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  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. Hua-Zhi Ling, Shu-Zhen Xu, Rui-Xue Leng, Jun Wu, Hai-Feng Pan, Yin-Guang Fan, Bin Wang, Yuan-Rui Xia, Qian Huang, Zong-Wen Shuai ... Show more Author Notes Rheumatology, kez634, https://doi.org/10.1093/rheumatology/kez634 Published: 03 January 2020 Abstract Objective Clinical diagnosis of SLE is currently challenging due to its heterogeneity. Many autoantibodies are associated with SLE and are considered potential diagnostic markers, but systematic screening and validation of such autoantibodies is lacking. This study aimed to systematically discover new autoantibodies that may be good biomarkers for use in SLE diagnosis. Methods Sera from 15 SLE patients and 5 healthy volunteers were analysed using human proteome microarrays to identify candidate SLE-related autoantibodies. The results were validated by screening of sera from 107 SLE patients, 94 healthy volunteers and 60 disease controls using focussed arrays comprised of autoantigens corresponding to the identified candidate antibodies. Logistic regression was used to derive and validate autoantibody panels that can discriminate SLE disease. Extensive ELISA screening of sera from 294 SLE patients and 461 controls was performed to validate one of the newly discovered autoantibodies. Results A total of 31, 11 and 18 autoantibodies were identified to be expressed at significantly higher levels in the SLE group than in the healthy volunteers, disease controls and healthy volunteers plus disease control groups, respectively, with 25, 7 and 13 of these differentially expressed autoantibodies being previously unreported. Diagnostic panels comprising anti-RPLP2, anti-SNRPC and anti-PARP1, and anti-RPLP2, anti-PARP1, anti-MAK16 and anti- RPL7A were selected. Performance of the newly discovered anti-MAK16 autoantibody was confirmed by ELISA. Some associations were seen with clinical characteristics of SLE patients, such as disease activity with the level of anti-PARP1 and rash with the level of anti-RPLP2, anti-MAK16 and anti- RPL7A. Conclusion The combined autoantibody panels identified here show promise for the diagnosis of SLE and for differential diagnosis of other major rheumatic immune diseases. Rheumatology key messages Many differentially expressed autoantibodies were newly identified in SLE patients. Autoantibody panels discovered in this study may be good biomarkers for SLE diagnosis. Some associations exist between the autoantibodies identified in this study and clinical characteristics of SLE patients. kez634.pdf
  6. 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
  7. DECEMBER 18, 2019 Breakthrough science provides hope for lupus patients by Monash University Credit: CC0 Public Domain Today the prestigious New England Journal of Medicine (NEJM) publishes research led by Monash University Professor Eric Morand that offers the first real hope for the treatment of lupus, a disease which affects 1.5 million people in the US and more than 5 million globally, 90% women and for which there is no cure. The results are of an international, three-year, Phase 3 trial of a potential new drug that treats this autoimmune disease (also known as systemic lupus erythematosus (SLE)). Lupus is an autoimmune disease in which the immune system attacks healthy parts of the body. It is particularly insidious disease as it has a ten-year mortality of 10%, "which if you are diagnosed in your early twenties is a terrible outcome," according to Professor Morand, who oversaw the global trial in over 360 people with SLE. The trial, called TULIP 2, evaluated AstraZeneca's anifrolumab and achieved a statistically-significant and clinically-meaningful reduction in disease activity versus placebo, with both arms receiving standard of care. Professor Morand has also been key in developing new lupus assessment criteria—which because the disease involves a number of organs in the body—can be difficult to both diagnose and monitor. According to Professor Morand, there has only been one new treatment approved for the disease in the last 60 years, which is not available on the Pharmaceutical Benefits Scheme in Australia. Between 60% and 80% of adults with SLE show increased interferon-induced genes, which reflect overproduction of the immune protein Type 1 interferon. While previous attempts to block this protein in lupus have failed, the potential new treatment, anifrolumab, works by blocking the receptor on all cells in the body, aiming to reverse the triggering of lupus symptoms. Professor Morand said that interferon is associated with other autoimmune diseases such as Scleroderma and Sjogren's disease "so there may be potential for using anifrolumab in the treatment of other interferon related diseases as well." In the TULIP 2 trial, eligible patients received a fixed-dose intravenous infusion of anifrolumab or placebo every four weeks. TULIP 2 assessed the effect of anifrolumab in reducing disease activity—noting a significant effect in global disease activity measures. The trial, from 2015 to 2018, involved 362 patients receiving either 300 mg of the drug or a placebo intravenously once every four weeks for 48 weeks. Benefit was measured using a defined clinical assessment of improvement in all organs as well as the number of flare ups (which see the patient experiencing fever, painful or swollen joints, fatigue, rashes or sores or ulcers in the mouth or nose). The volunteers were aged between 18 and 70 and had moderate to severe disease despite standard treatments. Patients with SLE typically die of organ failure. The study found that—52 weeks after the trial started—significantly more patients on the drug than the placebo had: A reduction in overall disease activity in all active organs improvement in lupus skin disease A reduction in steroid drug doses Reduced annual rate of flares The TULIP 2 trial followed on from the TULIP 1 trial which failed to meet its primary outcome. The second trial, published in the NEJM, used a different endpoint. "Measurement of treatment response in SLE has been very problematic and this represents a kind of second breakthrough of this trial," Professor Morand said. AstraZeneca will now work with regulators, to bring anifrolumab, a potential new medicine, to patients. The study was done in collaboration with colleagues in Japan, the UK, the US, France and South Korea. https://medicalxpress.com/news/2019-12-breakthrough-science-lupus-patients.html
  8. Pathogenic and Therapeutic Role of Vitamin D in Antiphospholipid Syndrome Patients By Svetlana Jelic, Dejan Nikolic, Dragomir Marisavljević and Ljudmila Stojanovich Submitted: November 5th 2015Reviewed: August 2nd 2016 Published: April 26th 2017 DOI: 10.5772/65071 Abstract In this chapter, the novel findings on interrelationship between vitamin D status and two well‐known prothrombotic states, antiphospholipid syndrome, particularly its thrombotic phenotype, and metabolic syndrome will be reviewed. We shall present the results obtained from patients included in Serbian National Antiphospholipid Syndrome Registry, 68 patients with primary antiphospholipid syndrome (PAPS) and 69 patients with antiphospholipid syndrome associated with certain autoimmune rheumatic disease (sAPS), as well as 50 patients with pure metabolic syndrome (MetS). These results will be analysed and compared with the novel literature data. Prevalence of MetS in APS is high, with the atherogenic dyslipidaemia as its most prevalent characteristic. Prevalence of thrombotic events was significantly higher in APS patients with coexisting MetS, compared with those without MetS. Among APS patients, prevalence of VitD deficiency was significantly higher than in patients with pure MetS. VitD level was also significantly lower in APS patients with coexisting MetS or previous thrombotic events than in those without them. Elucidating interrelationships between VitD