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QUARTERLY
Vol. 10, Issue 1 – Winter 2015 SSF Medical and Scientific
Advisory Board
Chair
Denise L. Faustman, MD, PhD
Members
Esen Akpek, MD
Richard Brasington, MD, FACR
Michael Brennan, DDS, MHS
Steven E. Carsons, MD*
Nancy L. Carteron, MD, FACR
Troy Daniels, DDS, MS*
H. Kenneth Fisher, MD, FACP, FCCP
Gary Foulks, MD, FACS
Theresa Lawrence Ford, MD
S. Lance Forstot, MD
Philip C. Fox, DDS*
Robert I. Fox, MD, PhD, FACP*
Tara Mardigan, MS, MPH, RD
Austin Mircheff, PhD
John Daniel Nelson, MD, FACS
Kelly Nichols, OD
Athena Papas, DMD, PhD
Ann Parke, MD
Andres Pinto, DMD
Nelson Rhodus, DMD, MPH
Vidya Sankar, DMD, MHS
Daniel Small, MD, FACP
Neil Stahl, MD
Frederick B. Vivino, MD, FACR
Jeffrey Wilson, MD, FACR
Associate Members
Simon J. Bowman, PhD, FCRP
Arthur Grayzel, MD, FACR*
Roland Jonsson, DMD, PhD
Stuart S. Kassan, MD, FACP*
Robert Lebovics, MD
Michael Lemp, MD*
Xavier Mariette, MD
Haralampos M. Moutsopoulos, MD*
Manuel Ramos-Casals, MD, PhD
James J. Sciubba, DMD, PhD*
Janine A. Smith, MD
Harry Spiera, MD*
Leo Sreebny, DDS, MS, PhD*
Norman Talal, MD*
Athanasios G. Tzioufas, MD
Claudio Vitali, MD
Daniel J. Wallace, MD
Pierre Youinou, MD, Dsc
*Counselor
Sjögren’s Syndrome Foundation
6707 Democracy Blvd., Ste 325
Bethesda, MD 20817
(301) 530-4420
www.sjogrens.org
©2015 Sjögren’s Syndrome Foundation
The Professionals’ Resource on Sjögren’s Syndrome
C l i n i c i a n ’s C o r n e r
Brand vs. Generics: Easy to Blame, but Hard to Prove
by Jeffrey M. Brewer, PharmD, BCACP, Associate Professor, Pharmacy Practice,
School of Pharmacy and Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York
S
ince 2009, the U.S. market share for generics has risen from
63% to 84%.1 This significant transformation has been
driven largely by the need to understand and contain rising
healthcare costs for private and government payers. Despite the
majority of patients taking generic medication, it is not unusual
to hear patients and providers voice frustration with coverage
issues or concern that a newly refilled medication is less effective
than the original prescription.
Jeffrey M. Brewer, PharmD
“A lot of times, the doctor gives you a sample and it is the brand
name. But when you go to get the medicine, it is too expensive. So you
end up with the generic. You can really tell the difference… just how effective they are.”
(Sewell K et al 2011)
This quote, from a 2011 focus group study in rural Alabama highlights what many patients
and providers perceive about prescription medication.2 The process of what happens once a
Continued on page 2 t
Treating Sjögren’s – The Future!
T
he Sjögren’s Syndrome Foundation (SSF) highlighted
the progress made in encouraging clinical trials during
November’s SSF luncheon meeting during the American
College of Rheumatology (ACR) annual conference. Topics included the SSF Clinical Trials Consortium and Targets for New
Therapeutics – The Science; in addition, updates on Outcome
Measures were mentioned, and the SSF hosted an international
meeting on Classification Criteria.
SSF Clinical Trials Consortium
By Theresa Lawrence Ford, MD
Chair, SSF Clinical Trials Consortium; and Medical Director,
North Georgia Rheumatology Group, PC, Lawrenceville, Georgia
Theresa Lawrence Ford, MD
The SSF Clinical Trials Consortium (CTC) held its first international meeting in 2014 and is now seeing many of its efforts come to fruition after working
with companies and clinical research centers to increase interest in Sjögren’s. First established by
the SSF with the late Elaine Alexander, MD, PhD as its chair, the CTC mission is to increase the
availability and accessibility of therapies for treating Sjögren’s. Three major goals were developed
Continued on page 6 t
2
“Clinician’s Corner – Brand vs. Generics” Continued from page 1 t
Sjögren’s Quarterly
was 53 years old with 66% female and most identified
as Caucasian/white. The patients overwhelmingly found
therapeutic decision has been made is not transpargenerics to be cost-effective, at least as safe from side-efent to most patients. Historically, once the provider
fects, and a better value. However, only 38% preferred to
diagnoses their patient’s disease, reviews the guidelines
take generics for themselves. This discrepancy between
and chooses a medication, their overt involvement in
the perceived efficacy, safety and value of generics and
the medication use process was essentially done. Over
the last ten to fifteen years, the complexity of insurance the patient’s personal preference for them also appeared
to be influenced by the lack of professional guidance
coverage, the number of medications available and the
from their medical team. Over half of the patients noted
rise of medication therapy management services have
that their provider seldom or never discussed brandmade it crystal clear that several of the biggest barriers
generic issues. One explanation for this finding could be
to achieving patients’ health goals are between providthat the complexity of the therapeutic decision-making
er’s visits. This article will review patient’s perceptions
captures the providers’ focus, and once the prescription
of generics, review the FDA’s process in determining
therapeutic equivalence and consider other factors that is written, the baton is handed off to the pharmacy and
patient to complete.
should influence provider’s communication of these
This theme was picked up in the 2011 article from
issues with their patients.
Sewell.2 Their study of 30 African-American adults from
Table 1
two counties in rural Alabama found several important
Patients’ perceptions of generics across two studies.
themes. These groups perceived differences between
Shrank et alKeenum et al brand and generic medications from efficacy to side
20093
20124
effects, even going as far as saying generics were “not the
Generic less expensive
94%
97.7%
real thing.” The last two themes, (lack of) trust in the
Generics as effective
—
76.7% medical system and settling for generics because of cost,
Generic better value
70%
60.5% appeared to drive their earlier views of generics being
Rather take generic
37.6%
45.3% inferior. On the topic of communication with providGeneric caused more side effects
< 10%
— ers, these patients were respectful of providers training
Generic did not cause more side effects
—
86.6% and knowledge but felt that the relationship with the
pharmaceutical companies significantly influenced their
Provider never did or seldom
talked about generics
—
53.7% prescribing habits.
The original perception study was redone in 2012
Provider talked about generics
—
29.7%
with 172 women from an OB/GYN practice in the
Two studies during this time span help to highlight
northeast.4 The average age was 29 years old, 84% were
how patients view this steady march of generics into
Caucasian, and 20% had not completed high school.
their homes. In 2009, a nationally mailed survey of com- The perception that generics were safe, effective and
mercially insured adults identified several very interest- comparable to their brand counterparts was similar to
ing but conflicting findings.3 The patient’s average age
the 2009 study. The patient’s personal preference for
generics was still low at 45% but higher than in 2009.
In spite of the significant increase of generics nationEditor
ally during this timeframe, only 30% discussed the issue
Katherine M. Hammitt, MA
with their provider.
