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  2. 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.
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  4. JANUARY 15, 2020 IQRA MUMAL, MSC BioMed X and Merck are establishing a combined research group that will focus on the role of the gut epithelial barrier in the development and progression of autoimmune diseases, including systemic lupus erythematosus (SLE) and multiple sclerosis. This new group will extend the companies’ continuing partnership to a total of six joint research projects to be conducted at the BioMed X Innovation Center in Heidelberg, Germany. The gut epithelial barrier, which lines the inner surface of both small and large intestines, is comprised of a layer of cells that prevent the entry of harmful molecules, including foreign microorganisms and their toxins, into the bloodstream. Studies have shown that loss of intestinal barrier function and an imbalance of the gut’s microbial population are associated with the development — and seen as potential therapeutic approaches — for several autoimmune diseases. Those include SLE, rheumatoid arthritis, spondyloarthritis (which includes ankylosing spondylitis among other disorders), and both Crohn’s disease and ulcerative colitis (two forms of inflammatory bowel disease). Based on these studies, the main goal of the joint group will be to understand the interaction between enterocytes — cells of the gut epithelial barrier — and dendritic cells, a type of immune cell frequently involved in autoimmune disorders. Researchers will use several techniques, including conventional and high-throughput metagenomics (the analysis and sequencing of DNA from an environmental sample) generation of miniature 3D gut models known as organoids, and isolation of immune cells. Importantly, the team will establish a 3D model system of the intestine to assess the interaction between gut epithelial barrier cells and immune cells. The long-term goal of this project is to identify new biomarkers and therapeutic targets for treating intestinal barrier loss. According to BioMed X, this could help prevent the development and progression of autoimmune diseases. “We are excited to further extend our collaboration with Merck”, Christian Tidona, founder and managing director of BioMed X, said in a press release. “This is our first joint research group with Merck beyond the field of oncology and we are looking forward to working with Merck’s Translational Innovation Platform Immunology in Billerica near Boston,” he said. Merck KGaA, based in Germany, is known as EMD Serono in the U.S. and Canada. Iqra Mumal, MSc Iqra holds a MSc in Cellular and Molecular Medicine from the University of Ottawa in Ottawa, Canada. She also holds a BSc in Life Sciences from Queen’s University in Kingston, Canada. Currently, she is completing a PhD in Laboratory Medicine and Pathobiology from the University of Toronto in Toronto, Canada. Her research has ranged from across various disease areas including Alzheimer’s disease, myelodysplastic syndrome, bleeding disorders and rare pediatric brain tumors. 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/2020/01/15/biomed-x-merck-study-gut-barrier-autoimmune-diseases-lupus/?utm_source=LUP+NEws+E-mail+List&utm_campaign=4073cc5dde-RSS_WEEKLY_EMAIL_CAMPAIGN_US&utm_medium=email&utm_term=0_50dac6e56f-4073cc5dde-71887989
  5. JANUARY 17, 2020 JOANA CARVALHO, MSC Excessive production of type I interferon (IFN-I) — a molecule that mediates immune and inflammatory responses — in people with systemic lupus erythematosus (SLE) may be caused by small fragments of mitochondrial DNA (mtDNA) that are released upon damage, a study suggested. The study, “VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease,” was published in the journal Science. Mitochondria are the small compartments in cells that are responsible for producing cellular energy. When damaged, due to things like oxidative stress, for example, small bits of mtDNA may be released into the cytosol, the liquid-like substance that fills the interior of cells. Oxidative stress refers to the damage to cells caused by high levels of oxidant molecules, or reactive oxygen species. After reaching the cytosol, these small mtDNA fragments may activate certain immunostimulatory DNA sensors, inducing excessive production of IFN-I and other molecules known to play a key role in several autoimmune diseases, including SLE. Previous studies found that mtDNA fragments are released from small holes (pores) located in the outer membrane of damaged mitochondria. How these pores form, however, was not known. Using mouse embryonic cells, researchers at the National Heart Lung and Blood Institute and colleagues found that these pores form through a process called oligomerization in a protein known as voltage-dependent anion channel (VDAC). (Oligomerization is the process by which different subunits interact to form a more complex protein.) VDAC sits on the outer membrane of mitochondria, and controls the flow of molecules. Specifically, the team discovered that the interaction between mtDNA fragments and a set of amino acids (the building blocks of proteins) in one of the terminals of VDAC1 — one of several VDAC proteins — was responsible for the creation of these pores. Their work also showed that mitochondria with high levels of reactive oxygen species released mtDNA fragments into the cell’s cytosol through these small pores, leading to excessive production of IFN-I. They found that this process could also be induced under milder stressful conditions, including microbial infections, suggesting that environmental factors may lead to excess levels of IFN-I. “In a disease like lupus, there are many kinds of stressors that can trigger the disease or flares of the disease, such as ultraviolet light or excessive fatigue,” Mary K. Crow, MD, chair of the Department of Medicine at the Hospital for Special Surgery (HSS) and author of a perspective article about the study, said in a press release. Researchers also found evidence of increased VDAC oligomerization in spleen cells isolated from a mouse model of SLE, and in white blood cells taken from patients with the disease. When they treated SLE mice with VBIT-4, which blocks VDAC oligomerization, they found a lesser accumulation of mtDNA in the cytosol, lower activity of genes under the control of IFN-I, and a reduced production of autoantibodies. “Thus, inhibiting VDAC oligomerization is a potential therapeutic approach for diseases associated with mtDNA release,” the investigators wrote. But in her perspective article, Crow wrote: “Although inhibitors of the VDAC pore might be effective in reducing stimulatory mtDNA, the importance of the VDAC pore for transport of essential metabolites could complicate use of VDAC inhibitors as therapeutics for SLE or other disorders.” Still, she noted that medications that block the activity of IFN-I, like AstraZeneca’s investigative treatment anifrolumab, seem to hold promise in helping those with SLE manage their disease. Indeed, findings from the Phase 3 TULIP-2 (NCT02446899) trial showed that anifrolumab lowered disease activity, corticosteroid usage, and eased the severity of skin lesions in people with moderate-to-severe SLE. “There is progress in developing therapies to inhibit interferon’s impact on the immune system and improve outcomes for patients with lupus,” Crow said. Joana Carvalho, MSc Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns. 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/2020/01/17/excessive-ifn-i-levels-sle-flares-possibly-linked-to-mitochondria-damage-study/?utm_source=LUP+NEws+E-mail+List&utm_campaign=4073cc5dde-RSS_WEEKLY_EMAIL_CAMPAIGN_US&utm_medium=email&utm_term=0_50dac6e56f-4073cc5dde-71887989
  6. January 16, 2020 The Lupus Research Alliance has invested millions in research to get us to the point we’re at with potential new treatments for LN. We are proud to share what just ten of our funded scientists are doing right now to discover what causes lupus nephritis and how it can be better diagnosed, monitored and treated. With our largest grant, the Distinguished Innovator Award, Nir Hacohen at Broad Institute is studying which specific cells are responsible for injuring the kidneys of people with lupus. His aim is to provide new targets for treatments that prevent this damage and a way to predict which patients will respond to which treatments. Another Distinguished Innovator awardee, Shu Man Fu at University of Virginia, is looking at the protein C1q as a culprit in promoting kidney failure and determining if measuring the levels of this protein can help diagnose lupus nephritis and monitor response to treatment. Vicki Kelley at Harvard Medical School has discovered a master switch, a protein Ptprz, that turns on kidney inflammation and her funded study will determine if turning off this switch can protect against damage. Next step would be to develop drugs that can flip the switch. Janos Peti-Peterdi at University of Southern California invented a highly sensitive microscope to examine kidneys of animals with lupus in fine detail and with his LRA grant will use that technology to determine what goes wrong with the kidneys and how they can be repaired. LRA is supporting the work of Anne Davidson at The Feinstein Institute for Medical Research to illuminate how lupus leads to kidney damage and why the disease is more common in women than in men. Erika Boesen at University of Nebraska is studying if a newly discovered type of cell death called ferroptosis contributes to kidney damage by promoting the inflammation that characterizes lupus nephritis. At University of Michigan, Jason Knight is mapping out how turning off a protein called elastase could prevent kidney damage and other dangerous complications. Laurence Morel, University of Florida is testing in lupus models combinations of drugs like the approved diabetes treatment metformin that reduce sugar levels can slow or reverse kidney damage. Vipin Kumar at University of California San Diego is testing a novel hypothesis backed by his own preliminary data to explore a drug already used to fight tropical parasites as a potential oral medication to prevent and treat kidney damage in lupus. Jeremy Tilstra at University of Pittsburgh is figuring out how to exhaust T cells so they are too tired to attack the kidneys and other organs. With your help, we look forward to funding more studies in 2020 that can crack the underlying cause of lupus nephritis with the aim to prevent and reverse disease in the future. https://www.lupusresearch.org/lra-uncovering-what-causes-lupus-nephritis-to-improve-treatment/
