Vol. 7, Issue 1 – Winter 2012 The Professionals’ Resource on Sjögren’s Syndrome
Syndrome
Save the DateSecretariat
Organized by
The 11th International Symposium on Sjögren’s Syndrome (ISSS), held in Athens from September 28 to October
1, 2011, was chaired by Professor Athanasios G. Tzioufas, MD, Department of Pathophysiol-ogy, School of Medicine, University of Ath-ens, and honored the lifelong contribution of Professor Harry M. Moutsopoulos, MD,
Top Stories 7OralQOLStudy& Commentary
9SSFACRAbsractAward& NIHBiomarkersGrant
13AutoantibodyPrevalance andmorefromNIEHS
15PatientEducation– BrittleNails
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A new database has just been launched to provide an easy-to-use and integrated view of existing data in Sjögren’s . The
Sjögren’s Syndrome Knowledge Base (SSKB; http://sskb.umn.edu) is open for use by all re-searchers and the public at large and includes genes and proteins linked to Sjögren’s. As found-ers of this tool, we hope and expect that it will have a profound impact on future research in this disease and ultimately stimulate the formulation and testing of new hypotheses and experimen-tal approaches to investigations into Sjögren’s.
by Sven-Ulrik Gorr, Seshagiri R. Nandula, and Trevor Wennblom, University of Minnesota; Sara Michie, Stanford University; Ammon B. Peck, University of Florida; Steve Horvath and David T.W. Wong, University of California at Los Angeles
Highlights on Disease Pathogenesis from the 11th International Symposium on Sjögren’s by Clio P. Mavragani, MD, Department of Experimental Physiology, School of Medicine, University of Athens; and Athanasios Tzioufas, MD, Department of Pathophysiology, School of Medicine, University of Athens
Editor’s Note: The International Symposium on Sjögren’s Syndrome is held every 2-3 years by leaders in the field of Sjögren’s and attracts clinicians and researchers from around the world. The symposium provides a unique opportunity for attendees to focus on Sjögren’s, hear presentations and engage in discussions on the latest research on all aspects of Sjögren’s.
Clio P. Mavragani, MD
Athanasios Tzioufas, MD
sskb.umn.edu
the Sjögren’s Syndrome Knowledge Base (SSKB) – a New tool for Sjögren’s research
DISCLAIMER: The Sjögren’s Syndrome Foundation Inc. in no way endorses any of the medications, treatments, or products mentioned in advertisements or articles.
SSKB Team
Photos L to R; top row: Sven-Ulrik Gorr, Seshagiri R. Nandula, and Trevor Wennblom, University of Minnesota; Sara Michie, Stanford University;
Photos L to R; bottom row; Ammon B. Peck, University of Florida; Steve Horvath and David T.W. Wong, University of California at Los Angeles
“Sjögren’s Database” Continued from page 1 t
Why develop the Sjögren’s Syndrome Knowledge Base?
Sjögren’s syndrome and other autoimmune diseases are complex diseas-es that involve many events that lead to disease initiation and progression. In Sjögren’s it is not clear how environmental triggering events combine with cellular and genetic factors to cause an immunologic attack on the salivary and tear glands that ultimately leads to the symptoms of dry mouth and dry eye. The observation that diagnosis often lags behind the onset of disease by a decade or more further complicates the understanding of disease initiation and progression.1,2 Thus, despite the substantial efforts by clinicians and researchers around the world, Sjögren’s still presents many questions: how is the disease triggered, what is the contribution of genetic susceptibility, how can we improve diagnosis, and what is the optimal treat-ment for any individual patient?
A recent report has proposed a model for Sjögren’s syndrome that in-cludes connected biological pathways: According to this model, hormonal predisposition and environmental factors combine to activate glandular epithelial cell death and autoantigen presentation, which leads to activa-tion of the type I interferon pathway, immune cell activation, production of autoantibodies and cytokines, and development of glandular and extrag-landular disease.3 Understanding the sequence of events that initiates and sustains this cascade of events remains a challenge for Sjögren’s research.
Biomedical research has undergone a revolution in the past decade, acceler-ated by the sequencing of the genomes of humans and research animals. Where
2 Sjögren’s Quarterly
researchers previously analyzed a handful of genes or pro-teins in biological samples, we can now analyze thousands of genes in a single experiment. This has changed our ability to ask questions from specific to general: whereas in the past we might ask, “Is this gene changed in Sjögren’s patients compared to healthy controls?” we can now ask “Are any genes changed in Sjögren’s compared to healthy controls?” Indeed, it is now clear that most biological processes depend on a network of connected genes where one gene affects the activation or function of one or more down-stream genes, ultimately leading to cellular changes. Our ability to understand these biological networks has been greatly improved in the past decade with the deci-phering of vast gene expression data sets of human disease and corresponding animal models. The ability to analyze every gene in the genome in a single experiment has led to an explosion of biological data. The importance of this revolution and its potential for new medical insight can-not be overstated. However, to realize the benefits of these data, new computational and bioinformatics tools had to be developed for data analysis.
Comprehensive, genome-based analyses have opened the possibility of identifying the biological pathways that are affected by a disease and designing new interven-tions to specifically target those pathways. Unfortunately, these comprehensive analyses are primarily applied to newly generated data since comprehensive resources to query existing data are generally lacking. Thus, decades of research data exist in the scientific literature but lack a uniform set of analytical tools that would allow easy integration with the newly generated data.
What is the SSKB, and how does it work?To address the lack of such an analytical tool, we
developed the Sjögren’s Syndrome Knowledge Base (SSKB), which is a comprehensive database of the exist-ing knowledge on Sjögren’s. The intent was to allow a ready identification of the proteins and genes that have already been associated with the disease and to acceler-ate the verification and validation of data generated by the new genome-based technologies. Without this database, investigators would have to identify genes of interest in their newly generated data sets and compare these individually to the existing literature. In many cases, descriptions and nomenclatures have changed over the years, further complicating a direct comparison of new and old data.
