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ADVANCES IN RHEUMA Affiliated with Columbia University Col ege of Physicians and Surgeons and Weill Cornell Medical College Addressing the Ongoing Challenges of
Systemic Lupus Erythematosus
The rheumatology program at NewYork-Presbyterian Hospital is comprised of As founder and Clinical Director of the new Lupus faculty affiliated with Weill Cornell Medical College and Hospital for Special Center and the Director of Rheumatology Clinical " We're still in the infancy stage with lupus. Surgery, and Columbia University Research at NewYork-Presbyterian/Columbia We need to come up with some unifying College of Physicians and Surgeons. University Medical Center, Anca D. Askanase, MD,
The program provides state-of-the-art diagnoses, outcome measures, and MPH, is well aware that a comprehensive under-
care to patients with the broad range of standing of lupus continues to elude the rheumatology treatment algorithms that work for the inflammatory and autoimmune diseases, pursues groundbreaking research at both the laboratory level and through clinical "We're still in the infancy stage with lupus," says – Dr. Anca D. Askanase studies, and offers comprehensive training Dr. Askanase, an internationally renowned clinician, to medical residents and fellows.
diagnostician, and researcher with more than 15 years specializing in lupus. "We need to come up with some and symptoms of lupus," says Dr. Askanase. "Many unifying diagnoses, outcome measures, and treatment patients may be experiencing some symptoms long algorithms that work for the whole disease." before they seek a doctor's opinion. I think the Joan M. Bathon, MD
Among the challenges, notes Dr. Askanase, are diagnosis is harder when things slowly add up, where that lupus can range from mild to life threatening it's a process that occurs over a period of years." Division of Rheumatology and it happens in stages. "It's an accumulation over It is an opinion widely shared. "Historically, we've time of immune system abnormalities that leads been using classification and diagnosis criteria for Columbia University to tissue inflammation, pathology, and the signs (continued on page 2) Mary K. Crow, MD, MACR
Systemic Lupus Erythematosus:
Physician-in-Chief and Chair Understanding and Managing Renal Involvement
Division of RheumatologyHospital for Special Surgery Twice a year on a Friday, Kyriakos A. Kirou, MD,
NewYork-Presbyterian/Weill Cornell Medical Center DSc, Clinical Co-Director of the Mary Kirkland
for the express purpose of an in-depth discussion Center for Lupus Care and Director of the Lupus of the care of challenging cases of patients with Nephritis Program at Hospital for Special lupus nephritis, their optimal therapy, and CONTINUING
Surgery, and other HSS rheumatologists are joined outcomes. Discussion of lupus nephritis cases by nephrologists and a renal pathologist from continues, less formally, every Friday, and literally at any time there is a need to do so, especially when For all upcoming rheumatology fellows need advice with their cases.
education events through "We established the Lupus Nephritis Program NewYork-Presbyterian Hospital, to allow us to focus specifically on this disease because it's complicated and it requires a multidisciplinary approach," says Dr. Kirou. "Our goal is to provide the best possible care for our lupus nephritis patients by using the exceptional resources available to us at Hospital for Special Surgery and NewYork-Presbyterian/Weill Cornell. Our approach includes the close collaboration of rheumatologists, nephrologists, a kidney pathologist, our nurse practitioner, and infusion room nurses." Dr. Kyriakos A. Kirou (continued on page 3) Advances in Rheumatology Addressing the Ongoing Challenges of Systemic Lupus Erythematosus (continued from page 1)
lupus," says Dr. Askanase. "There's currently in clinical trials not only for multiple myeloma but also currently an effort to update specifically for lupus." those by the Systemic Lupus Dr. Askanase is actively involved in clinical research to develop International Collaborating Clinic new therapeutics that could redefine outcomes for lupus. She has [SLICC], which is a group of been an investigator on multiple NIH and industry sponsored physicians from around the world clinical trials, including the Phase III clinical trial and several trying to redefine criteria and Phase IV clinical trials that allowed for the approval of Benlysta® redefine the diagnosis of lupus. The (belimumab) – a monoclonal antibody, which represents a aim of this change is to make the breakthrough in lupus drug development and the first FDA- diagnosis criteria more sensitive approved treatment for lupus in 50 years.