deficiency, MetS and thrombotic events in APS patients open up the possibility of distinguishing those subjects with the particularly high cardiovascular risk and ensuing need for the strict control of modifiable risk factors and VitD supplementation. Keywords vitamin D antiphospholipid syndrome metabolic syndrome classification criteria thrombosis Chapter and author info Show + 1. Introduction The antiphospholipid syndrome (APS), primary or associated with certain autoimmune rheumatic diseases, especially systemic lupus erythematosus, represents prothrombotic state. Coexistence of metabolic syndrome (MetS) and autoimmune rheumatic diseases is already recognized [1, 2], while clinical significance of MetS in patients with APS has not been systematically studied [3]. Recent recognition of certain pleiotropic functions of vitamin D (VitD) has enabled us to hypothesize on its role in the pathogenesis of obesity, MetS, APS, autoimmunity and thrombosis. Therefore, the aim of this review will be: (1) to clarify the possible linking role of VitD between APS and MetS, (2) to critically assess the need for estimation of VitD status in APS patients, depending on the coexistence of MetS and (3) to explore the potential therapeutic role which VitD, as an immunomodulator and anti‐thrombotic agent, could have in these patients. 2. Basic definitions Metabolic syndrome (MetS) and antiphospholipid syndrome (APS) are among most prevalent and still highly controversial syndromes. While clinical relevance of antiphospholipid antibodies (aPL) was recognized more than 30 years ago, definite classification criteria for antiphospholipid syndrome were given at the International Workshop in Sapporo, Japan 1998 [4] and revised 2006 in Sidney, Australia [5]. Very interesting proposal of APS criteria based on biological mechanisms is presented lately aiming at simplicity and greater accuracy and, at the same time, avoiding non‐specific formulations [6] (Table 1). Recent investigations have also shown that, beside characteristic thrombotic or obstetric symptoms, there is growing number of systemic non‐criteria manifestations (for example, thrombocytopenia, livedo reticularis, skin ulcerations, pseudovasculitis, migraine and epilepsy) correlating with certain type of aPL and with important predictive role [7, 8]. It is likely that a prominent place among these manifestations belongs to components of MetS, but it is still to be proved. The prevalence of APS in the general population is estimated to be around 2–4%. Initial Reaven's postulate in 1988, which draw attention to the causal association between insulin resistance with ensuing hyperinsulinemia and cardiovascular diseases [9], was followed by numerous definitions of MetS. Three of them, i.e. definitions given by World Health Organization (WHO) [10], the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) [11] and International Diabetes Federation (IDF) [12], were most frequently used and still neither of them is obsolete. While all three definitions share central obesity, atherogenic dyslipidaemia and arterial hypertension as common criteria, WHO definition put the insulin resistance in focus of metabolic syndrome while an obligatory criterion requested by IDF definition is elevated waist circumference (WC) with population‐ and country‐specific cut‐offs (Table 2). All of these three definitions are very similar but different enough, especially when used for the assessment of prevalence of MetS in some other entities, in this case, among patients with APS. Even the latest joint attempt of several major professional organizations (the IDF Task Force on Epidemiology and Prevention, National Heart, Lung and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society and International Association for the Study of Obesity) to unify interconnected cardio‐metabolic risk factors into a universal definition of metabolic syndrome did not seem to be final [13]. Table 1. Antiphospholipid syndrome definitions. Similar ambiguity exists concerning the definition of adequate circulating VitD level, as well as of its deficiency and insufficiency. Earlier definition of VitD insufficiency by its blood level of <20 ng/mL (50 nmol/L), given by the World Health Organization (WHO) [14], has been recently accepted by most researchers as a definition of the deficiency of this vitamin [15, 16]. Its insufficiency is defined as a VitD concentration between 20 and 30 ng/mL (50 and 75 nmol/L), while its concentrations >30 ng/mL (75 nmol/L) are regarded as sufficient [17, 18]. The WHO definition10 NCEP ATP III definition11 IDF definition12 Insulin resistance plus ≥ 2 of: ≥ 3 of: Central obesity plus 2 of: Atherogenic dyslipidaemia Hypertension Microalbuminuria Impaired fasting glucose/Glucose intolerance/Diabetes Table 2. Metabolic syndrome definitions—similar but different enough. 3. Experience from Serbian National APS Registry 3.1. Patients and methods Study included a total of 137 APS patients, attending outpatient clinic of the University Medical Center Bezanijska kosa, all Caucasians, who were previously enrolled in Serbian National APS Registry. These patients represented only the part of those so far included in this Registry, which is still growing and is still unable to appraise the prevalence of APS among general population in Serbia. Among studied patients, 68 were PAPS patients (59 females, nine males, mean age 43.51+10.58 years) and 69 sAPS patients (61 females, eight males; mean age 47.83+15.67 years). All studied APS patients have met 2006 updated Sydney criteria [5] which requested the presence of at least one clinical criteria (i.e. vascular thrombosis or multiple and recurrent foetal losses) and at least one of antiphospholipid antibodies (aPL), i.e. lupus anticoagulant (LA), anticardiolipin (aCL) and/or anti‐β2‐glycoprotein 1 (β2GP1) antibodies. Most of our sAPS patients had APS associated with systemic lupus erythematosus (SLE) (n=60; 87%), while the rest had Sjögren's syndrome (n=8; 11.5%) and ankylosing spondylitis (n=1; 1.5%). Mean duration of these rheumatic diseases in sAPS patients was 5.69+2.87 years, ranging from 1 to 13 years. Characteristics of two subgroups of APS patients were compared with 50 MetS patients (35 females, 15 males; mean age 47.68+11.66 years). The presence of metabolic syndrome among studied patients was determined according to the International Diabetes Federation (IDF) clinical definition [12]. An obligatory criterion for MetS requested by this definition is abdominal obesity defined by elevated waist circumference (WC) with gender‐ and ethnic‐specific cut‐offs, meaning 94 cm for males, and 80 cm for females belonging to European population. Besides abdominal obesity, two or more of the four additional criteria (a) hypertriglyceridemia >150 mg/L, confirmed or already treated; (b) high density lipoprotein (HDL) cholesterol <40 mg/dL in males or <50 mg/dL in females; (c) blood pressure >130/85 mmHg, newly diagnosed or already treated; (d) impaired fasting glycaemia, >100 mg/dL or previously diagnosed diabetes) are necessary for the diagnosis. For every participant, clinical data concerning thrombotic events, their appearance, management and follow‐up were obtained from medical charts review. As thrombotic events, the following were recorded: superficial and deep venous thrombosis, pulmonary embolism, peripheral arterial occlusion, cerebral vascular accident and myocardial infarction. After an overnight fast, height (m), weight (kg) and waist circumference (cm) were measured in every participant with underwear and without shoes. Waist circumference (WC) was measured at the level of the umbilicus while the participant was standing and breathing normally. Body mass index (BMI) was calculated according to the widely accepted formula dividing body weight by the square of individual's height. Morning samples of venous blood (3–5 mL) were withdrawn from every participant for the analysis of serum glucose and lipids. Serum vitamin D levels were determined in every participant . The study was approved by the Institutional Ethics Committee. All examinations were conducted according to the most recent amendment of Declaration of Helsinki (Edinburgh, 2000), only after obtaining an informed consent for participation in the study from every subject. Statistical analysis was performed using the STATISTICA 10 software program. Descriptive statistics was used. Prevalence of MetS as well as of its individual components, within studied groups of patients was expressed as percentage. Testing significance of their differences, the Student's t‐test and Fisher's exact test were used, considering p value <0.05 statistically significant. 