Helping Pregnant Women with Autoimmune Diseases
Rheumatoid arthritis and lupus disproportionately affect women, and diagnosis often happens during childbearing years. “A frequent question when women are first diagnosed is, ‘Can I have children?’” Clowse said. Through her research and patient care, Clowse is seeking to flesh out the answer to that not-so-simple question. “My goal is to transform and improve how women with rheumatologic diseases are managed during pregnancy,” she said, “so that women can build families they want.”
For women with rheumatoid arthritis, currently available medications often keep the disease well in check. Going off the medications during pregnancy can lead to significant and painful flairs, which are associated with pregnancy complications. “With rheumatoid arthritis, I tend to be much more aggressive with keeping women on medication and keeping their disease under control,” Clowse said. “What I’m working on is identifying which medications are safe to take during pregnancy and will improve their arthritis and their pregnancy outcomes.”
To help her do that, Clowse has established the Autoimmune Disease and Pregnancy Registry, which thus far contains clinical, lab, and medication data, and pregnancy outcomes for 250 women with lupus or rheumatoid arthritis. “We are looking for clues to what forms of treatment lead to the highest rates of pregnancy success,” Clowse said.
Years ago, lupus patients were advised to avoid pregnancy altogether. Today, many women with lupus can have a normal, healthy pregnancy. For others, particularly those with kidney disease, it’s still dangerous for mother and baby. Using the data in the registry, Clowse and colleagues discovered that in a particular subset of lupus patients, continuing to take a medicine called hydroxychloroquine during pregnancy seemed to protect babies from developing heart damage that can otherwise occur in the womb.
Exploring Lupus on the Molecular Level
A hallmark of lupus is the presence of antibodies that attack the patient’s own cells, damaging tissues and organs. Curiosity about why and how antibodies identify, attach, and attack the body’s own cells has fueled a career of research and clinical care for David Pisetsky, MD, PhD, professor of medicine. Pisetsky is a Master in the American College of Rheumatology, an honor bestowed on those who are at least 65 years old and have made significant contributions to the field.
“Questions about the recognition of foreign versus self are very profound,” he said. “My research is directed to understanding the production of antibodies to DNA that only occur in patients with lupus. How do the antibodies bind to DNA? How does DNA get outside of cells?”
Pisetsky has demonstrated that dying cells release microparticles that contain DNA. Dying cells also release a protein called HMGB1, which Pisetsky’s research shows is elevated in the blood of patients with lupus, making it a potential biomarker for assessing and monitoring the activity of disease in lupus. “What we’re trying to do is extend the importance of cell death, which is key to many diseases because a dead cell can induce inflammation,” he said.
In addition to his research and patient care at the Durham VA Medical Center, Pisetsky has served as editor of two journals (“Arthritis and Rheumatology” and “The Rheumatologist”) and continues to write columns for “Arthritis Research and Therapy.”
He is also the president-elect of the U.S. Bone and Joint Initiative—an organization active worldwide. “The main focus is multi-disciplinary and inter-disciplinary care,” he said. “Many patients with rheumatoid arthritis or other forms of arthritis are going to see multiple specialists. What we’re trying to do is build communication among these specialties dealing with the care of very complicated patients in whom bone and joint disease may be one of many problems.” The organization also advocates for prevention and care of musculoskeletal injury, which is a leading cause of disability around the world.
Developing New Therapies
Through basic science research and clinical trials, members of the division create or contribute to innovative drug therapies for rheumatoid or immunologic diseases. For example, Division Chief William St. Clair and Nancy Allen, MD, professor of medicine, worked on a clinical trial that supported FDA approval of rituximab receive FDA approval for treating ANCA vasculitis, an autoimmune disease that causes inflammation of the blood vessels. St. Clair is also the deputy director of the Immune Tolerance Network (ITN), an NIH-funded consortium formed to develop and test therapies that create immune tolerance in allergy and asthma, autoimmune disease, and organ transplants.