The National Library of Medicine, a component of the National Institutes of Health, maintains the PubMed da-tabase, a comprehensive catalog of the biomedical litera-ture (http://www.ncbi.nlm.nih.gov/pubmed/). Moreover,
all entries in this database are catalogued by a defined vocabulary (Medical Subject Headings – MeSH), which allows the retrieval of a record by key words, even if the specific search term is not directly used in the publica-tion. Our PubMed search for the MeSH term “Sjögren’s syndrome” retrieved 7700 publications dating back at least five decades. To identify the proteins and genes de-scribed in these publications, the text mining program EBIMed4 (http://www.ebi.ac.uk/Rebholz-srv/ebimed/) was then used to analyze the 7700 publications. This resulted in a preliminary database of approximately 900 poten-tial proteins and genes that had been described in the Sjögren’s literature. Since we focused on single genes or proteins, we eliminated about 400 genes that were identi-fied in a single study of Sjögren’s genes.5 The remaining genes were further verified and curated to reach the cur-rent database of 479 entries.
The Sjögren’s Syndrome Knowledge Base (SSKB) is freely available to the research community via the world-wide web at http://sskb.umn.edu. The data are or-ganized by primary names, as retrieved by EBIMed from the literature, as well as any synonyms identified by these literature searches. The corresponding gene names and symbols were assigned by an extensive review of the protein data and supporting evidence. In many cases, several gene names are listed, reflecting changes in public databases over time and different gene sym-bols assigned to the same gene. In the current version of the SSKB, all nonhuman genes have been converted to the human homolog. In future work, we will separate human and mouse genes to facilitate the comparison of human disease to mouse models of Sjögren’s.
The UniProt (Universal Protein resource) accession ID links to the UniProt knowledgebase (http://www.uniprot.org/) and provides access to extensive biological data for each gene/protein. Whenever possible, links are to the UniProtKB/Swiss-Prot database of reviewed and annotated data. The “Details” link provides access to the Uniprot entry and additional information, as available. Under “Protein class” we identify proteins that have been reported as autoantigens (AAG), viral antigens (VAG) or bacterial antigens (BAG). The tissues that express each entry are also identified. PubMed references are provided for verified (manually curated) references as well as ref-erences identified by automated searches using the gene/protein names listed. We caution that due to the use of abbreviations and gene symbols in the published litera-ture, the automated searches may identify references that are unrelated to the entry. Finally, each entry contains manually annotated notes as well as Gene Ontology
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Sjögren’s Quarterly 3
t cells and Salivary GlandsInsights from animal models came from the work
presented by Scott Lieberman of the Children’s Hospital of Philadelphia who reported that in a new NOD-based transfer model of SS, dysfunction of salivary gland-pro-tective T-regulatory cells (Tregs) was found to possibly account for the observed sialadenitis. In contrast, a sub-set of Tregs conferred protection in female mice against lacrimal gland involvement. Another cell population, the IL-17-producing double-negative T-cells (charac-terized by lack of both CD4 and CD8 molecules) have been found to be expanded in the periphery and sali-vary glands from SS patients and be resistant on dexa-methasone treatment, implying their contribution to the salivary gland immunopathological lesion observed in SS (Alessia Alunno et al, University of Perugia).
Insights for the generation of pathogenic autoim-mune responses in SS came from a study led by Marie Wahren-Herlenius of the Karolinska Institutet in Stock-holm who explored the immune responses in patients with primary SS compared to controls after immuniza-tion with an H1N1 influenza vaccine. While primary SS patients developed protective immune responses, they developed at the same time a skewed B-cell maturation and induction of proinflammatory cytokines with high avidity and titer IgG responses compared to controls, suggesting a mechanism for high titer autoantibody production in these patients.
as major autoantigens in primary SS might play a cen-tral role in disease pathogenesis. According to the find-ings by Kyungpyo Park’ s group in South Korea, mus-carinic-type 3 receptor internalization by IgG derived from primary SS patients might provide a potential mechanism for the observed SS-related exocrinopathy through inhibition of the receptor function. Of interest, data from Mana Iizuka et al from Ibaraki, Japan, identi-fied IFN-γ producing reactive T cells against muscarinic type 3 receptor as contributors in the pathogenesis of autoimmune sialoadenitis.
CytokinesData on emerging cytokines in SS pathogenesis such
as Interleukin-21 (IL-21) and BAFF has been reported. IL-21, found to be elevated in primary SS sera, corre-lated with heightened systemic disease activity and B-cell hyperactivity, while salivary gland epithelial cells (SGEC) directly induced the differentiation of IL-21-secreting follicular helper T cells (Jacques-Eric Gottenberg,
FRCP, FACP to advancements in the field of Sjögren’s (SS). More than 50 talks and 160 original research works were presented from around the globe. We will highlight some of the new insights in SS pathogen-esis, diagnosis and therapy. Importantly, the meeting led to a special issue dedicated to the symposium in an upcoming issue of the Journal of Autoimmunity.
GeneticsFrom a genetics point of view, the hypothesis of the
role of the X-chromosome in the female bias observed in lupus and SS patients has been reinforced by an inter-national multicenter study led by R. Hal Scofield at the Oklahoma Medical Research Foundation (OMRF). In this study, a higher prevalence of SS was observed in tri-ple X syndrome (47,XXX) compared to 46,XX women and 46,XY men, with 47,XXX women having a rate of disease 4-fold higher than normal women and 10-fold higher than 45,XO and 46,XY men. Additional data de-rived from the first-to-date high density genome-wide association study on SS (SGENE) led by OMRF’s Kathy Moser confirmed previously reported associations with MHC, IRF5 and BLK genes and identified novel disease susceptibility loci including SLC30A5, CTNNA2, VASP, FGFR1OP2 and LCK. Finally, interesting findings re-ported by Xavier Mariette’s group in Paris suggest both germinal and somatic abnormalities of the TNFAIP3 gene encoding for the A20 protein – a central gatekeeper of NF-kB activation in SS-related lymphomagenesis.