3.2. Results 3.2.1. Prevalence of MetS among patients with APS Metabolic syndrome was observed in high percentage of patients with APS. Its prevalence did not differ significantly between PAPS (36.76%) and sAPS (42.03%) patients (p=0.53). Anthropometric and metabolic syndrome characteristics among studied groups are given in Table 3. Borderline statistical significance of the difference in WC value was observed when two subgroups of APS patients were compared with MetS patients (F=2.77, p=0.065), while BMI has differed highly significantly between these groups (F=9.765, p=0.0001). In spite of slightly lower BMI and slightly higher WC in PAPS patients, neither BMI (p=0.434) nor WC (p=0.275) did differ significantly between two subgroups of APS patients. Atherogenic dyslipidaemia, represented by hypertriglyceridemia and low HDL cholesterol, was the most prevalent characteristic of metabolic syndrome among PAPS patients. In spite of this, prevalence of low HDL cholesterol among PAPS patients were significantly lower than in MetS patients (48.3% vs. 70%, p=0.02). Prevalence of hypertriglyceridemia (45.59% vs. 42.03%, p=0.67) and low HDL cholesterol (48.53% vs. 53.62%, p=0.55) did not differ significantly between PAPS and sAPS patients. Hypertension was significantly less prevalent among these patients compared with MetS (23.53% vs. 58%, p=0.0002) and even with sAPS (23.53% vs. 52.17%, p=0.0007) patients. The least prevalent characteristic of metabolic syndrome among patients with APS was hyperglycaemic disorder. Compared with MetS patients in whom impaired fasting glycaemia, glucose intolerance or diabetes were present in as much as 36%, these disorders were observed in only 5.88% of PAPS patients (p=0.0001) and 4.35% of sAPS patients (p<0.0001). MetS PAPS sAPS BMI (kg/m2) 32.09+6.14 27.81+5.98 28.54+4.22 WC (cm) 93.67+14.36 90.73+9.18 88.53+11.91 TG > 150 mg/dL (%) 58 45.59 42.03 HDL < 40/50 mg/dL (%) 70 48.53** 53.62 Hypertension (%) 58 23.53**** 52.17§§ IFG, IGT, DM (%) 36## 5.88**** 4.35 Table 3. Anthropometric and metabolic syndrome characteristics among studied groups. *p < 0.05, PAPS vs. MetS. **p < 0.01, PAPS vs. MetS. #p < 0.01, sAPS vs. MetS. §p < 0.01, PAPS vs. sAPS. 3.2.2. Prevalence of thrombotic events among APS patients with or without MetS Compared with patients with metabolic syndrome, prevalence of thrombotic events was significantly higher among patients with PAPS (52.94% vs. 22%, p=0.0009) and sAPS (56.52% vs. 22%, p=0.0003). Thrombotic events were reported with similar prevalence in PAPS and sAPS patients (p=0.674). When compared with APS patients without characteristics of MetS, thrombotic events were significantly more frequent among MetS positive patients with sAPS (75.86% vs. 42.5%, p=0.0075). Although higher among MetS positive, compared with MetS negative patients with PAPS, difference of prevalence of thrombotic events among these two subgroups of PAPS patients did not reach statistical significance (68% vs. 44.19%, p=0.0622). 3.2.3. Vitamin D status among APS patients depending on MetS and/or thrombotic events Low VitD status (insufficiency or deficiency) was highly prevalent among PAPS (insufficiency in 27.94% and deficiency in 36.76%) and sAPS patients (insufficiency in 30.43% and deficiency in 40.58%), as well as among patients with pure MetS (insufficiency in 20% and deficiency in 32%). In comparison with patients with pure MetS (28.58+14.32 ng/mL), VitD concentrations were lower in PAPS (25.76+12.18 ng/mL) and sAPS patients (23.81+11.22 ng/mL), but with statistically significant difference only between these concentrations in sAPS patients and patients only with MetS (p=0.04). Significantly lower VitD level was observed in those with coexisting MetS (MetS +), compared with those without it (MetS -) both in PAPS (MetS +: 22.0+8.52 vs. MetS -: 27.0+13.49 ng/mL, p=0.05 ) and sAPS patients (MetS +: 18.83+9.16 vs. MetS -: 27.42+11.28 ng/mL, p=0.0012). Also, significantly lower VitD level was observed in APS patients with thrombotic events (TE+), compared with those without these events (TE -), both in PAPS (TE +: 20.61+12.18 vs. TE -: 31.56+12.72 ng/mL, p=0.0001 ) and sAPS patients (TE +: 20.67+10.43 vs. TE -: 27.9+11.04 ng/mL, p=0.007). In 11 (22%) of patients with MetS, but without APS, some thrombotic event was confirmed. In those patients, VitD levels were also significantly lower than in those without these events (TE +: 18.45+10.66 vs. TE -: 31.43+13.63 ng/mL, p=0.003). However, both in PAPS and sAPS patients, with coexisting MetS, previous thrombotic events did not influence serum VitD levels (PAPS: p=0.12; SAPS: p=0.93). 4. Relationship between antiphospholipid syndrome and metabolic syndrome Estimation of prevalence of MetS in general population seems to depend to a substantial degree on the used definition, at least in certain countries or in certain ethnic groups [19–22]. Its prevalence varies between <10% in China and as much as 60% among women of Samoa [23]. Different prevalences of MetS, ranging between 18 and 48%, were also recorded among populations of different European countries and regions [20–22, 24–26]. It is interesting to emphasize that even in populations in which comparable prevalence of MetS was found using each of three already mentioned definitions, level of agreement between them was not good. As could be expected, worse agreement was found between WHO‐NCEP ATP III and WHO‐IDF than between NCEP ATP III‐IDF definitions because of the central obesity as common denominator of the last two definitions [20, 21, 23]. This observation raised the possibility that in fact different individuals were identified as having MetS by different definitions of this syndrome [23]. In a search for factors that contribute to the manifestations of APS, MetS came into a focus surprisingly late. Data on coexistence of these two syndromes are still relatively scarce, particularly considering that of MetS and primary APS (PAPS). 4.1. Metabolic syndrome in primary antiphospholipid syndrome patients Recently, prevalence of MetS among PAPS patients has been assessed by Medina et al. [3] and Rodrigues et al. [27]. Both surveys were performed in Hispanics among whom MetS has the highest prevalence [28]. Defined by the IDF criteria, the prevalence of MetS among 71 Brazilian PAPS patients was 33.8% [27]. Comparable prevalences of MetS were recorded among 58 Mexican PAPS patients, using NCEP ATP III (34.5%) or IDF definitions (37.9%), while it was only 17.2% when WHO definition was applied [3]. It has been hypothesized that these cases, identified by WHO definition, were insulin resistant and with more severe forms of MetS [3, 29]. However, in investigation conducted by Medina et al., prevalence of MetS among PAPS patients was higher than in corresponding general population (17.2% vs. 13.6%) when WHO definition was used [3]. Same as in general population without APS [20, 21, 23], among PAPS patients agreement between WHO and NCEP ATP III definitions of MetS was low (κ value 0.394), moderate between WHO and IDF definitions (κ value 0.427), while only between NCEP ATP III and IDF definitions agreement was good (κ value 0.851) [3]. Regarding individual components of MetS, atherogenic dyslipidaemia was most prevalent