Tyrosine kinases are enzymes that play central roles in signaling by cytokines involved in the pathogenesis of autoimmune diseases, including lupus. A recent phase 2 clinical trial published by Wiley in Arthritis & Rheumatologyhas generated promising results for deucravacitinib, an oral inhibitor of tyrosine kinase 2 (TYK2), in patients with active lupus.
In the trial, 363 patients were randomized 1:1:1:1 to placebo or deucravacitinib 3 mg twice daily, 6 mg twice daily, or 12 mg once daily. At week 32, the percentage of patients who experienced a beneficial response (as assessed by various measures of disease activity) was 34% with placebo compared with 58%, 50%, and 45% with the respective deucravacitinib regimens.
Rates of adverse events were similar across groups, except for higher rates of infections and skin-related events, including rash and acne, with deucravacitinib. Rates of serious adverse events were comparable, with no deaths, opportunistic infections, tuberculosis, major adverse cardiovascular events, or thrombotic events reported.
“TYK2 transducer signals a unique set of cytokines that are highly relevant to SLE,” said corresponding author Eric Morand, MBBS, PhD, of Monash University. “These results put TYK2 on the map as a target for lupus and encourage further development of deucravacitinib in this disease.”
The balance between the risk of autoimmune disease and the risk of infection credit Dr David Lester Morris, Robert Lester Morris, Dr Deborah Cunninghame Graham, and Professor Timothy Vyse (CC-BY 4.0, https://creativecommons.org/licenses/by/4.0/)
Some genetic variants may put people at risk of autoimmune diseases while conferring protection against the outcome of viral infection. A study published November 3rd in the open access journal PLOS Genetics by David Morris and Timothy Vyse at King’s College London, UK and colleagues suggest that genetic predisposition for systemic lupus erythematosus (SLE) may be protective against severe COVID-19 infection.
Scientists have observed a correlation between the genes associated with severe COVID-19 and those with SLE. To locate associated genes and gain insight into the shared genetic effects, researchers compared the genetics of severe COVID-19 with those of SLE using multiple analyses, including an approach that can focus on specific areas of the genome. The authors then accessed data on genes and the genome structure obtained from several biomedical databases to understand the biology of shared genetics.
The researchers found that TYK2, a gene associated with both SLE and severe COVID-19 provides protection against viral infection, but increases risk for autoimmune disease. Future studies will be needed to fully understand the genetic relationships between COVID-19 and other diseases. The study has its limitations, such as the overrepresentation of European ancestry in the datasets used to perform the analyses.
According to the authors, “Our results indicate that there are shared genetic effects between the autoimmune disease SLE and the clinical consequences of COVID-19. The locus with the most evidence of shared association (TYK2) is involved in interferon production, a process that is important in response to viral infection and known to be dysregulated in SLE patients. In seeking to uncover the mechanisms underlying these relationships it was apparent that the functional effects of the risk and protective genotypes are complex.”
Dr. David Morris and Professor Timothy Vyse, who led the study, add that “this is an exciting result made possible by the large genetic studies in COVID-19 and Lupus, and opens the door to our understanding of how the biology of the immune system is calibrated to protect us against infection from viruses and other infectious agents, but at the risk of developing autoimmune disease.”
A multi-institutional team of scientists, led by researchers at Weill Cornell Medicine’s Gale and Ira Drukier Institute for Children’s Health, have received a five-year $8.297 grant to continue funding a Center for Lupus Research. The grant, awarded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health, will allow researchers to explore the underlying mechanisms of systemic lupus erythematosus (SLE) in children with the goal of better tailoring treatment.
“Pediatric lupus is often underrecognized, but up to a quarter of people with the illness have disease that starts in childhood,” said Dr. Virginia Pascual, program director of the Center for Lupus Research and the Drukier Director of the Drukier Institute for Children’s Health at Weill Cornell Medicine.
SLE, a chronic immune disease, tends to be more aggressive in children than in adults. Symptoms can include joint pain, rash, fatigue, fever and sensitivity to light. “There is a tremendous need to understand the complexity of pediatric lupus,” said Dr. Pascual, who is also the Ronay Menschel Professor of Pediatrics at Weill Cornell Medicine.
Dr. Pascual and her colleagues received funding based on their prior research. They discovered that children with lupus have red blood cells that are a rich and unusual source of nucleic acids that activate other cells to cause inflammation. These cells, called macrophages, produce cytokines, or molecules that activate the immune system, creating an inflammatory response. The research team wants to better understand the underlying mechanisms of this inflammatory process.
They also want to determine why up to a third of children with lupus do not respond to standard of care, which consists of high doses of steroids and immunosuppressive medications.
“We want to apply all of the molecular techniques we have developed for studying this disease to understanding what’s going on in these patients at the time of diagnosis and through flares and remissions,” said Dr. Pascual.