  7. January 16, 2020 Up to half of people with lupus will have lupus nephritis – damage to the kidneys that affects the ability to clear the body of wastes and toxins. In 2020, we expect to see significant progress in new drug development for lupus and lupus nephritis in particular with submissions for FDA approval in progress and many opportunities to join studies exploring other potential treatments! Two companies – GSK and Aurinia Pharmaceuticals – expect to go to the U.S. Food and Drug Administration (FDA) for approval of their drugs to treat lupus nephritis based on positive Phase III trial results with Benlysta® (belimumab) and voclosporin respectively. Two new Phase III trials are starting up to test potential treatments – Gazyva® (obinutuzumab) and secukinumab. Two potential lupus nephritis treatments – Gazyva and itolizumab – are on an accelerated track for development thanks to special designations by the FDA. Plus two Phase III trials and several Phase 2 trials for lupus nephritis are already underway. https://www.lupusresearch.org/lra-shares-excitement-for-whats-ahead-in-lupus-nephritis/
  8. December 17, 2019 The Lupus Research Alliance is thrilled to share exciting news from GSK that Benlysta (belimumab) demonstrated positive clinical trial results in treating lupus nephritis (LN), a common complication of lupus causing inflammation of the kidneys that can result in end-stage kidney disease. Called BLISS-LN, this Phase 3 trial is the largest one ever conducted among patients with lupus nephritis and paves the way for a new treatment for this disease. Although belimumab is already approved by the U.S. FDA to treat systemic lupus erythematosus (SLE), it had not been tested in patients specifically for lupus nephritis and has not yet been approved for this use. The BLISS-LN trial is the last stage in clinical development before GSK submits its data with a formal request for the FDA to approve the drug as a new treatment for lupus nephritis. The company expects to file with the FDA in the first half of 2020. Kenneth M. Farber, President and CEO of the Lupus Research Alliance said: “We are very gratified that at long last additional treatment options may be emerging for lupus nephritis. Belimumab is the only drug specifically developed and approved for lupus in decades, and the fact that it has shown benefit, not only for generalized SLE, but also now for lupus nephritis, is great news. GSK has long been a terrific partner to the Lupus Research Alliance, and we extend our congratulations as well as appreciation to GSK, to the investigators who enrolled patients in the study, and especially to the people with lupus who generously participated.” As background, belimumab, like all drugs reviewed by the FDA, go through extensive clinical trials to test for safety and efficacy. Phase 1 studies test a drug’s safety in a small number of healthy people and establish dosing, and Phase 2 studies test the drug’s effectiveness in a patients and monitor safety. Phase 3 studies test the drug in a large group of patients with randomized, double-blinded trial designs. That means people are randomly selected to receive the drug being tested or placebo and, no one knows who received what until the end of the study. Phase 3 studies compare the new treatment plus standard of care (the treatment most accepted in medical practice) versus placebo plus standard of care. Companies submit filings of their data to the FDA for review after the Phase 3 trials are completed. “We encourage people with lupus and their families to visit our website LupusTrials.org and learn about clinical research. Talk to your doctor and see if there’s a study that’s right for you. Your participation is critical – we can’t deliver new treatments without your help,” ended Ken Farber. Read Announcement from GSK https://www.lupusresearch.org/new-phase-3-study-shows-positive-results-for-benlysta-in-lupus-nephritis/
  9. December 18, 2019 The Lupus Research Alliance (LRA) welcomes additional positive results published today in the New England Journal of Medicine online edition from AstraZeneca’s Phase 3 TULIP-2 trial studying the investigational biologic anifrolumab as a treatment for systemic lupus erythematosus (SLE or lupus). The new study provides further details showing that anifrolumab, which targets type I interferon, met its primary endpoint to significantly lessen disease activity. Of those treated with anifrolumab, 47.8 percent responded to treatment compared with 31.5 percent of those given a placebo. Kenneth M. Farber, President and CEO of the Lupus Research Alliance commented, “We are finally seeing the light at the end of the tunnel with this and other Phase 3 trials delivering the promise of much-needed new therapies for people with lupus. The LRA is particularly proud to see decades of work by our funded scientists on understanding the type I interferon pathway lead to the development of anifrolumab as a potential new treatment.” Anifrolumab an Outcome of Early Interferon Research Anifrolumab works by disrupting a group of proteins produced by the immune system called type I interferons that promote inflammation. Research has shown that 30-50 percent of adults and most children with lupus have high interferon levels. The Lupus Research Alliance has played a key role in unraveling the role of interferon in lupus over the past two decades. Principal investigator and author of the NEJM paper Professor Eric Morand of Monash University in Australia commented, “As an LRA-funded researcher I am both humbled and very proud to be involved in this landmark program, and so happy to see years of collective work on the IFN pathway by scientists all around the world formally validated in human SLE. It is a major validation of the scientific process and of translational research, as well as potentially a breakthrough new medicine for lupus. I hope the major learnings on trial endpoints from this program can help other programs advance towards approval.” “The Lupus Research Alliance and its legacy organizations have sponsored nearly two dozen studies on type I interferons, including work that identified a unique combination of genes that is switched on in the blood of lupus patients,” Mr. Farber said. “The LRA is particularly proud to see decades of work by our funded scientists on understanding the type I interferon pathway lead to the development of anifrolumab as a potential new treatment.” The Journal featured an accompanying editorial by long-time LRA Scientific Advisory Board member Dr. Jane Salmon, Hospital for Special Surgery and Weill Cornell Medicine, and LRA-funded investigator and reviewer Dr. Timothy Niewold, Colton Center for Autoimmunity, NYU School of Medicine. Anifrolumab Shows Promise for Reducing Disease Activity and Flares In TULIP-2, anifrolumab met its primary endpoint which is the most important result that is measured at the end of the study to see if the drug worked. Treatment with anifrolumab resulted in significant and meaningful reduction in disease activity in all organs with no new flares as measured by a standard tool called the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA). Of those treated with anifrolumab, 47.8% of patients responded to treatment compared with 31.5 who received placebo. The rate of flares was also somewhat lower among those treated with anifrolumab. The study also succeeded in meeting key secondary endpoints which measure other effects of the drug: 51.5% of those treated with anifrolumab reduced doses of the steroid prednisone versus 30.2% taking placebo. According to standard measurement tool CLASI, 49% of patients showed improvement in severity and degree of skin damage compared with 25.0% of those on placebo. No new information on safety was seen. Among patients on anifrolumab, 7.2% developed herpes zoster versus 1.1 percent of those given placebo. Less adverse events occurred in the anifrolumab group (8.3%) than the 17.0% of people in the placebo group. Also, more people given placebo discontinued the trial (7.1%) than the 2.8% on anifrolumab. One person in the anifrolumab group died from pneumonia. Click here for full background on Type I Interferon in lupus. https://www.lupusresearch.org/more-positive-results-on-anifrolumab-for-lupus-published-in-new-england-journal-of-medicine/
