Although systemic lupus erythematosus still does not have a definite cause or cure, rheumatologists and researchers over the past 50 years have witnessed and contributed to a great deal of progress that helps patients, says Peter H. Schur, MD, director emeritus of the Lupus Center, Brigham and Women’s Hospital, and professor, Harvard Medical School, Boston.
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Dr. Schur’s long career began after he attended Harvard Medical School and completed a residency in internal medicine at the Bronx Municipal Hospital Center, The Bronx, New York, in the early 1960s. Subsequently, he served in the U.S. Army (Medical Corps), doing research at the Walter Reed Army Institute of Research in Washington, D.C. During a fellowship at Rockefeller University in New York, Dr. Schur worked in the lab of Henry G. Kunkel, MD, a pioneer in immunological research. While there, Dr. Schur helped develop a complement assay to detect antibodies for DNA.
Dr. Schur has been at the helm of bench research related to lupus while also remaining a clinician. Among other career highlights, he has served as editor in chief of Arthritis & Rheumatism, editor of the rheumatology section of the medical resource UpToDate (a role he continues today), and co-author of the book In Search of the Sun with one of his patients. Dr. Schur also helped found the Lupus Foundation of America.
With this rich background, Dr. Schur was able to offer The Rheumatologist a unique perspective on some of the biggest milestones in lupus over the past 50 years.
Better Drugs & Survival—But Not a Perfect Scenario
Lupus may not have made the same drug-related advances that rheumatoid arthritis (RA) has, but there have been enough positive changes that survival rates have significantly improved in comparison to 50 years ago, Dr. Schur says. “If you look at survival statistics, in the late 1950s, there was a 50% chance of four-year survival. Now, 90% of lupus patients have a 10- to 20-year survival rate. That’s a whopping difference,” he says.
A proliferation of new drugs to treat lupus has not occurred over the past few decades, but corticosteroids have remained a steady part of the treatment mix. “The major trend I’ve seen is that less [steroids] may be better, but we’re still using pulse steroids,” he says. Corticosteroids remain a key part of treatment even though no randomized controlled trials exist to identify the optimal dose for patients with lupus. Although research has found an increased risk in cardiovascular disease associated with long-term corticosteroid use, the bottom line remains that people with lupus are living longer and better with current treatments, Dr. Schur says.
Fifty years ago, the only immunosuppressants available for lupus were cyclophosphamide and azathioprine. Since then, mycophenolate has been developed as well. There’s only one biologic geared toward lupus—belimumab—but Dr. Schur finds its efficacy mediocre, at best. “This is in contrast to dramatic changes in RA. There have been many biologic trials [in lupus], but they’ve mostly failed,” he says. The clinical trials may not have insightful results, because all patients with lupus are lumped together, rather than separating them by which organs are affected and how active the disease is, Dr. Schur says.
Tailoring the use of treatment protocols is often determined today by the clinical stratification of disease, Dr. Schur says. In fact, some patients may not need treatment initially. “We now recognize that some patients have such mild disease that it needs no treatment or intermittent illness that is best responded to by treatment guided by careful consideration of the long-term consequences of therapy, such as steroid-induced osteoporosis or osteonecrosis,” he says.
Research through time has also shed light on how race may affect how patients respond—or don’t respond—to medications. This includes the finding of African American patients not responding as well to treatments with mycophenolate. These types of findings will continue to affect medical management in the future, Dr. Schur says.
Medical research also continues to reveal immune-based targets for therapy, including innate immune mechanisms, adaptive immunity, effector cells, effector pathways, soluble inflammatory mediators and signaling molecules, Dr. Schur explained.
More Effective Management of Concurrent Conditions
Another area that has helped boost the survival rate for lupus patients is better treatment for concurrent skin, renal and joint conditions commonly associated with lupus, Dr. Schur says. Fifty years ago, there was only a crude version of sunscreen available, unlike the sophisticated and potent formulations available now. Better use of sunscreen has helped protect patients from related skin conditions. Lupus patients now also commonly use hydroxychloroquine (Plaquenil), which has reduced the incidence and severity of skin disease. Dermatologists also have become more sophisticated with their classification and treatments for patients with lupus and skin conditions.