Associate Editor
Michele Champigny
It is clear from the sources above that there are
Medical & Scientific Editor
multiple social and economic factors that may afNancy Carteron, MD
fect patient’s views and usage of generics. Even with
Co-Medical & Scientific Editors
the increasing use of generics from 2009 to 2012, the
Vidya Sankar, DMD
S. Lance Forstot, MD
communication between providers and their patients
remained low. I believe this is the key to resolving the
At-Large Medical
The Sjögren’s Quarterly® newsletter is
& Scientific Reviewers
published by the Sjögren’s Syndrome
mistrust of the system and perception of differences in
Esen K. Akpek, MD
Foundation Inc., 6707 Democracy
Herbert Baraf, MD, MACR
the medications. When providers include the patient
Blvd., Suite 325, Bethesda, MD 20817.
Jeffrey Wilson, MD, FACR
Copyright ©2015 Sjögren’s Syndrome
in the complex prescribing decision-making process,
Foundation Inc. ISSN 0899-637.
SSF CEO
the provider will be able to identify important patient
Steven Taylor
DISCLAIMER: The Sjögren’s Syndrome Foundaconcerns as well as communicate their own perceptions
tion Inc. in no way endorses any of the medie-mail: sq @ sjogrens.org
cations, treatments, or products mentioned in
regarding the importance of brand, generic, route, dose,
www.sjogrens.org
advertisements or articles.
frequency and other important aspects Continued on page 4 t
Rx Only
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1
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substitute in relieving dry mouth symptoms.2,3
• No side effects repor ted in clinical studies
• One application lasts up to 4 hours 2,3
• Nonpharmacologic, nonsystemic therapy
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• Gluten free4
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INDICATIONS: Aquoral is intended to provide relief from chronic and
temporary xerostomia (dry mouth), which may be a result of disease such as
Sjögren’s Syndrome, oral inflammation, medication, chemo or radiotherapy,
stress or aging. Aquoral relieves symptoms of dr y mouth such as difficulties
in swallowing, speech, and changes in taste.
IMPORTANT SAFETY INFORMATION
Visit aquoral.com
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CONTRAINDICATIONS: Aquoral is contraindicated for any patient with a
known histor y of hypersensitivity to any of its ingredients.
PRECAUTIONS: Read package insert carefully before using this spray. Avoid
For a 6-8 Week
contact with eyes. Flush eyes with water if accidental introduction into eyes
Supply
should occur.
INTERACTIONS: There are no known interactions with medicinal or other products.
Please see full Prescribing Information provided.
25
References: 1. Aquoral [package insert]. San Antonio: TX. Mission Pharmacal Company; 2013. 2. Mouly SJ et al. Efficacy of a new oral lubricant solution in the management
of psychotropic drug-induced xerostomia: a randomized,controlled trial. J Clin Psychopharmacol. 2007;27(5):437-443. 3. Mouly SJ et al. Management of xerostomia in
older patients: a randomised controlled trial evaluating the efficacy of a new oral lubricant solution. Drugs Aging. 2007;24(1):957-965. 4. Data on file.
Please see full Prescribing Information on next page.
Copyright © 2014 Mission Pharmacal Company. All rights reserved. missionpharmacal.com AQU-14003
4
Sjögren’s Quarterly
“Clinician’s Corner – Brand vs. Generics” Continued from page 2 t
of the specific medication needed to solve the patient’s
medical problem.
Therapeutic equivalence
Beginning in the late 1970’s, and due to increasing
pressure at the state level to curtail costs, the FDA began
a process to determine the biologic and therapeutic
equivalence of prescription medications.5 According to
the FDA, a generic drug is bioequivalent to its brand
name reference drug only if it meets the four criteria in
Table 2. For a drug product to be approved as a generic,
its maximum concentration (Cmax) and “Area Under
the Curve” (AUC) must fall within an 80%-125% range
of the reference product (brand medication) with an
inclusive 90% confidence interval. In practice, the mean
of the study data lies in the center of the 90% confidence
Rx Only –Prescription Medical Device
INGREDIENTS: Oxidized glycerol triesters (TGO), silicon dioxide, aspartame, and
artificial flavoring.
ACTIONS: Aquoral® is a lipid-based solution resembling human saliva designed to
moisten and lubricate the oral cavity, including the oral mucosa of the mouth, tongue
and throat, by formation of a lipid film which limits loss of water and restores the
viscoelasticity of the oral mucosa. Aquoral also provides protective action against
further inflammation of the oral mucosa. Xerostomia (dry mouth) has harmful effects
on the oral cavity and quality of life; consequently, management of dry mouth is
primarily based on relief of symptoms.
INDICATIONS: Aquoral is intended to provide relief from chronic and temporary
xerostomia (dry mouth), which may be a result of disease such as Sjögren’s Syndrome, oral inflammation, medication, chemo or radiotherapy, stress or aging.
Aquoral relieves symptoms of dry mouth such as difficulties in swallowing, speech,
and changes in taste.
CONTRAINDICATIONS: Aquoral is contraindicated for any patient with a known
history of hypersensitivity to any of its ingredients.
PRECAUTIONS: Read package insert carefully before using this spray. Avoid contact with eyes. Flush eyes with water if accidental introduction into eyes should
occur.
INTERACTIONS: There are no known interactions with medicinal or other products.
DIRECTIONS FOR USE: Shake gently. One dose (2 sprays) into the mouth 3 to 4
times a day. Spread product on to inflamed and/or dry areas of the mouth with the
tongue. Pump may require priming for initial use.
To report a serious adverse event or obtain product information call (800) 531-3333.
HOW SUPPLIED: Aluminum canister with 0.1 ml spray pump containing 40 ml
(1.4 fl. oz.) (net content) of solution which corresponds to 400 sprays of Aquoral
(NHRIC 0178-0420-40).
KEEP OUT OF REACH OF CHILDREN.
Manufactured for:
MISSION PHARMACAL COMPANY
San Antonio, TX USA 78230 1355
MADE IN FRANCE
Aquoral® artificial saliva is a medical
device registered with the United
States Food and Drug Administration.
C01 Rev 005130
U.S. Patent: 8,367,650
over 315°C / 599°F
Copyright © 2014 Mission Pharmacal Company. All rights reserved.
AQU-14004
interval. Therefore, the mean of the data is very close
to a test/reference ratio of 1 (or 100% equal). This also
means that a small number of individual medication lots
can vary significantly, up to 20% and still be considered
equivalent. The importance lies in identifying and communicating when the patient variables or medication
variables are important enough to check the “Dispense
As Written” (DAW) box on the prescription or spend the
extra time to go through the prior authorization process
with the insurance company.
Table 2
U.S. FDA Orange Book Definitions, 34th edition
Pharmaceutical Equivalents Drug products with: same active ingredient, same dosage form, same route of
administration, identical strength
Therapeutic Equivalents
Drug products with: same pharmaceutical equivalence, expected to have same
clinical effect and safety profile
The Orange Book6 is the compendium that contains
the list of the test (generic) and reference (brand) medications. When there are no known or suspected bioequivalence problems, these medications receive a rating
of AA (conventional dosage form), AN (solutions), AO
(oil injectable), AP (aqueous injectable), and AT (topical). When there are actual or potential bioequivalence
problems between two or more medications, the issue
has to be resolved with “adequate” in vivo (tested in
whole living organisms) or in vitro testing (tested in a
laboratory environment). These medications receive an
AB rating. Generic and brand medications that do not
pass the bioequivalence standard are given a B rating.
An example of the hidden complexity of this system
is levothyroxine sodium. First, it is considered a narrow
therapeutic index (NTI) medication. These medications are defined in the federal register as having less
than a 2-fold difference in median lethal and effective
dose. This means the traditional margin for error is
much smaller than normal. The safe and effective use of
these medications requires careful titration and patient
monitoring. The second reason is that there are multiple reference-listed brands for levothyroxine sodium.