among Mexican PAPS patients, being present in approximately half of them [3]. Significantly higher mean triglyceride levels and significantly lower mean HDL levels were previously reported among PAPS patients in comparison with controls [30–33]. Some specific autoantibodies could influence lipoprotein levels and effects in these patients. These antibodies may interfere with paraoxonase (PON) activity of HDL and, indirectly, beta‐2‐glycoprotein I (beta‐2‐GPI) [32, 33], thus promoting LDL oxidation. Relationships between lipid profile, certain anti‐lipoprotein antibodies, inflammatory markers and clinical manifestations of PAPS were meticulously investigated [31–33], but on relatively small number of patients and with inconsistent results. Delgado Aves et al. have not demonstrated any correlation between the observed decrease in PON activity and either aPL nor antibodies against HDL (anti‐HDL) in PAPS patients [33]. However, pro‐inflammatory and prothrombotic roles were proposed for anti‐HDL, being present in higher titre among asymptomatic persistently aPL positive subjects, as well as in PAPS patients with thrombotic events, when compared with patients with inherited thrombophilia and healthy controls [32]. It has been also hypothesized that hypertriglyceridemia could be the result of decreased degradation as a consequence of an inhibition of lipoprotein lipase (LPL) by aPL [3]. Currently, there are only scarce data on prevalence of antibodies against LPL (anti‐LPL) in PAPS patients, speaking against their existence and influence [31]. Different authors have observed similar prevalences of hypertension among PAPS patients (22.4 and 26.3%) [3, 31], not differing significantly from that in controls (20%). Nevertheless, among PAPS patients, hypertension was significantly more frequent in those with arterial thrombosis, with which it was independently associated [31]. It is interesting that in spite of highly prevalent insulin resistance (32.8%), hyperglycaemic disorders were present in only 5% of PAPS patients [3]. 4.2. Metabolic syndrome in patients with antiphospholipid syndrome associated with autoimmune rheumatic diseases. The literature data on coexistence of MetS and numerous rheumatic diseases (i.e. systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, ankylosing spondylitis, osteoarthritis, gout) are fairly extensive [1, 34–42]. The prevalence of MetS among patients with these disorders ranges between 14 and 62.8% [1, 3]. Qualifier “antiphospholipid syndrome associated with certain autoimmune rheumatic disease” (sAPS), which replace currently obsolete term “secondary APS”, refers mainly to the systemic lupus erythematosus (SLE) despite the still unscrambled puzzle of their relations [5]. It has been speculated that high prevalence of MetS among these patients might be the consequence of certain pharmacologic interventions, particularly of chronic corticosteroid therapy [43]. However, the presence of MetS in as much as 16% of 1494 young (35.2+13.4 years) SLE patients with rather short disease duration (24.1+18.0 weeks) seems to be enough to reject this relationship as causal [2]. Nevertheless, it should be kept in mind that duration and magnitude of corticosteroid exposure could aggravate well‐known cardiovascular risk factors clustering as characteristics of MetS. On the other hand, other pharmacological interventions, primarily methotrexate (MTX) use in patients with rheumatoid arthritis, have been depicted as independent factors for reduced prevalence of MetS in these patients, especially those older than 60 years [44, 45]. This beneficial effect of MTX was attributed to its anti‐inflammatory, as well as to some still unclear drug‐specific effects, i.e. affecting adenosine levels and, concomitantly, glucose and lipid metabolism, or decreasing homocysteine levels as an indirect effect of simultaneous use of folic acid [44]. However, other authors reported somewhat conflicting results not being able to confirm decreasing prevalence of MetS in subjects treated with MTX, among total of 353 patients with rheumatoid arthritis [46]. 5. Vitamin D and thrombosis Prothrombotic state is one of the well‐known characteristics of both antiphospholipid and metabolic syndrome. It has rather complex pathogenesis in which VitD status has an important role affecting primarily immune‐mediated thrombosis. Indirect proofs for this relationship are as follows: (a) existence of nuclear VitD receptors in vascular smooth muscle cells, endothelial cells, cardiomyocytes, platelets, as well as in most types of the immune cells [47–51], and (b) expression of cytochrome P450 enzyme, CYP27B1 activity by the same cell types, enabling local synthesis of biologically active form of VitD, 1,25(OH)2D [52]. There is substantial experimental data indicating that VitD plays significant role in maintenance of physiological balance between thrombosis and haemostasis [47]. It has been demonstrated that VitD exerts following actions: in monocytes, expression of tissue factor (TF) is downregulated, while the expression of thrombomodulin (TM) is upregulated [53]; in vascular smooth muscle cells, the expression of TM is upregulated, but there is also downregulation of plasminogen activator inhibitor‐1 (PAI‐1) and thrombospondin‐1 (THSP‐1) [54]; in endothelial cells, platelet activation is attenuated as well as the expression of vascular cell adhesion molecule‐1 (VCAM‐1) [55]. Net result of numerous effects of this vitamin on different haemostatic factors is its antithrombotic role. Prothrombotic state that exists in VitD receptor knockout animal models proves the importance of these extra‐skeletal effects of VitD as well as the observation that all of them are VitD receptor‐mediated [47, 56]. However, there are still relatively few indirect and even less direct clinical evidences for the association between VitD status and thrombotic events in humans. First of them came from the epidemiological studies in which have been observed that cardiovascular morbidity and mortality depended on season of the year and latitude [47, 57, 58]. Seasonal variations were also demonstrated for tissue plasminogen activator (tPA) antigen, fibrinogen, D‐dimer and von Willebrand factor (vWF) concentrations in 6538 British subjects without significant cardiovascular disorders, aged 45 years [59]. In this population, negative correlation between VitD level and tPA, fibrinogen and D‐dimer concentrations was observed indicating that at least some of the seasonal variations of these thrombotic markers could be attributed to the VitD status. More direct proof for the association between VitD status and thrombosis came from the research conducted in huge population of 18 791 subjects from general population of Copenhagen [60]. Authors have observed that every quartile of a decrease in VitD concentrations was accompanied by an increase in risk of venous thromboembolism (VTE), resulting in a 37% increased VTE risk between subjects with the VitD concentrations, in the lowest quartile and those in highest quartile. Recent publication which retested the seasonality of different cardiovascular events in regard to VitD levels, in the Scottish Heart Health Extended Cohort (SHHEC), brings a dose of confusion in previously proposed relations. Namely, it failed to prove that seasonal appearance of cardiovascular events resembled seasonal variations in serum VitD concentrations nor that these events expressed more pronounced seasonality in those with lower VitD concentrations, compared with those with its higher concentrations [61]. But, during follow‐up, significant correlations were observed between lower baseline concentrations of VitD and subsequent incident cardiovascular morbidity and incident cardiovascular and all‐cause mortality [61]. Results of recent trials assessing the effects of VitD supplementation on the risk of thromboembolism were inconclusive [62–64]. In the Multiple Environmental and Genetic Assessment (MEGA) case‐control study which included 2506 patients with venous thrombosis, thrombotic risk was 37% lower in those supplemented with various vitamins including VitD [62]. However, in a large cohort of postmenopausal women (n=36282) from the Women's Health Initiative, daily supplementation with calcium and VitD failed to reduce the overall risk of thromboembolism [63]. Even when high doses (300,000 IU) of VitD were given intramuscularly, in a small group of patients with proven deep vein thrombosis and pulmonary embolism, observed reduction in plasma concentrations of P‐selectin and high‐sensitive C‐reactive protein (hs‐CRP) did not reached statistical significance [64]. Additional information could be expected from the ongoing Vitamin D and OmegA‐3 Trial (VITAL) and that is why the results of this investigation are eagerly awaited [65]. 6. Role of vitamin D in metabolic syndrome Currently, increasing prevalence and co‐existence of obesity, MetS and hypovitaminosis D represent serious public health concern [66, 67]. New data have considerably changed hierarchy of MetS components, with the shift of the focus from obesity and insulin resistance, firstly toward fatty liver and now toward VitD deficiency [68]. It is still questionable if relationship between VitD status and obesity is unidirectional or bidirectional, with the accumulating evidence favouring the influence of VitD on body composition and not vice versa. Namely, few years ago tempting hypothesis on essential role of VitD in evolvement of obesity has been postulated [68]. It started from a situation that is completely opposite to the “thrifty genotype hypothesis” proposed long ago [69] and gave the feasible explanation not only for obesity and MetS epidemic in adults but also for their growing prevalence among children [70]. According to this hypothesis, we are living in “obesogenic” environment, loaded with energy resources and unsuitable for efficient metabolism. It has been proposed that VitD as an ultraviolet (UV)‐B radiation sensor (i.e. decline in its concentrations) could induce shift toward “winter metabolism”, characteristic for MetS [68]. If this is true, then it could be expected that VitD supplementation may be efficient in prevention and treatment of obesity and MetS. Significant decrease in body fat mass after 12 week of VitD repletion (25 μg of cholecalciferol daily), compared to placebo (−2.7+2.0 kg vs. −0.4+2.0 kg, p<0.001), could be the proof for this presumption [71]. It was also speculated that VitD deficiency during pregnancy could lead to the epigenetic changes predisposing, in that manner, new‐born children to obesity and MetS later in life [68, 70]. Experimental support for these assumptions is the expression of VitD receptors on adipocytes and its involvement in adipogenesis which is regulated by the intracellular concentrations of VitD [72], as well as inhibition of lipid accumulation in adipocytes and their atrophy achieved by the knock‐down of VitD receptors [72, 73]. Nowadays, VitD deficiency is common even in general population (49%), but significantly more prevalent (p=0.006) and quite similar in overweight/obese patients with MetS (72%) and without MetS (69%) [74]. Premise that exaggerated adiposity could lead to VitD insufficiency or deficiency by its seclusion within adipose tissue could not be confirmed. It has been shown that VitD concentrations varied considerably (range 4–2470 ng/g) in the subcutaneous abdominal fat of 17 severely obese patients (BMI=48.7+8.1 kg/m2) undergoing bariatric surgery [75]. In spite of the average weight loss of 54.8 kg after one year and continuous VitD supplementation with more than 2500 IU/day, mean serum VitD concentrations did not change significantly during this period (23.1+12.6 vs. 26.2+5.36, p=0.58) [75]. Most of the studies have confirmed that serum VitD concentrations significantly inversely correlated with obesity parameters, BMI (r=-0.159, p=0.007) [74], or waist circumference (p<0.001) [76] as well as with serum triglycerides (r=-0.149, p=0.012) [76]. In the lowest quartiles of VitD concentrations corresponding to its severe deficiency, odds ratio (OR) for hypertriglyceridemia was 2.74 (95% CI: 1.64–4.57) [77]. This association between serum concentrations of VitD and triglycerides could be explained by the activation of lipoprotein lipase by VitD in adipocytes [76]. No significant relation could be demonstrated between VitD status and total‐ (r=-0.044, p=0.461) [74], low density lipoprotein (LDL)‐ (r=-0.005, p=0.932) and high density lipoprotein (HDL)‐cholesterol (r=0.065, p=0.276) [74]. Interestingly, hypothesis was proposed ten years ago stating the possibility that statins could be the analogues of VitD, acting via same receptors, particularly when we are talking about their mutual effect of enhancement of immune competence [78]. So, it seems that this absence of association between VitD status and parameters of cholesterol metabolism made this hypothesis shaky to some extent. Another component of MetS for which association with VitD status has not been unequivocally confirmed is hypertension. Variability of blood pressure driven by the seasons or latitude speaks for the existence of this association, as well as the results of experimental studies pointing to VitD as an inhibitor of the renin‐angiotensin‐aldosterone axis [79, 80]. Negative correlation between VitD concentrations and blood pressure was demonstrated in most but not all of the surveys. This negative association was stronger in subjects younger than 50 years [81–83], while the absence of any relationship between VitD status and hypertension was also registered in some of the trials [74, 76, 84, 85], particularly those conducted in older subjects [84, 85]. However, in postmenopausal women with the VitD concentrations in the lowest quartiles corresponding to its severe deficiency, odds ratio (OR) for hypertension was 1.81 (95% CI: 1.15–2.85) [77]. 7. Role of vitamin D in antiphospholipid syndrome Although APS represents acquired, autoimmune condition, its pathophysiology and, especially pathophysiology of thrombosis in APS is highly heterogeneous, involving different genes and acquired factors [86], VitD insufficiency/deficiency being among them. Same as for relationship between MetS and APS, much more is known about the impact of VitD status on antiphospholipid syndrome, associated with autoimmune rheumatic diseases, than on primary antiphospholipid syndrome. Patients with PAPS represent the population of particular interest for the investigation of interrelations with components of MetS and/or VitD status since these patients, unlike those with sAPS, were not treated with drugs (i.e. corticosteroids, immunosuppressants) which may affect expression of most of the MetS characteristics as well as VitD level. One of the first announcements on the prevalence of VitD insufficiency or deficiency in PAPS and their impact on its manifestations dated from 2010 [87]. This letter to the editor presented the results of research conducted by Brazilian investigators in the group of forty‐six PAPS patients, younger than 60 years, in whom the VitD levels were assessed in the autumn, when it was expected to be highest. VitD deficiency was found in 11% and insufficiency in 74% of these PAPS patients, resembling the findings of Italian authors [88] which have reported the prevalence of VitD deficiency in 17% and insufficiency in 60% of PAPS patients. It is interesting that Brazilian authors have noticed that VitD insufficient PAPS patients tended to be more overweighed than those with adequate VitD level [87]. Also, it seems that thrombotic APS is characterized with significantly lower concentrations of VitD than purely obstetric clinical syndrome (20.8 vs. 33.3 ng/ml, p<0.01) [88] highlighting once again the role of this vitamin in thrombosis. High prevalence of VitD deficiency among patients with APS (49.5%) and its significant correlation with thrombotic