with an attempt to include a larger She also was lead author on a report of observational studies of number of patients." Benlysta® published in Rheumatic Diseases Clinics of North America. In addition to her membership The paper discusses three post-marketing experiences that on the SLICC, Dr. Askanase examined the clinical use of belimumab in the treatment of SLE Dr. Anca D. Askanase serves on the Medical-Scientific patients outside of clinical trials in real-world practices. "Each of Advisory Council of the Lupus Foundation of America, where the three observational studies demonstrated that belimumab was she and her colleagues are working to define a more user-friendly generally well tolerated and was safe to incorporate into standard and comprehensive outcome measure.
SLE therapy," says Dr. Askanase. "No new safety signals were These types of initiatives have precedent. "Until relatively noted with regards to infections, malignancies, depression, or recently, the lupus community could not agree on a definition of a lupus flare, a situation that created a barrier to the development Ideally, down the road, Dr. Askanase hopes researchers will be of new, safe, and more tolerable treatments for lupus," notes able to identify what drives lupus manifestations – the cytokine or Dr. Askanase. "As a result, the Lupus Foundation of America several cytokines and their role in the pathogenesis of lupus. Out spearheaded a four-year, worldwide initiative to develop the of that discovery could come the right anticytokine, antisignaling first universally accepted definition of a lupus flare. It seemed molecule, or a combination of both that would enable physicians to a foundational step that was necessary for us and our patients. control lupus and put it into permanent remission.
Basically we agreed that a flare is a change in lupus signs and "Obviously, there are many pressing questions surrounding this symptoms, as well as the way patients feel, that could potentially disease that need to be more accurately and rapidly answered," trigger a change in treatment, and further refinement of the says Dr. Askanase. "Those answers may ultimately emerge from definition is underway." large-scale international collaborations, such as the SLICC, which are pooling cohorts of lupus patients to create a comprehensive On the Road to New Therapeutics
database. There is strength in numbers. Having a very large The standard armamentarium for lupus includes antimalarials, database of patients will help us to answer some of the very nonsteroidal anti-inflammatory drugs, corticosteroids, cytotoxics, important questions. These include actual risk for malignancy and immune suppressants – all of which improve disease activity or central nervous involvement, long-term sequela of lupus, but put patients at risk for long-term consequences from both and whether we are able to make an impact on mortality and low-level, active SLE and from the medications themselves. So morbidity over time." new therapeutics developed specifically for lupus are desperately needed. "Steroids are both our ‘biggest friend' because of the major Askanase AD, Yazdany J, Molta CT. Post-marketing experiences with impact they have made on the survival rate of lupus patients, belimumab in the treatment of SLE patients. Rheumatic Diseases Clinics of North America. 2014 Aug;40(3):507-17.
but also our ‘biggest enemy' because of the long-term damage they can cause," says Dr. Askanase. "There is a strong interest Bernatsky S, Ramsey-Goldman R, Joseph L, Boivin JF, Costenbader KH, in replacing steroids with effective alternatives; but the major Urowitz MB, Gladman DD, Fortin PR, Nived O, Petri MA, Jacobsen S, Manzi S, Ginzler EM, Isenberg D, Rahman A, Gordon C, Ruiz-Irastorza G, hurdle is that all of the drugs that we've been looking at Yelin E, Bae SC, Wallace DJ, Peschken CA, Dooley MA, Edworthy SM, recently are drugs that require a loading period and time for the Aranow C, Kamen DL, Romero-Diaz J, Askanase A, et al. Lymphoma risk biologic effect to take place. Prednisone, non-specifically and in systemic lupus: effects of disease activity versus treatment. Annals of the indiscriminately, shuts down the immune systems very fast.