Unithroid, Synthroid, Levoxyl and Levothroid have all
completed studies to establish their therapeutic equivalence to other reference-listed brands and generics.
Therefore, while Synthroid and levothyroxine sodium
are AB2 rated AND Levoxyl and levothyroxine sodium
are AB3 rated, Synthroid and Levoxyl are not AB rated
and therefore are not therapeutically interchangeable.
Unlike medications with a broader difference between effective and lethal doses, drugs that have an NTI
are of special concern to the FDA and providers due to
their small margin of error. Examples of NTI medica-
Sjögren’s Quarterly
tion include: levothyroxine, warfarin, lithium, phenytoin,
and digoxin. Switching between brand and generic or
different generic products is particularly concerning with
these medications and may require increased vigilance
to recommended monitoring. To address this issue, the
FDA passed a ruling that NTI medications should require a tighter range (90% to 105%). The hope was that
by tightening the range, this would lead to less variability
and address what providers and patients were finding
when refills were processed and clinical markers were
found or perceived to be different.
Layered on top of the therapeutic equivalent system
are the pharmaceutical alternatives NOT addressed in
the Orange Book or by the FDA.7 These medications
have the same active ingredients but may dissolve, absorb, or function in a specific patient’s body very differently than the original medication prescribed. Examples
of these include:
Tetracycline hydrochloride 250mg vs. Tetracycline
phosphate complex 250mg
OR
quinidine sulfate 200mg caps vs. quinidine sulfate
200mg tabs
OR
verapamil hydrochloride 120mg extended-release vs.
verapamil hydrochloride 120mg sustained-release
5
pare one generic to another. Yet, it is possible for a pharmacy to receive shipment from a different manufacturer
and, with a sticker notification on the bottle, send the
new generic medication to the patient.
Conclusion
The federal government has been in the business
of standardizing medications that are therapeutically
equivalent for the last 40 years. This process does a great
job for the majority of patients and medications. However, individual patients (organ function, complexity of
disease) or specific medications (NTI) may be outliers
in the normal distribution of biologic and therapeutic
equivalency. These outliers may be perceived, or actually
found to be, different enough to affect health outcomes.
By improving the communication between provider
and patient during the final therapeutic decision-making process regarding the most important parts of their
therapy (dose, route, administration, adherence, monitoring, etc), the provider can empower their patient to
advocate for consistent medication therapy. In the event
that the exact medication product is required, dispense
as written or prior authorization are important tools for
providers to use, when appropriate. An educated patient
who is an active participant in their healthcare can help
providers and pharmacists correctly manage the complexity inherent in our medication use system. n
The author wishes to note special thanks to Albany
College of Pharmacy and Health Sciences senior students
Ashleigh Tallman and Charmi Shah for their research and
initial draft work.
Depending on what the difference was and how the
prescription was written, the patient could receive a
medication that performs very differently compared to
what they used in the past. Vigilant pharmacists and paReferences
tients catch many of these differences before they leave
1. Kleinrock M, Aitken M. IMS report for healthcare informatics. Declining
the pharmacy, but some are very subtle. By definition,
medication use and costs: For Better or Worse. May 2013.
any of the above changes at the pharmacy would need
2. Sewell K, Andreae S, Luke E, Safford MM. Perceptions of and Barriers to
use of generic medications in a rural African American population, Alato be relayed back to the provider and a new prescripbama, 2011. Prev Chronic Dis 2012;9:120010.
tion written. The final piece of evidence on this issue
3. Shrank WH, Cox ER, Fischer MA, Mehta J, Choudhry NK. Patient’s Perceptions of generic medications. Health Affairs, 2009;2:546-556.
from the Orange Book preface is both self-explanatory
4. Keenum AJ, DeVoe JE, Chisolm DJ, Wallace LS. Generic medications
and insightful towards the solution to several of the
for you, but brand-name medications for me. Res Soc Admin Pharmacy
concerns raised:
2012;8:574-578.
“The FDA evaluation of therapeutic equivalence
in no way relieves practitioners of their professional
responsibilities in prescribing and dispensing such
products with due care and with appropriate information to individual patients.”5
Regardless of the perception or reality of differences
between brand and generic medications, it is important
to note that the system is not currently set up to com-
5. US Food and Drug Administration. Drugs. Generic drugs: questions and
answers.http://www.fda.gov/drugs/resourcesforyou/consumers/questionsanswers/ucm100100.htm Accessed September 7th, 2014.
6. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research. Office of Pharmaceutical
Science. Office of Generic Drugs. Approved Drug Products With Therapeutic Equivalence Evaluations. 34th ed. December, 31st 2013. www.fda.gov/
downloads/Drugs/Developmentapprovalprocess/UCM071436.pdf Accessed
September 8, 2014.
7. Howland RH. When is a “generic” medication not really a generic? Confusion about medication products containing the same active ingredient.
Psychopharmacology. 2010;2(48):13-16.
6
Sjögren’s Quarterly
“Treating Sjögren’s – The Future” Continued from page 1 t
to accomplish this mission: 1) support and promote
objectives that facilitate the design of clinical trials; 2)
increase industry partnerships with the SSF; and 3) engage in dialogue with government agencies that oversee
therapy approval. (i.e. FDA, EMA).
While many barriers exist in getting new therapies
to market in Sjögren’s, tremendous progress has been
made or is underway. Several factors are contributing to the increased interest and subsequent plans for
clinical trials in Sjögren’s, including the development of
biomarkers; novel diagnostics that are coming onto the
market to speed up and increase precision of diagnosis
as well as the number of those diagnosed; internationally-accepted classification criteria becoming finalized
over the next year; and internationally-accepted outcome measures finally being in place. The SSF made the
development of biomarkers and novel diagnostics a top
priority for its research grants over the last few years,
and it is partnering with companies that are interested
in or already developing biomarkers or marketing diagnostics that have been approved. It also has hosted and
participated in international meetings to gain international agreement on criteria and outcome measures.
(Editor’s Note: Please see the update on Outcome Measures in this newsletter. An update on Classification Criteria will be provided in a future issue of the Quarterly.)
Interest in Sjögren’s is increasing substantially – especially compared to just one year ago. The Foundation
now has more than half a dozen Corporate Members
with whom it’s working closely on programs and initiatives that will increase attention for Sjögren’s. The SSF
is increasing industry partnerships by letting companies
know that the SSF can be a key player in assisting them
from the earliest stages of initial interest and discussions
about Sjögren’s all the way through identification of potential therapies, design of and subsequent recruitment
for clinical trials, navigation of government agency
processes, and post-approval marketing. The SSF currently is connecting Corporate Members to key opinion
leaders and specialty centers in Sjögren’s, spearheading
patient surveys and convening patient focus groups.
Finally, the SSF is initiating a dialogue with government agencies that oversee therapy approval and
learning what it can do to assist with the development
of guidelines for new drug/product approval, speed
approval of new Sjögren’s therapies, and, subsequently,
ensure corporate interest in drug development. For the
November 2014 SSF luncheon meeting at the ACR, an
FDA Regulatory Update was provided by Nikolay Nikolov, MD, Clinical Team Leader, Division of Pulmonary,
Allergy and Rheumatology Products (DPARP), Center
for Drug Evaluation and Research (CDER), Food and
Drug Administration. Dr. Nikolov discussed aspects that
are critical in the development of therapies in Sjögren’s,
including clearly defining the population for a specific
therapy and endpoints that reflect the proposed benefits
of that therapy, efficacy and safety considerations, and
trial design. The CTC Steering Committee deemed development of a Guidance Document for drug approval
in Sjögren’s as its top priority and will be engaging in
dialogue related to this priority in 2015.