events were confirmed by Israeli authors [68]. In vitro, they have also demonstrated VitD ability to inhibit anti‐β2‐glycoprotein I autoantibody (anti‐β2‐GPI Ab)‐mediated TF expression [89]. Seasonal variations in VitD concentrations were demonstrated in PAPS patients same as in healthy controls, with preserved differences in its level between these two groups through all seasons [88, 90]. These differences were most pronounced during summer, while they were not statistically significant only during the spring. This observation was somewhat surprising, given the lack of banning from sun exposure in these patients. That sun avoidance is not a cause of highly prevalent VitD deficiency and insufficiency in PAPS patients was indirectly demonstrated in previous Italian studies [88, 90] by observed absence of any difference in VitD levels between antinuclear antibodies (ANA)‐positive and negative PAPS patients. Until now, there is no valid explanation for the probable cause‐and‐effect relationship between insufficient VitD level, on one side, and PAPS or sAPS, on the other. There are only assumptions, and even they are much better clarified for sAPS [91–93], especially that accompanying SLE [91, 94, 95]. It is obvious that low levels of vitamin D in sAPS could not be attributed purely to banning of sun exposure or the use of certain medication in these patients. In an Israeli and European cohort of patients with SLE, significant negative correlation (r=-0.12, p=0.018) was demonstrated between the serum VitD concentrations and disease activity, assessed by SLE disease activity‐2000 (SLEDAI‐2K) and European Consensus Lupus Activity Measurement (ECLAM), which were converted into standardized z‐value [94]. Severe VitD deficiency was found in 17.89% of 123 SLE patients with short disease duration, while the presence of renal disease (OR 13.3, 95% CI 2.3–76.7, p<0.01) and photosensitivity (OR 12.9, 95% CI 2.2–75.5, p<0.01) were its strongest predictors [95]. Investigation conducted in a small group of young women with newly diagnosed SLE, from one of the sunny places in Iran, gave very interesting results. VitD deficiency was highly prevalent among these patients, mild in 12.5%, moderate in 62.5% and severe in 17.5% of them [96]. It was much more pronounced in them than in general population of the similar age in that region, in whom mild VitD was present in 15.5%, moderate in 47.1% and severe in 7.1%. Very interesting was also an observation that serum VitD concentrations showed significant negative correlation with another disease activity score, the British Isles Lupus Assessment Group (BILAG) (r=-0.486, p=0.001), in spite of the short duration of disease [97]. Hypothetical explanation for the low serum concentrations of VitD in SLE patients by the existence of inhibiting anti‐VitD antibodies in circulation could not be confirmed by the literature data [97, 98]. Their existence could be proven in 4–6% of patients with SLE and 3.5% of APS patients. Its association with anti‐dsDNA (p=0.0004) could point to its potential role in this condition, but being only one of 116 different antibodies present in SLE patients characterized by the polyclonal B lymphocyte activation, it is still uncertain if it is pathogenic [97]. It seems that their presence did not affect VitD levels in these patients [97, 98], and it was speculated that they could be the consequence of high‐dose VitD consumption rather than the cause of this vitamin deficiency [99]. Once again, it is important to emphasize that VitD deficiency is more pronounced in more severe APS phenotypes, i.e. thrombotic APS [88]. It could be speculated that supplementation of this vitamin in these very patients may have certain beneficial effects [88, 99], but there is still no prospective studies proving them. Hypothesis of statins as VitD analogues has not still been tested in well‐designed, randomized prospective trials [78]. However, since its proposal, there have been many experimental and small clinical studies confirming statins therapeutic value in APS patients, particularly in those with its thrombotic form [99–103]. So, future studies are badly needed to determine all the aspects of VitD repletion in APS prevention/therapy (choice between VitD precursors, its active form or VitD analogues, their dosage and treatment goals). 8. Key messages Prevalence of metabolic syndrome in APS, primary or associated with certain rheumatic diseases, is high. Atherogenic dyslipidaemia is the most prevalent characteristic of metabolic syndrome in APS patients. Prevalence of thrombotic events was significantly higher in APS patients with coexisting metabolic syndrome, compared with APS patients without metabolic syndrome characteristics. Among APS patients, prevalence of vitamin D deficiency was significantly higher in patients with coexisting metabolic syndrome, compared with those without it. Among APS patients, vitamin D level was also significantly lower in patients with previous thrombotic events than in those without them. In the contemporary literature, there are much more data in favour of pathogenic than therapeutic role of vitamin D in thrombotic events characterizing APS and/or metabolic syndrome. So, prospective studies designed to test all the aspects of VitD repletion in prevention and/or therapy of thrombotic events in APS and/or metabolic syndrome are badly needed. 9. Conclusions Elucidating interrelationships between vitamin D deficiency, metabolic syndrome phenotype and thrombotic events in APS patients open up the possibility of distinguishing those subjects with the particularly high cardiovascular risk and ensuing need for the strict control of modifiable risk factors and vitamin D supplementation. https://www.intechopen.com/books/a-critical-evaluation-of-vitamin-d-clinical-overview/pathogenic-and-therapeutic-role-of-vitamin-d-in-antiphospholipid-syndrome-patients?fbclid=IwAR13oFb5S8e5R6f1L-vx0pxauf2symfpH-6HRvRStXPftkvKgEoOZUc1xrk
  9. 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
  10. 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
  11. Pregnant SLE Patients Discontinue Meds When They Shouldn't (©SydaProductionsShutterStock.com) Gregory M. Weiss, M.D. August 7, 2019 Lupus, Modern Medicine News, News, Rheumatology Recent evidence shows that pregnant women with systemic lupus erythematosus (SLE) often discontinue their lupus medications during pregnancy despite recommendations to continue them. The findings, reported by Mary A. De Vera, M.D., of the University of British Columbia, appear in the July 16 online issue of Lupus. “Considering the patterns of medication use seen in this study, it appears that expectant mothers with SLE would benefit from having a discussion with their care providers about how to manage their disease during their pregnancy, which medications are safe to take, and which should be avoided,” the authors wrote. “Knowing medication use in pregnant women with SLE is key to understanding how to support patients with family planning and pregnancy decisions.” Since lupus primarily affects women in their childbearing years, pregnancy can be a time fraught with risk and complications such as stillbirth, preterm labor and miscarriage. A significant portion of pregnant women with systemic lupus erythematosus will experience flares late in the pregnancy or after the birth. While concerns over taking medications during pregnancy exist, it is recommended that women with lupus continue their antimalarial drugs like hydroxychloroquine throughout gestation and during breast-feeding, according to GR de Jesus, et al. writing in the July 12, 2015 online issue of Autoimmune Diseases. The authors of the Lupus study sought to characterize the frequency of use of anti-malarial drugs, immunosuppressants and other medications, before, during and after pregnancy with particular interest on discontinuation of antimalarials and immunosuppressants during pregnancy. THE STUDY This was a population-based study of 284 women with systemic lupus erythematosus and 376 pregnancies. They were assessed for the discontinuation of antimalarials and immunosuppressants. Use of other lupus medications were also recorded. Rates of antimalarial use and azathioprine during the study period were 33.2 percent and 11.4 percent respectively. The authors further found that 26.3 percent of pregnancies in lupus patients were exposed to glucocorticosteroids and 23.7 percent to non-steroidal anti-inflammatory drugs. Pre-pregnancy antimalarial use stood at 36.2 percent, which dropped to 19.1 percent during the first trimester, 16.7 percent in the second, and held relatively steady at 17 percent in the third. Use rebounded to 31.1 percent after delivery. Pre-Pregnancy azathioprine was used by 11.7 percent, which dropped to 6.6 percent in the first trimester, 6.4 percent during the second, 6.9 percent in the third and rose to 10.4 percent after delivery. 