International Research Registries for Sjögren's Syndrome

OBJECTIVE

We are seeking Concept Clearance for a Request for Proposal (RFP). The purpose of this initiative is:

• to establish uniformly accepted diagnostic criteria for primary and secondary Sjögren's syndrome that will be used by all countries for all research purposes including clinical research, diagnosis and treatment of patients with Sjögren's syndrome; and
• to establish one or more research registries for families with Sjögren's syndrome in the United States, Europe, Asia and Pacific Ocean countries.

It is envisioned that the registries will serve as a national and international resource to provide: 1) standardization of the methods used in collecting, maintaining, storing, analyzing, processing patient information and biological specimens; 2) a resource of well characterized patient populations and biological specimens (e.g., blood, saliva, salivary gland tissues, genetic materials); 3) information on the prevalence of the disorder in the general population and in various population subgroups including males, females, different age groups, racial or ethnic groups; 4) enhancement of genetic studies by providing a resource of individuals with a consistent disease phenotype, 5) clarification of the clinical characteristics of the disorder by comparing linkage to different chromosomal sites with the expressed phenotype; 6) characterization of the genetic mutations or gene interactions which result in the disorder; 7) measurement of pathological parameters including determinations of antigens, antibodies, cytokines, morphological alterations in the involved tissues, as well as any additional necessary analyses;and 8) evaluation of the efficacy of current therapies used for Sjögren's syndrome.

Clearly, such a resource is very important for the promotion and facilitation of substantive national and/or international research projects including basic studies and clinical trials for Sjögren's syndrome.

BACKGROUND

Sjögren's syndrome is a systemic autoimmune disorder characterized by keratoconjunctivitis sicca (dry eyes); xerostomia (dry mouth) and dryness of other organs due to lymphocytic infiltrates of exocrine glands, typically salivary and lacrimal glands; destruction of glandular epithelial cells; and loss of the function of secretory epithelia. The prevalence of Sjögren's syndrome in the general population is not clear due to the absence of uniformly accepted or standardized diagnostic criteria. The U.S., Europe and Japan have their own criteria and a major differences exist among these criteria.  For example, only 15% of patients diagnosed according to European (EEC) criteria for Sjögren's syndrome would meet the U.S. (the San Diego) criteria. Therefore, there is difficulty in the diagnosis, evaluation and management of the disorder and its related complications. Other major factors that contribute to the difficulty of diagnosing, preventing and treating Sjögren's syndrome are the complex and controversial etiology of Sjögren's syndrome as well as the pathogenesis of the disorder. To date possible etiological factors include the failure of tolerance mechanisms and viral infections.  The former is characterized by antibodies against autoantigens including IgG (rheumatoid factor), nuclear antigens (SS-A and SS-B), and other proteins such as fodrin and muscarinic cholinergic receptor type 3; and the latter include Epstain-Barr virus (EBV).  In regard to the pathogenesis of Sjögren's syndrome, it has been shown that lymphatic infiltration and increase in the expression of a variety of cytokines by epithelial cells and lymphocytes are associated with destruction of glandular epithelial cells. However, it is still not clear why the residual acinar and ductal structures are dysfunctional.  Moreover, the mechanisms mediating expression of autoantigens, production of cytokines, lymphatic infiltration, glandular cell apoptosis, and residual glandular cell dysfunction are also poorly understood.

Due to the lack of sufficient knowledge about the etiology and pathogenesis, the treatment of Sjögren's syndrome is still palliative.  Most therapies to date are directed towards temporary relief of the dryness of the mouth and eyes or other complications. Therefore, there is a need to increase the understanding of the prevalence of Sjögren's syndrome and uncovering the etiology, pathogenesis and impact of this disorder on oral and general health. It is envisioned that the registries will provide standardized and uniformly accepted diagnostic criteria, well characterized patient populations, biological specimens (e.g., genetic materials for gene mapping and tissue samples to evaluate inflammatory mediators) and to test novel therapeutic strategies. 

