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Lupus Research at Hospital for Special Surgery: An Introduction

Adapted and updated in part from past presentations of the SLE Workshop on the topic of Lupus Research

Pretima Persad, MPH

Mary Kirkland Center for Lupus Care
Hospital for Special Surgery


Doruk Erkan, MD, MPH

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

Kyriakos A. Kirou, MD, DSc, FACP

Director, Lupus Nephritis Program, Hospital for Special Surgery
Clinical Co-Director, Mary Kirkland Center for Lupus Care, Hospital for Special Surgery
Assistant Attending Physician, Hospital for Special Surgery
Assistant Scientist, Hospital for Special Surgery
Assistant Attending Physician, NewYork-Presbyterian Hospital/Weil Cornell
Assistant Clinical Member, Memorial Sloan-Kettering Cancer Center
Assistant Professor of Clinical Medicine, Weill Cornell Medical College

Stephen A. Paget, MD, FACP, FACR

Physician-in-Chief Emeritus, Hospital for Special Surgery

  1. Lupus
  2. Basic Research
  3. Clinical Research
  4. Lupus Research at Hospital for Special Surgery
  5. Antiphospholipid (APS) Research at Hospital for Special Surgery
  6. Multidisciplinary Approaches at Hospital for Special Surgery

I. Lupus

Systemic Lupus Erythematosus (SLE – also known as “lupus”) is a systemic autoimmune disease. Systemic means that it can cause generalized symptoms like fever, joint pains and swelling, and fatigue, to name a few. Lupus can affect any organ in the body, including the heart, lungs, eyes, skin, blood, kidney, and liver. Autoimmune means that someone’s immune system attacks itself.

Lupus occurs more commonly in women of reproductive age, at a ratio of 9 to 1. It is most commonly characterized by skin rashes (typically a butterfly rash across the face), arthritis, kidney disease, oral ulcers (sores), neuropsychiatric problems, hair loss, fever, and fatigue.

While treating lupus patients, the goals of rheumatologists are to: a) relieve symptoms of active lupus; b) prevent organ damage from lupus, such as kidney failure requiring hemodialysis; c) prevent adverse events of medication, such as osteoporosis due to corticosteroids; and d) ultimately achieve clinical remission of the disease. There are many medication options to treat lupus, such as corticosteroids, antimalarial medications (e.g., hydroxychloroquine, also known as Plaquenil), and immunosuppressive medications (e.g., azathioprine or mycophenolate mofetil).

Lupus research around the world has recently flourished, in terms of the number of studies performed, their quality of work, and the support available, which results in remarkable advances. Through the Mary Kirkland Centers for Lupus Research and Lupus Care, Hospital for Special Surgery is able to advance basic, translational, and clinical research for lupus. Dissecting out the mechanisms leading to disease in lupus will help lead to better therapies for this disease.

II. Basic Research

Basic research is laboratory research that studies nucleic acids and proteins that are considered important for a disease such as lupus, by experimenting with cells (animal or human) and animal models of the disease. In lupus, basic researchers investigate genetic causes of the disease, factors (proteins) in the blood or tissues, and their interplay.

Basic research is called translational when it directly studies human material and has direct potential to lead to practical applications in diagnosis and therapy for the disease.

In order to better understand basic research, the following information may be beneficial:

The immune system is designed to prevent invaders, such as viruses or bacteria, from damaging our bodies. The system has multiple "troops" in our blood with different tasks (such as the Army, the Marines, and Special Forces), and has an armamentarium ranging from bullets to cruise missiles. It is primarily set to prevent infections. If a cold virus invades, for example, you have two to three days of sniffles and a runny nose, but within a few days, you're better because these troops have done their job.

Antigens are what trigger the immune system into action. Antigens are any proteins that the body sees as foreign - the invaders.

T lymphocytes are the prime immune movers - the traffic cops. They also have memory, so they know what invader they are dealing with. T lymphocytes decide whether to bring in other battalions. One of the cell types that T lymphocytes often stimulate to action are B lymphocytes.

B lymphocytes are instructed to produce antibodies that attach to the invader in order to destroy it or block its action.