  10. January 6, 2020 New research published in Arthritis and Rheumatology shows that peripheral nervous system (PNS) disease is an important part of neuropsychiatric lupus with significant effects on quality of life. The peripheral nervous system is the network that sends signals between the brain and spinal cord (the central nervous system) with all the other parts of the body. Many of the scientists who participated in this study are part of the leadership of the LRA affiliate Lupus Therapeutics and its Lupus Clinical Trials Network (LuCIN). Conducted at research centers throughout the world, the study assessed 1,827 people with lupus every year over an average of 7.6 years for the frequency of 19 neuropsychiatric events, including seven types of PNS disease. The researchers also measured SLE disease activity, organ damage, and autoantibodies, as well as outcomes as reported by both patients and physicians. Nearly 8 percent of participants had PNS events. The most common PNS events included three types of neuropathy – a disorder that causes nerve damage. Of those with PNS events, 41.0 percent experienced peripheral neuropathy; 27.3 percent had mononeuropathy, and 24.2 percent had cranial neuropathy Peripheral neuropathy refers to the many conditions that involve damage to the peripheral nervous system. Mononeuropathy is a type of damage to a nerve outside the brain and spinal cord while cranial neuropathy refers to damage to nerves in the brain or brainstem People with periphereal neuropathy scored significantly lower than those who had no nerve damage on standard tools that measure physical and mental function. Most of the neuropathies resolved or improved over time. Study authors concluded: “PNS disease is an important component of total NPSLE and has a significant negative impact on health‐related quality of life. The outcome is favorable for most patients, but our findings indicate that several factors are associated with longer time to resolution.” https://www.lupusresearch.org/lupus-has-some-nerve-shows-large-international-study/
  11. January 7, 2020 2019 was a phenomenal, breakthrough year for lupus research on both the clinical development and basic science fronts. The Lupus Research Alliance (LRA) is incredibly proud that every new discovery leading to a brand new medicine for lupus had its origin in work funded by LRA years ago. The past 12 months delivered many exciting “firsts” for lupus — three positive Phase III clinical trials, Fast Track and Breakthrough Therapy designations from the U.S. Food and Drug Administration including one in lupus nephritis (a serious form of lupus affecting the kidneys), and the first treatment approved for pediatric lupus, among other developments. Watch this video to hear the highlights from LRA President & CEO Kenneth Farber while Chief Scientific Officer Dr. Teodora Staeva describes major break throughs in basic research science supported by the LRA. 2019 Was a Year of Many “Firsts” in Lupus Drug Development First Positive Phase 3 Lupus Results in 8 Years — Phase 3 TULIP-2 trial demonstrated the effectiveness of Astra Zeneca’s treatment anifrolumab in reducing lupus disease activity. The LRA has supported numerous studies identifying and unraveling the type I interferon pathway that anifrolumab targets. First Positive Phase 3 Data in Lupus Nephritis — Lupus nephritis, which affects the kidneys, is one of the most dangerous forms of lupus. A late stage trial (AURORA) conducted by Aurinia affirmed the safety and effectiveness of voclosporin. If approved by the FDA, this would be the first medicine specifically approved for this form of lupus. Because of the great need for a new treatment, the company received Fast Track designation from the U.S. FDA. First and Only Lupus Treatment Approved for Use in Children — Benlysta (belimumab) was approved by the U.S. FDA to treat children with lupus who are five years old or above. Pediatric lupus typically hits children harder than adults and comes with extra health issues since children are affected by the disease longer, impacting organ damage. First Breakthrough Therapy Designation for Gazyva Phase 2 Trials Show Effective in Treating Proliferative Lupus Nephritis, the Most Severe Form of Lupus Nephritis – The Phase 2 NOBILITY trial, conducted by Genentech, demonstrated the effectiveness of Gazyva® (obinutuzumab) in combination with mycophenyolate mofetil in treating proliferative lupus nephritis, the most severe form of lupus nephritis that affects the kidneys. The FDA recently granted obinutuzumab Breakthrough Therapy Designation which aims to speed up the development and review of drugs which may demonstrate substantial improvement over available therapy. First Promising, Phase 2 Trial Demonstrates Effectiveness of a Second Interferon Inhibitor — Positive Phase 2 trial results for Biogen’s type I interferon inhibitor BIIB059 demonstrated that it met clinical endpoints in patients with cutaneous lupus (skin related lupus) as well as in systemic lupus. Second Potential Lupus Nephritis Drug Fast Tracked by FDA — A new drug in development by Equillium for lupus nephritis, itolizumab, was just granted Fast Track Designation by the U.S. FDA. The LRA was involved in the design of the clinical trial through its affiliate Lupus Therapeutics and enlisted its patient advisory board to provide the patient perspective on clinical trial education materials. 2019 Discoveries that May Advance New Treatments and a Cure Evidence that Diet May Offer a Treatment — Pieces of bacteria that escape from the intestines may trigger lupus and associated disease flares in some patients, according to a new study led by LRA-grantee Dr. Gregg Silverman. These findings may allow disease treatment with probiotics or diets that alter the mix of bacterial species in the intestines. In addition, a study partly funded by an LRA grant to Dr. Martin Kriegel showed how a diet of high fiber may suppress harmful bacteria and enrich good bacteria in the gut microbiome. Novel Research on Biomarkers is Emerging — Novel research on biomarkers or molecules in the urine, skin and blood in lupus could minimize invasive kidney biopsies. This groundbreaking research is emerging from the Accelerating Medicines Partnership, a RA/SLE initiative involving the NIH, FNIH, industry and LRA. New Targets for Drug Development — Researchers partly funded by the LRA have found possible new targets for drugs to treat lupus after discovering that stopping a molecule BRISC from connecting to another molecule SHMT2 can reduce inflammation. Back to the Future with B Cells — Depleting the number of harmful B cells with a novel immunotherapy that employs modified T cells called CAR T cells may offer an effective strategy to treat lupus, according to results of a study led by LRA-grantee Dr. Marko Radic. These findings offer a renewed optimism for the elimination of B cells to provide a therapeutic option in lupus and pave the way for clinical research to test this new approach. Why the Immune System Goes on the Attack — A new study partly funded by the LRA may help explain how the immune system attacks patients’ DNA in lupus. Together with the laboratory of Dr. David Raulet, Dr. Joshua Woodward and his colleagues discovered a protein door in cells that allows messenger molecules that may promote these attacks to spread. The Lupus Research Alliance is the world’s leading private funder of lupus research, created to improve treatments for lupus while advancing toward a cure. We believe that scientific research is the most powerful way we can improve the lives of people living with lupus, today and over the long term. By pushing the limits of scientific exploration and shepherding new discoveries into potential treatments, we aim to seize every opportunity that will help ease the burden of people living with this difficult disease. As part of the organization’s commitment to advance lupus research and find effective and safer treatments for people living with lupus, the Lupus Research Alliance established Lupus Therapeutics. As the administrative and fiscal entity of the only Lupus Clinical Investigators Network (LuCIN), Lupus Therapeutics manages the Alliance’s clinical trial programs. LuCIN is comprised of more than 200 clinician-scientists at 57 academic medical centers and more than 20,000 active lupus patients. Supported by the Lupus Research Alliance and Lupus Therapeutics, LuCIN scientists work collaboratively to identify potentially transformative treatments and conduct related clinical trials. The LRA celebrates this year’s achievements and looks forward to continued positive developments in 2020. https://www.lupusresearch.org/lra-celebrates-major-research-breakthroughs-in-2019/
