On August 2, 2021, the US Food and Drug Administration approved the drug anifrolumab (Saphnelo) for the treatment of adult patients with moderate to severe systemic lupus erythematosus (SLE) who are receiving standard therapy. Much of the groundwork for the development of this drug was done in laboratories at Hospital for Special Surgery (HSS) in the early 2000s.
SLE, commonly just called lupus, is an autoimmune disease that affects as many as 500,000 people in the United States. In people with the condition, the immune system malfunctions and, instead of attacking infections like it’s supposed to, it attacks healthy tissues. The organs and systems, most commonly affected by lupus include the skin, joints, kidneys and lungs.
“There are not many drugs that are currently effective against lupus, and many of those that are used tend to have a lot of side effects,” says Mary K. “Peggy” Crow, MD, Physician-in-Chief Emerita at HSS, Director of the Autoimmunity and Inflammation Research Program and Co-Director of the Mary Kirkland Center for Lupus Research at the HSS Research Institute. “I think the approval of this drug will be met with a lot of excitement, both by patients and the doctors who treat this disease.”
Anifrolumab is a monoclonal antibody that works by blocking the receptor for a family of molecules called type I interferon. These molecules are essential for the body’s natural defense against viral infections: When they detect an invader, they bind to the interferon receptor, which turns on a number of genes that rally the immune system to fight the infection. In lupus, however, this receptor is activated even when no infection is present, causing the immune system to instead attack its host.
The link between interferon and lupus was made thanks to decades of research. “There were observations going back to the 1970s that interferon was elevated in certain autoimmune diseases, including lupus,” Dr. Crow says. “But it wasn’t until the availability of gene microarrays in about 2000 that my lab was able to begin figuring out exactly what interferon’s role is in the disease.”
In the lab, Dr. Crow and her team began studying the blood of people with lupus and comparing it to the blood of healthy individuals. They looked at which genes were being transcribed in each group, and when they compared the lists they saw that there were substantial differences. “It was like a puzzle, trying to figure out what the data meant,” she remembers. “But as we took a closer look, it became clear that many of the differences between patients and healthy donors were genes that were regulated by type I interferon.”
In 2003, Dr. Crow and her HSS team were one of three groups to publish research confirming interferon’s pivotal role in lupus. Additional important findings came from mouse models of lupus. “The mouse studies helped to make the case that this type I interferon pathway really is contributing to disease pathogenesis,” she says. “They confirmed that this was an appropriate therapeutic target.”
One of the members of Dr. Crow’s lab who worked on this research was physician-scientist Kyriakos A. Kirou, MD, DSc, FACP, an Associate Attending Physician at HSS. Dr. Kirou now leads clinical trials for lupus at HSS and was involved in the anifrolumab trial. “Lupus is a very heterogeneous disease, and it’s difficult to bring it under control,” he says. “One of things that makes anifrolumab so promising is that it appears to work particularly well for patients whose disease is more severe. It was especially effective against the skin rashes that are common in lupus patients.”
He added that because the drug is targeted only at the type I interferon receptor, it appears to have relatively few side effects compared to drugs with more wide-ranging effects like steroids. But because it acts on the immune system, it does appear to increase the risk of upper respiratory infections. People who got the drug were also more likely to develop shingles, so it may be recommended that people get the shingles vaccine before starting the drug.
Dr. Crow says that because interferon is also implicated in other autoimmune diseases, it’s possible that anifrolumab may work in them as well. She adds that there are other promising drugs for lupus currently under investigation. “As an investigator who focuses on translational research, my goal is always to discover something that can benefit patients,” she says. “It’s very gratifying when your research can have a positive impact on people’s lives.”
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Tracy Hickenbottom / Noelle Carnevale / Grace Naugle
HSS is the world’s leading academic medical center focused on musculoskeletal health. At its core is Hospital for Special Surgery, nationally ranked No. 1 in orthopedics (for the 12th consecutive year), No. 4 in rheumatology by U.S. News & World Report (2021-2022), and the best pediatric orthopedic hospital in NY, NJ and CT by U.S. News & World Report “Best Children’s Hospitals” list (2021-2022). HSS is ranked world #1 in orthopedics by Newsweek (2020-2021). Founded in 1863, the Hospital has the lowest complication and readmission rates in the nation for orthopedics, and among the lowest infection rates. HSS was the first in New York State to receive Magnet Recognition for Excellence in Nursing Service from the American Nurses Credentialing Center five consecutive times. The global standard total knee replacement was developed at HSS in 1969. An affiliate of Weill Cornell Medical College, HSS has a main campus in New York City and facilities in New Jersey, Connecticut and in the Long Island and Westchester County regions of New York State, as well as in Florida. In addition to patient care, HSS leads the field in research, innovation and education. The HSS Research Institute comprises 20 laboratories and 300 staff members focused on leading the advancement of musculoskeletal health through prevention of degeneration, tissue repair and tissue regeneration. The HSS Global Innovation Institute was formed in 2016 to realize the potential of new drugs, therapeutics and devices. The HSS Education Institute is a trusted leader in advancing musculoskeletal knowledge and research for physicians, nurses, allied health professionals, academic trainees, and consumers in more than 130 countries. The institution is collaborating with medical centers and other organizations to advance the quality and value of musculoskeletal care and to make world-class HSS care more widely accessible nationally and internationally. www.hss.edu.