Decades ago, clinicians thought patients with lupus could not get kidney transplants if renal disease struck them. “It was thought that they wouldn’t do well, but they do as well as anybody else. … I have a patient with a kidney transplant from more than 30 years ago who continues to do well, with normal renal function. That’s been dramatic,” Dr. Schur says.
The growth in treatments for RA and arthritis has also benefited lupus patients with concurrent RA or arthritis issues, Dr. Schur says—a condition that a trainee of Dr. Schur coined rhupus. In fact, physicians have often had to look toward medications used for other conditions to find some benefit for lupus patients. For example, hydroxychloroquine was originally developed as an antimalarial.
As knowledge about the interaction of lupus with related systemic conditions has grown, clinicians have realized that becoming pregnant is not the contraindication it once was. “We now know that it is safe for many, and we can much more easily predict complications by knowing autoantibody and renal function status,” he says.
Better Recognition of Lupus Classifications
“Fifty years ago, lupus was more or less a one-size-fits-all field,” Dr. Schur says. “Now, its extreme variability is recognized. Different guidelines for different scenarios are now the norm.”
Much of the bench work done by Dr. Schur and colleagues decades ago has led to easier and more convenient testing of lupus patients to help pinpoint disease specifics. The first lab test for the diagnosis, the LE cell prep, is long gone, replaced by better diagnostic tests, such as ANA and anti-DNA. The way these tests are done has shifted from labor-intensive, not very sensitive, immunodiffusion assays to automated solid-phase immunoassays that are more sensitive and highly reproducible. This includes stratification by clinical status, autoantibody, and complement, such that anti-DNA- and anti-Sm-positive patients with and without hypocomplementemia are known to be different from anti-Ro/SSA- and La/SSB-positive patients and different from antiphospholipid-positive patients, Dr. Schur says.
Similarly, many more ways exist for clinicians to assess disease activity, including the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the Systemic Lupus Activity Measure (SLAM) and the European Consensus Lupus Activity Measurement (ECLAM), to name a few.
“Clinical trials are also using combinations of indices to create composite assessment measures for determining trial outcomes. Examples include the Systemic Lupus Erythematosus Response Index, used in the pivotal belimumab trails, and the BILAG-based Combined Lupus Assessment, used in a trial of epratuzumab,” Dr. Schur says.
Honing in on Pathogenesis
Researchers continue to examine lupus from different perspectives to hone in on its causes, Dr. Schur says. The study of genetics has become important for many conditions; although more than 50 genetic markers are associated with lupus, all are weak except certain genetic deficiencies of complement, Dr. Schur says. “Just because there’s a homozygous deficiency, it’s not clear how that’s affected clinical manifestations of the disease,” he says.
The role of immunity is another crucial area under investigation. “The identification of receptors by which DNA can stimulate immune responses would include TLRs and other internal nucleic acid receptors. Major questions in lupus relate to the origin of the anti-DNA response and the ways in which DNA can stimulate immunity. The discovery of the TLRs and other sensors provides insight into how DNA may drive immune responses,” Dr. Schur says. The use of transgenic mice, such as those that express anti-DNA antibodies, have been important to help understand issues of tolerance and defining events such as receptor editing.
“The identification of cytokines, chemokines, interferon, BAFF, B cells, T cells and other cells of regulating are key steps in lupus. I would include the studies on the interferon signature in this category and the characterization of cytokines, such as BAFF, including mouse models to understand its role,” he says. “These studies have been important in understanding functional immune disturbances contributing to lupus, as well as presenting new targets for therapy.”
The study of epigenetics within lupus also has evolved, Dr. Schur says. Epigenetics has helped pinpoint that smoking and sun exposure are two major things that those with lupus should avoid.
Vanessa Caceres is a medical writer in Bradenton, Fla.