take oral contraceptives and in those exposed to xenoestrogens such as BPA, a chemical found in plastics. Implications for physicians • Physicians and particularly rheumatologists who treat patients with SLE should vigorously encourage positive lifestyle modifications such as smoking cessation and avoidance of direct sunlight. • Patients with SLE should be advised to always wear sunscreen. • Rheumatologists should provide regular surveillance to their patients with SLE as changes in disease activity and treatment are warranted. References: Gulati G, Brunner HI. Environmental triggers in systemic lupus erythematosus. Semin Arthritis Rheum. 2017 Oct 5. pii: S0049-0172(17)30469-9. doi: 10.1016/j.semarthrit.2017.10.001. [Epub ahead of print]
  22. Sex Differences in Lupus Mortality Mariah Zebrowski Leach, JD, MS Monday, December 4, 2017 A comprehensive US population-based study identified an average 22-year and 12-year deficit in life expectancy among females and males with systemic lupus erythematosus (SLE), respectively, compared with the general population. Background In the United States, SLE is a source of significantly decreased life expectancy. While marked differences have been observed between the sexes in terms of the incidence, prevalence, and clinical manifestations of SLE, this area is still poorly understood. Falasinnu and colleagues1 at Stanford School of Medicine identified sex-based differences in the causes of death among SLE decedents in the United States and recognized clinically relevant comorbidities that may warrant careful consideration in patients’ clinical management. The study This study examined SLE-related deaths using the 2014 National Center for Health Statistics multiple cause of death (MCOD) database, a population-based electronic medical recording of all death certificates issued in the United States. The analysis considered not only the number of death certificates listing SLE as the underlying cause of death, but also those listing SLE in general. Demographic information considered included age, race/ethnicity, sex, educational attainment, foreign-born status, marital status, and pregnancy status. SLE decedents were compared with non-SLE decedents in the general population belonging to the same age group. The findings In 2014, there were 2,660,497 deaths in the United States, of which 2036 (0.1%) listed SLE among the causes of death. Approximately 86.2% of SLE deaths occurred among females, with a median age at death of 59 years and the highest proportion of deaths occurring between 45 and 64 years of age. In comparison, the overall median age at death for females in the general population was 81 years, and the majority of deaths occurred among females over 65 years of age. Black females experienced the greatest burden of SLE mortality. Approximately 32% of all female SLE decedents were black, compared with only 11% of non–SLE-related deaths in the general population. Female decedents with SLE had a slightly higher proportion of foreign-born individuals than the general population, but there were no other significant demographic differences. The most frequently listed comorbidities among female decedents with SLE were septicemia (4.32%) and hypertension (3.04%). Among male decedents with SLE, the median age at death was 61 years, compared with 73 years in the general population. Of male decedents with SLE, 23.5% were black, compared with only 12% in the general population. The age-standardized mortality was highest among American Indian males. There were no other demographic differences related to SLE among male decedents. The most frequently listed comorbidities among male decedents with SLE were heart disease (3.70%) and diabetes mellitus with complications (3.61%). Implications for physicians and future research This study offers an opportunity to better describe the association between SLE and related comorbidities in the context of mortality, although the MCOD data have a number of limitations. Inaccuracy on death certificates can lead to the underestimation of the SLE mortality burden, and researchers were unable to differentiate between causes of death that were related to the natural age process, disease activity, and drug therapy. Still, the MCOD data provide a comprehensive understanding of the population-based burden of SLE mortality. While female SLE patients tend to have more frequent disease exacerbations, male patients appear to have significantly greater multisystemic damage accrual and disease severity. Greater disease severity among male SLE patients may be related to under diagnosis due to selective attention given to females by physicians during clinical decision-making. This potential for gender bias needs to be carefully considered. Racial minorities generally have a disproportionately higher burden of mortality. The scope and degree of these differences in SLE are particularly pronounced, with mortality rates among black females nearly four times as high as those in white females. “Our findings reinforce the urgent need for interventions that reduce morbidity and mortality in patients with SLE to improve health outcomes and ultimately reduce health disparities,” the researchers write. They note that novel translational research programs are currently underway to attempt to address these disparities. Clinically relevant comorbidities also need to be considered more carefully in the course of patients’ clinical management and the natural history of SLE. This study revealed future targets for the investigation of sex-based differences and directions for epidemiological research. “A comprehensive understanding of causes of death and the related comorbidities can improve clinical diagnostic and therapeutic strategies, impact survival outcomes in patients living with SLE, and enhance population-based disease surveillance estimates,” the researchers conclude. References: 1. Falasinnu T, Chaichian Y, Simard JF. Impact of sex on systemic lupus erythematosus-related causes of premature mortality in the United States. J Womens Health (Larchmt). 2017;26:1214-1221. doi: 10.1089/jwh.2017.6334.