Rheumatic Diseases. 2014 Jan;73(1):138-42.
"We have also borrowed medications from both the transplant Bernatsky S, Ramsey-Goldman R, Labrecque J, Joseph L, Boivin JF, repertoire and the chemotherapy repertoire to suppress the Petri M, Zoma A, Manzi S, Urowitz MB, Gladman D, Fortin PR, Ginzler E, disease's over-driven immune system," says Dr. Askanase. "These Yelin E, Bae SC, Wallace DJ, Edworthy S, Jacobsen S, Gordon C, Dooley include the immunosupressants mycophenolate mofetil and MA, Peschken CA, Hanly JG, Alarcón GS, Nived O, Ruiz-Irastorza G, azathioprine, as well as cytoxan and methotrexate. Researchers are Isenberg D, Rahman A, Witte T, Aranow C, Kamen DL, Steinsson K, continuing to look at drugs used in chemotherapeutic indications, Askanase A, et al. Cancer risk in systemic lupus: an updated international multi-centre cohort study. Journal of Autoimmunity. 2013 May;42:130-35.
but also at drugs that are more specifically developed for lupus. There is interest in using some of the multiple myeloma drugs, For More Information
such as Velcade®, and a similar compound, ixazomib, which is Dr. Anca D. Askanase • [email protected] Advances in Rheumatology Systemic Lupus Erythematosus: Understanding and Managing Renal Involvement (continued from page 1)
of the kidneys and is not significant clinically. Class II also indicates a very mild degree of disease, with some inflammation present but not enough to trigger therapy," explains Dr. Kirou. "The disease becomes more serious with Class III and Class IV, representing the proliferation of cells within the kidney or other cells coming from blood in the kidney, which will eventually cause trouble with scarring and kidney function." Class V may exist by itself or in (From left) Surya V. Seshan, MD, kidney pathologist, Miriam Chung, MD, and James M. Chevalier, MD, association with Classes III and IV and nephrologists, and Kyriakos A. Kirou, MD, and Doruk Erkan, MD, rheumatologists, during a weekly is different than those. "With Class V, conference of the Lupus Nephritis Program lupus nephritis is a membranous disease," says Dr. Kirou. "So now the problem is In addition to many other complica- but the lower they become, the more likely in the basement membrane where the tions of lupus – including cardiovascular, they are to be indicative of severe disease." glomerular capillaries – small blood pulmonary, musculoskeletal, gastroin- While symptom presentation and vessels where blood filtration to form the testinal, and neuro-psychiatric – lupus laboratory tests can indicate a diagnosis urine takes place – are attached. This nephritis is a prominent feature of the of lupus nephritis, Dr. Kirou notes that Class V lupus nephritis, or membranous disease. "Approximately half of lupus renal ultrasound may be recommended nephritis, can be mild or more severe patients develop lupus nephritis, to first rule out other causes of kidney depending on the amount of protein usually early in the course of SLE," says disease. A kidney biopsy is then typically leaking into the urine. Classes III, IV, Dr. Kirou, "and approximately 10 to 20 performed on all patients with clinical and V often require aggressive treatment. percent of those will progress to dialysis evidence of previously untreated active Most doctors will use steroids or similar or transplantation.
lupus nephritis. compounds because they work quickly. "The biopsy will allow us to determine The treatment may begin with a high the degree of activity, the degree of dosage administered intravenously for Clinical Presentation of Lupus Nephritis inflammation in the kidney, and the one to three days just to get a head start degree of scarring," says Dr. Kirou. "If a on attacking the inflammation. This • Microscopic hematuria lot of scarring is present but not much would be followed by an oral regimen of disease activity, then we generally do about 40 to 60 mg of prednisone per day.