Antibodies are proteins that battle the invaders. When antibodies lock on to the invading proteins, they destroy them. The immune system uses complex regulatory mechanisms to avoid reactivity against self-antigens. In lupus, these mechanisms are not well functioning, and this allows for the generation of some antibodies to target themselves; these are called “autoantibodies.” A typical example is the antinuclear antibodies (ANA) that are present in more than 95% of lupus patients.

The Complement System is another group of proteins in our blood that improves and complements the function of antibodies. Therefore, in the case of lupus, it might lead to damage in conjunction with the ANA.

Immune Abnormalities – Although in a healthy person the immune system is always on patrol, keeping us healthy, in lupus, the immune system overreacts and forms antibodies against cells in our joints, skin, or other parts of the body. In lupus, T lymphocytes stimulate B lymphocytes to produce autoantibodies that attack the individual’s organ systems. We are looking for ways to suppress the production of those abnormal antibodies without tamping down the rest of the immune system that we need to protect us against and fight infection. Such targeted immune system suppression would not cause many of the infectious risks that currently blanket immune suppression causes.

III. Clinical Research

Clinical research involves patients in studies of the safety and efficacy of new drugs, largely in order to obtain approval from the Food and Drug Administration (FDA) before the drug can be made available to the general public.

Clinical research trials are usually done in three phases:

  • Phase I trials are the first use of a medication in humans simply to determine its safety. This phase usually involves only a few subjects, usually healthy volunteers, but also patient volunteers with mild disease. 
  • Phase II trials are designed to detect the therapeutic effect of the drugs, as well as how the drug is handled by the body (how it is absorbed and eliminated, and the optimal doses), while continuing to monitor safety. Volunteer patients who have the disease are studied. These are larger than the phase I trials.
  • Phase III trials are large trials that compare the therapeutic effect of the new drug to the prior standard of treatment or, in some cases, to a placebo (inactive pill). Again, volunteer patients who have the disease are studied.

In addition, even after a drug is approved by the FDA for one disease, further research may be conducted to further evaluate their safety, the use of the drug in different doses or in patients with different diseases, etc.

Every clinical trial has inclusion criteria, such as requiring that you have to fulfill the diagnostic criteria for lupus, have active disease, and be in a certain age group, and exclusion criteria, such as requiring that you do not have cancer, serious infections, serious kidney problems etc. These criteria are different for every clinical trial.

The "gold standard" design of clinical trials is:

  • Randomized and controlled, in which half of the patients are randomly chosen to get the new drug, while the other half, receiving an older drug or a placebo (sugar tablet), serves as the control group.
  • Double-blinded, in which neither the physician nor the patient knows who is getting the new versus the old or placebo drug, so that they won't be biased in their reporting.

Another form of clinical research involves health outcome studies, which look at how the patient does as a result of the treatment, with a focus on the patient's quality of life.

IV. Lupus Research at Hospital for Special Surgery

There is vast, ongoing clinical research being done with lupus patients all over the world. Clinical trials have been set up with the intention of learning more about the disease by monitoring patients who are undergoing various treatments.

The Mary Kirkland Center for Lupus Research was generously founded and supported at the Hospital for Special Surgery by Katherine and Arnold Snider through their foundation called Rheuminations, Inc. The goal of the Mary Kirkland Center for Lupus Research is to expand basic, translational, and clinical research initiatives.

The Mary Kirkland Center for Lupus Care, founded in July 2009, provides a multi-disciplinary approach to lupus care and treatments and encompasses clinical patient care, physician education, educational activities and programs; as well as social work support and programs. The Center is heavily involved in enrollment and implementation of lupus research.

Translational research is also a major part of our lupus research activities at our institution. This research aims to bring new discoveries in basic research directly to the patient. It is also known as “bench to bedside” research.

HSS is part of the Lupus Clinical Trials Consortium, Inc. (LCTC), also supported by the Sniders. Formed because the last four decades have been quite slow in producing FDA-approved lupus medications, the LCTC is comprised of over twenty of the best lupus centers in North America whose shared mission is to support the process of getting promising new therapies to market for people with lupus. The LCTC engages in many different types of educational activities aimed at demonstrating the need for lupus clinical research and highlighting issues that are unique to lupus clinical research and has recently initiated a North America-wide registry of lupus patients.