  23. Treatment Target Shows Promise in Systemic Lupus Erythematosus Mariah Zebrowski Leach, JD, MS Monday, December 4, 2017 The lupus low disease activity state (LLDAS) is a promising treatment target in systemic lupus erythematosus (SLE), according to new research. Background Successfully applied in rheumatoid arthritis as well as in non-rheumatic conditions, a treat-to-target approach aims to improve disease outcomes through the achievement of a pre-specified goal. An international task force suggested such a strategy for the treatment of SLE.1 They recommended that the treatment target should be remission or—when that is unachievable—the lowest possible disease activity. LLDAS is a composite definition of minimal acceptable disease activity proposed by the Asia-Pacific Lupus Collaboration (APLC). LLDAS is based on the following criteria: 1. SLE Disease Activity Index 2000 (SLEDAI-2K) ≤ 4, with no activity in major organ systems 2. No new lupus disease activity compared with the previous assessment 3. Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment (PGA) ≤ 1 4. Current prednisolone (or equivalent) dose ≤ 7.5 mg daily 5. Well-tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents To be considered a valid treatment target, LLDAS should be protective against damage accrual in the early SLE stages. Piga and colleagues2 at the University Clinic and AOU of Cagliari in Italy sought to determine the frequency of LLDAS achievement and its association with early damage accrual in a homogenous cohort of Caucasian patients with SLE prospectively assessed during the first 18 months of treatment after diagnosis. The study This study primarily aimed to assess the frequency of LLDAS achievement and its association with early damage, with a secondary aim to identify the main reasons for failure to achieve LLDAS. The study cohort consisted of 107 patients from the Cagliari (Italy) SLE cohort between January 2006 and December 2016. To assess LLDAS as a goal for initial treatment, the primary study endpoint was set at 6 months, with 18 months considered an appropriate time to evaluate the effect of maintenance treatment and early damage accrual. At each visit, disease activity was assessed using the SLEDAI-2K score and the PGA. At 18 months, damage accrual was assessed by the SDI and the possible attribution to corticosteroids was done according to a previous definition. Average daily dose of prednisolone (or equivalent) and ongoing use and new prescription of medications were assessed at every visit. The findings At the 6-month point, LLDAS had been achieved by 47 patients (43.9%). At 18 months, 48 patients (44.9%) were in LLDAS; 33 of them had achieved LLDAS at 6 months and were still in this condition and 15 had reached LLDAS for the first time. Of the 59 patients who were not in LLDAS at 18 months, 45 had never been in LLDAS and 14 had been in LLDAS at 6 months but no longer were at 18 months. Thus, despite a seemingly overall stable LLDAS rate, these results demonstrate the dynamic nature of this condition. On univariate analysis, the following factors were significantly associated with failure to achieve LLDAS at 6 months: renal involvement, higher SLEDAI-2K score, positive (> 10 UL/mL) anti-dsDNA antibodies, lower serum C3 and C4 values, and higher prednisolone dose and immunosuppressant drug use. On multivariate analysis, renal involvement and C4 levels were confirmed to be associated with failure to achieve LLDAS. Implications for physicians The limitations of this study are the relatively small sample size, which may have hampered study results, and the retrospective design, which prevented researchers from testing LLDAS criterion validity by comparing it with other treatment targets such as the SLE Responder Index. Nevertheless, by enrolling consecutively diagnosed patients at the time of treatment initiation and following them prospectively, the researchers were able to provide novel data on LLDAS as a potential treatment target. In this study, the most frequent reason for failure to achieve LLDAS 6 months after therapy initiation was daily prednisolone dosage > 7.5 