33.2 percent of patients were exposed to glucocorticosteroids before pregnancy, 14.9 percent in the first trimester, 13.3 percent in the second trimester, 19.7 percent in the third trimester and 25.3 percent after delivery. 34.8 percent were exposed to NSIADs before pregnancy and 19.1 percent after pregnancy. Antimalarials were discontinued at a rate of 28.9 percent in the 12 months preceding pregnancy and 9.7 percent during pregnancy from the first trimester to the second and 26 percent from the second trimester to the third. Having had more children was associated with discontinuing antimalarials before pregnancy and time since lupus diagnosis was associated with higher odds of discontinuing antimalarials during pregnancy. Azathioprine was discontinued at a rate of 29.2 percent before pregnancy, 8.0 percent from the first to the second trimester and 9.1 percent from the second to third. Take-home points for clinicians and final thoughts The high rates of discontinuation, in particular antimalarial treatment underscore the disconnect between the recommended treatment for lupus during pregnancy and the reality. “As these findings conflict with the afore- mentioned recommendations regarding the continued use of antimalarials during SLE pregnancies, they suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy,” the authors write. Compliance is a serious concern. Strong evidence and concise recommendations are useless if patients are not following the treatment plan. The responsibility rests with the clinician to disseminate the knowledge pregnant women need to make the right choices about continuing their medication regimen when both systemic lupus erythematosus and pregnancy coincide. REFERENCE Zusman, E. Z., Sayre, E. C., Aviña-Zubieta, J. A., & De Vera, M. A. (2019). “Patterns of medication use before, during and after pregnancy in women with systemic lupus erythematosus: a population-based cohort study.” Lupus. July 16, 2019 https://doi.org/10.1177/0961203319863111 https://www.rheumatologynetwork.com/lupus/pregnant-sle-patients-discontinue-meds-when-they-shouldnt
  12. Pregnant SLE Patients Discontinue Meds When They Shouldn't (©SydaProductionsShutterStock.com) Gregory M. Weiss, M.D. August 7, 2019 Lupus, Modern Medicine News, News, Rheumatology Recent evidence shows that pregnant women with systemic lupus erythematosus (SLE) often discontinue their lupus medications during pregnancy despite recommendations to continue them. The findings, reported by Mary A. De Vera, M.D., of the University of British Columbia, appear in the July 16 online issue of Lupus. “Considering the patterns of medication use seen in this study, it appears that expectant mothers with SLE would benefit from having a discussion with their care providers about how to manage their disease during their pregnancy, which medications are safe to take, and which should be avoided,” the authors wrote. “Knowing medication use in pregnant women with SLE is key to understanding how to support patients with family planning and pregnancy decisions.” Since lupus primarily affects women in their childbearing years, pregnancy can be a time fraught with risk and complications such as stillbirth, preterm labor and miscarriage. A significant portion of pregnant women with systemic lupus erythematosus will experience flares late in the pregnancy or after the birth. While concerns over taking medications during pregnancy exist, it is recommended that women with lupus continue their antimalarial drugs like hydroxychloroquine throughout gestation and during breast-feeding, according to GR de Jesus, et al. writing in the July 12, 2015 online issue of Autoimmune Diseases. The authors of the Lupus study sought to characterize the frequency of use of anti-malarial drugs, immunosuppressants and other medications, before, during and after pregnancy with particular interest on discontinuation of antimalarials and immunosuppressants during pregnancy. THE STUDY This was a population-based study of 284 women with systemic lupus erythematosus and 376 pregnancies. They were assessed for the discontinuation of antimalarials and immunosuppressants. Use of other lupus medications were also recorded. Rates of antimalarial use and azathioprine during the study period were 33.2 percent and 11.4 percent respectively. The authors further found that 26.3 percent of pregnancies in lupus patients were exposed to glucocorticosteroids and 23.7 percent to non-steroidal anti-inflammatory drugs. Pre-pregnancy antimalarial use stood at 36.2 percent, which dropped to 19.1 percent during the first trimester, 16.7 percent in the second, and held relatively steady at 17 percent in the third. Use rebounded to 31.1 percent after delivery. Pre-Pregnancy azathioprine was used by 11.7 percent, which dropped to 6.6 percent in the first trimester, 6.4 percent during the second, 6.9 percent in the third and rose to 10.4 percent after delivery. 33.2 percent of patients were exposed to glucocorticosteroids before pregnancy, 14.9 percent in the first trimester, 13.3 percent in the second trimester, 19.7 percent in the third trimester and 25.3 percent after delivery. 34.8 percent were exposed to NSIADs before pregnancy and 19.1 percent after pregnancy. Antimalarials were discontinued at a rate of 28.9 percent in the 12 months preceding pregnancy and 9.7 percent during pregnancy from the first trimester to the second and 26 percent from the second trimester to the third. Having had more children was associated with discontinuing antimalarials before pregnancy and time since lupus diagnosis was associated with higher odds of discontinuing antimalarials during pregnancy. Azathioprine was discontinued at a rate of 29.2 percent before pregnancy, 8.0 percent from the first to the second trimester and 9.1 percent from the second to third. Take-home points for clinicians and final thoughts The high rates of discontinuation, in particular antimalarial treatment underscore the disconnect between the recommended treatment for lupus during pregnancy and the reality. “As these findings conflict with the afore- mentioned recommendations regarding the continued use of antimalarials during SLE pregnancies, they suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy,” the authors write. Compliance is a serious concern. Strong evidence and concise recommendations are useless if patients are not following the treatment plan. The responsibility rests with the clinician to disseminate the knowledge pregnant women need to make the right choices about continuing their medication regimen when both systemic lupus erythematosus and pregnancy coincide. REFERENCE Zusman, E. Z., Sayre, E. C., Aviña-Zubieta, J. A., & De Vera, M. A. (2019). “Patterns of medication use before, during and after pregnancy in women with systemic lupus erythematosus: a population-based cohort study.” Lupus. July 16, 2019 https://doi.org/10.1177/0961203319863111 https://www.rheumatologynetwork.com/lupus/pregnant-sle-patients-discontinue-meds-when-they-shouldnt