MicrorNasOn the other hand, the potential role of microRNAs
(small ribonucleic acids regulating gene expression) in SS pathogenesis has been increasingly recognized. Data from Ilias Alevizos’s group at the NIDCR, National In-stitutes of Health, suggested the viral EBV-Mir-BART13- microRNA, previously found to be upregulated in SS, might be implicated in disease pathogenesis through suppression of the STIM1, an Endoplasmic Reticulum-Ca2+ sensor protein known to be a critical component in salivary gland secretion. The same group also revealed that reduced expression levels of hsa-miR-183 and 22 in salivary glands of SS patients compared with healthy vol-unteers might account for the increased expression levels of ezrin, a protein overexpressed in SS and implicated in alterations of salivary gland epithelial cells. Another set of microRNAs, namely hsa-mir-574-3p and hsa-mir-768-3p, have been suggested as potential biomarkers of salivary gland and systemic inflammation in the SS setting and may correlate with focus scores, according to a study led by Gabor Ilei at NIDCR.
“Sjögren’s Symposium” Continued from page 1 t
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4 Sjögren’s Quarterly
Proven Results. Proven Relief.
IMPORTANT SAFETY INFORMATIONEVOXAC (cevimeline HCl) is indicated to treatthe symptoms of dry mouth in patients withSjögren’s syndrome.• Cevimeline HCl is contraindicated in patients withuncontrolled asthma, known hypersensitivity to the drug,and when miosis is undesirable, e.g., in acute iritis andnarrow-angle (angle-closure) glaucoma
• Cevimeline HCl can potentially alter cardiac conductionand heart rate and produce transient changes inhemodynamics. Cevimeline HCl should be administeredwith caution and under close medical supervision topatients with a history of cardiac disease, controlledasthma, chronic bronchitis, or chronic obstructivepulmonary disease
• Cevimeline HCl should be administered with caution topatients taking beta-adrenergic antagonists because ofthe possibility of conduction disturbances and to patientswith a history of nephrolithiasis or cholelithiasis
• If a patient sweats excessively while taking cevimeline HCl,dehydration may develop
• Caution should be advised while driving at night orperforming hazardous activities in reduced lighting
• Safety and effectiveness in pediatric patients have notbeen established
• Cevimeline HCl is metabolized by the P-450 isozymesCYP2D6 and CYP3A3/4. Thus, there may be potential forinteraction between cevimeline HCl and other compounds
• Special care should be exercised when cevimeline HClis taken by geriatric patients, considering the greaterfrequency of decreased hepatic, renal, or cardiac function
• The most frequently reported adverse events associatedwith the pharmacologic action of a muscarinic agonist(>10% incidence) in clinical trials of cevimeline HCl were:excessive sweating, nausea, rhinitis, and diarrhea. Consultthe full Prescribing Information for other adverse events
Please see next page for brief summary of thefull Prescribing Information about EVOXAC.
References: 1. Fife RS, Chase WF, Dore RK, et al. Cevimeline for the treatment of xerostomia in patients withSjögren syndrome: a randomized trial. Arch Intern Med. 2002;162(11):1293-1300. 2. Petrone D, Condemi JJ,Fife R, Gluck O, Cohen S, Dalgin P. A double-blind, randomized, placebo-controlled study of cevimelinein Sjögren’s syndrome patients with xerostomia and keratoconjunctivitis sicca. Arthritis Rheum.2002;46(3):748-754. 3. EVOXAC [package insert]. Edison, NJ: Daiichi Sankyo, Inc.; November 2006.
DAIEVO010_Quarterly_Ad_R2b:DSEV08000074 7/11/11 11:26 AM Page 1
Summary and commentary from Janicke L. Jensen
The variety of symptoms and complications make primary Sjögren’s syndrome (pSS) a com-plex disease, where oral distress – defined as oral dysfunction, dis-
ability, and discomfort – seems to be essential in patient perception of health-related quality of life (HRQoL). The aims of the present study were to:
• Evaluate oral distress and HRQoL in a large Norwe-gian pSS cohort compared with age- and sex-matched Norwegian normative data
• Estimate the occurrence of oral symptoms in pSS
• Evaluate the impact of oral distress on HRQoL in pSS
Three questionnaires were used:
• The Oral Health Impact Profile 14 (OHIP-14) which consists of 14 items organized into seven dimensions (functional limitations, physical pain, psychological discomfort, physical disability, psychological disability, social disability, and handicap) and addresses differ-ent aspects of oral health. The sum of the ratings from the 14 questions generates an OHIP-14 additive score ranging from 0 to 56, where a high score indicates low oral HRQoL and high oral distress. Based on the OHIP-14 results, we divided the patients into three equal-size subgroups with different degrees of oral distress: low (< 4), moderate (4–15) and high (> 15) additive scores.
• Health-related quality of life was measured using SF-36, which is a multipurpose, generic, health survey instrument, measuring HRQoL by 36 items covering eight subscales (physical functioning, physical role functioning, bodily pain, general health, vitality, social functioning, role emotional, and mental health). The answers from the eight subscales are transformed to generate a score between 0 and 100, where a high score indicates better HRQoL and better functioning.
• Oral symptoms were further explored in a ques-tionnaire designed for the current study in order to supplement disease history. Specific questions ad-dressed oral and systemic symptoms related to pSS as well as sociodemographic characteristics.