mg. Damage was definitely attributable to steroid use in 40% of cases in this cohort. However, supported by this data and literature evidence on damage development, the researchers consider 7.5 mg/d an acceptable cutoff to define low disease activity during initial treatment. Still, they recommend a lower cutoff should be targeted to minimize risk of steroid-related damage during maintenance therapy in patients with SLE. In this cohort, patients with renal involvement and serological disorders had the lowest remission rate, and renal involvement at baseline was the most important factor associated with failure to achieve LLDAS. “LLDAS is a promising treatment target in SLE, being attainable and negatively associated with damage accrual in the early stages of the disease,” the researchers write. “However, it seems to poorly fit with the heterogeneity of clinical presentation in patients with SLE, mostly in those with renal involvement,” they conclude. References: 1. van Vollenhoven R, Voskuyl A, Bertsias G, et al. Treat-to-target in systemic lupus erythematosus: recommendations from an international task force. Ann Rheum Dis. 2014;73:958-967. 2. Piga M, Floris A, Cappellazzo G, et al. Failure to achieve lupus low disease activity state (LLDAS) six months after diagnosis is associated with early damage accrual in Caucasian patients with systemic lupus erythematosus. Arthritis Res Ther. 2017;19:247. doi: 10.1186/s13075-017-1451-5.
  24. An evidence-based approach to pre-pregnancy counselling for patients with systemic lupus Y K Onno Teng Edwin O W Bredewold Ton J Rabelink Tom W J HuizingaH C Jeroen Eikenboom Maarten Limper Ruth D E Fritsch-StorkKitty W M Bloemenkamp Marieke Sueters Rheumatology, kex374, https://doi.org/10.1093/rheumatology/kex374 Published: 20 November 2017 Abstract Patients with SLE are often young females of childbearing age and a pregnancy wish in this patient group is common. However, SLE patients are at high risk for adverse pregnancy outcomes that require adequate guidance. It is widely acknowledged that pre-pregnancy counselling is the pivotal first step in the management of SLE patients with a wish to become pregnant. Next, management of these patients is usually multidisciplinary and often requires specific expertise from the different physicians involved. Very recently a EULAR recommendation was published emphasizing the need for adequate preconception counselling and risk stratification. Therefore the present review specifically addresses the issue of pre-pregnancy counselling for SLE patients with an evidence-based approach. The review summarizes data retrieved from recently published, high-quality cohort studies that have contributed to a better understanding and estimation of pregnancy-related risks for SLE patients. The present review categorizes risks from a patient-oriented point of view, that is, the influence of pregnancy on SLE, of SLE on pregnancy, of SLE on the foetus/neonate and of SLE-related medication. Lastly, pre-pregnancy counselling of SLE patients with additional secondary APS is reviewed. Collectively these data can guide clinicians to formulate appropriate preventive strategies and patient-tailored monitoring plans during pre-pregnancy counselling of SLE patients. https://academic.oup.com/rheumatology/advance-article-abstract/doi/10.1093/rheumatology/kex374/4641853?redirectedFrom=fulltext
  25. 21 November, 2017 SAN DIEGO — At the American College of Rheumatology Annual Meeting, Joan Merrill, MD, spoke about a study that she said is further demonstration that atacicept should continue being developed as a potential treatment for lupus. According to Merrill, the results also suggest that measurements of low-disease activity may represent not just clinically meaningful endpoints, but may also “work as endpoints in clinical trials to discriminate drug from placebo.” https://www.healio.com/rheumatology/lupus/news/online/{1b289264-6a9b-47a3-86c6-9b0eb8a3980f}/video-atacicept-is-a-potential-exciting-treatment-for-lupus?utm_source=selligent&utm_medium=email&utm_campaign=rheumatology news&m_bt=1879111151405
  • Create New...

Important Information