The CTC regularly reviews therapeutics that are
promising, under consideration, or already in clinical
trials for Sjögren’s so that it can work with companies
to ensure their success. In addition, the SSF maintains a
list of clinical centers around the world that have the infrastructure, expertise, interest and patient populations
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Sjögren’s Quarterly
to conduct clinical trials in Sjögren’s. Currently, that list
includes nearly 80 physicians and dentists at about 50
U.S. medical centers and many more worldwide.
We must recognize that the international community
as a whole needs to work together and be involved in
key initiatives in Sjögren’s and especially in encouraging new therapies. The SSF has started with a very small
Steering Committee as top priorities are determined
and will expand to include many members who are
leaders in the Sjögren’s community as it moves forward.
Led by myself, members of the Steering Committee include Hendrika Bootsma (Netherlands); Simon
Bowman (UK); Steven Carsons (US); Denise Faustman (US); Xavier Mariette (France); Stanley Pillemer
(US); Kathy Sivils (US); Claudio Vitali (Italy); Frederick
Vivino (US); and Daniel Wallace (US).
All of us working in Sjögren’s and connected with the
SSF are looking forward to the next decade in Sjögren’s and
the start of major changes in the treatment of this disease!
Targets for New
Therapeutics – The Science
by Denise Faustman, MD, PhD
Director, Immunology Laboratory, Massachusetts General Hospital;
Associate Professor of Medicine, Harvard Medical School;
Chair, SSF Medical and Scientific Advisory Board
W
hile Sjögren’s
patients face
potential
complications in any
body organ or system,
we are all aware that the
clinical picture can differ
greatly from one patient
to another and present
different spectrums of the
Denise Faustman, MD, PhD
disease. Currently, our
ability to treat the many
symptoms is negligible, and, in fact, no systemic therapies
currently are available and FDA-approved for Sjögren’s.
The complexity presented by the variation in patient
symptoms in addition to previously lacking key elements
needed for the successful conduction of clinical trials in
Sjögren’s has meant that developing systemic treatments
for Sjögren’s has faced numerous obstacles. However, future prospects for treating Sjögren’s are rapidly changing.
Many needed variables are coming together to set the
stage for a burgeoning interest in and development of
potential new therapies. As mentioned in the summary
on the SSF Clinical Trials Consortium and presented in
this issue, we finally have established outcome measures.
7
We also are close to validating classification criteria that
are embraced by the international community. These
initiatives will substantially increase corporate interest in developing new therapies and already are doing
so. In addition, our experience with immunological
therapies in other diseases and knowledge of the many
options that exist for intervening in the cascade of immunological events that take place in the development
of Sjögren’s is escalating. In fact, more therapies for
Sjögren’s than at any previous time are in the planning or preliminary stages of development while others
already are in clinical trials for Sjögren’s. In Sjögren’s,
opportunities are available for objective measurements
(such as dry mouth and dry eye) that don’t exist for
closely-related diseases, a fact that contributes to the
increasing interest in clinical trials in Sjögren’s.
We will start by taking a brief look at just a few of the
potential therapies under investigation or being considered for use in Sjögren’s.
B Cell Inhibitors or Modulators
Rituximab
This chimeric monoclonal antibody depletes all B
cells (but not plasma cells) and specifically targets the
receptor CD20, the role of which is unclear. It requires antibody-dependent cell-mediated cytotoxicity
(ADCC). Like other therapies either used off-label or
considered promising for Sjögren’s, rituximab was developed originally for B cell lymphoma. It subsequently
was approved for use with methotrexate in severe rheumatoid arthritis (RA).
Results from Phase III trials using rituximab in
Sjögren’s are expected in late 2015. Carubbi et al in late
2014 remarked on the growing evidence for efficacy of
rituximab in Sjögren’s,1 although the use of rituximab
was questioned by the 2014 publication by DevauchellePensac et al following a randomized trial showing lack
of effectiveness at week 24 in alleviating symptoms and
disease activity.2 (SSF Medical and Scientific Advisory
Board leaders commented on this latter study in Faustman DL et al in Ann Int Med, Sep 2014).
Epratuzumab
Epratuzumab has a slightly different B cell target:
CD22, in the Ig superfamily. Rather than depleting B
cells, it modulates and inhibits B cell proliferation, and
binding results in rapid internalization of cell surface
CD22. In contrast with rituximab, epratuzumab is a
humanized IgG1-kappa monoclonal antibody. Phase 3
trials currently are wrapping up in lupus, and, if deemed
successful, trials may be conducted in Sjögren’s. Initial
open-label trials in Europe showed promise.3
Continued on page 8 t
8
“Treating Sjögren’s – The Future” Continued from page 7 t
BAFF/BLyS Targets
Belimumab
This human monoclonal antibody inhibits B-cell
activating factor (BAFF), which is also known as Blymphocyte stimulator (BLyS). Belimumab was the first
FDA-approved therapy (March 2011) for systemic lupus
erythematosus (SLE). While Phase II trials in RA failed,
belimumab appears promising for Sjögren’s after Phase
II open-label trials were carried out in Paris, France and
Pisa, Italy.4 Dryness, fatigue, musculoskeletal joint pain,
global disease activity and reduction of B cell biomarkers were primary endpoints. In addition to a reduction in signs and symptoms of Sjögren’s, lymphocytic
infiltration was decreased in some cases. Interestingly,
another study carried out in Pisa and published in 2014
showed efficacy for sequential therapy with belimumab
followed by rituximab in treating B cell lymphoproliferation in Sjögren’s.5 Patients had been followed for
3½ years by the time of publication and highlighted
the need for future longer-term studies of the therapies
given both sequentially and concomitantly.
VAY736
VAY736 targets BAFF-R. Clinical trials for this fully
human HuCAL-based antibody in Sjögren’s are just now
getting underway in Germany, the U.S., France and the
Netherlands. Patients with relapsing remitting multiple
sclerosis and pemphigus vulgaris also are being recruited for studies of VAY736.
T Cell Regulation and Cytokine Targets
Abatacept
Initially developed for RA, this Fc fusion protein
with extracellular domain of CTLA-4 binds to CD80/
CD86 (B7-1, B7-2) and prevents T cell signaling. It also
inhibits TNF (tumor necrosis factor) alpha, interferongamma & interferon-2. Randomized, placebo doubleblinded clinical trials are recruiting patients at the University Medical Centre Groningen, the Netherlands (PI
Hendrika Bootsma), and an open-label Phase II study
is underway at the Cleveland Clinic Foundation (PI
Qingping Yao) for patients with inflammatory arthritis
associated with Sjögren’s.
Baminercept
Baminercept is a lymphotoxin-β receptor IgG1 fusion protein that leads to reduced activation of T cells,
dendritic cells and possibly the vascular endothelium.
Phase II trials have completed enrollment and currently
are underway at nine centers in the U.S. Sponsored by
the National Institute of Allergy and Infectious Diseases
(NIAID) at the National Institutes of Health (NIH), the
trials are led by Principle Investigators (PIs) E. Wil-
Sjögren’s Quarterly
liam St. Clair, MD, at Duke and Judith James, MD at
the Oklahoma Medical Research Foundation. While the
therapy did not meet endpoints in rheumatoid arthritis
(RA), it remains a potential candidate for Sjögren’s.
