Kathleen Nolan, RN, was diagnosed with Systemic Lupus Erythematosus (SLE) when she was 26. Two years ago, her rheumatologist handed her the bad news: There was nothing else they could do for her. She took 12 pills in the morning and two at night, and an injection of another medicine once a week. Her symptoms — joint pain, ulcers, fatigue and constant fever — were unrelenting despite her medication regimen. The doctor’s proverbial black bag was empty.
A colleague gave Ms. Nolan a copy of Focus on Research, published by The Feinstein Institute for Medical Research, which detailed an extensive lupus research program and a number of experimental drug studies at the institute. There hasn’t been a new lupus drug in more than 50 years. Most of the medicines now used were designed for other conditions.
Ms. Nolan enrolled in a Phase III study of Benlysta, which showed promise in laboratory models of lupus and in early studies in humans. Last summer, after spending a year in the trial not knowing whether she got the real drug or a placebo dose, Ms. Nolan — and the rest of the lupus world — learned about the results of a similar multicentered study of Benlysta being conducted outside the United States. It seemed to be working. Patients on the drug fared better than those in the placebo group. After one year, patients were all put on one of two doses of the study drug.
Progress for patients
“This is a major step forward,” said Cynthia Aranow, MD, a rheumatologist at the Feinstein who was an investigator in the study. Dr. Aranow said there are about 10 other lupus clinical drug trials under way in the Feinstein’s Center for Autoimmune and Musculoskeletal Disorders and a number of other studies to figure out why the disease starts and progresses. Benlysta, which is the brand name for belimumab, is a monoclonal antibody against BAFF, which is a B lymphocyte stimulator. BAFF is an immune system cytokine that is important for B cell activation and B cell survival. Lupus patients make too much BAFF and this drug blocks BAFF.
“This is the first time in decades that a lupus drug study had positive results,” added Meggan Mackay, MD, codirector with Dr. Aranow of the center’s Clinical Research Unit. The unit works through the General Clinical Research Center.
The Feinstein Institute for Medical Research is one of the leading centers in the world exploring SLE. Led by Betty Diamond, MD, director of the Center for Autoimmune and Musculoskeletal Disorders, Feinstein scientists are committed to unraveling the puzzle of this abnormal immune response to identify pathways to stop this rogue process. Lupus is an autoimmune disease.
To understand autoimmune disease, scientists turn to the inner workings of the B cell repertoire. In producing antibodies against things that are foreign to itself, the body on more than a rare occasion wages war against its own tissues. About eight percent of the population has an autoimmune disease.
The body produces millions of antibodies that protect against infection. In general, it is an efficient system. But every once in a while, the immune system sees the self as foreign and wages an attack. This process is the underlying problem at work in scores of autoimmune diseases, including common ones like diabetes, rheumatoid arthritis, lupus and multiple sclerosis.
Genetic and Environmental Triggers
Lupus is characterized by a high serum of auto-antibodies — specifically antibodies to double-stranded DNA. Lupus is unusual (and therefore a good model) in that it can affect so many different organs of the body. Dr. Diamond’s interest in understanding the induction of anti-DNA antibodies and how these antibodies become toxic to that environment is at the heart of the research. In demystifying this process, the Diamond team has discovered that the condition has both genetic roots and environmental triggers. For instance, scientists on Dr. Diamond’s team are fascinated by a finding that sex hormones can trigger SLE. Lupus is far more common in women, which is why they are now focusing on estrogen. They are exposing B cells to sex hormones to see how the hormones change B cell receptor signaling and B cell maturation. They are also studying whether genes regulated by hormones alter the response of the immune system.
Dr. Diamond’s team has identified foreign antigens (microbes from the environment) that cross-react with the anti-DNA antibodies that they believe play a major role in lupus. What is the normal way to regulate or prevent this cross-reactive system? How does the immune system make this mistake? These are some of the questions the team is answering.
Her team is also working to discover how this cross-reactivity alters a very important population of glutamate receptors called NMDA receptors. These receptors are all over the brain and regulate a lot of excitatory synaptic activity. Dr. Diamond has shown that a subset of anti-DNA antibodies cross-react with NMDA receptors and contribute to neuropsychiatric lupus. It has become clear in recent years that many lupus patients have a long list of cognitive and mood complaints that until now were ignored or not linked to the underlying pathological lupus process. As part of the effort, Dr. Diamond’s colleagues, Drs. Mackay and Aranow, are working cross-institute with David Eidelberg, MD, head of the Susan and Leonard Feinstein Center for Neurosciences, to image the brains of lupus patients to figure out whether there are observable brain changes and whether more changes occur with advancing illness. They are using magnetic resonance imaging and positron emission tomography scans to identify the functional and structural problems that underlie these brain symptoms.
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