  13. 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
  14. 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/
  15. Entry Requirements for Lupus Nephritis Clinical Trials Exclude Majority of Patients in UK Registry, Study Says JULY 10, 2019 BY IQRA MUMAL IN NEWS. Click Here to receive Lupus News via e-mail How clinical trials into lupus nephritis define their requirements for patient eligibility are too strict, leaving many people with active and severe disease ineligible for participation, according to a study that looked at six lupus trials and how well their “inclusion and exclusion criteria” matched patients in a large U.K. registry. Its researchers reported that a majority of registry patients, 50.6%, would not have been enrolled under published entry requirements. These findings were presented at the recent 2019 European Congress of Rheumatology(EULAR 2019), in a poster titled “How Well Do Clinical Trials Represent Real World Lupus Nephritis Patients?” Lupus nephritis (inflammation of the kidneys) can be a serious complication of systemic lupus erythematosus (SLE). The standard of care for lupus nephritis is treatment using glucocorticoids or conventional immunosuppressants. Rituxan (rituximab), an antibody that dampens some immune cells, has been used off-label to treat some with lupus nephritis, but has not shown efficacy across several clinical trials. Finding better treatments for these people requires clinical studies that determine safety and effectiveness. But stringent requirements for trial participation, often done to ensure patient homogeneity in the group studied, can result in criteria that does not accurately reflect real-world patients, the study notes. Researchers set out to evaluate clinical trial criteria for lupus nephritis by determining how closely they reflected a general population. They reviewed six recently published clinical trials involving these patients. Then they compared inclusion and exclusion criteria common across the trials to patients with active lupus nephritis in a U.K.-wide database of SLE patients called the BILAG-Biologics Register (BILAG-BR). Inclusion criteria define the characteristics that potential participants must have to be in a study, while exclusion criteria define those that disqualify from participation. The registry showed 259 people with active lupus nephritis, corresponding to 28.9% of its population. Among them, 230 had been treated with Rituxan, while the 29 others were given standard of care. Analysis showed that 70 people (30.4%) in the Rituxan group and 10 (34.5%) in the standard-of-care group that would not meet all inclusion criteria common to the six trials. The requirement that patients most often missed was not having a urine protein/creatinine ratio below 100 mg/mmol. This would exclude people with more severe kidney impairment. A majority, 118 patients or 51.3%, in the Rituxan group and six patients (20.7%) in standard-of-care also met one or more common exclusion criteria for the trials. Most often, the excluding criteria was active disease in the central nervous system and low levels of antibodies implying an immune system disorder (hypogammaglobulinaemia). Overall, more than half of registry patients (50.6%) with active lupus nephritis would not satisfy all inclusion and exclusion criteria, and likely be ineligible for clinical trial entry, the study found. Among patients deemed ineligible, those in the Rituxan group were younger (mean age, 36) compared to those given standard of care (mean age, 49). Most were also minorities (non-Caucasian) and female. “In a large national cohort of active LN [lupus nephritis] we found that 50.6% of patients would not be eligible for clinical trial entry using published entry criteria,” the researchers wrote. “This poses significant implications on the study of LN treatment in patients with more severe disease. When designing clinical trials, the stringency of eligibility criteria should be reviewed in order to provide greater representation of the target disease population,” they concluded. https://lupusnewstoday.com/2019/07/10/entry-criteria-for-lupus-nephritis-trials-exclude-majority-patients-in-uk-registry-study-finds/?utm_source=LUP+NEws+E-mail+List&utm_campaign=4dbb72aad6-RSS_WEEKLY_EMAIL_CAMPAIGN_US&utm_medium=email&utm_term=0_50dac6e56f-4dbb72aad6-71887989
  16. Understanding the Role of Polyautoimmunity in Rheumatic Diseases (©Zerbor,Shutterstock.com) Linda Peckel July 16, 2019 Rheumatology, Autoimmune Diseases, Modern Medicine News, News, Rheumatoid Arthritis An estimated 5 percent of the world’s population is diagnosed with one of a group of heterogeneous autoimmune rheumatic diseases (ARDs) including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren’s syndrome (SS). Not only do these diseases share mechanisms and risk factors, they are often comorbid conditions recognized as polyautoimmune (PolyA) manifestations of the same underlying dysfunction. Patients with SLE are frequently positive for anti-rheumatoid factor (RF) and less often for anti-citrullinated protein antibodies associated with RA, although less than 10% are diagnosed with concomitant SLE/RA, known as rhupus. Another 10% of SLE patients are recognized to have antiphospholipid syndrome (APS) although up to 54% have been shown to carry antibodies. Other PolyA’s may include SLE/hypothyroidism, RA/autoimmune thyroid disease (AITD), and concomitant symptoms of SS with SLE, AITD, or systemic sclerosis (SSc). According to studies by Gonzalez and colleagues (the most recent of which is published in the Journal of Autoimmunity)1 , 2 patterns of PolyA have emerged: 1) Overt PolyA, which reflects more than one well-defined ARD in a single patient, and 2) Latent PolyA, in which underlying patterns of autoantibodies are identified that do not correspond to the main diagnosis, and may be predictive of 1 or more additional ARDs. The authors conducted a cross-sectional cluster analysis of patients with the most common ARDs for antibody and cytokine patterns in a cohort of 187 individuals with diagnoses of SLE, RA, SSc, and SS (n = 70, 51, 35, and 31). They found that the frequency of PolyA did not differ across all 4 ARDs, although SLE and SS were associated with a younger age of onset. Rheumatoid factor and CCP3 were identified in 84.3% and76.5% of patients with RA, who also had the highest levels of Interleukin (IL)-6, interferon (IFN)-α, and IL-12/23p40 cytokines. Antinuclear antibodies (ANAs) were most prevalent in patients with SSc (97% positive) and SLE patients (71.4%), with distinctive patterns of additional antibodies and cytokines to each disease. The study revealed six main PolyA clusters involving the 4 ARDs that may provide biomarkers useful for diagnosis of current disease as well as prediction of other ARDs over time. The authors suggested that particular attention should be paid to latent PolyA, and to the strong association of IL-12/23p40 to 3 of the 6 cluster groups. REFERENCE 1. Molano-González N, Rojas M, Monsalve DM. "Cluster analysis of autoimmune rheumatic diseases based on autoantibodies. New insights for polyautoimmunity." J Autoimmun 2019;98:24-32. https://www.rheumatologynetwork.com/rheumatology/understanding-role-polyautoimmunity-rheumatic-diseases?rememberme=1&elq_mid=7781&elq_cid=1830808&GUID=9D824BFE-EF27-47A3-BAE0-900DC34C90C7
  17. 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
  18. 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
  19. 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.
  20. 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/
  21. 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
  22. 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
  23. 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
  24. 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!
  25. 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
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