not recommend immunosuppressant • Rising serum Cr level medications since there's little or no room • Nephrotic syndrome for improvement. These patients will likely go on to need hemodialysis or kidney transplant. Patients who are active on the "When the kidney is affected, a very biopsy will need aggressive therapy. The common finding is swelling of the feet," biopsy also helps us decide what therapy explains Dr. Kirou. "Blood pressure can be to administer. Our renal pathologist, high, which can cause headaches. And in Dr. Surya Seshan, reads the biopsies of a minority of patients, the urine becomes all of our patients and helps us arrive at dark signifying the presence of blood, or the right diagnosis and then the right foamy because protein is present. These are treatment approach for each patient." all clues for the rheumatologist to consider Kidney biopsy from a patient with Class IV lupus that the patient may have nephritis." Classifying and Treating Lupus Nephritis
nephritis showing a glomerulus with narrowing/closing of the capillaries from an abnormal increase of cells Dr. Kirou notes that as the disease A kidney biopsy also enables the lupus within those vessels. (Courtesy of Dr. Surya V. Seshan, Professor becomes more active, the patient may nephritis to be classified according to the of Clinical Pathology and Laboratory Medicine at Weill Cornell have a high ANA titer and a positive International Society of Nephrology/Renal anti-double-stranded DNA test. "The Pathology Society 2003 Classification of levels of complement proteins C3 and Lupus Nephritis and evaluated in terms of "At the same time we know that the C4 are often low, especially in lupus its activity and chronicity. The biopsy can prednisone doesn't have a long-lasting effect nephritis, reflecting the activation of the also help exclude other causes for the renal so we will start an induction regimen with immune system," explains Dr. Kirou. disease such as acute tubular necrosis due other agents to bring the disease under "Below 90 mg/dl for C3 and below to medications or hypovolemia.
control," says Dr. Kirou. "These would be 16 mg/dl for the C4 are considered low, "Class I represents very minor involvement (continued on page 4) Top Ranked Hospital in New York.
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New York, NY 10065 STATEN ISLAND, NY Systemic Lupus Erythematosus: Understanding and Managing Renal Involvement (continued from page 3)
classically either cyclophosphamide or mycophenolate mofetil. organization of clinicians and scientists is to foster collaborations After we achieve some control, hopefully the disease will respond that include clinical trials designed to prevent chronic kidney and we will start to see reduced swelling and a decrease in disease and end-stage renal failure in patients with lupus; develop proteinuria and blood in the urine, as well as an improvement in guidelines for assessing and treating patients with lupus nephritis; blood pressure. When we reach that stage, we want to maintain and pursue investigations on a wide variety of therapeutic agents, it because if we don't, the disease will come back. It's a relapsing treatment methodologies, and biomarkers of disease.
disease. So we will want to give a maintenance therapy for at Dr. Kirou is also an investigator in the ALLURE study, a least two years or so." Phase III randomized, double-blind, placebo controlled study to evaluate the efficacy and safety of abatacept or placebo in combination with mycophenolate mofetil and corticosteroids in subjects with Dr. Kirou recommends that in the immediate future "physicians active Class III or IV lupus nephritis. The study is expected to enroll should be more sensitized to treating lupus nephritis very approximately 400 patients in 120 sites worldwide.
aggressively and very early on. "Time is kidney," says Dr. Kirou. "It's important to act quickly and effectively, especially to prevent scarring, which is irreversible. The more attacks there Reference Articles
Pan N, Amigues I, Lyman S, Duculan R, Aziz F, Crow MK, Kirou KA.
are on the kidney, the more likely the patient will need dialysis." A surge in anti-dsDNA titer predicts a severe lupus flare within six months. The work of Dr. Kirou and his colleagues at HSS and NewYork- Lupus. 2014 Mar;23(3):293-98.
Presbyterian extends to collaborations with rheumatologists Kyriakos A. Kirou, MD, and Michael D. Lockshin, MD. Systemic Lupus and nephrologists with an interest in lupus nephritis across the Erythematosus. ACP Medicine. Decker Intellectual Properties Inc. 2013.
country and around the world through organizations such as the Lupus Nephritis Trials Network. The mission of this international For More Information
Dr. Kyriakos A. Kirou • [email protected]

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