Michael Hershfield, MD, professor of medicine, has developed two FDA-approved medicines that use a similar strategy to treat two very different diseases. The strategy consists of attaching a polyethylene glycol (PEG) molecule to an enzyme to keep the enzyme circulating in the blood for a longer time before becoming inactive.
The idea of attaching PEG molecules to enzymes was developed elsewhere about 35 years ago, but in 1986 Hershfield and his colleagues at Duke were the first to demonstrate a clinical application—a PEGylated version of an enzyme called ADA1, used to treat children with severe combined immunodeficiency (SCID) as a result of a genetic insufficiency of ADA1. The drug is called Adagen.
Based on that experience, Hershfield said, “I got the idea that you might be able to use a different enzyme to treat patients with very severe gout.” In gout, uric acid crystallizes in the joints, causing inflammation, pain, and visible nodules. For most patients, two medicines that have long been on the market are effective. But those medicines don’t work for some patients, and the uric acid crystals continue to accumulate, causing more severe problems. “It interferes with simple things like putting on your shoes or handling keys,” Hershfield said.
Many mammals, from cats to cows, make an enzyme called uricase that breaks down uric acid, but humans don’t. Hershfield created a recombinant uricase enzyme and attached PEG to it. The drug, called peglocitcase or Krystexxa, can not only lower levels of uric acid in the blood, but also dissolve away uric acid crystals in the joints, allowing patients to regain mobility and function.
While the drug is life-changing for many, Hershfield said, “There is an Achilles heel with the drug. While most patients do benefit, a substantial percentage develops antibodies against it, directed at the PEG, not the uricase enzyme. That was very unexpected.”
Hershfield, who is a Master in the American College of Rheumatology, recently began working on another rare disease involving a deficiency in the enzyme ADA2, which causes repeated strokes in children.
Discovering Biomarkers for Osteoarthritis
“Osteoarthritis is probably the most prevalent disease in the world, and the most disabling,” said Virginia Byers Kraus, MD, PhD, professor of medicine. She is in on the forefront of some new developments in diagnosing and monitoring the disease using biochemical and imaging biomarkers. “It’s very exciting,” she said. “It’s a period of time when we can make a big difference in the world.”
She’s a principal investigator on two large studies that are identifying biomarkers that could provide an early diagnosis using minimally invasive procedures, such as an MRI or sample of blood or urine. “It’s our hope that we would be able to detect problems before the illness is manifested,” she said. Because different joints are made of different components, such tests might be able to predict which joints are on the way to developing osteoarthritis.
One of the studies is looking at both biochemical compounds and imaging techniques; Kraus is in charge of the biochemical side, which is looking for biomarkers among compounds for which there are already commercially available test kits. The study is funded by the Foundation for the National Institutes of Health.
Her other study casts a wider net, using mass spectroscopy to comprehensively compare thousands of proteins in blood and joint fluid of different groups of people, looking for any proteins that might function as biomarkers for osteoarthritis. That study is funded by the Biomarker Factory.
In addition to making early diagnosis possible, biomarkers could increase the efficiency of clinical trials in several ways. For one, biomarkers could be used to quickly identify people in an active phase of the disease, which would make it easier to assemble a cohort for a clinical trial. Biomarkers could also provide a more nuanced and timely description of the progression and activity of the disease, and would be less expensive and less onerous for patients and participants in trials.
Kraus is the president of OARSI, the Osteoarthritis Research Society International. “OARSI is working very hard to fix what’s broken about the clinical trials pathway for osteoarthritis,” Kraus said. The multi-pronged approach includes advocating for the FDA to define osteoarthritis as a serious disease, and to approve certain biomarkers as drug development tools and as surrogates to augment or replace the current gold standard endpoint in clinical trials, which is X-ray. Kraus is hopeful that these efforts will succeed. “It opens up a whole avenue for doing research and clinical trials in a way that will finally lead to success,” she said.