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
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
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
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
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
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.
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.
"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.
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
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.
Fourteen Years Running.
Advances in Rheumatology
NewYork-Presbyterian Hospital525 East 68th Street
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
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-
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]
Goran Koevski * PARALLEL IMPORTS OF MEDICINES (DRUGS) IN THE REPUBLIC OF MACEDONIA - COMPETITION LAW ISSUES I. Introduction As from the beginning of 2012, in the Republic of Macedonian, a legal framework was created for parallel imports of medicines. This regulatory reform raised a lot of dilemmas. Namely, the government wanted to make drugs (either branded or generic) more available, affordable and accessible, for as much as of the general public with reasonable prices, by reducing at the same time the governmental spending, according to its own healthcare policy. On the other hand, authorized drug wholesalers for a long time were facing negative publicity by making huge profits on the pharmaceutical market. Finally, the parallel imports possibility deteriorated the existing producer - distributor relations on the market. Exclusive distributors feel frustrated with the possibility of an additional potential competition and they expect producers to take some remedies in order to eliminate or to restrict this competition. In this Article, we expect to clarify some of these dilemmas and give comparative view of the solutions existing in other countries. II. What is the notion of parallel imports?
CONSIGLIO REGIONALE VIII LEGISLATURA — DOCUMENTI — PROPOSTE DI LEGGE E DI ATTO AMMINISTRATIVO — RELAZIONI proposta di atto amministrativo n. 57/07 a iniziativa della Giunta regionale presentata in data 24 aprile 2007 PIANO DEL PARCO NATURALE DEL SASSO SIMONE E SIMONCELLO APPROVAZIONE CON PRESCRIZIONI LEGGE REGIONALE 28 APRILE 1994, N. 15, ARTICOLO 15