Lupus Care: the Past, the Present, and the Future

Adapted from a presentation at the SLE Workshop at the Hospital for Special Surgery


Michael D. Lockshin, MD

Attending Rheumatologist, Hospital for Special Surgery
Professor of Medicine, Weill Cornell Medical College
Director, Barbara Volcker Center for Women and Rheumatic Disease

Michael D. Lockshin, MD, Director of the Barbara Volcker Center for Women and Rheumatic Diseases addressed the evolution of lupus care and treatment at the SLE Workshop, before an audience of 150 attendees. Dr. Lockshin has a special relationship with the workshop: he was the group’s first guest speaker in 1985, he serves as Medical Advisor Emeritus, and he continues to be a frequent contributor to the workshop.

Micahel D. Lockshin, MD SLE workshop group

In this presentation Dr. Lockshin addressed advances in lupus care, diagnosis and treatments by decade, beginning in 1963, the year of his graduation from medical school and continuing into the present. He also presented his thoughts on the future of lupus treatment and research.

His topics included:


Antibodies and Diagnosis

Dr. Lockshin began the presentation with personal stories regarding his training in medical school and the lack of knowledge about lupus during that period. Reading from an excerpt from Dancing at the Rivers Edge: a Patient and Her Doctor Negotiate Life with Chronic Illness, a book he co-wrote with patient, Alida Brill, Dr. Lockshin related his experience with patients with lupus during his medical residency. He stated, “I was disconcerted to witness confusion, if not fright, among my professors, in response to the symptoms of the sick young woman before their eyes.”

In the 1960’s, Dr. Lockshin noted, diagnosis for lupus was much different than it is now. In 1963, the necessary criterion was the presence of the Lupus Erythematosus cell (an abnormal cell initially found in the bone marrow of patients with Systemic Lupus Erythematosus - SLE). It did not include tests for antinuclear antibody, complement or any other antibodies. Additionally, in the 1960’s there were very few treatments for people with lupus, resulting in 50% mortality rate within three years of diagnosis.

In the early 1970’s, findings in a 16-year old patient seemed to change everything. The patient clearly had lupus; however, she did not have anti-DNA antibody, leading to questions from physicians regarding diagnosis of lupus. From this discovery and the collaboration of researchers at HSS with those at Rockefeller University, a new antibody test to diagnose SLE was identified - one that identifies an antibody called Sm (for Smith, the patient at Rockefeller University) in whom it was first found.

Dr. Lockshin told his audience that “this experience and this patient taught us to keep our minds open to things we did not yet know” and that his patient enjoyed teaching students and residents about herself. After Sm was identified, 3 more “mystery” antibodies were found (listed below); all apply to lupus, and all are used today.

These findings changed our understanding of SLE and its diagnosis in the following ways:

  • Now all patients are tested for anti-DNA, Sm, SSA/Ro, La/SSB, RNP, complement, antiphospholipid, and many others
  • It is understood that there are many subsets of SLE
  • Treatment management is based on following these antibodies which produce different symptoms
  • Study of these antibodiesm ay one day help us understand the reason the disease occurs

Brain Disease

In 1963, physicians had a limited understanding of how lupus affected the brain. A condition called lupus “cerebritis” was recognized and treated with extremely high doses of steroids, e.g., doubling the steroid dose daily until the patient improved. The condition was often fatal.

In 1975, Dr. John Sergent, an HSS-trained rheumatologist now at Vanderbilt University made clear for the first time that there are many kinds of brain disease in lupus patients. In addition, he discovered that there are multiple kinds of neurological lupus and that very high doses of steroids can do more harm than good to the brain. Shortly after this, Dr. Stuart Kassan found that some of the different types of neurological lupus can be distinguished from one another based on what the CT scan showed.

In 1990, Dr. Judah Denburg began a process to create diagnostic criteria for neuropsychiatric systemic lupus erythematosus, thereby helping to sort out these different types of neurological lupus. In 1999, Dr. Matthew Liang headed an American College of Rheumatology initiative to codify these criteria leading to a greater understanding of the symptoms and manifestations associated with specific types of neurological lupus and to appropriate treatment by type.

The combined work of Dr. Eloisa Bonfa and Dr. Keith Elkon and others in 1987, as well as Dr. Betty Diamond in 2001, determined the antibodies related to brain function; as a result, important new approaches to how we think about cognitive dysfunction and lupus emerged.