FDA-approved drugs for lupus over the last 40 years have included only one medication (Plaquenil) while others such as azathioprine, cyclophosphamide, and prednisone are used based on clinical experience. In contrast, there are now 20 to 30 clinical trials for new lupus drugs currently underway.

Active or recently completed multi-center lupus clinical trials that HSS researchers have participated in are (selected):

  • Anti-BlyS (HGS 1006-C1056): A Phase III, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 76-Week Study to Evaluate the Efficacy and Safety of Belimumab in Subjects With SLE; sponsored by Human Genome Sciences
  • LISA (MI-CP126): A Phase I, Randomized, Double-Blind, Placebo Controlled, Dose-Escalation Study with an Open-Label Extension to Evaluate Safety and Tolerability of a Single IV Dose of Medi-545, A Fully Human Monoclonal Antibody Directed Against Interferon Alpha Subtypes, in Patients with Systemic Lupus Erythematosus; sponsored by MedImmune.
  • APRIL (27646): A Phase II/III Randomized, Double-blind, Placebo-controlled, Multicenter Prospective Dose Finding Phase II/III Study with Atacicept Given SQ to Subjects Having Recently Experienced a Flare of SLE, sponsored by EMD SERONO
  • IFN3958g: A Phase I, Randomized, Double-Blind, Placebo Controlled, Escalating Single-And-Multiple Dose Study of the Safety, Tolerability and Pharmakokinetics of rhuMAb INFalpha in Adults with Systemic Lupus Erythematosus; sponsored by Genentech.
  • ROSE (IFN4575g): A Phase II, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Rontalizumab (rhuMAb INFalpha) in Patients with Moderately to Severely Active Systemic Lupus Erythematosus; sponsored by Genentech.
  • EXPLORER (U2971g): A Randomized, Double-Blind, Placebo-Controlled, Phase II/III Study to Evaluate the Efficacy and Safety of Rituximab in Subjects with Moderate to Severe Systemic Lupus Erythematosus; sponsored by Genentech.
  • LUNAR (U2970g): A phase III, Randomized, Double-Blind, placebo-controlled, Multicenter study to evaluate the efficacy and safety of Rituximab in subjects with class III or IV lupus nephritis; sponsored by Genentech.
  • BELONG (WA20500): A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Two doses of Ocrelizumab in Patients with WHO or ISN Class III or IV Nephritis due to SLE; sponsored by Genentech.
  • NN8360-3559:   
  • PROMISSE: Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus 
  • Mycophenolate Mofetil for Lupus Nephritis: A Prospective, Randomized, Double-Blind, active controlled, Multicenter trial to assess the efficacy and safety of mycophenolate mofetil (MMF) in maintaining remission and renal function in subjects with lupus nephritis who underwent successful induction therapy with either MMF or cyclophosphamide; sponsored by Aspreva.
  • IM101075: A Phase II/III Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Abatacept Versus Placebo on a Background of Mycophenolate Mofetil and Glucocorticosteroids in Subjects with Active Proliferative Glomerulonephritis Due to Systemic Lupus Erythematosus; sponsored by Bristol-Myers Squibb.
  • SL105: The Systemic Lupus Erythematosus (SLE) Activity Gene Expression (SAGE) Study; sponsored by Expression Diagnostics.

Lupus Registry & Repository: In our Lupus Registry database we collect information about patients diagnosed with SLE, including clinical manifestations of lupus, medications, and laboratory tests. The Repository is a collection of patient blood samples stored for research studies. The purpose of the SLE Registry and Repository is to maintain a collection of patients and samples for research studies that will identify causes of, and treatments for, SLE. While participating in the Registry and Repository will not have a direct impact on an individual’s care, the information gathered has the potential to advance knowledge about the mechanisms of organ damage and the causes of SLE.

Over 1000 SLE patients from HSS are enrolled in the Registry and Repository. Our extensive data and sample collection has been used in local research and in collaborations with institutions throughout the United States. We share our material with an international consortia dedicated to studying genetic risk factors and biomarkers that may predict the risk for lupus and the severity of disease. Data and samples have also been used to identify patients who may respond to one treatment versus another. We hope that the SLE Registry and Repository will accelerate the discovery and development of new treatments, either through identifying patients eligible for participation in clinical trials or through mechanistic studies that seek to better understand the etiology of SLE.