BCG Vaccine
This vaccine already has a 95-year safety profile
due to its use worldwide for TB and at very high dose
for bladder cancer. BCG induces TNF, a cytokine that
promotes Treg generation and death of autoreactive T
cells. Ongoing Phase III trials are taking place in Multiple Sclerosis (MS) in Italy, Phase II type 1 diabetes in
Boston, Massachusetts and Phase II prevention trials
in Denmark, Australia, and Turkey. Phase I trials in
Sjögren’s are in the planning stages at the NIH. In multiple sclerosis, the use of BCG shows outstanding efficacy
and safety in new onset disease and with seven years of
follow-up is showing better outcomes than currently
licensed drugs on the market.
Tocilizumab
Tocilizumab is an IL-6 inhibitor that is FDA-approved for polyarticular juvenile idiopathic arthritis.
Phase II trials are currently underway by PI Jacques-Eric
Gottenberg in Strasbourg, France for Sjögren’s.
Genetics and Epigenetics
The fields of genetics and epigenetics are entering an
explosive new era. While we can only touch briefly on
these areas here, these fields will open up a wide array of
potential biomarkers and therapeutic targets. As reported in late 20136 and discussed in the summer 2014
issue of the Sjögren’s Quarterly by Kathy Sivils, PhD,
Oklahoma Medical Research Foundation (OMRF), 7 the
first definitive genes associated with Sjögren’s have been
identified. Lead author on the genetics article, a member
of Dr. Sivils’ lab at OMRF and a current SSF research
grantee, Christopher Lessard, PhD is studying long noncoding RNAs (lncRNAs) in Sjögren’s. Gene expression
can vary based on complex mechanisms involving both
proteins (such as transcription factors) and thousands
of non-coding regulatory RNAs. A substantial number of dysregulated lncRNAs have been identified in
Sjögren’s by the OMRF group and could open novel
lines of investigation for diagnosis and treatment.
Other genomics-related studies were highly visible
at the latest ACR annual meeting, including an abstract
from the SSF Outstanding Abstract Honorable Mention
awardee, Jessica Tarn, from Newcastle University, U.K.
Tarn reported on “Whole Blood microRNA Signature
for Primary Sjögren’s Syndrome-Related Lymphoma.”8
A greater focus on biomarkers associated with specific
complications and symptoms eventually will enable
physicians to assess patients for risks so personalized
Continued on page 10 t
©2015 Ortek Therapeutics, Inc. BasicBites is a registered trademark of Ortek Therapeutics, Inc.
Therapeutics, Inc.
10
“Treating Sjögren’s – The Future” Continued from page 8 t
monitoring and treatment plans can be followed. As
noted by Konsta OD et al, several epigenetic mechanisms are defective in Sjögren’s and involve microRNA
expression, DNA demethylation, and abnormal chromatin positioning associated with autoantibody production. Interestingly, epigenetic modifications may be
reversible as evident in minor salivary glands after use
of rituximab in Sjögren’s patients.9
The Future
Sjögren’s is poised to benefit from the new era of
drug development that we are entering for many diseases with the increasing possibility of tailoring therapies to a specific patient’s needs. Therapies of the future
most likely will be highly individualized by targeting
specific signs and symptoms of Sjögren’s. In addition
to learning more about what gene expression can tell
us about risk, serum levels of other markers are being
identified. For example, an ACR abstract by former
SSF Outstanding Abstract Awardee Gaetane Nocturne
et al demonstrated an association between the chemokine CXCL13 and the development of lymphoma in
Sjögren’s.10 Serum levels of CXCL13 also were associated
with B cell markers and high disease activity. Another
2014 ACR abstract by Rosaria Irace et al showed that
serum levels of the chemokine CXCL4 were associated
with microvascular impairment in Sjögren’s.11 And,
2014 SSF Outstanding Abstract awardee Maria Lauvsnes
of Stavanger University Hospital in Norway reported on
the association between anti-NR2 antibodies and hippocampal atrophy in Sjögren’s as well as lupus. 12
In addition to new biologics currently under investigation, a combination or sequential use of different therapies may be found most efficacious. As mentioned earlier,
a study published in 2014 by Salvatore De Vita et al using
belimumb followed by rituximab demonstrated initial
success and projected potential long-term benefits.5 We
look forward to a better future in which more studies will
expand our knowledge of the science exponentially and
lead to more precise biomarkers and potential targets for
therapeutics. That future is not far away.
References
1. Carubbi F et al. Rituximab in primary Sjögren’s syndrome: a ten-year
journey. Lupus. 2014 Nov;23(13):1337-49.
2. Devauchelle-Pensec V et al. Treatment of primary Sjogren syndrome with
rituximab: a randomized trial. Ann Intern Med. 2014 Feb 18;160(4):233-42.
3. Steinfeld SD et al. Epratuzumab (humanized anti-CD22 antibody) in primary Sjögren’s syndrome: an open-lable phase I/II study. Arthritis Res Ther.
2006;8(4):R129.
4. Mariette X et al. Efficacy and safety of belimumab in primary Sjögren’s
syndrome: results of the BELISS open-label phase II study. Ann Rheum
Dis. 2013 Dec 17. Lessard CJ et al. Variants at multiple loci implicated in
both innate and adaptive immune responses are associated with Sjögren’s
syndrome. Nat Genet. 2013 45, 1284-92.
5. De Vita S et al. Sequential therapy with belimumab followed by rituximab
Sjögren’s Quarterly
in Sjögren’s syndrome associated with B-cell lymphoproliferation and overexpression of BAFF: evidence for long-term efficacy. Clin Exp Rheumatol.
2014 Jul-Aug;32(4):490-4.
6. Lessard CJ et al. Variants at multiple loci implicated in both innate and
adaptive immune responses are associated with Sjögren’s syndrome. Nat
Genet. 2013; 45:1284-92.
7. Sivils K. First Genetic Associations Established for Sjögren’s. Sjögren’s Quarterly. Summer 2014, v 9; (3)1.
8. Tarn J. Whole Blood microRNA Signature for Primary Sjögren’s SyndromeRelated Lymphoma. Poster #522, American College of Rheumatology meeting, November 2014.
9. Konsta OD, Thabet Y, Le Dantec C, Brooks WH, Tzioufas AG, Pers JO, Renaudineau Y. The contribution of epigenetics in Sjögren’s Syndrome. Front
Genet. 2014 Apr 3;5:71.
10.Nocturne G et al. CXCL13 Serum Levels Is Associated with Lymphoma,
High B Cells Markers and Diseases activity. Poster #521, American College
of Rheumatology meeting, November 2014.
11.Irace R et al. Serum CXCL4 Is Increased in Patients with Primary Sjögren’s
Syndrome and Is Associated with Features of Microvascular Impairment.
Poster #523, American College of Rheumatology meeting, November 2014.
12.Lauvsnes M et al. Hippocampal Atrophy Is Associated with Anti-NR2
Antibodies in Patients with Systemic Lupus Erythematosus and Primary
Sjögren’s Syndrome. Poster #1169, American College of Rheumatology
meeting, November 2014.