Continued on page 8 t
Editor’s Note: The Editors found the following article, published in December 2011, of great interest to our read-ers and requested a Summary and Commentary from the senior author.
the article is: Enger TB, Palm Ø, Garen T, Sandvik L, Jensen JL. Oral distress in primary Sjögren’s syndrome: impli-cations for health-related quality of life. Eur J Oral Sci. 2011 Dec;119(6):474-80. doi: 10.1111/j.1600-0722.2011.00891.x. PMID: 22112034.
abstract:Tone B. Enger1, Øyvind Palm2, Torhild Garen2,
Leiv Sandvik1, Janicke L. Jensen1
1Department of Oral Surgery and Oral Medicine, Faculty of Dentistry, University of Oslo, Oslo;
2Department of Rheumatology, Oslo University Hospital, Oslo, Norway
The aims of the study were to evaluate oral distress in patients with primary Sjögren’s syndrome (pSS) compared with age- and sex-matched Norwegian nor-mative data, to estimate the occurrence of oral symp-toms in pSS and to evaluate the impact of oral distress on health-related quality of life (HRQoL). The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) was used to assess HRQoL, and the Oral Health Impact Profile 14 (OHIP-14) was used to measure oral distress. Of the 246 pSS patients invited to participate in the study, 177 (72%) responded. Data were analysed for the female participants (n = 163). Significant deviations from normative estimates were found in all OHIP-14 item results, and the findings indicated a high level of oral distress among the pSS patients. Health-related quality of life was decreased among pSS patients, with the largest deviations from normative estimates related to “general health” and “role physical.” The patients with high levels of oral distress scored significantly lower than patients with low levels of oral distress in five of the SF-36 subscales, indicating that oral conditions have a marked impact on general quality of life. In conclu-sion, oral distress in pSS is pronounced and severe, and should receive increased attention with a view to improving the quality of life for these patients.
Oral Distress in Primary Sjögren’s syndrome: Implications for Health-related Quality of life
Sjögren’s Quarterly 7
Strasbourg, France). In order to elucidate the underlying mechanisms of BAFF overproduction in SS, Jacques-Olivier Pers et al from Brest, France discovered that an alternate-splice isoform of BAFF, which lacks the exon 3, can act as a transcription factor for the BAFF gene itself. Data from the same group also revealed height-ened TLR9 levels of transitional B cells in SS salivary glands implying their potential sensitivity to microbial or endogenous DNA triggers, which subsequently could lead to differentiation into autoantibody-secreting cells.
“Sjögren’s Symposium” Continued from page 4 t
The mean age and disease duration in the female patients were 63 and 11.7 years, respectively. The mean OHIP-14 additive score among the pSS patients was 12.7 (versus 4.5 in the normative data), and the range was 0–53. Significant differences from the norma-tive data were observed for all 14 items, with the most prominent deviations reported in the dimension for physical pain (aching in mouth and discomfort eating food), which was reported by 23% of the SS patients versus 5% in the normal population.
The SF-36 results, adjusted for age, indicated sig-nificantly impaired HRQoL in patients with pSS compared with normative data for all eight subscales, with the largest dif-ferences observed for “general health” and “role physical.”
Other oral dryness-related complications, such as recur-rent oral fungal infections and disturbed sleep, were com-monly reported among the pSS patients. Among the oral symptoms that were more frequent in the group with high oral distress than in the group with low oral distress were recurrent oral fungal infections, altered taste, aching in the mouth, problems with eating, increased dental decay, and recurrent swollen salivary glands. Statistically significant differences between the groups with high and low oral distress were observed in five of the eight SF-36
“Our results clearly indicate increased oral distress and
reduced HRQoL in pSS patients compared with
normative data.”
subscales: role physical, general health, social functioning, role emotional, and mental health.
Our results clearly indicate increased oral distress and reduced HRQoL in pSS patients compared with normative data. Oral distress in pSS has a significant impact on general health, affecting both mental and physical components of HRQoL. However, pSS is a complex disease, and in addition to oral distress, rheu-matic pain, internal organ involvement, fatigue, risk of lymphoma and ocular symptoms also may influence HRQoL in pSS. In order to help pSS patients manage
their oral distress, dentists and other health profes-sionals treating pSS patients should be more aware of the patients’ oral complaints. By recognizing and treating oral distress in pSS, an increase in HRQoL is likely to occur. Oral management, including intensive and regular dental
care, should be a central focus for clinicians treating pSS patients.Efforts to treat candidiasis, oral ulcers, and dental decay early may reduce discomfort and pain and be preventive. Unfortunately, there is a lack of effective remedies to treat symptoms such as hyposalivation and fungal infections. The results of the present study un-derline the importance of the development of effective therapeutics for oral complications in pSS. n
Additional data from Salvatore De Vita’s group in Udine, Italy suggest a contributory role of BAFF in pathogenesis of SS-related lymphoma, since it has been found to be increased in patients with SS-related lymphoproliferative disorders in correlation with clonal B-cell expansion in salivary glands. Finally, Chiara Baldini et al in Pisa, Italy suggested proteomic analysis of saliva as a promising tool for identifying novel biomarkers for SS diagnosis.
The 12th International Symposium will be held in Kyoto, Japan and organized by Professor Takayuki Sumida in 2013. n
“Oral Distress” Continued from page 7 t
Do we have your e-mail address?If you want to receive all the latest updates from the Sjögren’s Syndrome Foundation, then you should make sure we have your most up-to-date e-mail address! The SSF is starting to share more information via e-mail, from news about the SSF and Sjögren’s, to information about the latest treatments and medicines, to local Support Group updates and more. So contact us at [email protected] to be certain we have your latest e-mail address in our database, and then keep an eye out in your Inbox for Sjögren’s news.
Just like all information you provide the Foundation, your e-mail address will remain private and will never be given or sold to an outside organization.