  12. JANUARY 8, 2020 Using glucocorticoids to treat inflammation in systemic lupus erythematosus (SLE) was associated with organ damage in patients without active disease, a large study found. These findings draw attention to the possible harmful effects of glucocorticoids — a type of corticosteroid hormone — and indicate that these therapies should be avoided by people with SLE when possible, the investigators said. The study, “Factors associated with damage accrual in patients with systemic lupus erythematosus with no clinical or serological disease activity: a multicentre cohort study,” was published in the journal The Lancet Rheumatology. Glucocorticoids such as prednisone are prescribed for patients with active disease due to their immunosuppressive and anti-inflammatory properties. While glucocorticoids work quickly to reduce inflammation, extended use has been associated with organ damage. This makes it difficult to determine if such damage seen in people with SLE is caused by active disease or the use of these treatments. To better understand the source of organ damage in SLE patients on glucocorticoids, researchers from 13 centers collaborated to determine if these medications also are associated with organ damage in SLE patients without active disease. The 13 centers were located in Australia, Indonesia, Japan, Malaysia, the Philippines, Singapore, Taiwan, and Thailand. Adults with SLE were identified from the Asia-Pacific Lupus Collaboration — a large, international partnership of lupus clinicians and researchers. Among the 1,707 patients recruited, 1,591 (93.2%) were women. Participants’ median age was 29 years and median SLE disease duration was 8 years. Clinical information was collected at the study’s start. Follow-up visits were conducted at least once every six months for a median follow-up period of 2.2 years. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), a tool based on 24 factors of disease activity in nine organ systems. A score of 0 in SLEDAI-2K represented no disease activity. Clinicians collected information on prednisolone use at each visit. A Physician Global Assessment (PGA) was determined with a scale from 0 — for no disease activity — to 3, for maximally active disease. Organ damage was assessed using the Systemic Lupus International Collaborating Clinics Damage Index (SDI) at a minimum of one follow-up visit. The results showed that 709 patients (41.5%) had irreversible organ damage at the start of the study (baseline). Over the study period, increased organ damage was reported in 255 participants (14.9%). The factors linked to organ damage included previous damage, SLEDAI-2K score (disease activity over time), the mean PGA score, current smoking, and both age and disease duration at study enrollment. Interestingly, people of Asian ethnicity showed protection against accumulation with organ damage compared with non-Asians. However, organ damage was significantly associated with use of prednisolone, and both the mean dose and cumulative amount taken. During the study’s course, 157 patients (9.2%) showed no signs of disease activity. Yet, irreversible organ damage was reported in 21 (13.4%) of these participants. This was a similar rate compared with the overall study group, the researchers noted. These findings support the link between glucocorticoids and damage accumulation in SLE, with a 14% increase in the risk of organ damage for each 1 mg increase in the mean daily dose of prednisolone, the scientists said. While most patients were taking prednisolone during the study period, 302 (17.7%) participants had no exposure to oral glucocorticoids. Of these, 108 (35.8%) had organ damage before the study, and 31 (10.3%) developed such damage over the study period. This damage was linked to age, disease duration, and PGA score. “These findings add evidence in support of the harmful effects of glucocorticoids in SLE,” the team said. “In the absence of more effective and safer treatments for SLE, glucocorticoid use remains essential in patients with significant disease activity. However, these findings suggest that unnecessary use of glucocorticoids should be avoided in the management of the disease where possible,” the investigators added. 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. https://lupusnewstoday.com/2020/01/08/glucocorticoids-use-linked-organ-damage-in-sle/
  13. The U.S. Food and Drug Administration (FDA) has granted fast track designation to itolizumab as a potential therapy for lupus nephritis, a common and serious complication of systemic lupus erythematosus (SLE) that can lead to kidney failure. This designation is given to compounds that show considerable potential in treating serious conditions for which available treatments fall short. It is meant to expedite clinical development, regulatory review, and entry into the market upon approval. “While existing immunosuppressive therapies have improved five-year survival for lupus nephritis patients, more than half don’t have an adequate response to treatment, and many progress to end-stage [kidney] disease requiring dialysis or transplant,” Kenneth Kalunian, MD, the lead principal investigator of the ongoing EQUALISE Phase 1b study (NCT04128579) of itolizumab, said in a press release. “There are no FDA approved therapies for lupus nephritis; however, the evaluation of itolizumab provides optimism that we may alleviate this significant unmet medical need for lupus nephritis patients,” he added. Equillium’s itolizumab (EQ001) is a monoclonal antibody that selectively targets the CD6 receptor on the surface of immune T-cells. While T-cells are essential to fight infections and cancer, when abnormally activated, they can lead to inflammatory and autoimmune diseases, such as SLE. The experimental treatment works by blocking the binding between CD6 and one of its ligands — ALCAM — which is found at higher levels in the urine of people with active lupus nephritis. By suppressing their interaction, itolizumab is thought to prevent immune responses mediated by T-cells, reduce kidney inflammation, and prevent further damage. Preclinical data presented last month at the 2019 American College of Rheumatology and the Association of Rheumatology Professionals Annual Meeting supported the treatment’s potential. In mouse models of SLE and lupus nephritis, itolizumab was found to ease kidney disease, while also decreasing the migration of T-cells to inflamed sites and increasing levels of interleukin (IL)-10, an anti-inflammatory molecule. Data also showed that, compared to healthy controls, the number of CD6- and ALCAM-positive cells were increased in kidneys of people with lupus nephritis and were associated with disease activity. Urinary levels of ALCAM were significantly higher in active lupus nephritis — showing potential to be used to discriminate the active disease from inactive SLE or active SLE without lupus nephritis. According to the company, itolizumab also suppressed T-cell development and proliferation, as well as inflammatory responses and molecules such as interferon-gamma, TNF-alpha, IL-6, and IL-17. “Receiving Fast Track designation recognizes the promising therapeutic potential of itolizumab for the treatment for lupus nephritis, particularly given its ability to modulate both the activity and trafficking of effector T cells,” said Krishna Polu, MD, Equillium’s chief medical officer. The EQUALISE study, initiated in September 2019, is evaluating itolizumab’s safety, pharmacokinetics (uptake, distribution, and elimination in the body), pharmacodynamics (the therapy’s effects on the body), and early effectiveness in up to 56 SLE patients with and without active lupus nephritis. EQUALISE includes two groups of participants and treatment regimens. Type A consists of SLE patients to be treated with itolizumab for four weeks, while type B comprises people with active lupus nephritis randomly assigned to receive either itolizumab or a placebo for 12 weeks. Both itolizumab or a placebo will be given subcutaneously (under the skin) every two weeks. Importantly, the EQUALISE trial is also measuring the levels of urinary biomarkers, including ALCAM and CD6, to assess their potential to predict disease progression and treatment response. “y monitoring levels of the CD6-ALCAM pathway in the urine in the EQUALISE trial we will be assessing the opportunity to take a personalized medicine approach to identify patients where the CD6-ALCAM pathway may be a dominant driver of the disease,” Polu said. Marta Figueiredo Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development. 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/2019/12/18/itolizumab-granted-fda-fast-track-designation-as-lupus-nephritis-treatment/?utm_source=LUP+NEws+E-mail+List&utm_campaign=e9b1eeb097-RSS_WEEKLY_EMAIL_CAMPAIGN_US&utm_medium=email&utm_term=0_50dac6e56f-e9b1eeb097-71887989