Research publications in 2006 and 2008 provided additional discussion around cognitive dysfunction, specifically those based on work presented by Dr. Paul Greengard in 2008 at the Mary Kirkland Center for Lupus Care and Research Conference at HSS.

In 2013, we have arrived at a more advanced understanding of brain disease and lupus that includes the following facts:

  • Not all brain disease in SLE is due to having SLE
  • There are many different forms of SLE brain disease, with many different treatments
  • Cognitive dysfunction is a separate problem from brain disease, but equally important
  • An increased knowledge of the mechanisms responsible for these symptoms is leading to new treatments

Genes and Gender

In 1963, researchers were aware that 90% of lupus cases were diagnosed in women. It was believed - but it was not commonly understood - that there was a possibility of familial incidence.

In 1975, the familial nature of the illness was tested in a study of twins that were diagnosed with systemic lupus erythematosus. This study concluded that SLE is highly heritable, and marked the beginning of genetic studies in SLE.

Shortly after, in 1982, Dr. Lockshin spoke of his work looking into SLE in men, to gather a better sense of the role of gender in lupus. There was argument that when lupus occurred in men, it was much worse than when occurring in women. What they found was that lupus was equally severe in both genders and that the cause was most likely not hormonal.

The opening of the Barbara Volcker Center for Women and Rheumatic Diseases in 1997 marked an exciting year for the Hospital for Special Surgery and Dr. Lockshin. This center is known for the extensive research that has been completed and is ongoing on rheumatic diseases such as SLE including exploring whether sex matters in the diagnosis of lupus. Specifically, in 1999, 2001, and 2007, the biology of sex and age distribution in SLE was explored in conferences and a national Institutes of Medicine focus on this topic.

Dr. Lockshin explored what we currently know about the connection between sex, genes, and lupus. There is now extensive knowledge in the medical community about which genes and mechanisms - as well as differences in men and women - predispose people to lupus. This has given rheumatologists, such as Dr. Lockshin, greater opportunity to provide interventions.

Pregnancy

In 1963, medical professionals had limited knowledge regarding lupus and pregnancy; physicians believed that:

  • Lupus flares in pregnancy
  • Pregnancy during lupus was contraindicated
  • There were high rates of miscarriage with lupus pregnancies

(A lupus diagnosis constituted one of the few circumstances in which a legal abortion was permitted prior to Roe vs Wade, Dr. Lockshin noted.)

In 1983, research indicated that there was a way to predict rare fetal complications in pregnancy with women living with lupus - a condition known as neonatal lupus. In 1984 and in 1989, Dr. Lockshin published research demonstrating that pregnancy does not cause SLE to worsen.

Dr. Lockshin’s work in the field was further recognized when he chaired the First International Conference on Rheumatic Diseases in Pregnancy; he has been participating in ever since.

The first publication from the PROMISSE study, led by Jane E. Salmon, MD, attending physician at HSS, which details pregnancy and adverse outcomes in patients with lupus and antiphospholipid antibody syndrome, was published in July of 2012 . (PROMISSE stands for Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus.) The PROMISSE study provided new detail that predicted who would encounter problems with pregnancy and how to best treat them. PROMISSE is the largest, most detailed prospective study of lupus pregnancies ever conducted and will contribute to the rewriting of the formal literature on lupus and pregnancy, Dr. Lockshin told the workshop audience.

Through Dr. Lockshin’s extraordinary and diligent work, we now know that women with lupus can conceive a child and tolerate pregnancy under the close care of her physician Moreover, research has demonstrated that:

  • Pregnancy does not cause lupus to flare
  • The risk for pregnancy is predictable
  • There are available interventions for this predicted risk
  • Neonatal Lupus Syndrome is predictable; a syndrome that occurs in 1 to 2 percent of infants born to mothers with autoimmune disease, primarily SLE and Sjögren’s syndrome
  • Rheumatologists have had the opportunity to see children born from mothers with lupus through their teens and young adulthood without any adverse effects

Antiphospholipid Antibody Syndrome (APS)

Antiphospholipid Antibody Syndrome (APS) is a syndrome in which antibodies can cause blood clots and block arteries and veins, thereby increasing risk of stroke. This syndrome can cause pregnancy-related complications such as miscarriage, stillbirth, and preterm delivery. In 1963 a lupus anticoagulant (which paradoxically causes clotting, and which is now understood to be one type of antiphospholipid antibody) was identified, but its role was not understood.

