Focus Area: Systemic Lupus Erythematosus
Improvements in the care and understanding of systemic lupus erythematosus (SLE, or "lupus") have helped slow the death rate due to this complex autoimmune disease that often strikes women in the prime of life.
Although it remains fatal for some people, especially minority populations, lupus has become a manageable chronic condition that demands a multi-pronged approach to achieve the best outcomes for patients. The clinical research programs in the Division of Rheumatology at Northwestern University Feinberg School of Medicine have focused on both the immediate and long-term effects of the disease, including pregnancy complications, osteoporosis, cardiovascular disease, and cancer. Under the leadership of renowned lupus expert Rosalind Ramsey-Goldman, MD, DrPH, the Patient-oriented Clinical Research Program in Systemic Lupus Erythematosus [funded by National Institutes of Health (NIH) grants and foundation support] focuses on improving the quality of life for individuals with lupus by investigating SLE prevention and its related complications. Ramsey-Goldman, Solovy/Arthritis Research Society Research Professor, serves as the program’s principal investigator.
Caring for the pregnant lupus patient, for example, is a particular strength of the clinical program because of Dr. Ramsey-Goldman’s early interest in women’s health issues honed during her primary care training. Later, as a rheumatology fellow, she concentrated on helping women with lupus achieve successful pregnancies. She and a Division of Rheumatology nurse practitioner, Patricia Murphy, RNC, MSN, WHNP, CNM, who is also a trained midwife, combine their expertise with that of the high-risk obstetrics specialists at Northwestern Memorial Hospital’s Prentice Women’s Hospital to help women with lupus achieve what was once considered unachievable. Attracting patients from throughout the Midwest, the team manages the pregnancy complications that can arise from lupus or counsels patients with the disease who are considering pregnancy.
“Due to our experience with providing state-of-the-art lupus care, we offer these women support they may not be able to find elsewhere,” says Dr. Ramsey-Goldman. “Many of them have thought they couldn’t have a baby before they came here.” Diane Herr was such a patient. Learning she had lupus at age 36, she was unsure how she would manage her disease if she became pregnant. So Herr sought the advice of Dr. Ramsey-Goldman in 1995. Since that time, Herr has remained a patient of the lupus Program because of the cutting-edge care she receives from leaders in the field, such as Dr. Ramsey-Goldman.
Solving the Baffling Riddle of Lupus
As associate director for the Multidisciplinary Clinical Research Center (MCRC) in Rheumatology at Feinberg, Dr. Ramsey-Goldman and her team have significantly contributed to the advancement of effective lupus prevention and treatment through several ongoing translational research efforts. The microarray study SOLVABLE (Study of Lupus Vascular and Bone Long-term Endpoints)—an MCRC project focusing on heart disease and bone loss problems of women with and without lupus—continues to provide valuable information gleaned from the examination of lipid metabolism gene expression profiles in monocytes and macrophages. By looking at the differential expression pattern between these cells in study participants and relating them to clinical observations, the SOLVABLE team hopes to define potential mechanisms contributing to the development of atherosclerosis.
The identification of one or two of the more responsible genes contributing to this disease process could greatly enhance the tailoring of therapy to prevent complications of vascular injury and tissue damage. Data collected over a five-year period (2002 to 2007) for the SOLVABLE study, which enrolled 186 women with lupus and 157 without the disease, has yielded unique findings. For example, low levels of vitamin D in women with lupus may put them at risk for certain cardiovascular risk factors. This revealing discovery has prompted the SOLVABLE team to now examine vitamin D levels as a predictor of disease progression on imaging tests used to detect the presence of atherosclerosis. Dr. Ramsey-Goldman and her colleagues plan to expand upon this observation linking vitamin D levels and lupus to cardiovascular disease events such as heart attacks and strokes in a large international cohort of newly diagnosed lupus patients. These study participants are enrolled in a multicenter research project sponsored by Systemic Lupus International Coordinating Clinics (SLICC), one of the premier groups advancing lupus research around the world. Christine Hsieh, MD, instructor of medicine, helps recruit patients for the study. Dr. Ramsey-Goldman recently completed a five-year term as the chair of SLICC.