  14. Fatigue has a major impact on quality of life in people with systemic lupus erythematosus, and measuring it using a patient-reported tool may prove useful in clinical trials, new research shows. The findings were presented at the recent 2019 American College of Rheumatology/Association for Rheumatology Professionals Annual Meeting in a session, titled “Assessment of Fatigue in Adults with Moderate to Severe Systemic Lupus Erythematosus (SLE): A Qualitative Study to Explore What Patients Feel Should Be Measured in Clinical Trials.” Fatigue has a well-known impact on people with SLE, but it has not been measured using self-reported feedback from patients, which poses a challenge for assessing the symptom in clinical studies. To address this gap, a team at Evidera, Idorsia Pharmaceuticals, Stanford University, and the Lupus Foundation of America studied how people with SLE view their fatigue and whether it could be assessed with the FACIT-F (Functional Assessment of Chronic Illness Therapy-Fatigue) questionnaire, which has been used in medical research. The study involved 28 adults with moderate to severe SLE (27 women, mean age of 45.5 years). The researchers first conducted focus groups, then 13 one-on-one interviews. Both rounds focused on the role of SLE-related fatigue in participants’ daily lives and their opinions on FACIT-F. Twenty-three patients (82%) had moderate disease activity and five (18%) had severe SLE. All were being treated for SLE during the study. Results showed that 23 participants (82%) identified fatigue as one of the top three most impactful symptoms of SLE. They said that fatigue had a profound impact on daily life, “including the ability to perform chores, work-related activities, maintain personal hygiene, exercise, and participate in hobbies,” the researchers wrote. FACIT-F was generally viewed as a satisfactory tool by the participants, who said that they were able to understand the questionnaire, and it was relevant to their experience of fatigue. Overall, the study confirmed the significant impact of fatigue in the life of people with SLE and showed that it can be measured using FACIT-F. The tool is being used by Idorsia in its CARE Phase 2b clinical trial (NCT03742037) of the potential oral therapy cenerimod. This international study is still enrolling adults with SLE; more information about contacts and locations is available here. Marisa Wexler, MS Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club. 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. Source: https://lupusnewstoday.com/2019/12/13/study-supports-patient-reported-tool-measuring-fatigue-impact-daily-activities/?utm_source=LUP+NEws+E-mail+List&utm_campaign=e9b1eeb097-RSS_WEEKLY_EMAIL_CAMPAIGN_US&utm_medium=email&utm_term=0_50dac6e56f-e9b1eeb097-71887989
  15. January 7, 2020 2019 was a phenomenal, breakthrough year for lupus research on both the clinical development and basic science fronts. The Lupus Research Alliance (LRA) is incredibly proud that every new discovery leading to a brand new medicine for lupus had its origin in work funded by LRA years ago. The past 12 months delivered many exciting “firsts” for lupus — three positive Phase III clinical trials, Fast Track and Breakthrough Therapy designations from the U.S. Food and Drug Administration including one in lupus nephritis (a serious form of lupus affecting the kidneys), and the first treatment approved for pediatric lupus, among other developments. Watch this video to hear the highlights from LRA President & CEO Kenneth Farber while Chief Scientific Officer Dr. Teodora Staeva describes major break throughs in basic research science supported by the LRA. 2019 Was a Year of Many “Firsts” in Lupus Drug Development First Positive Phase 3 Lupus Results in 8 Years — Phase 3 TULIP-2 trial demonstrated the effectiveness of Astra Zeneca’s treatment anifrolumab in reducing lupus disease activity. The LRA has supported numerous studies identifying and unraveling the type I interferon pathway that anifrolumab targets. First Positive Phase 3 Data in Lupus Nephritis — Lupus nephritis, which affects the kidneys, is one of the most dangerous forms of lupus. A late stage trial (AURORA) conducted by Aurinia affirmed the safety and effectiveness of voclosporin. If approved by the FDA, this would be the first medicine specifically approved for this form of lupus. Because of the great need for a new treatment, the company received Fast Track designation from the U.S. FDA. First and Only Lupus Treatment Approved for Use in Children — Benlysta (belimumab) was approved by the U.S. FDA to treat children with lupus who are five years old or above. Pediatric lupus typically hits children harder than adults and comes with extra health issues since children are affected by the disease longer, impacting organ damage. First Breakthrough Therapy Designation for Gazyva Phase 2 Trials Show Effective in Treating Proliferative Lupus Nephritis, the Most Severe Form of Lupus Nephritis – The Phase 2 NOBILITY trial, conducted by Genentech, demonstrated the effectiveness of Gazyva® (obinutuzumab) in combination with mycophenyolate mofetil in treating proliferative lupus nephritis, the most severe form of lupus nephritis that affects the kidneys. The FDA recently granted obinutuzumab Breakthrough Therapy Designation which aims to speed up the development and review of drugs which may demonstrate substantial improvement over available therapy. First Promising, Phase 2 Trial Demonstrates Effectiveness of a Second Interferon Inhibitor — Positive Phase 2 trial results for Biogen’s type I interferon inhibitor BIIB059 demonstrated that it met clinical endpoints in patients with cutaneous lupus (skin related lupus) as well as in systemic lupus. Second Potential Lupus Nephritis Drug Fast Tracked by FDA — A new drug in development by Equillium for lupus nephritis, itolizumab, was just granted Fast Track Designation by the U.S. FDA. The LRA was involved in the design of the clinical trial through its affiliate Lupus Therapeutics and enlisted its patient advisory board to provide the patient perspective on clinical trial education materials. 2019 Discoveries that May Advance New Treatments and a Cure Evidence that Diet May Offer a Treatment — Pieces of bacteria that escape from the intestines may trigger lupus and associated disease flares in some patients, according to a new study led by LRA-grantee Dr. Gregg Silverman. These findings may allow disease treatment with probiotics or diets that alter the mix of bacterial species in the intestines. In addition, a study partly funded by an LRA grant to Dr. Martin Kriegel showed how a diet of high fiber may suppress harmful bacteria and enrich good bacteria in the gut microbiome. Novel Research on Biomarkers is Emerging — Novel research on biomarkers or molecules in the urine, skin and blood in lupus could minimize invasive kidney biopsies. This groundbreaking research is emerging from the Accelerating Medicines Partnership, a RA/SLE initiative involving the NIH, FNIH, industry and LRA. New Targets for Drug Development — Researchers partly funded by the LRA have found possible new targets for drugs to treat lupus after discovering that stopping a molecule BRISC from connecting to another molecule SHMT2 can reduce inflammation. Back to the Future with B Cells — Depleting the number of harmful B cells with a novel immunotherapy that employs modified T cells called CAR T cells may offer an effective strategy to treat lupus, according to results of a study led by LRA-grantee Dr. Marko Radic. These findings offer a renewed optimism for the elimination of B cells to provide a therapeutic option in lupus and pave the way for clinical research to test this new approach. Why the Immune System Goes on the Attack — A new study partly funded by the LRA may help explain how the immune system attacks patients’ DNA in lupus. Together with the laboratory of Dr. David Raulet, Dr. Joshua Woodward and his colleagues discovered a protein door in cells that allows messenger molecules that may promote these attacks to spread. The Lupus Research Alliance is the world’s leading private funder of lupus research, created to improve treatments for lupus while advancing toward a cure. We believe that scientific research is the most powerful way we can improve the lives of people living with lupus, today and over the long term. By pushing the limits of scientific exploration and shepherding new discoveries into potential treatments, we aim to seize every opportunity that will help ease the burden of people living with this difficult disease. As part of the organization’s commitment to advance lupus research and find effective and safer treatments for people living with lupus, the Lupus Research Alliance established Lupus Therapeutics. As the administrative and fiscal entity of the only Lupus Clinical Investigators Network (LuCIN), Lupus Therapeutics manages the Alliance’s clinical trial programs. LuCIN is comprised of more than 200 clinician-scientists at 57 academic medical centers and more than 20,000 active lupus patients. Supported by the Lupus Research Alliance and Lupus Therapeutics, LuCIN scientists work collaboratively to identify potentially transformative treatments and conduct related clinical trials. The LRA celebrates this year’s achievements and looks forward to continued positive developments in 2020. https://www.lupusresearch.org/lra-celebrates-major-research-breakthroughs-in-2019/
  16. 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
  17. 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