Outcome Measures
Validated for Sjögren’s
by Raphaèle Seror, MD, Steering Committee, EULAR Outcome
Measures in Sjögren’s Syndrome, Hôpital Bicêtre, Paris
Clinical trial design
for Sjögren’s has made
a major leap forward
with the final validation
of the EULAR-endorsed
outcome measures
known as the EULAR SS
Disease Activity Index
(ESSDAI) and EULAR
SS Patient-Reported InRaphaèle Seror, MD
dex (ESSPRI). The validation study,1 published
in March 2014, concludes a nearly decade-long effort by
researchers to develop outcome measures that could be
embraced consensually by the international community
at large. The ESSDAI includes the 12 following domains:
constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, muscular, peripheral
nervous system, central nervous system, haematological, and biological.2 The ESSPRI includes dryness, pain
and fatigue that were considered by patients as the most
important areas for needed improvement.3
More recently, two large prospective cohorts involving 790 patients were used to define the relevant
thresholds of ESSDAI and ESSPRI to help both clinicians and the conduction of clinical trials.4 This large
Continued on page 12 t
Sjögren’s Quarterly
11
2014 ACR Annual Meeting SSF Abstract Winners
E
very year the Sjögren’s Syndrome Foundation (SSF) recognizes the best abstracts on Sjögren’s from the
American College of Rheumatology (ACR) annual meeting. An emphasis is placed on highlighting investigators who are early in their careers and show potential for accelerating future research in Sjögren’s. This year,
almost 75 abstracts included research with a potential to make an impact on Sjögren’s, making the receipt of this
award quite an accomplishment! The following recipients were recognized for their exciting and promising research.
The 2014 Outstanding
Abstract Award went to Maria
Lauvsnes, MD from Stavanger
University Hospital, Stavanger, Norway. Dr. Lauvsnes
was awarded for her research
entitled Hippocampal Atrophy
Is Associated with Anti-NR2
Maria Lauvsnes, MD
Antibodies in Patients with
Systemic Lupus Erythematosus
and Primary Sjögren’s Syndrome. She shared the below
summary of her work with us.
The study presented in the abstract was part of my PhD
work. As cognitive impairment is common in primary SS,
one of the aims of my PhD work has been to explore whether
anti-NR2 antibodies could play a role in the development
of cognitive impairment in primary SS. Anti-NR2 antibodies are autoantibodies directed against the NR2 receptors,
a glutamate receptor subtype that is very important for
memory and learning and which are especially abundant
in the hippocampus. Murine systemic lupus erythematosus
(SLE) studies have demonstrated that these antibodies can
cause cognitive dysfunction and hippocampal atrophy when
they gain access to mouse brains, and they have been linked
to cognitive dysfunction and depression in SLE patients.
In a study published last year, we found that anti-NR2
antibodies were associated with poorer performance in
several memory tests in primary SS patients, and we found
these antibodies in a higher proportion of the depressed
primary SS patients than the non-depressed primary SS
patients. In the same study, we demonstrated that the hippocampus was smaller in primary SS patients compared to
healthy control subjects. Though demonstrated in murine
models, hippocampal atrophy has not been linked to antiNR2 antibodies in humans previously.
In the current study, we wanted to explore whether
hippocampal size differed between SLE and primary SS
patients with anti-NR2 antibodies compared to patients
without. We analyzed MRI images with computer-based
methods and found that the patients with anti-NR2
antibodies had atrophy in some parts of the hippocampus
compared to the patients without these antibodies. There
were no difference in hippocampal size between SLE and
primary SS patients, and we did not find any association
between hippocampal size and disease duration, anti-phospholipid antibodies or current use of corticosteroids. To read the abstract in its entirety please visit this
link: http://acrabstracts.org/advanced-search/ and
search for abstract #1169 or on the SSF website at http://
www.sjogrens.org/home/research-programs/outstanding-abstract.
The SSF Abstract Review
Committee was so impressed
with the abstracts this year that
it was hard to choose just one,
and an Honorable Mention
also was selected. Jessica Tarn,
a PhD candidate from NewJessica Tarn
castle University, Newcastle
upon Tyne, United Kingdom
was awarded the SSF abstract Honorable Mention for
her work entitled Whole Blood microRNA Signature for
Primary Sjögren’s Syndrome-Related Lymphoma. Below
you will find Jessica’s summary of her work.
This research project was undertaken for my PhD
studies at Newcastle University, UK, under the supervision of Professors Wan-Fai Ng and David Young and with
funding from the Sir Jules Thorne Charitable Trust. Micro
RNAs (miRNAs) are 18-25nt non-coding RNAs that fine
tune gene expression and have implications in health and
disease. However, the role of miRNAs in primary Sjögren’s
syndrome (pSS) and pSS-related lymphoma remains poorly
understood. Investigation into the expression pattern of
miRNAs in disease may improve our understanding of the
biological basis of pSS and identify potential biomarkers.
Through the use of high throughput miRNA profiling
methods, we identified a miRNA signature for pSS-related
lymphoma. The miRNA array profiling of a cohort of
36 healthy controls, and pSS patients with and without
historical lymphoma revealed a clear clustering of the pSS
and pSS-associated lymphoma. Further validation of the
expression signature in an independent cohort helped to
establish a 5-miRNA signature associated with the lymphoma related pSS patients. The sensitivity and specificity of
the signature is excellent with an area under the ROC curve
of 0.92. I am currently following up on the project with
further validation of the putative signature and investigations into the potential target transcripts of the ‘signature
miRNAs’ in order to assess their biological relevance to
lymphoma development in pSS.
To read the abstract in its entirety please visit this
link: http://acrabstracts.org/advanced-search/ and
search for abstract #522 or on the SSF website at http://
www.sjogrens.org/home/research-programs/outstanding-abstract. n
12
“Treating Sjögren’s – The Future” Continued from page 12 t
study allowed us to define disease activity levels with
the ESSDAI, ranging from low (less than 5 points on
the ESSDAI scale), moderate (between 5 and 13 points)
and high (14 points and higher). Those with moderate
disease activity were deemed as the most likely group
for inclusion in clinical trials, as ethical considerations
might prevent using a placebo in severe disease activity
patients. Minimal Clinically Important Improvement
(MCII) was defined as a decrease of at least 3 points for
the ESSDAI. For ESSPRI, patients rated each of their
main symptoms (dryness, fatigue, and pain) on a 0-10
scale, and they also answered a question to determine
whether their health status had significantly improved
using a 5-point Likert scale. Based on these answers,
MCII for the ESSPRI was defined as a decrease of at
least 1 point or 15%.
While objective measures have been available for the
dry mouth and dry eye that occur in Sjögren’s, no activity index previously has gone through the rigorous validation and obtained the broad acceptance for measuring all systemic manifestations for this multi-system and
complex disease until the development of the ESSDAI
and ESSPRI. These latest outcome measures were tested
against other indexes currently in use, including the
Physician Global Assessment (PGA), Profile of Fatigue
and Discomfort (PROFAD), Sicca Symptoms Inventory
(SSI), SS Disease Activity Index (SSDAI) and Sjögren’s
Systemic Clinical Activity Index (SCAI).5 ESSDAI was
found to provide greater sensitivity to change compared
with ESSPRI. ESSDAI and ESSPRI were poorly correlated with each other, demonstrating that they assessed
two different components of the disease.