8 Sjögren’s Quarterly
SSF Outstanding abstract award at aCr announced
The recipient of this year’s SSF Outstanding Ab-stract Award at the Ameri-can College of Rheumatol-ogy (ACR) Annual Meeting is Joanne Reed, PhD, of the New York School of Medi-cine. The award is given out each year to a young or new
investigator who dem-onstrates exceptional research efforts as seen
in their abstract on Sjögren’s presented at the ACR. Dr. Reed received the award for her abstract, “A Point
Mutation in the SSA/Ro60 Autoantigen Which Prevents Y RNA Binding Attenuates a Requisite Signal for Cell Surface Expression and TLR-Dependent Inflammation Syndrome.” As stated in the abstract’s conclusion, her data suggests “that an alteration of the Ro60 domain which prevents Y RNA binding attenuates a permissive signal that is required for its participation as an antigen to form immune complexes in apoptotic cells and gener-ate a TLR dependent proinflammatory cascade. Accord-ingly, the Y RNA moiety of the Ro/SSA ribonucleoprotein imparts a critical role in the pathogenicity of anti-Ro60 autoantibodies.” For the full abstract, go to www.sjogrens.org/research and select “Outstanding Abstract Award.”
Authors include Joanne H. Reed1, Soyeong Sim2, Sandra L. Wolin2, Jill P. Buyon1 and Robert M. Clancy1 (1New York University School of Medicine, New York, New York, 2Yale University School of Medicine, New Haven, Connecticut). Dr. Reed received a US$500 award and framed certificate during the annual SSF luncheon meeting during the ACR in November 2011. n
uCla receives $2.8 million NIH grant for Sjögren’s research
A multi-center clinical trial of a potential diagnostic test for
Sjögren’s will now move forward thanks to a major grant from the National In-stitutes of Health (NIH) to the UCLA School of Den-tistry. The saliva test would
provide a simple, non-invasive and quick means for diag-nosis. Currently, a lip
biopsy and serum tests provide the gold standard for di-agnosing Sjögren’s, and patients receive a diagnosis near-ly 7 years on average after onset of symptoms. (Of note, the Sjögren’s Syndrome Foundation has just launched a major Breakthrough Goal to improve the long delay in Sjögren’s diagnosis. See www.sjogrens.org for more information.) The National Institute of Dental and Cra-niofacial Research, NIH, awarded the $2.8 million grant.
Three major centers will participate in the clinical trial. They are the University Medical Center Groningen in the Netherlands, the University of Minnesota and the Oklahoma Medical Research Foundation. The project is led by David T. Wong, PhD, Associate Dean for Research and the Felix and Mildred Yip Endowed Professor in Dentistry at the UCLA School of Dentistry in Los An-geles. Dr. Wong’s group has been an international leader in research into and discovery of salivary biomarkers in oral cancer, early-stage pancreatic cancer and, more recently, in Sjögren’s. Identification of salivary bio-markers could not only be used for diagnosis and early
David T. Wong, PhD
Joanne Reed, PhD
detection of Sjögren’s, but it could help provide critical information on disease processes and lead to discovery of potential therapeutic targets.
For more background information on Dr. Wong’s work in salivary biomarkers and diagnostics, see the Spring 2008 issue of the Sjögren’s Quarterly for his ar-ticle, “Salivary Biomarkers for Primary Sjögren’s Syn-drome – A Breakthrough?”. If you do not have the issue, email [email protected] for a pdf copy. n
Available from libraries offeringSpringer’s eBook Collection, orfor individual purchase via onlinebookstores.A free preview is available onSpringerLink.▶ springer.com/ebooks
R.I. Fox, Rheumatology Clinic, Scripps Memorial Hospital and Research Foundation, LaJolla, CA, USA; C.M. Fox, Rheumatology Clinic, Scripps Memorial Hospital and ResearchFoundation, La Jolla, CA, USA (Eds.)
Sjögren’s SyndromePractical Guidelines to Diagnosis and Therapy
▶ Integrates the experiences of international experts in the spectrum ofinvolved disciplines
▶ Offers a practical approach to the diagnosis and treatment ofSjögren’s Syndrome
▶ Provides the latest information made possible only by multi-disciplinary communication
▶ Presents a global perspective on this prevalent autoimmune disease
The key knowledge assembled in this book comprises today’s most comprehensiveresource on Sjögren’s syndrome. Sjögren’s patients require the care of a wide varietyof clinical and surgical specialists to treat their disease and improve their quality of life. This volume presents a broad multi-disciplinary approach, enlisting the expertise ofwell-respected authors from around the world, covering the specialties of rheumatology,ophthalmology, oral medicine, oral surgery, otolaryngology, hematology, and others. This practical clinical resource begins with an overview of Sjögren’s myths, pearlsand tips, information for referring physicians, and diagnostic and classification andcriteria. The second section covers pathogenesis, providing the backbone for ourunderstanding current diagnostics and therapeutics. The third section is devoted toclinical manifestations and therapeutic considerations. It covers the entire spectrum ofsymptoms and treatment, infused with the experience and astute clinical observations ofthe book’s contributors. With system-wide coverage of local and systemic therapy, thebook examines current therapy, biologics, and emerging therapeutic targets. Presentingmany international perspectives, this book creates an inter-connective conduit for theglobal community of Sjögren’s patients and physicians.
Order online at springer.com ▶ or for the Americas call (toll free) 1-800-SPRINGER ▶ or email us at: [email protected]. ▶ or for the Americas call (toll free) 1-800-SPRINGER ▶ or email us at: [email protected].
The first € price and the £ and $ price are net prices, subject to local VAT. Prices indicated with * inlude VAT for books; the €(D) includes 7% forGermany, the €(A) includes 10% for Austria. Prices indicated with ** include VAT for electronic products; 19% for Germany, 20% for Austria. All pricesexclusive of carriage charges. Prices and other details are subject to change without notice. All errors and omissions excepted.
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In addition to the many Sjögren’s experts and SSF friends who authored chapters for this book, the SSF was pleased to contribute a chapter under “Future Perspectives,” entitled “Looking into the Crystal Ball: Initiatives from the Sjögren’s Syndrome Foundation That Will Impact Patient Care.”