  18. I'm a Doctor With Chronic Illness. Here Are 12 Things I Wish People Knew. Amy Stenehjem, M.D. February 6, 2017 I’ve written this article to help educate those who want to learn about chronic illness. It is written from my perspective, that of a doctor who treated patients with chronic illness for many years, and who spent five years of my life homebound due to chronic illness. I want to spread awareness so that friends, family, employers, coworkers, and health care professionals can better understand chronic illness. My hope is that an increase in awareness will help strengthen relationships, reduce misunderstandings, and improve support systems for those with chronic illness. About Chronic Illness Chronic illness is a disease, condition, or injury that can last years or a lifetime and is typically not curable, though in some cases it may go into remission. It can vary in its severity, with some people able to work and live active or seemingly “normal” lives; while others are very sick and may even be homebound. Many people with chronic illness have an invisible chronic illness. The severity of their symptoms is not clearly noticeable, which may lead to a lack of understanding and support from doctors, family, friends, and coworkers. 1. Nobody wants to feel sick. In all my years as a doctor treating patients with chronic illness, I never saw a patient who enjoyed feeling ill. I saw the opposite, patients who were once very active, desperately trying to find answers and treatment for their overwhelming symptoms. 2. Many doctors don’t understand chronic illness. For years, doctors were under the misperception that some chronic illnesses were caused by depression or anxiety and the only treatment available for these patients was psychiatric care. Despite medical evidence disproving this perception, some doctors are “set in their ways” and do not truly understand chronic illness or how to appropriately address it. Therefore, patients often have to spend precious time searching for a doctor who understands their illness and provides appropriate treatment options while their symptoms potentially worsen. 3. Being unable to work is not a vacation. Those who are not able to work due to chronic illness are not “on vacation.” They are instead, struggling every day to do simple tasks: getting out of bed, getting dressed, making a meal, bathing, etc. They are often homebound, too sick to leave their homes except for doctor appointments. Have you ever been stuck indoors for a couple of days due to bad weather or a temporary health issue? Remember feeling annoyed with the inability to leave your home and be active? Now imagine not being able to leave your home for weeks or months at a time. Frustrating, right? 4. Chronic illness can trigger many emotions. Chronic illness itself can change the biochemical makeup of the mood control center in the brain. In addition, frustrations such as the following can affect a person’s mood and lead to depression and/or anxiety: the wait/search for a diagnosis inability to work and feel productive change in family dynamics loss of social interactions and isolation financial stress the struggle to deal with symptoms and perform simple daily tasks Those with chronic illness often feel a great loss. It is not unusual to experience some or all of the stages of grief (i.e. denial, anger, bargaining, depression, acceptance). They grieve for the life they once lived. They grieve for the life they must endure now. They grieve for the life they dreamed of having. Many people with chronic illness also feel very isolated. Even though they crave social interactions, their symptoms may make it very difficult and at times impossible to talk on the phone or type an email or Facebook post. 5. The symptoms of chronic illness are very complex. The symptoms experienced by those with chronic illness vary depending on the illness; however, many people experience some or all of the following symptoms: extreme fatigue, pain, headaches, brain fog, nausea, and/or dizziness. It is not unusual for the symptoms of chronic illness to wax and wane over time (sometimes even from hour to hour), so planning activities ahead of time can be very difficult. A “good day” for those with chronic illness would likely be considered a sick day for most others. 6. Chronic illness fatigue is much more than being tired. Fatigue is a common symptom in chronic illness and in many cases it is severe, often debilitating. It can be easily triggered by simple daily activities or by more elaborate events such as holidays. Those with chronic illness will often have to “pay the price” for engaging in an activity and then require days, weeks, or even months of recovery. Those with chronic illness may need to rest often and may have to cancel events last minute. This does not mean they are lazy or trying to avoid activities. Once fatigue kicks in, there is no other option other than to rest. It’s as if the body “hits a wall” and can’t go further, no matter what. To better understand the fatigue and limited energy of a person with chronic illness, read this helpful article about the spoon theory. Have you ever been stuck in bed for a few days from a really bad infection, surgery, or hospitalization? Think back to how that felt. You could barely get out of bed and simple tasks were exhausting. Now consider feeling that way every day, all day, for months or years? 7. Pain is a common symptom in those with chronic illness. Those with chronic illness often experience severe pain, including headaches, joint pain, muscle pain, nerve pain, back pain, and/or neck pain. 8. Brain fog is extremely frustrating. Brain fog is frustrating because it is a difficult symptom to describe so that others understand its impact. Brain fog is a cognitive dysfunction common in chronic illness, which can include issues with word finding, concentration, and recall. Those with brain fog often know what they want to say, but can’t find the thoughts or words to communicate effectively. 9. There is a greater risk of dangerous infections. The immune system in those with chronic illness may be overactive and instead of attacking infections the chronic illness immune system wastes time and energy fighting the body’s own organs, joints, nerves, and/or muscles. Many people with chronic illness are on medicines to suppress their overactive immune systems and consequently, need to avoid being around sick people. A minor cold in a healthy person could progress to a dangerous infection in someone with chronic illness. 10. Certain foods can aggravate symptoms. Certain foods may aggravate the symptoms of those with chronic illness. Common culprits are gluten, dairy, sugar, soy, yeast, alcohol, and processed foods. These trigger foods increase inflammation which can cause a significant increase in symptoms which may last for hours or days (sometimes weeks). Because so many of these trigger foods are in our diet, it is often difficult to pinpoint which foods aggravate symptoms and staying away from favorite foods can be a challenge. 11. Sensitivity to smells is common. Certain smells including perfumes, colognes, cleaning agents, and smoke can trigger headaches, brain fog, nausea, and other symptoms in those with chronic illness. Also, some of the medicines used to treat chronic illnesses are low-dose versions of chemotherapy drugs. The sensitivity is similar to that seen in those who are pregnant or on chemotherapy and have a sensitivity to smells. 12. It takes a lot of effort to manage chronic illness. Those with chronic illness have to be very regimented to make sure they get adequate rest, avoid trigger foods, take medications at the correct times, and avoid flares. It is understandable that sometimes they just want to feel “normal” and eat some pizza or stay up late, even if they know they will “pay for it later.” *** Despite struggling with grief, isolation, and often debilitating symptoms, those with chronic illness (and their caregivers) warrior on. They fight daily to be able to understand their bodies and to do things others take for granted. They are often surrounded by a society that does not understand their challenges, and therefore, is unable to provide adequate support. You can make a big difference in the lives of those with chronic illness by learning more about their symptoms and approaching them with compassion and support. Gaining an understanding of chronic illness will help make these conditions less “invisible.” This is why it is so important you are taking the time to read this article. Thank you! This story was originally published on Mastering Health & Happiness. We want to hear your story. Become a Mighty contributor here. Lead photo by Thinkstock Images Amy Stenehjem, M.D. • Follow Dr. Stenehjem works as a Health Consultant using her unique perspective of being a physician who was previously home-bound due to illness. She uses this insight to help her clients, from all over the United States, navigate their symptoms, diagnoses, and healthcare systems to find the answers they need to transform their health. Dr. Stenehjem works with clients experiencing any level of illness, from those just starting to notice a minor change in their health, to those who are home-bound. You can learn more about her work by visiting her website: masteringhealthhappiness.com amy-stenehjem-m-d https://themighty.com/2017/02/doctor-with-chronic-illness-things-to-know/