No single score is perfect for all therapies and for all
patients with Sjögren’s. However, a new system has been
desperately needed to improve the design of clinical trials, and the ESSDAI and ESSPRI are now established as
rigorously validated and are hopefully consistent activity
indexes for measuring how well therapies are working
for Sjögren’s patients. Until recently, ESSDAI and ESSPRI
have most frequently been designated as secondary outcome measures, while primary endpoints have focused
on dryness, and, to a lesser extent, fatigue, quality of life
Sjögren’s Quarterly
measures, and serology. For therapies of the future, a
critical issue will be to determine which Sjögren’s patients are most likely to benefit from a specific treatment
and ensure selection of these patients for a clinical trial
testing this specific treament. These factors will greatly
influence the designation of a primary endpoint. The
ESSDAI could be used in patient selection by requiring
a minimum ESSDAI score for inclusion in clinical trials
testing biologically active therapies, whereas therapies
focusing on symptom relief might use the ESSPRI as
the main endpoint. Regardless, having validated global
scores through ESSDAI and ESSPRI that together include
systemic, dryness and patient measures add critical tools
needed for the design of clinical trials in Sjögren’s. n
References
1. Seror R, Theander E, Brun JG, Ramos-Casals M, Valim V, Dörner T,
Bootsma H, Tzioufas A, Solans-Laqué R, Mandl T, Gottenberg JE, Hachulla
E, Sivils KL, Ng WF, Fauchais AL, Bombardieri S, Valesini G, Bartoloni
E, Saraux A, Tomsic M, Sumida T, Nishiyama S, Caporali R, Kruize AA,
Vollenweider C, Ravaud P, Vitali C, Mariette X, Bowman SJ; on behalf of
the EULAR Sjögren’s Task Force. Validation of EULAR primary Sjögren’s
syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann
Rheum Dis. 2014 Mar 11. PMID: 24442883
2. Seror R, Ravaud P, Bowman SJ, Baron G, Tzioufas A, Theander E, Gottenberg JE, Bootsma H, Mariette X, Vitali C; EULAR Sjögren’s Task Force. EULAR Sjögren’s syndrome disease activity index: development of a consensus
systemic disease activity index for primary Sjögren’s syndrome. Ann Rheum
Dis. 2010 Jun;69(6):1103-9.
3. Seror R, Ravaud P, Mariette X, Bootsma H, Theander E, Hansen A, RamosCasals M, Dörner T, Bombardieri S, Hachulla E, Brun JG, Kruize AA, Praprotnik S, Tomsic M, Gottenberg JE, Devauchelle V, Devita S, Vollenweider
C, Mandl T, Tzioufas A, Carsons S, Saraux A, Sutcliffe N, Vitali C, Bowman
SJ; EULAR Sjögren’s Task Force. EULAR Sjögren’s Syndrome Patient
Reported Index (ESSPRI): development of a consensus patient index for
primary Sjögren’s syndrome. Ann Rheum Dis. 2011 Jun;70(6):968-72.
4. Seror R, Bootsma H, Saraux A, Bowman SJ, Theander E, Brun JG, Baron
G, Le Guern V, Devauchelle-Pensec V, Ramos-Casals M, Valim V, Dörner
T, Tzioufas A, Gottenberg JE, Solans Laqué R, Mandl T, Hachulla E, Sivils
KL, Ng WF, Fauchais AL, Bombardieri S, Priori R, Bartoloni E, Goeb V,
Praprotnik S, Sumida T, Nishiyama S, Caporali R, Kruize AA, Vollenweider
C, Ravaud P, Meiners P, Brito-Zerón P, Vitali C, Mariette X; on behalf of the
EULAR Sjögren’s Task Force. Defining disease activity states and clinically
meaningful improvement in primary Sjögren’s syndrome with EULAR primary Sjögren’s syndrome disease activity (ESSDAI) and patient-reported
indexes (ESSPRI). Ann Rheum Dis. 2014 Dec 5. PMID: 25480887
5. Seror R, Gottenberg JE, Devauchelle-Pensec V, Dubost JJ, Le Guern V,
Hayem G, Fauchais AL, Goeb V, Hachulla E, Hatron PY, Larroche C, Morel
J, Pedriger A, Puechal X, Rist S, Saraux A, Sene D, Sibilia J, Vittecoq O,
Zarnitsky C, Labetoulle M, Ravaud P, Mariette X. European League Against
Rheumatism Sjögren’s Syndrome Disease Activity Index and European
League Against Rheumatism Sjögren’s Syndrome Patient-Reported Index: a
complete picture of primary Sjögren’s syndrome patients. Arthritis Care Res
(Hoboken). 2013 Aug;65(8):1358-64.
Sjögren’s Quarterly
13
Transitions…
Frederick Vivino, MD, former Chair of the SSF Medical
and Scientific Advisory Board,
has been named Professor
of Clinical Medicine at the
Perelman School of Medicine,
University of Pennsylvania in
Frederick Vivino, MD
Philadelphia. Dr. Vivino also is
Chief of the Division of Rheumatology for the Penn Presbyterian Medical Center and
is Director of the Penn Sjögren’s Center at the university. Dr. Vivino chairs the SSF Clinical Practice Guidelines
initiative and serves on the Steering Committee of the
SSF Clinical Trials Consortium.
Julie Frantsve-Hawley,
RDH, PhD has been named
Executive Director of the
American Association of Public
Health Dentistry (AAPHD).
Dr. Hawley formerly was Director of the Research Institute
Julie Frantsve-Hawley,
and Center for Evidence-based
RDH, PhD
Dentistry at the American Dental Association (ADA). In her
role at the ADA, she was and continues to be instrumental in working with the SSF on its Oral Clinical Practice
Guidelines in Sjögren’s.
The Sjögren’s International Collaborative
Clinical Alliance (SICCA): A Data Registry
and Biorepository for Public Use Access
T
he Sjögren’s International Collaborative Clinical Alliance (SICCA) registry is an NIH-funded
international resource that was developed with
the primary goal to provide data and biospecimens for
the Sjögren’s syndrome (SS) scientific community that
will advance the field of SS research, ultimately leading
to effective management strategies and therapies.
The SICCA registry was initiated in 2003 by Drs.
Troy Daniels and John Greenspan in five academicallybased research groups located in Argentina, China, Denmark, Japan and the United States and directed from
Vidya Sankar, DMD, MHS the University of California San Francisco. One group
and Dr. Frantsve-Hawley
in the United Kingdom joined the effort in 2007, and
recently joined the Board of
three groups - two from the U.S. (Johns Hopkins UniDirectors for the Friends of the versity and University of Pennsylvania) and one from
National Institute for Dental
India joined in 2009. Each of the nine groups included
and Craniofacial Research
rheumatologists, ophthalmologists, and oral medicine/
(FNIDCR).
Dr.
Sankar
is
an
pathology specialists with extensive track records in the
Vidya Sankar,
Associate Professor in the
DMD, MHS
diagnosis and management of SS. All groups enrolled
Department of Comprehenparticipants using broad criteria to include individusive Dentistry at the University of Texas Health Science als who have symptoms or signs indicating they may
Center, San Antonio Dental School and also serves on
have or may develop SS as well as those with established
the SSF Board of Directors.
disease. A standardized set of clinical and biological
parameters and information from standardized quesFNIDCR is a broad-based coalition of individuals,
tionnaires were collected at study entry and at two-year
academic institutions, dental schools, patient advocate
follow-up (the latter for a subset of participants).
organizations, dental societies and corporations that
As of September 30, 2012, when enrollment ended,
understand the critical importance of dental, oral and
3,516 participants had enrolled in SICCA and uncraniofacial research to the health and well-being of
dergone a standardized set of evaluations. Nearly a
people in the U.S. and globally. It focuses on support
quarter (774) presented for a two-year follow-up visit.
for the NIDCR and educates the public and key deciThe cohort consists predominantly of women (91%)
sion makers about the importance of investing in the
NIDCR. The SSF has long been a member and leader in over the age of 50 (60%) with a high level of education
(57% graduated from or attended a college/university).
the FNIDCR, with SSF staff member Katherine HamContinued on page 14 t
mitt currently serving as FNIDCR Vice President. n
14
“Print” Continued from page 13 t
A large majority reported dry mouth (90%), dry eyes
(86%), or both (80%). More than one third of participants had positive serologic test results (anti-SSA,
rheumatoid factor, and/or antinuclear antibody titer
≥ 1:320), and hypergammaglobulinemia (IgG > 1445
mg/dL). More than half had salivary hypofunction
defined by unstimulated whole salivary flow < 0.1mL/
min and focal lymphocytic sialadenitis on labial salivary
gland biopsy (among whom 68% had a focus score ≥
1 foci/4mm2). Bilateral parotid enlargement was seen
in 12% at baseline. Nearly half the cohort (1574 participants) satisfied the provisional American College of
Rheumatology classification criteria for SS.