In 1983, the first easy evaluation for lupus anticoagulant was published, marking the beginning of a better understanding of antiphospholipid syndrome. Shortly after, in 1985, research indicated that the presence of the antibody to cardiolipin - a hallmark of APS - is a predictor of pregnancy loss or death in pregnant patients.

The work of Dr. Stewart Greisman, published in 1991, provided the first description of the rare but serious event that is now known as Catastrophic Antiphospholipid Syndrome.

In July of 1999, Dr. Lockshin along with colleagues around the world came together to write the International Consensus Statement on Preliminary Classification Criteria for Definite Antiphospholipid Syndrome, giving the world international criteria for APS.

Ten years later, in 2009, researchers discovered new approaches for managing antiphospholipid syndrome, beyond anticoagulation therapy.

As stated earlier, in 2012, results from the PROMISSE study led to improved methods for predicting problems with pregnancy due to APS and lupus.

As of 2013, antiphospholipid syndrome has become widely recognized as a different illness than lupus. Research has detailed the differences about how it develops and in whom. Additionally, there are many new treatments that have been found over the years for the syndrome, as well as different approaches. This can in part be attributed to the APS Action Alliance for Clinical Trials and International Networking, an international network focused on conducting clinical research studies with a commitment to preventing, treating, and curing AP-associated symptoms.

Clinical Management and Treatment:

Medication
As of 1963, there were few treatments for SLE. Everyone with a lupus diagnosis was placed on a high dose of oral prednisone. Hydroxychloroquine and cyclophosphamide were also offered, in addition to aspirin for arthritis pain.

A decade later, in 1973, Dr. Lockshin questioned the need for high dose steroids for all SLE patients, as he had seen patients that clearly were not in need of this method of treatment.

Years later, in 1981, Dr. Lockshin had been working with others on high-dose intravenous administration of treatments. This, and other developments, led to the introduction of the ‘bolus’ steroid, a high dose intravenous steroid dosing that has become the standard for SLE treatment.

Today the role of prednisone has been reduced and treatment recommendations are based on the need of the individual patient. Other effective treatments, recommended for specific reasons in specific patients, now include hydroxychloroquine, mycophenolate, azathioprine, cyclophosphamide in an intravenous form, belimumab, and rituximab. Many others are being tested.

Contraceptives
Other changes in lupus treatment were also made. In 1963, patients with SLE were advised against using oral contraceptives because estrogen was recognized to play a role in the disease. A large change occurred in 2005 when research showed that some women can take oral contraceptives with estrogen safely, although it must be monitored by their rheumatologist. In 2013, oral contraceptives - including estrogen-based contraceptives - are known to be safe for many patients.

Joint, Cardiac, and Renal Problems
Additionally, in 1963 providers had little concept of atherosclerosis (hardening of the arteries) or osteoporosis (bones become brittle and fragile from loss of tissue), as potentially severe long-term complications that lupus patients are at increased risk of developing early as they age. Furthermore, renal transplants were a new treatment, but, were inadvisable for people with lupus.

In 2003, researchers found that people can live for a long time with lupus; however, there is a tendency for early development of atherosclerosis in this population. Today, physicians are highly alert to the potential long-term complications of SLE, including atherosclerosis. Furthermore, renal transplants are now available as a form of treatment for serious renal problems into people living with lupus.

Physicians and researchers are working diligently through clinical trials to find new therapies for lupus. Twenty academic institutions have been awarded funding to support this goal through the Lupus Clinical Trials Consortium, Inc., founded in 2002 by Katherine and Arnold Snider. Mr. and Mrs. Snider also funded the Mary Kirkland Center for Lupus Research at Hospital for Special Surgery, which is dedicated to advancing research in the field and developing new treatment plans for the future.

Looking to the Future

Dr. Lockshin concluded his presentation by addressing treatment and research in the future. He spoke about his belief that the cause of SLE will prove to be an environmental trigger, such as an infection, and that estrogen will ruled out as a cause. Additionally, he speculated that the reasons why young female adults and African Americans are particularly susceptible to SLE will become obvious to researchers once the cause of the disease is found.

Moreover, Dr. Lockshin believes prevention will become possible. Measures would involve identifying what makes people susceptible to lupus, as well as eliminating or preventing exposure to the perceived cause.

In addition, once disease onset has occurred, treatment will be tailored to each person’s biological and personal historical profile thereby preventing damage from occurring within the body. People with SLE will be able to live long, normal lives. There is hope!


Summary prepared by Jill Orrock, MSW intern and SLE Workshop Coordinator.

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