  19. Omega-3 Fatty Acids For the New Year! Posted by Kathleen Hoffman on Dec 27, 2019 Sav I’ve been eating a load of holiday foods and thinking that I’m going to need to make some dietary adjustments. Like me, you may have read or heard in the news that clinical trials looking at omega-3 fatty acids (omega-3 acid ethyl esters – O3AEE) did NOT significantly reduce major cardiovascular events. In fact, the news may have said that two recent clinical trials had failed. Sometimes, the news media doesn’t take a close enough look at research results! An article reviewing a couple of recent clinical trial results points out that the news media might have got it wrong. The VITAL Clinical Trial The first clinical trial that was reviewed, called VITAL, for Vitamin D and Omega-3 Trial, compared four groups of people (totaling 25,000 participants). The first group took one gram of O3AEE per day, the second group took 2000 IU of vitamin D3 per day, the third group took both O3AEE and Vitamin D3 per day and the fourth group took placebos for five years. When there was a comparison of the four groups after five years, there was no difference overall (that is composite) incidence of cancers or major cardiovascular events. BUT, and this is a major BUT, these are not the only results. There were actually a number of significant results: “28% reduced risk for heart attacks, 50% reduced risk for fatal heart attacks, and 17% reduced risk for total coronary heart disease events,” 1 according to the review. In addition, people who didn’t eat fish or whose fish intake was low (less than 1.5 servings per week) had a significant 19% reduction in overall incidence of major cardiovascular events. Moreover, “For African Americans, there was a significant 77% reduction in heart attacks in the O3AEE group, a 49% reduction in the need for coronary revascularization, and a 53% reduction in total coronary heart disease.”1 The ASCEND Clinical Trial A second study, conducted in the UK, looked at over 15,000 people who had diabetes and no cardiovascular disease diagnosis. Half took the same dosage of O3AEE and the other half (placebo) took a capsule containing olive oil. The news media again just reported the overall endpoint, which was not significant for “a composite of risk for nonfatal MI, nonfatal stroke, transient ischemic attacks, and “vascular death” (including fatal CHD, fatal stroke, and death from other “vascular” causes, in other words, CVD death).” Yet they failed to report one important finding: cardiovascular disease death was reduced by 19%.1 Low Intake of Omega-3 Fatty Acids Image by cattalin from Pixabay Unfortunately, intake of omega-3 fatty acids is low in the US, Australia, Canada and much of the European Union. Omega-3 fatty acids are found in oily fish like salmon, herring, anchovies, sardines, and rainbow trout. The authors of this review recommend that people eat at “least one to two fish/seafood servings per week, which is consistent with current dietary guidelines. Following this recommendation would improve omega-3 intake and status in most individuals…”1 However, a final clinical trial discussed in this review article seemed to support doing more than just trying to eat oily fish. The REDUCE-IT Clinical Trial A different version of omega-3 “icosapent ethyl (IPE; brand name Vascepa”) was used in this clinical trial. This study compared over 8000 people, half who were taking statins while the other half took statins with omega-3 (IPE version). In this study, the omega-3 fatty acid dosage was upped to 4 grams per day. The results were powerful: people taking both the omega-3 fatty acid and the statin had significantly fewer (by 25%) cardiovascular events, than those taking the statins alone. In addition to this overall response, the study also found significant reductions in: “CV death, heart attack, or stroke in the secondary prevention population: 28% (P < .001) CV death or nonfatal heart attack: 26% (P < .001) Fatal or nonfatal heart attack: 31% (P < .001) Urgent or emergent revascularization: 35% (P < .001) CV death: 20% (P < .03) Hospitalization or unstable angina: 32% (P < .002) Fatal or nonfatal stroke: 28% (P < .01) Total mortality, nonfatal heart attack, or nonfatal stroke: 23% (P < .001)”1 The results of this clinical trial, with a higher dosage of omega-3 fatty acids, are impressive. The authors of the review voiced concern that using only the dietary guideline “would likely not be sufficient to reach an intake of 1 g/d of omega-3 fatty acids, a level that provides significant CV benefit for many patients.”1 New Year’s Resolution So, even though you may have heard in the news that omega-3 fatty acid supplements are not worth it and that fish oil Image by Gerd Altmann from Pixabay supplements don’t work, think again. I have. I haven’t been taking my fish oil supplements. And I haven’t been able to eat that much fish every week. My New Year’s resolution? I’m going back on those fish oil pills. Maybe you would like to join me and increase your intake of omega-3 fatty acids. Consider taking an omega-3 fatty acid supplement for your heart’s sake! Kris-Etherton PM, Richter CK, Bowen KJ, et al. Recent Clinical Trials Shed New Light on the Cardiovascular Benefits of Omega-3 Fatty Acids. Methodist DeBakey Cardiovasc J. 2019;15(3):171-8. Feature Image by Elias Shariff Falla Mardini from Pixabay https://medivizor.com/blog/2019/12/27/omega-3-fatty-acids-benefits/
  20. Uric Acid, Gout and the Heart Posted by Kathleen Hoffman on Dec 16, 2019 S You may think of Henry VIII when you think of gout. Called the disease of kings, many associate it with excess. Gout is actually a common disease. Over three million people in the US diagnosed with gout every year. Gout is a builds up of uric acid in tissues, especially in the joints. Uric acid is a byproduct the digestion of purines, a natural substance found in steak, seafood, alcohol (especially beer) and in drinks sweetened with fructose. Usually the body eliminates uric acid through the kidneys but if the kidneys are overwhelmed or unable to process all the uric acid, it builds up in the body. The first joint of the big toe may be where you first experience the pain, redness and burning of gout. Other joints may become involved. However, a recent case study reported in the Annals of Internal Medicine describes uric acid crystals in the heart muscle of a man with uncontrolled gout. The crystals were found in the cells (cardiomyocytes) of the heart muscle and caused myocarditis, an inflammation of the heart muscle. Myocarditis can cause arrhythmias, fluid retention and can lead to heart failure if it is severe and untreated. Risk factors of gout include diet, obesity and a family history. Men are affected more than women but, after menopause, women and men have the same risk of developing gout. Read about gout, uric acid and kidney stones here. Below we share an infographic from the Cleveland Clinic, “Surprising Facts about Gout.” https://medivizor.com/blog/2019/12/16/uric-acid-gout-heart/
  21. Music Can Help: Ending the Year with Music Posted by Kathleen Hoffman on Dec 30, 2019 in Blog | 0 comments A review of studies on the effects of music for patients undergoing urological procedures found that music helped to reduce pain and anxiety. For the last few years I have shared music that readers have found healing or helpful for coping during times of stress and anxiety. Today’s post continues the tradition as we come to the end of 2019. The Bach Cello Suite Number 1 in G Major Gabriel’s Oboe Somewhere over the Rainbow – Israel “IZ” Kamakawiwoʻole Mononoke Hime – ANÚNA Kind and Generous – Natalie Merchant We wish you a happy, healthy and joyous 2020! https://medivizor.com/blog/2019/12/30/music-can-help/
  22. Medical cannabis startup finds way to get full weed benefits, without the smoke Company says it uses process that preserves all properties from the plant that are otherwise lost in extraction By SHOSHANNA SOLOMON Illustrative image of someone smoking cannabis (Tunatura; iStock by Getty Images) Smoking the cannabis leaf, users get the full spectrum of its properties — the flavor and the variety of cannabinoids that are present in the weed. Also, when smoking, the impact goes straight to the brain. But when extracting the components of the weed to make cannabis-based products including oils, creams, food and drinks, some of these properties are lost, through the commonly used alcohol or CO₂-based extraction processes. Medical cannabis startup Curo seeks to undo this loss. The Omer, Israel-based firm has developed a new method, using an algorithmic extraction process that manipulates temperature, that is able to extract all the cannabinoids, terpenes (a large class of organic compounds), and water-based materials that are in the plant. These provide the full range of properties, exactly like when the weed is smoked. Prof. Zvi Bentwich, left, and Meir Alboher of Curo, a medical cannabis startup (Itay Barnea) “Our novel extraction and exploitation method makes optimal use of the plant,” said Prof. Zvi Bentwich, the co-founder and chairman of Curo, in an interview. “We are able to take all the ingredients of what you get while smoking, all, and create a product that can be ingested in a pill or as a strip under the tongue. Because of the new extraction method, the elements that are active in the weed get absorbed straight into the brain, without going via the digestive system. This gives the patients the full equivalent of smoking,” but without the smoke. The new formulation, he said, “better reflects the combined effects of the weed,” and that is what has “huge potential.” The method enables physicians to decide whether to utilize weed extract with the tetrahydrocannabinol (THC) component, which gives users the “high,” or without. In many medical indications some degree of THC is required. Bentwich worked on the project with Dr. Joseph Maloul, a mathematician who has worked for many years in the field of cosmetics, specializing in the extraction of beneficial properties from plants. Samples of the cannabis product strips created by startup Curo (Courtesy) Bentwich was the first physician who dealt with AIDS patients in Israel in the late 80s and 90s, and already then had recommended that his patients use cannabis for its beneficial properties, especially in overcoming nausea and weight loss, he said. “The first patient that got an official license to use cannabis in Israel was my AIDS patient at the Kaplan hospital,” he said. The Kaplan Medical Center is a hospital in the city of Rehovot. An immunologist by profession, Bentwich was also the chief scientist for Tikkun Olam Ltd., a medical cannabis grower, from 2012 to 2018. Curo Medical is now planning to embark on a series of clinical trials to prove the efficacy of its product on alleviating such conditions as glaucoma, Parkinson’s disease, and sleep insomnia. “We need to prove its potential,” said Bentwich. To raise money for the trials, the three-year old firm is planning to hold an initial public offering of shares on the Toronto Stock Exchange sometime next year, said Meir Alboher, the chief executive of Curo. The firm has raised some $2 million to date from angel investors for its activities, but is seeking to raise more funds for the trials and to start licensing the extraction method to medical cannabis producers in the US and Europe. “If our preliminary studies are accurate, then we will have revolutionized the world of cannabis,” Alboher said. He said the new cannabis formulation has the potential of becoming the next Viagra, the medication used to treat erectile dysfunction, or the next contraceptive pill. “We want future medical cannabis products produced with our method to be identified as such,” he said. “Just as computers get sold with the ‘Intel inside’ label.” https://www.timesofisrael.com/cannabis-startup-finds-new-way-to-get-full-weed-benefits-but-without-the-smoke/?utm_source=The+Weekend+Edition&utm_campaign=weekend-edition-2019-12-29&utm_medium=email
  23. Varda Shoshan-Barmatz. (Dani Machlis/BGU) A discovery at Israel’s Ben-Gurion University represents a major step toward curing lupus, an autoimmune disease that damages the kidneys, blood, heart, and lungs. By Arye Green, TPS Researchers from Israel’s Ben-Gurion University (BGU) in cooperation with the National Institute for Biotechnology of the Negev (NIBN) and the U.S.’ National Institutes of Health (NIH) have made a breakthrough in the fight against a disease called lupus, identifying the path used by mitochondrial DNA to exit cells in order to trigger autoimmune diseases and developing a way block that escape route. The research was published in Science on Friday, spreading the knowledge to researchers around the globe to hopefully develop a cure for lupus based on the breakthrough. Professor Varda Shoshan-Barmatz of the Department of Life Sciences and the founding Director of the NIBN, in collaboration with Dr. Jay Chung of the NIH, have successfully demonstrated that the mitochondrial protein VDAC1 is critical for the release of mitochondrial DNA (mtDNA) associated with lupus. They demonstrated that restricting of VDAC1 with a newly developed molecule resulted in substantial improvement in pathological aspects of the disease. “When VDAC1 is over-expressed, as found in several diseases, a large pore composed of several VDAC1 units is formed, allowing the release of pro-cell death factors and mtDNA,” BGU explained in a statement. The new molecule hinders cell death and revitalizes mitochondrial function, helping to combat several diseases, including lupus. “Our breakthrough is identifying a new pathway for the exit of mtDNA that we can either trigger under controlled conditions or inhibit using our novel molecule that we specifically developed to prevent the formation of this pathway,” explained Prof. Shoshan-Barmatz. “Since the results thus far with lupus have been so promising, we believe that the molecule will be beneficial with regards to other diseases such as Alzheimer’s, Crohn’s and ulcerative colitis – as our preliminary results already support,” she added. Lupus is a chronic autoimmune disease that can attack various parts of the body. According to the Lupus Foundation, there are five million cases around the world. The researchers have had remarkable success in lupus mouse models so far and are beginning to take the next steps towards other diseases. mtDNA has also been found in the plasma of patients of other autoimmune diseases such as Colitis and Crohn’s diseases. The researchers hope that the new molecule will lead to more cures in several other diseases. https://unitedwithisrael.org/israeli-researchers-make-breakthrough-in-the-fight-against-lupus/?utm_source=MadMimi&utm_medium=email&utm_content=Israel+Attacks+Hamas%3B+Amazon+Caught+Selling+Anti-Semitic+Islamic+Tracts+that+Promote+Violence%3B+UN+Ambassadors+Witness+Terror+Tunnel%2C+Iron+Dome&utm_campaign=20191226_m156064126_Israel+Attacks+Hamas%3B+Amazon+Caught+Selling+Anti-Semitic+Islamic+Tracts+that+Promote+Violence%3B+UN+Ambassadors+Witness+Terror+Tunnel%2C+Iron+Dome&utm_term=Israeli+Researchers+Make+Breakthrough+in+Fight+Against+Lupus
  24. 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
  25. Wishing everyone Seasons Greetings & a Happy & Healthy 2020! Wishing all our Members & Visitors, Happy Holidays! Happy Chanukah: חג חנוכה שמח Wishing you a Diwali that brings happiness prosperity and joy to you and all your family. Happy Diwali! Merry Christmas! Wishing Everyone a Happy, Healthy and Peaceful 2020! Thanking you all for your support! With good wishes, Ros
  26. 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
  27. High Doses of Hydroxychloroquine May Protect Against Thrombosis in SLE Emily Pond Hydroxychloroquine has been known to have a primary role in the treatment of systemic lupus erythematosus. The following article is a part of conference coverage from the 2019 American College of Rheumatology/The Association of Rheumatology Professionals (ACR/ARP) Annual Meeting, being held in Atlanta, Georgia. The team at Rheumatology Advisor will be reporting on the latest news and research conducted by leading experts in rheumatology. Check back for more from the 2019 ACR/ARP Annual Meeting. ATLANTA — Higher prescribed doses of hydroxychloroquine (HCQ) may be associated with lower odds of thrombotic events in patients with systemic lupus erythematosus (SLE), according to study results presented at the 2019 The American College of Rheumatology/Association of Rheumatology Professionals (ACR/ARP) Annual Meeting, held November 8 to 13, 2019, in Atlanta, Georgia. Related Articles Novel Diagnostic Test Demonstrates Clinical Utility in Systemic Lupus Erythematosus Anifrolumab Effectively Reduced Disease Activity in Lupus in Phase 3 Trial 2017 Weighted Criteria Validated for Pediatric Systemic Lupus Erythematosus Investigators conducted a prospective cohort study of patients with SLE, and HCQ blood levels were ascertained at study visits by liquid chromatography-tandem mass spectrometry. Thromboses were defined as venous, including deep vein thrombosis/pulmonary embolism, or arterial, including stroke, myocardial infarction digital gangrene, or other arterial thrombosis. Patients were followed-up until index thrombotic event. Mean HCQ blood levels were calculated by averaging values obtained at all cohort visits before thrombosis. The study cohort comprised 812 patients with SLE, among whom 93% were women, 43% were black, and 46% were white. During follow-up, researchers observed thrombosis in 44 patients (5.4%): 3.0% with venous thrombosis and 2.5% with arterial thrombosis. Lupus anticoagulant was significantly associated with a prior history of any thrombosis (odds ratio [OR], 3.25; P <.0001), venous thrombosis (OR, 3.53; P <.0001), and arterial thrombosis (OR, 3.08; P <.0001). Mean HCQ blood levels were significantly reduced in patients with any thrombosis (P =.0393) and venous thrombosis (P =.0616 with superficial; P =.0249 without superficial), compared with patients with no thrombosis. In addition, higher prescribed doses of HCQ were associated with decreased odds of any thrombosis and venous thrombosis (OR, 0.88; P =.04 and OR, 0.83; P =.009, respectively, for each 1 mg/kg increase in HCQ dose). In this prospective analysis, high HCQ blood levels appeared to be protective against thrombosis in patients with SLE. The American Academy of Ophthalmologists suggests that clinicians reduce HCQ dosing; however, such adjustments “could reduce or eliminate the benefit of [HCQ] to prevent thrombosis,” the investigators wrote. Disclosure: One study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures. Visit Rheumatology Advisor for live coverage and more news from the 2019 ACR/ARP Annual Meeting. Reference Konig M, Li J, Petri M. Hydroxychloroquine blood levels and risk of thrombotic events in systemic lupus erythematosus. Presented at: 2019 ACR/ARP Annual Meeting; November 8-13, 2019; Atlanta, GA. Abstract 2783. https://www.rheumatologyadvisor.com/home/conference-highlights/acr-2019/high-doses-of-hydroxychloroquine-may-protect-against-thrombosis-in-sle/ Please note: before taking hydroxychloroquine, it is important to see an ophthalmologist and to have annual check ups to ensure there is no eye toxicity. Do not be alarmed because this medication has been used effectively for many years. Stopping the drug will ensure there is no damage with the check ups.
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