V. Antiphospholipid Research at Hospital for Special Surgery

A clotting disorder called antiphospholipid syndrome (APS) can develop all by itself or in association with lupus. It may cause miscarriages or clotting problems, leading to heart attacks and strokes. Antiphospholipid syndrome is treated with blood thinners (anticoagulants) to help prevent the recurrence of blood clots. Depending on its severity, this may include aspirin, warfarin (brand named Coumadin), and heparin. HSS has many premier physicians and basic/clinical researchers who have vast experience and knowledge of APS.

Active or recently completed APS clinical studies that HSS researchers have initiated are (selected):

  • RITAPS: A Pilot Study of Rituximab For the Anticoagulation-Resistant Manifestations of Antiphospholipid Syndrome 
  • STATINS: Effects of Fluvastatin on Pro-inflammatory and Pro-thrombotic Markers in Antiphospholipid Syndrome Patients
  • Cognition: Cognitive Dysfunction, Diffusion Tensor Imaging and Functional Magnetic Resonance Imaging (MRI) in Antiphospholipid Antibody (aPL)-negative Systemic Lupus Erythematosus (SLE) versus aPL-positive non-SLE Patients
  • PROMISSE: Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus 
  • APLASA: Determining the role of aspirin for thrombosis prophylaxis in antiphospholipid syndrome

VI. Multidisciplinary Approaches at Hospital for Special Surgery - Integrating patient care with research:

Perhaps the most important facet of modern lupus research and treatment is the focus on multidisciplinary care. This refers to numerous professionals with different skills providing a total treatment approach for each patient by focusing on the varying aspects of the physical and psychological effects of the disease. The complexity of lupus requires such a complex and multi-faceted approach.

With over fifty adult and pediatric rheumatologists, the rheumatology program at HSS is the largest in the world. These physicians are tightly integrated with the rest of the staff of HSS nurses, social workers, and radiologists. Additionally, there are eight rheumatologists, known as “Lupus Attendings,” who all have a special interest in lupus and are part of the Mary Kirkland Center for Lupus Care (mentioned above).

The Cardiovascular Disease (CVD) Prevention Counseling Program provides FREE cardiovascular disease assessment and education. The CVD program evaluates traditional cardiac risk factors such as blood pressure, blood glucose, cholesterol levels, body mass index, diet and exercise habits, smoking status, as well as non-traditional and lupus-specific risk factors. In order to take part in this program, patients need to be cared for by a Hospital for Special Surgery rheumatologist and carry the diagnosis of SLE (lupus) and/or aPL (antiphospholipid antibody)-positivity.

Although the treatment program focuses on medical management of the disease and its symptoms, critical work by each of the HSS lupus support programs, offered by the Department of Social Work Programs, including LupusLine®, Charla de Lupus/Lupus Chat® , LANtern® (Lupus Asian Network), and the SLE Workshop, have addressed the emotional and educational concerns of culturally diverse communities. Patients may not always feel comfortable speaking about these concerns with their doctor, and may benefit from connecting with others who have the illness. These programs are all lead by professional social workers, and are open free to the public. 

There is also specific support and advocacy for older adults through the VOICES 60+ Senior Advocacy Program, available for our hospital’s patients, as well as assistance  navigating through the complex maze of Medicaid managed care, through the VOICES Medicaid Managed Care Education Program. In addition, HSS provides other patient support services such as case management, pastoral care, and patient advocacy.

The lupus clinic, which meets on Friday mornings, brings together all of the different aspects of lupus patient care. In this forum, many physicians (including rheumatologists, kidney and skin specialists, psychiatrists, and gynecologists), as well as nurses, social workers, and research coordinators come together to discuss and provide expert help to the individual lupus patient’s problems.

If you are interested in participating in - or finding out more about - the studies and programs mentioned in this article, call Pretima Persad, M.P.H., Manager of the Mary Kirkland Center for Lupus Care, at (646) 797-8839.

Some of the information given in this article was originally presented at Hospital for Special Surgery’s SLE Workshop.


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