CURRENT PORTFOLIO OVERVIEW

Although NIDCR is the lead institute in Sjögren's syndrome research, its extramural program has only a few projects studying the pathogenesis of this disease.  Investigators in one project are studying whether autoantibodies and autoreactive T cells are necessary and sufficient to induce loss of salivary function in non-obese diabetic (NOD) mice, and whether Sjögren's syndrome patients show evidence of responses to autoantigens.  Researchers in another project are defining the role of granule-mediated cellular cytotoxicity in salivary cell apoptosis.  A third project is a study of the mechanism of FAS-mediated apoptosis. The slow progress in this area of oral medicine stems from the paucity of molecular and cellular details regarding salivary gland biogenesis and function. Therefore, the Branch wishes to encourage and stimulate research initiatives that take advantage of materials provided by the registries to gain an understanding of the mechanisms and processes that underlie salivary gland disease and disorders in order to develop strategies for their treatment.

RECOMMENDATIONS FROM RECENT WORKSHOPS

The NIDCR, recognizing the importance of acquired and inherited disorders of salivary gland function, has supported and held two workshops. The fist workshop on "Salivary Gland Biogenesis and Function" was held on November 7-10, 1996. This workshop brought together leading scientists in the fields of biology, genetics, immunology and clinical sciences. The charge to the participants was to develop a set of recommendations to help NIH create a program in the areas of basic and clinical research in salivary gland function and dysfunction. Briefly, the experts agreed that there is a need to:

• establish uniformly accepted diagnostic criteria for Sjögren's syndrome
• use model organisms such as Drosophila, C.elegans, Zebrafish and transgenic mice to determine the function of genes which regulate salivary gland development and function.
• create national resources for transgenic mouse construction (over-expression of genes, ablation of genes, conditional expression of genes).
• support human genetic studies of syndromes affecting salivary glands and their secretions (e.g. Prader-Willy Syndrome, Sjögren's syndrome) to provide new insights into the mechanisms regulating salivary gland function.
• support a national repository of genetic materials collected from affected patients and their families to provide a resource of well characterized biological specimens.

The proceedings of this workshop were published in the Annals of the New York Academy of Science (see reference below).

The second NIDCR workshop, "Enhancing Clinical Research in Sjögren's Syndrome: Critical Issues," was held on September 25-26, 2000.  A group of prominent researchers and clinicians in this area was invited to participate. The charge to the participants was to discuss the major difficulties in clinical research on Sjögren's syndrome, and provide a set of recommendations. The experts emphasized that research on Sjögren's syndrome is severely hampered by two obstacles: 1) the deficiency of enough patients and specimens, and 2) the lack of uniformly accepted diagnostic criteria.  Their strongest recommendation was that the Institute should establish an international registry network in order to provide enough resources for basic and clinical studies on this destructive disorder.

SCIENTIFIC OPPORTUNITIES

The availability of a resource of patient information and collection of biological specimens will greatly accelerate scientific investigations in this area. It is expected that this initiative would serve to attract scientists from different scientific disciplines to address problems related to Sjögren's syndrome. 

COLLABORATIVE ACTIVITIES

The Officeof Research on Women's Health (ORWH), the National Institute of Arthritis and Musculoskeletal Disorders (NIAMS) and the National Eye Institute (NEI) have expressed an interest in supporting this initiative.

FUNDING MECHANISMS

The Chronic Diseases Branch recommends the use of the contract mechanism, as this would allow the Institute to insure the availability of all registry records and materials to the scientific community, as well as having the Government retain ownership to them.

REFERENCES

Casciola-Rosen, L., Andrade, Felipe, Ulanet, D., Wong, W. B., Rosen, A.  Cleavage by granzyme B is strongly predictive of autoantigen status:  implications for initiation of autoimmunity.  J. Exp. Med.  190, 815-825, 1999.

Fox, R. I., Michelson, P., Casiano, C. A., Hayashi, J., Stern, M.  Sjögren's syndrome.  Clinics Dermatol.  18, 589-600, 2000.

Humphreys-Beher, M. G., Peck, A. B., Dang, H., Talal, N.  The role of apoptosis in the initiation of the autoimmune response in Sjögren's syndrome.  Clin. Exp. Immunol.  116, 383-387, 1999.

Kukuruzinska, M. A. and Tabak L. A. (Editors). Salivary Gland Biogenesis and Function. Annals of the New York Academy of Science. Volume. 842, 1998.

van der Reijden, W. A., Vissink, A., Veerman, E. C. I., Amerongen, A. V. N.  Treatment of oral dryness related complains (xerostomia) in Sjögren's syndrome.  Ann Rheum. Dis.  58, 465-473, 1999.