The researchers will compare this data to information collected from children who do respond to treatment. The goal is to identify biomarkers of drug resistance and to develop new approaches to care.
Dr. Pascual’s research colleagues include Dr. Patrick Wilson, who was recruited as a professor of pediatrics and member of the Drukier Institute at Weill Cornell Medicine and a principal investigator at the Center for Lupus Research; Dr. Simone Caielli, assistant professor of immunology research in pediatrics and a junior investigator at the center. Other members include Dr. Duygu Ucar, associate professor at the Jackson Laboratory and the center’s administrative core associate director and co-investigator; Dr. Tracey Wright, chief of the Division of Pediatric Rheumatology at UT Southwestern Medical Center and principal investigator for the center’s clinical sample core; and several pediatric rheumatologists from Nationwide Children’s Hospital, who will contribute patients for the study.
“I am very fortunate to have received this award and to work with this amazing group of colleagues,” Dr. Pascual said. “Together, we have already generated some interesting data, and we hope to continue advancing the field.”
A unique 3D-printed light-sensing medical device could help millions of people worldwide with lupus and other light-sensitive diseases by providing access to real-time data for more personalized treatments. CREDIT McAlpine Group, University of Minnesota
A team of engineers and doctors at the University of Minnesota Twin Cities have designed a unique 3D-printed light-sensing medical device that is placed directly on the skin and gives real-time feedback to correlate light exposure with disease flare-ups. The device could help millions of people worldwide with lupus and other light-sensitive diseases by providing access to more personalized treatments and information to determine what causes their symptoms.
The research was published in Advanced Science, an interdisciplinary premium open access scientific journal. The researchers have also filed a patent on the device and the technology is available for licensing.
According to the Lupus Foundation of America about 1.5 million Americans, and at least 5 million people worldwide, have a form of lupus. Light sensitivity is common in people with lupus with 40 to 70 percent of people with lupus finding that their disease is made worse by exposure to sunlight or even artificial light indoors. The symptoms of these flare ups for patients with lupus include rashes, joint pain, and fatigue.
“I treat a lot of patients with lupus or related diseases, and clinically, it is challenging to predict when patients’ symptoms are going to flare,” said University of Minnesota Medical School dermatologist Dr. David Pearson and co-author of the study. “We know that ultraviolet light and, in some cases visible light, can cause flares of symptoms—both on their skin, as well as internally—but we don’t always know what combinations of light wavelengths are contributing to the symptoms.”
Pearson had heard about the groundbreaking, customized 3D-printing of wearable devices developed by University of Minnesota mechanical engineering Professor Michael McAlpine and his team and contacted him to collaborate on finding a solution for his problem.
McAlpine’s research group worked with Pearson to develop a first-of-its-kind fully 3D-printed device with a flexible UV-visible light detector that could be placed on the skin. The device is integrated with a custom-built portable console to continuously monitor and correlate light exposure to symptoms.
“This research builds upon our previous work where we developed a fully 3D printed light-emitting device, but this time instead of emitting light, it is receiving light,” said McAlpine, a co-author of the study and Kuhrmeyer Family Chair Professor in the Department of Mechanical Engineering. “The light is converted to electrical signals to measure it, which in the future can then be correlated with the patient’s symptoms flare ups.”
McAlpine said that developing the device, however, was no easy task. The 3D-printed device consists of multiple layers of materials printed on a biocompatible silicone base. The layers include electrodes and optical filters. Filters could be changed out depending on the wavelength of light that needs to be assessed. The research team also used zinc oxide to collect the ultraviolet (UV) light and convert it to electrical signals. The device is mounted on the skin and a custom-built console is attached to capture and store the data.
The research team has received approval to begin testing the device on human subjects and will soon begin enrolling participants in the study.
“We know these devices work in the lab, but our next step is really to put them into the hands of patients to see how they work in real life,” Pearson said. “We can give them to participants and track what light they were exposed to and determine how we can predict symptoms. We will also continue testing in the lab to improve the device.”
McAlpine and Pearson said the 3D-printing process is relatively low-cost and could someday provide easy, quick access to the device without the expensive fabrication processes of traditional devices.
“There is no other device like this right now with this potential for personalization and such easy fabrication,” Pearson said. “The dream would be to have one of these 3D printers right in my office. I could see a patient and assess what light wavelengths we want to evaluate. Then I could just print it off for the patient and give it to them. It could be 100 percent personalized to their needs. That’s where the future of medicine is going.”
This is a TRUE story of a young “healthy” patient diagnosed with lupus after a few trips to the ED. After a few misdiagnoses, he becomes unconscious and was admitted to the ICU. The patient was later diagnosed with lupus involving his brain. Hard time followed, but with the right diagnosis and treatment, the patient recovered completely.
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