To date, nearly 35 applications for dissemination of
data and/or specimens have been received, the majority
of which have been approved and fulfilled. Examples
of project topics include “Autoantibody Landscape in
Sjögren’s Syndrome,” “Epigenetic Profiling of Multiple
Cell and Tissue Types in Sjögren’s Syndrome, ” “IL-27
Suppression of TH17 Cell Functions In-vitro, ” and
“Mass Spectrometry Tools in Pursuit of Salivary Biomarkers of Sjögren’s Syndrome,” to name a few.
SICCA is a unique public resource providing epidemiologic data and biospecimens to support rigorous
research related to epidemiologic, pathogenesis, and
genetic studies of SS. It is currently led by Drs. Caroline
Shiboski and Lindsey Criswell. Details on how to submit a proposal to obtain SICCA biospecimens and/or
data may be found at: http://sicca.ucsf.edu.
The SICCA biorepository and data registry is
supported by NIH/NIDCR contract # HHSN26S201300057C n
Recruitment Underway for Clinical Trials
NIH Clinical Trial for Vasculitis
Volunteers are needed for a study on vasculitis as an
autoimmune/rheumatic symptom or disease conducted
by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes
of Health (NIH). Goals include learning the signs, symptoms, imaging tests, genetic markers and blood tests that
can help identify vasculitis and predict what will happen
over time. All study-related costs and tests are provided
at no cost.
Participation includes a visit to the NIH Clinical Center for screening along with follow-up visits as
needed; donation of blood samples (either at NIH or via
a patient’s physician); and completion of questionnaires.
Sjögren’s Quarterly
Both those with vasculitis and those who are healthy to
serve as controls may be eligible for participation. More
information on the “Studies of the Natural History,
Pathogenesis, and Outcome of Idiopathic Systemic Vasculitis” can be found at https://clinicaltrials.gov, identifier NCT02257866, or by calling 301-451-1450.
DREAM Clinical Trial for Dry Eye Patients
The Dry Eye Assessment and Management
(DREAM) Trial is recruiting patients for its randomized
clinical trial to determine efficacy and safety of Omega
3 for dry eye disease. Trials will take place at twenty sites
across the U.S. and are funded by the National Eye Institute (NEI) at the NIH. Penny Asbell, MD, MBA, FACS,
Professor of Ophthalmology at the Mount Sinai School
of Medicine in New York, is the Study Chair.
Essential Fatty Acids (EFA) have been shown to
reduce inflammatory responses, but randomized
controlled trials for dry eye disease that provide strong
empirical data are lacking. This is the first NEI-funded
dry eye trial in which a wealth of information on dry
eye disease will be collected independently of commercial concerns. The trial also will develop evidencebased information on the effects of Omega 3 on dry eye
disease. Final data collection is expected in 2016 with
an estimated study completion date of April 2017. For
more information on clinical trial sites for this study,
visit https://clinicaltrials.gov, identifier NCT02128763
or contact Dr. Penny Asbell by email at penny.asbell@
mssm.edu or phone by calling 212-241-7977. n
NIDCR FY2016 Research Concepts Approved
Research concepts for the National Institute of Dental and Craniofacial Research (NIDCR), NIH for Fiscal
Year 2016 have been approved. Those of particular
interest to researchers in Sjögren’s include:
lImmune System Plasticity in the Pathogenesis and
Treatment of Complex Dental, Oral, and Craniofacial
Diseases
lNovel or Enhanced Dental Restorative Materials for
Class V Lesions
Sjögren’s research also might fall under the concepts
of Pharmacogenomics of Orofacial Pain Management
and the NIDCR Institutional Research Training Programs. Concepts represent early planning stages for
initiatives in which NIDCR seeks to support research in
an understudied and significant area of science. n
Patient Education Sheet
Health Insurance Tips – Part 2
How to Draft an Insurance Appeal Letter
The Patient Education Sheet, Health Insurance Tips – Part 1, contains tips on obtaining healthcare
reimbursement. Part 2 addresses how to appeal a decision if you are denied coverage. Always appeal a
denial! Be persistent and do not give up when first denied.
Information and documentation that will help you appeal a denial
n Your policy and claim numbers, employer name if your policy is through an employer, and the full
name of the insured
n The therapy or procedure for which you were denied and why the denial letter stated you
were denied
n Medical records that back up your diagnosis and medical problem that relates to the therapy
in question
n A cost-benefit analysis when relevant - For example, you can compare the cost savings of obtaining punctal plugs or cauterization compared to the higher cost of having to pay for more moisture
drops and ointment over a long period of time.
Letter of Medical Necessity
n This letter is usually written by the physician explaining why a therapy or other treatment is medically necessary.
n If the Letter of Medical Necessity is not signed by your physician, have your physician provide a letter of support for your appeal and reason for recommending or prescribing your therapy.
n A Sample Letter of Medical Necessity for dental treatment can be found on the SSF
website under “Brochures and Resource Sheets.”
Quotes from your health insurance policy that are helpful to your case
n For example, if your policy states that coverage is provided for a closely-related disease and/or
similar symptom, quote that back to the insurance company. If the company cites a reason for
covering the related disease or symptoms, such as an inflammatory response, use that. Quoting
such statements and providing documentation about similar occurrences in Sjögren’s increases
your chance for the success of an appeal.
n Cite two or more articles from respected medical journals backing your claim of
medical necessity.
Refer to the SSF website as an authoritative source of medical information on Sjögren’s.
For more information on Sjögren’s, contact the Sjögren’s Syndrome Foundation at:
6707 Democracy Blvd, Suite 325, Bethesda, MD 20817 • 800-475-6473 • www.sjogrens.org • [email protected].
Clinicians: Please make multiple copies of this Patient Education Sheet and distribute to your patients.
Sjögren’s Quarterly
Sjögren’s Syndrome Foundation Inc.
6707 Democracy Blvd., Ste 325
Bethesda, MD 20817
13
th
INTERNATIONAL
SYMPOSIUM ON
SJÖGREN’S
SYNDROME
New Product for
Sjögren’s Patients
A
May 19th — May 22nd, 2015
Bergen, Norway
www.sicca.org/isss2015
new product for dry mouth has been created
containing technology developed at Stony Brook
University School of Dental Medicine. Ortek
Therapeutics has developed sugar free chocolate soft
chews named “BasicBites.”
BasicBites contain saliva-mimicking AlkaGen Technology™. This super saliva technology consists of two
main ingredients - arginine bicarbonate and calcium
carbonate. Arginine is a common amino acid found
in saliva and is naturally present in many foods. It was
discovered that certain healthy bacteria found on tooth
surfaces use arginine to generate sustained base or alkali
production. This helps keep teeth in the existing normal pH range. Calcium, which is also found in saliva,
is available to coat and support healthy tooth structure.
The bicarbonate and carbonate ingredients provide additional buffering and support arginine and calcium.
For more information about BasicBites, visit
www.basicbites.com n