Available online at totalblock.comand other major internet retailers.Available online at totalblock.comand other major internet retailers.Available online at totalblock.comand other major internet retailers.Available online at totalblock.comand other major internet retailers.
Sun Protection for dry, sensitive lipsSun Protection for dry, sensitive lips
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News in Dry eye
LipiFlow® for Treating MGD and Dry Eye Wins FDA Approval
TearScience® of Morrisville, North Carolina won FDA regulatory approval this fall for its system to diag-nose and treat Meibomian Gland Dysfunction (MGD). The LipiFlow® Thermal Pulsation System was shown in a recent study to significantly improve meibomian gland secretion, tear break-up time (TBUT) and dry eye symptoms in patients suffering from MGD and dry eye. The device unclogs the meibomian gland and subse-quently may help reduce the need to apply eyedrops and warm compresses for MGD treatment. Visit www.lipiflow.com for more information. n
For further reading: Lane SS, Dubiner HB, Epstein RJ, Ernest PH, Greiner JV, Hardten
DR, Holland EJ, Lemp MA, McDonald JE 2nd, Silbert DI, Blackie CA, Stevens CA, Bedi R. A New System, the LipiFlow, for the Treatment of Meibomian Gland Dysfunction (MGD). Cornea. 2012 Jan 4. PMID: 22222996 [Epub ahead of print].
New Eye Drop in Development for Dry EyeRegeneRx Biopharmaceuticals, Inc. is wrapping up
its Phase 2 study of a sterile, preservative-free eye drop RGN-259 for use in dry eye. The Tβ4eye drop has been shown to address both inflammation and corneal heal-ing. The double-masked, placebo-controlled clinical trial is assessing safety and efficacy and measuring both signs and symptoms of dry eye. For more information, visit www.regenerx.com. n
TearLab® Osmolarity System for Diagnosing and Measuring Dry Eye Clears Major Hurdle
A new tool that can be used to diagnose and classify severity of dry eye disease by measuring tear osmolar-ity is now more readily available to private practitioners who diagnose and manage dry eye patients. A waiver of Clinical Laboratory Improvement Amendment standards has been granted by the U.S. Food and Drug Administration (FDA) to TearLab Corporation for its TearLab® Osmolarity System. The FDA action will sig-nificantly reduce former burdensome requirements for offices that want to utilize the system.
In contrast to normal patients, dry eye patients expe-rience marked variability in their tear film, making such a measurement an objective and valid test for dry eye disease and simpler than many tests currently used and on the market. The new test uses a microchip system that can determine results in less than 30 seconds.
The TearLab® Osmolarity System was recently added to the American Academy of Ophthalmology Preferred Practice Pattern Guidelines. For more information, visit www.tearlab.com. n
For further reading: Lemp MA, Bron AJ, Baudouin C, Benítez Del Castillo JM, Geffen D,
Tauber J, Foulks GN, Pepose JS, Sullivan BD. Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol. 2011 May;151(5):792-798.e1. PMID: 21310379
Oncel BA, Pinarci E, Akova YA. Diurnal variation of the tear osmolarity in normal subjects measured by a new microchip system. Eur J Ophthal-mol. 2011 Dec 6:0. doi: 10.5301/ejo.5000084. PMID: 22180151 [Epub ahead of print]
Sullivan BD, Whitmer D, Nichols KK, Tomlinson A, Foulks GN, Geerling G, Pepose JS, Kosheleff V, Porreco A, Lemp MA. An objective approach to dry eye disease severity. Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6125-30. PMID: 20631232.
Continued on page 12 t
Sjögren’s Quarterly 11
(GO) terms (http://www.geneontology.org/)6 and Reac-tome terms (http://www.reactome.org/ReactomeGWT/entrypoint.html) retrieved by automatic searches.
The SSKB database can be viewed as individual pages, which provides faster downloads, or as a single file by using the link on the upper right. Moreover, the entire database can be exported as a text file using links at the bottom of the screen. A drop-down box on the upper left allows the user to select a “brief” view, which fits on a single screen, or select a “detailed” view, which includes additional information otherwise found under “Details” for each entry. Each column can be sorted by clicking the appropriate heading. As an example, clicking the PubMed heading in the “detailed” view allows the user to sort the entries by the number of PubMed references identified for each gene/protein by automated searches. With the caveat of false-positives, as explained above, this view provides an estimate of the previous work involving any given entry in the database. In fact only 352 entries are represented by more than one publication while 152 entries are represented by more than 10 publications.
An analysis of the SSKB revealed that about 100 of the included proteins have been reported to function as autoantigens in Sjögren’s syndrome. Subcellular loca-tion data available for 70 of these proteins reveals that they are distributed widely in cells. Twenty-one proteins are located in the nucleus (including the Sjögren’s anti-gen SSB/La), eight are located in the plasma membrane, 13 are cytoplasmic proteins (including 60 kD SSA/Ro), and 10 are secreted proteins. Other proteins are located in mitochondria, endoplasmic reticulum, Golgi ap-paratus and other locations. This analysis reveals that autoantigens may arise from almost any location in the cell and typically are intracellular proteins that likely are exposed to the immune system as a result of cell dam-age or death (apoptosis). These proteins may trigger an immune response but may otherwise not play a direct functional role in the disease. A notable exception is the muscarinic acetylcholine receptor type-3 (M3R), which acts both as an autoantigen and affects the ability to
“Sjögren’s Database” Continued from page 3 t
“Industry Watch” Continued from page 11 t
Partnership Formed to Offer PROSE Treatment for Corneal Disease
The Boston Foundation for Sight, which focuses on the treatment of patients with complex corneal diseases such as Sjögren’s, announced in January that it will part-ner with the Johns Hopkins Wilmer Eye Institute to offer patients a prosthetic replacement of the ocular surface system (PROSE). Pioneered by the Boston Foundation for Sight, PROSE is used to help restore vision, support
stimulate salivary secretion7.Our research group is using the SSKB for discov-
ery research to identify biological pathways and gene ontologies involved in Sjögren’s syndrome. Already, initial analysis of the biological pathways represented by the genes in the SSKB revealed that pathways associ-ated with immunological processes are highly abundant, suggesting that the database reflects the genes associated with this autoimmune disease (Gorr et al., submitted).