The fatigue, joint pain, and osteoporosis that come with her lupus serve as a constant reminder to Herr that clinical research offers the best hope for improvements in SLE care. Herr anticipates she will benefit some day from several of the translational research programs offered by the lupus Program. “I expect from studies like SOLVABLE that new approaches to treatment will be developed which will, in the long run, directly affect my care,” she says. “It’s because of Dr. Ramsey-Goldman’s involvement in this groundbreaking work that I am confident she is doing all she can for me.”
Taming the ‘Wolf Within’ through New Discoveries
Derived from the Latin word for wolf, lupus urgently needs “taming”—through improved medications and other therapies—if patients are to avoid the serious complications of this autoimmune disease. Partnering with industry, the Division has been instrumental in pioneering the discovery of new drugs for lupus, including participating in Phase I and II trials of the human monoclonal antibody drug belimumab (Benlysta™). This BLyS®-specific inhibitor has the potential to become the first new approved drug for people living with lupus in more than 50 years, offering another much-needed treatment option where there are woefully few. Dr. Ramsey-Goldman currently serves on the scientific advisory committee for Benlysta™ co-developers Human Genome Sciences and GlaxoSmithKline. The Division of Rheumatology has also initiated clinical trials to analyze the efficacy of a number of drug therapies for lupus under the direction of faculty member Dr. Hsieh.
As these clinical programs get off the ground, they will help pave the way for translating the bench discoveries of the laboratory of Syamal K. Datta, MD, previously director of Feinberg’s Biomedical Research Component, Multipurpose Arthritis Center. The Datta laboratory has patented a novel peptide-based tolerance therapy targeted specifically against autoimmune cells that could spare lupus patients from receiving mutagenic cytotoxic agents, corticosteroids, and global immunosuppressants to treat their disease. Administered as a vaccine, this therapy—using naturally occurring peptides—has the potential to restore immunoregulation in lupus patients in remission and prevent the initiation or progression of renal disease in individuals at risk. Additionally, Dr. Datta’s group has shown that the therapy generates highly useful biomarkers, such as regulatory T (Treg) cells, that could allow clinicians to more precisely monitor true immunologic remission in lupus patients.
“Our nucleosomal peptide epitope vaccine is a natural and non-toxic therapy that produces such Treg cells that cause immunologic remission of disease in preclinical studies,” explains Dr. Datta, Solovy/Arthritis Research Society Professor of Medicine. “By manufacturing tools from these peptides, we might be able to predict who is at risk of a lupus relapse or flare or who, among a lupus patient’s family members, is at risk for developing the disease.” For his discoveries, Dr. Datta has received a MERIT award from the National Institute of Arthritis and Musculoskeletal Diseases and Skin Diseases and was elected to the Association of American Physicians.
Mentoring the Next Generation of Leaders
The future of lupus prevention and care relies on those who can learn from top investigators and then forge their own paths. From medical students to fellows, the Division of Rheumatology provides a strong grounding in SLE, with many trainees choosing to specialize in lupus and later disseminating their knowledge in clinical practice, industry, and/or academia. Dr. Ramsey-Goldman, associate director for the Division’s training grant in rheumatology, has ensured that knowledge is shared beyond Feinberg by mentoring young investigators at other institutions. Recently recognized for her teaching by two named professorships, she was the Pfizer Visiting Professor at Medical University of South Carolina in 2009 and presented the Thomas Lecture at Virginia Commonwealth University in 2008.
Dr. Datta has mentored several up-and-coming investigators in his laboratory who have gone on to prominent positions in academics as well as at the NIH. Among Dr. Datta’s trainees are Chandra Mohan, MD, PhD, Walter M. and Helen D. Bader Professor in Arthritis and Autoimmune Disease Research at University of Texas Southwestern Medical School in Dallas, and Robert Seder, MD, chief of the Cellular Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases.