SJOGREN'S SYNDROME AND SALIVARY DYSFUNCTION NIH GUIDE, Volume 21, Number 20, May 29, 1992 PA: PA-92-82 P.T. 34 Keywords: Oral Diseases Physiological Processes Etiology Epidemiology Diagnosis, Medical Pathogenesis National Institute of Dental Research PURPOSE Sjogren's syndrome is one of the major causes of xerostomia, the most common manifestation of salivary gland dysfunction. The National Institute of Dental Research (NIDR) supports studies to improve knowledge of the development, structure, function, and diseases of the salivary glands and to determine the influence of salivary constituents on oral health. Toward this end, the NIDR seeks to stimulate basic and clinical research, research training, and manpower development in the broad area of the epidemiology, etiology, pathogenesis, diagnosis, and treatment of xerostomia, particularly in relation to Sjogren's syndrome. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Program Announcement (PA), Sjogren's Syndrome and Salivary Dysfunction, is related to the priority area of oral health. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Domestic applications may include international components. Applications from minority individuals and women are encouraged. Special eligibility requirements specified in the pertinent guidelines for the various mechanisms available for support of this program must be met. Foreign institutions are not eligible for the First Independent Research Support and Transition (FIRST) Award. MECHANISMS OF SUPPORT The mechanisms available for support of this program include the traditional Research Project Grant (R01), the Program Project Grant (P01), the FIRST Award (R29), the small grant (R03), the Postdoctoral Individual Fellowship (F32), and Senior Fellowship (F33) Awards, and the following career development awards: the Modified Research Career Development Award (K04), the Physician Scientist for Dentist Award (K11), and the Individual Dentist Scientist Award (K15). RESEARCH OBJECTIVES Background The importance of saliva in oral health has become increasingly apparent in the expanding aged population. Here, advances in medical procedures and utilization of medication have been combined in an effort to maintain the "quality of life." However, a common sequela to this effort is an increased prevalence of salivary dysfunctions. The most common clinical manifestation of salivary dysfunction is a decreased output of secretion, termed "dry mouth" (hyposalivation, xerostomia, or asialorrhea). Clinically, dry mouth may vary from a slight reduction in salivary flow with transitory inconvenience to a total xerostomia with severe difficulties in speech, mastication, swallowing, digestion, and concomitant physical and psychological indisposition. The major causes of xerostomia include local and systemic disease, pharmacological agents, radiation therapy, immunological disorders, menopause, and environmental pollution. Hyposalivation may lead to qualitative and/or quantitative changes in the protective salivary films or pellicles that coat hard and soft tissues. This loss of an enamel or cemental pellicle could result in an increase in plaque-mediated diseases, namely, dental caries and gingivitis, that ultimately result in tooth loss. Alteration in mucosal pellicle may make the oral soft tissues more susceptible to desiccation and environmental insult, leading to colonization by an opportunistic microflora. The end result may be painful ulcerations and/or local infections with a very sensitive mucous membrane, with consequent difficulties in accepting dental prostheses. There are, apparently, no available prevalence or incidence data to describe the frequency of Sjogren's syndrome in any population. It has been estimated that in the United States there are, at minimum, two million such patients--the vast majority being postmenopausal women. Another two million undiagnosed victims are estimated to suffer with the disease. Some cases may develop during childhood. About half of the cases are primary; the remainder are secondary. Similarly, there are no accurate data describing the frequency of iatrogenic salivary dysfunctions, especially those related to specific pharmaceutical use. It has been suggested that over 400 drugs in the Physician's Desk Reference result in salivary gland dysfunction. This claim, however, is often based on subjective and anecdotal information and not objective evaluations of gland performance. Specifically, detailed epidemiologic data are required for the prevalence and incidence of Sjogren's Syndrome and for various iatrogenic disorders. The etiology and pathogenesis of Sjogren's syndrome are not clearly understood. Sjogren's syndrome is a chronic, multisystem, autoimmune disorder. The lesion in this disease is an immunologically mediated inflammatory exocrinopathy that starts with periductal infiltration of the salivary tissue by plasma cells and lymphocytes. The glandular acini atrophy and progressively disappear, being replaced by a dense infiltrate of lymphocytes. Sjogren's syndrome may be caused by T-cell abnormalities or a deficiency of T lymphocytes and subsequent overactivity of other lymphocytes and the production of autoantibodies. Specific antinuclear antibodies, the SS-A (Ro) and SS-B (La) antibodies, are found in Sjogren's syndrome and may have diagnostic value in patients with unexplained parotid swelling or other features such as renal and pulmonary lesions. These antibodies may antedate clinical evidence of Sjogren's syndrome by months or years. Salivary duct autoantibodies are another characteristic finding in this disease, but it appears that these antibodies may be causally unrelated to the duct damage. Whether the apparent disturbance in immunoregulation in Sjogren's syndrome is due to predominantly environmental or genetic factors is unknown. In addition to the existence of genetic predisposition to Sjogren's syndrome, it appears that the two variants (i.e., primary and secondary) of this disorder, though related, have distinct differences in genetics. Although the Epstein-Barr virus has received, over the past decade, continued attention as one virus that might possibly play a role in Sjogren's syndrome, a causal relationship has not been proven. It was recently reported that a newly discovered human retrovirus (the human intracisternal A-type retroviral particle) might be involved in Sjogren's syndrome and perhaps in a variety of other autoimmune diseases. The finding of this virus in relation to Sjogren's syndrome is important and needs to be confirmed. Many investigators feel that estrogen may also be a factor since 90 percent of those with this disease are women. There is a real need for rigorous clinical trials to test the efficacy and safety of various treatment