In addition, we have used this database as a resource for comparative studies with newly developed gene expression data in human patients and animal models of Sjögren’s syndrome. The results of these studies will be published elsewhere. n
DisclaimerThe Sjögren’s Syndrome Knowledge Base is freely available and the data is linked
to other online resources, whenever possible. Registration is not required for use. SSKB is not a wiki, however, and suggestions for modifications should be submitted to the email address provided on the site.
SSKB is a research database and not intended to provide specific medical ad-vice. Patients are urged to contact a qualified physician for diagnosis or questions related to individual medical problems.
The information in SSKB is extracted from public sources. The information provided in the database, including links to external sites, is not warranted, and no legal responsibility or liability is assumed for the accuracy or completeness of the data.
FundingThe development of the SSKB is supported by Public Health Service Grant
R01DE019255 from the National Institute of Dental and Craniofacial Research.
2. Meijer, J.M., et al., Health-related quality of life, employment and disability in patients with Sjögren’s syndrome. Rheumatology, 2009. 48(9): 1077-82.
3. Segal, B.M., et al., Genetics and genomics of Sjögren’s syndrome: re-search provides clues to pathogenesis and novel therapies. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, 2011. 111(6): 673-680.
4. Rebholz-Schuhmann, D., et al., EBIMed—text crunching to gather facts for proteins from Medline. Bioinformatics, 2007. 23(2): e237-e244.
5. Gottenberg, J.-E., et al., Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjögren’s syn-drome. Proc Natl Acad Sci USA, 2006. 103(8): 2770-2775.
6. The Gene Ontology. [cited version 1.1.974 01/21/2010: Available from: http://www.geneontology.org/.
7. Nguyen, K.H., et al., Evidence for antimuscarinic acetylcholine recep-tor antibody-mediated secretory dysfunction in NOD mice. Arthritis Rheum, 2000. 43(10): 2297-306.
healing, and reduce eye pain and light sensitivity. Dr. Esen K. Akpek, MD, Associate Professor of
Ophthalmology, is Director of the new Ocular Surface Diseases and Dry Eye Clinic at Wilmer Eye Institute. That clinic began offering PROSE to Sjögren’s and other dry eye patients in January 2012. More information on PROSE can be found at www.bostonsight.org, and more information on the clinic at Wilmer Eye Institute is at http://www.hopkinsmedicine.org/wilmer/services/cor-nea_dryeye.html. n
12 Sjögren’s Quarterly
Sjögren’s Quarterly 13
Focus on Sjögren’sStina K. Carlsson, PhD published her doctoral thesis on dry eye and Sjögren’s in
the fall 2011 at Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences, Kalmar, Sweden. Entitled “Effects of Adenosine and Acetylcholine on the Lacrimal Gland,” Dr. Carlsson studied the effects of adenosine and acetylcho-line on intracellular signaling pathways and lacrimal gland secretion. The abstract can be viewed at http://lnu.diva-portal.org/smash/record.jsf;jsessionid=729031da26aaa3d804e37fc3fdda?parentRecord=diva2:432886&pid=diva2:432893.
In her Introduction, Dr. Carlsson paraphrases from SSF Vice President of Re-search Katherine Hammitt’s oral presentation (“The voice of a patient”) during the Tear Film and Ocular Surface Society (TFOS) Experts’ Meeting in September 2010, Florence, Italy in which Hammitt describes how tears make us human and connect us with others on an emotional level. One of Dr. Carlsson’s two supervisors, Professor J. Peter Gierow, was the first-ever recipient of a Sjögren’s Syn-drome Foundation research grant (1992 and 1993).
For questions about her work or to obtain copies of her thesis, Dr. Carlsson may be contacted at [email protected]. n
More than 32 million Americans have autoan-tibodies, according to a study that was just released by the National Institutes of Health
(NIH) and published in Arthritis and Rheumatism in January 2012. The National Institute of Environmental Health Sciences (NIEHS), NIH, and the University of Florida at Gainesville looked at the prevalence of the most common type of autoantibody, the antinuclear an-tibody or ANA, which is usually positive in Sjögren’s pa-tients as well as those with other autoimmune diseases.
The most common autoantibody was found to be anti-SSA (Ro), which is a marker of Sjögren’s and found in about 70% of those who are diagnosed with Sjögren’s. It also can be found in other autoimmune dis-eases, especially SLE. The percentage of the U.S. popu-lation ages 12 and older who had a positive ANA was nearly 14% (13.8%). Prevalence was higher in females, older individuals and in African Americans. Education, family income, alcohol use, history of smoking and C-reactive protein levels were not linked with a positive ANA. Researchers analyzed serum samples from 4,754 individuals from the National Health and Nutrition Examination Survey, 1999-2004.
Antinuclear antibodies can develop years before an autoimmune disease is diagnosed. Their presence, how-ever, does not mean that a person will definitely get an autoimmune disease.
This groundbreaking study sets the stage for future
investigations into why ANA prevalence is so high, whether the numbers will continue to increase over time, and what triggers development of an autoimmune disease such as Sjögren’s. The citation article for the article is:
Satoh M, Chan EK, Ho LA, Rose KM, Parks CG, Cohn RD, Jusko TA, Walker NJ, Germolec DR, Whitt IZ, Crockett PW, Pauley BA, Chan JY, Ross SJ, Birnbaum LS, Zeldin DC, Miller FW. 2012. Prevalence and sociode-mographic correlates of antinuclear antibodies in the United States. Arthritis and Rheumatism; doi: 10.1002/art.34380. PMID: 22237992.