regimens designed to correct or improve specific salivary dysfunctions. These include trials to improve secretory capabilities of patients who retain functional gland parenchyma (responder patients). Pilocarpine is one parasympathomimetic drug that has been extensively and rigorously tested and that has been shown to be useful for many patients. Other pharmaceuticals that have been suggested to benefit responder patients include bromhexine (bisolvin) and anethole-trithione (sialor). Clinically, artificial salivas have served as a replacement modality for individuals exhibiting hyposalivation and those lacking functional glands (nonresponder patients). For sale as an "over-the-counter" item, artificial salivas have been traditionally formulated to replenish particular functions of saliva such as lubrication, viscosity, tissue hydration, surface tension, and/or antimicrobial properties. Currently available products appear to be less than ideal, since their effects are of limited duration, and they may either have an unpleasant taste or irritate the mucosa. Since a clearly promising saliva substitute does not yet exist, proposed studies would very likely be of the pilot or screening type. Additionally, it has been suggested that active stimulation of salivary secretion during head and neck radiation may reduce the iatrogenic salivary hypofunction associated with this therapeutic procedure. It would be useful to test the utility of a proven, effective sialogogue, like pilocarpine, for such preventive therapy. Research Goals and Scope Based on recommendations by the Dental Research Programs Advisory Committee at its June 7-8, 1988 and April 7-8, 1992 meetings, the NIDR "Broadening the Scope: Long-Range Research Plan for the Nineties," and the NIDR/Fogarty International Center Report on "International Collaboration for Oral Health Research" (Philip J. Holloway, April 1989), applications are invited for research project grants (including minority research supplements), program project grants, FIRST awards, small grants, career development awards, and postdoctoral fellowships in the broad area of the epidemiology, etiology, pathogenesis, diagnosis, and treatment of xerostomia, particularly in relation to Sjogren's syndrome. Some examples of research areas of interest include, but are not limited to: o Development of reliable epidemiological data on the prevalence and incidence of salivary gland disorders, such as Sjogren's syndrome and xerostomia related to systemic medications, particularly among target populations such as the aged and others at high risk. o Further investigations on the etiology and pathogenesis of diseases and conditions that cause xerostomia. This research should include development of sophisticated model systems (cell culture and transgenic animals) to investigate normal cellular processes and those evident in disease. o Development of improved methods, including more sensitive and specific assays using saliva, to diagnose specific salivary gland disorders. o Development and improvement of treatments for salivary hypofunction, including genetic manipulation and development of organoids. o Development of new sialogogues and improved, long-acting saliva substitutes. o Development of methods to expand and improve function of residual salivary gland tissue after destructive disease or therapy (e.g., radiation and chemotherapy to treat head and neck cancers). This research should include methods aimed at tissue repair and regeneration. o Development of techniques for the preservation and transplantation of salivary glands. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 in items 1-4 of the Research Plan AND summarized in item 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans [including American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups must be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the review will be deferred until the information is provided. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. APPLICATION PROCEDURES Applications will be accepted on an indefinite basis in accordance with the receipt, Initial Review Group, National Advisory Council and earliest possible beginning dates specified in the pertinent application kits. The specific application forms and kits required in this connection are available at most institutional business offices and may be obtained from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone (301) 496-7441. The application form PHS 398 must be used for research projects (R01, R29, P01, and R03) and the Career Development Awards (K07, K11, and K15). The application form PHS 416-1 must be used for fellowships (F32 and F33). The YES box must be checked and the title and number of the announcement must be typed in item 2a on the face page of the application form PHS 398 (rev. 9/91). In the case of fellowship applications, the announcement title must be typed in item 3 on the face page of form PHS 416-1 (rev. 7/88). The completed original application form PHS 398 and five legible copies must be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** When using the PHS 416-1 fellowship application, submit the original and two copies to the above address. REVIEW PROCEDURES Applications will be assigned on the basis of established PHS referral guidelines. Applications will be reviewed for scientific and technical merit by study sections of either the Division of Research Grants, NIH or the NIDR, in accordance with the standard NIH peer review procedures and the review criteria customary for the support mechanism selected. Following scientific-technical review, the applications will receive a second-level review by an appropriate national advisory council or board. AWARD CRITERIA Applications recommended for further consideration will compete for available funds with all other applications. The following will be considered in making funding decisions: o quality of the proposed project as determined by peer review o availability of funds o program balance among research areas of the announcement INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: G.G. Roussos, Ph.D. Director, Salivary Research and Oral Biology Centers Program Extramural Program National Institute of Dental Research Westwood Building, Room 505 Bethesda, MD 20892 Telephone: (301) 496-7884 Direct inquiries regarding fiscal matters to: Ms. Theresa Ringler Chief, Grants Management Office Extramural Program National Institute of Dental Research Westwood Building, Room 518 Bethesda, MD 20892 Telephone: (301) 496-7437 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.121. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-77788-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. .
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