NIeHS Strategic PlanDevelopment of the next 5-year strategic plan that
will set priorities and direction for the NIEHS from 2012-2017 is underway. The Sjögren’s Syndrome Founda-tion encourages professionals in the field of Sjögren’s to provide input to ensure investigations into environmental triggers that might lead to development of Sjögren’s and other autoimmune diseases is a priority. Instructions on submitting comments can be found at: http://www.niehs.nih.gov/about/od/strategicplan/index.cfm.
The environment and autoimmune disease has been a hot topic and led to the following recommendation dur-ing the July 2011 NIEHS Strategic Planning Stakeholder Community Workshop: “To make investigation of the in-teractions between the environment and the immune sys-tem and its relationship to human development, health and disease a major research priority for NIEHS.” n
From the NIeHSAutoantibody Prevalence in the U.S. Population
Stina K. Carlsson, PhD
2012 SSF National Patient Conference
“Charting the Course”April 20-21, 2012San Diego Marriott La Jolla, La Jolla, California
SSF programs have helped thousands gain a better under-standing of Sjögren’s. This two-day event will feature an array of presentations from the country’s leading Sjögren’s experts – physicians, dentists, eye care providers, and researchers discussing key aspects of the disease. Presenta-tion topics will include:
Overview of Sjögren’s SyndromeSleep Disorders and Sjögren’s Dermatological Issues and Sjögren’sGastrointestinal Issues of Sjögren’sGynecological and Urinary Issues with Sjögren’sSjögren’s Survival: A Patient PerspectiveIs it Lupus or Sjögren’s?Management of Dry EyeDry Mouth and Sjögren’sTesting New Drugs and Future DirectionsSjögren’s Research Update
So this April 20-21, we invite you to join with us in “Charting the Course” to an amazing opportunity for heightening your understanding of Sjögren’s at the 2012 National Patient Conference in La Jolla, California!
The SSF provides a few complimentary registrations for the National Patient Conference for clinicians, researchers and graduate students who focus on Sjögren’s and want to learn more. Contact the SSF for more information.
Brittle nails are characterized by hardness, peeling, crumbling, fissures, excess longitudinal ridges or lack of flexibility of the finger and toe nails. This sometimes causes pain and interferes with normal daily activities. Although no clear association between Sjögren’s and nail disorders has been reported, Sjögren’s patients frequently complain of this problem. Many different dermatologic conditions including some autoimmune disorders, infections, dryness and certain medications can affect the nails. Here’s what you can do to help:
• Keep the nails short. This prevents the nails from catching on things or acting as a lever and causing further damage.
• Avoid biting the nails, pulling on them or other tasks that cause repeated trauma.
• Avoid excess contact with water or chemicals (including nail polish remover) which can cause dryness.
• Protect the nails when performing wet work by using rubber gloves and cotton glove liners.
• Avoid excess handwashing and exposure of nails to water.
• Use moisturizer on your nails multiple times per day and reapply the moisturizer after your hands come in contact with water. You can use the same moisturizer used for your dry skin.
• Steer clear of cosmetic products such as artificial nails and nail wraps which can cause damage.
• Avoid nail polish and hardeners. However, if used, leave on as long as possible to help retain moisture. After removing polish, moisturize the nails and give them a break from cosmetic products before re-application.
• If your dermatologist approves, try a course of biotin if you have brittle nails.
• If you’re diagnosed with a fungal infection of your nails, your dermatologist can discuss a variety of treatment options which are available.
For more information on Sjögren’s syndrome contact the Sjögren’s Syndrome Foundation at: 6707 Democracy Blvd, Suite 325, Bethesda, MD 20817 • 800-475-6473 • www.sjogrens.org • [email protected].
Patient Education SheetTips for Brittle Nails
The SSF thanks Adam I. Rubin, MD for authoring this Patient Education Sheet. Dr. Rubin is Director of the Nail Practice and Assistant Professor of Dermatology,
Perleman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Clinicians: Please make multiple copies of this Patient Education Sheet and distribute to your patients.
Sjögren’s QuarterlySjögren’s Syndrome Foundation Inc.6707 Democracy Blvd., Ste 325
Bethesda, MD 20817
New Product for Dry VaginaA new vaginal lubricant is now available that
Sjögren’s patients might find helpful. Valera™ Or-ganic Personal Lubricant is USDA-certified organic and has been clinically tested to show improvement in moisturizing the vaginal tissue, vaginal dryness, vaginal comfort and sexual pleasure. It contains nat-ural, plant-based organic ingredients including aloe vera, shea butter and evening primrose oil and also is pH balanced and free of hormones, sulfa preser-vatives, fragrances, and other ingredients that might irritate sensitive and dry tissue. To learn more, visit www.myvalera.com.
Flaxseed Oil Might Help Dry EyesDuring the October 2011 annual meeting of the
American Academy of Ophthalmology, a prelimi-nary study was reported showing improvement of dry eye symptoms with use of flaxseed oil supple-ments. The results were based on an initial small sample size of 12 subjects, and the ultimate study dose was 9,000 milligrams a day. So that people might better tolerate the high dose, those enrolled in the study started by taking three 1,000 mg cap-sules a day for two weeks and gradually increased the amount. Dryness and accompanying symptoms of itching, burning and eye fatigue were reportedly reduced. Prior research studies have shown that Omega-3s improve dry eye symptoms. The study was led by Jack V. Greiner, DO, PhD, FAASS, clini-cal instructor in ophthalmology at Harvard Medi-cal School and clinical scientist at Schepens Eye Re-search Institute, Boston, Massachusetts.
The Sjögren’s Book – Fourth EditionEdited by Daniel J. Wallace, MDThe NEW 2011 Edition of the Sjögren’s handbook has been completely revised and expanded with All NEW chapters and the latest information on Sjögren’s!
This book can be purchased online at www.sjogrens.org/ssfstore or by contacting the Sjögren’s Syndrome Foundation office at 800-475-6473.
