The Pathogenesis and Natural History of Sjogren s Syndrome
The Pathogenesis and Natural History of Sjogren s Syndrome
Background:

 -Sjogren s syndrome is a disease that affects about 1-4 million Americans. It is more common
 in women. It mainly affects the glands that produce saliva and tears, leading to dry eyes and
 dry mouth. The cause of Sjogren s syndrome is unknown, but inflammation plays an important
 role. The purpose of this study is to learn more about Sjogren s syndrome.

 Objectives:

 -To better understand how Sjogren s syndrome begins and how it affects patients so that we
 can develop better ways to treat them.

 Eligibility:

 -  Participants must be 16 years of age or older.

 -  They must have a diagnosis of Sjogren s syndrome or have at least two symptoms of
 Sjogren s syndrome.

 Design:

 -  People taking part in the study will come to the NIH Clinical Center for at least three
 visits.

 -  During these visits, participants will have a medical history and physical exam. They
 will have oral and dental assessments, and saliva collection. Lab tests (blood and
 urine) and dry eye exams will be done. Participants will answer questionnaires and have
 salivary scintigraphy (adults only unless required for diagnosis).

 -  Other optional tests may also be done. Participants may have to come in for additional
 visits if they have these optional tests or if their disease changes.

 -  The only treatment provided as part of this study is for medical emergencies or
 complications that occur while you are at NIH for evaluation.
BACKGROUND

 Sj(SqrRoot)(Delta)gren s syndrome (SS) is an autoimmune disease characterized by chronic
 inflammation

 involving the exocrine glands. Salivary and lacrimal glands are predominantly affected
 leading to dry mouth and dry eyes but other exocrine organs are also frequently involved. It
 is one of the most common rheumatic autoimmune diseases, which effects between 1-4 million
 Americans, predominantly women with a female to male ratio of 9:1. Sj(SqrRoot)(Delta)gren s
 syndrome may occur alone (primary SS), or may coexist with other systemic connective tissue
 disorders (secondary SS). In many cases systemic manifestations, such as fatigue, arthritis,
 vasculitis, lung disease, peripheral or central neuropathy and autonomic nervous system
 dysfunction accompany glandular involvement. Patients with systemic manifestations are at
 higher risk of lymphoma, the incidence of which is increased in SS. The treatment of sicca
 symptoms is mainly symptomatic, whereas management of extraglandular manifestations is
 similar to other autoimmune diseases.

 The cause and pathogenesis of Sj(SqrRoot)(Delta)gren s syndrome is still largely unknown. In
 a genetically predisposed individual various environmental factors, such as viral infections,
 may lead to epithelial cell activation and a protracted inflammatory response with features
 of autoimmunity. Autoreactive lymphocytes and autoantibodies are considered important in this
 process although the pathogenic role of any particular autoantibody is still undefined.
 Although inflammation may contribute to the exocrinopathy of SS, the relationship between
 inflammation and exocrine dysfunction is poorly understood. Moreover, the model does not
 explain many of the extraglandular manifestations of SS patients, such as fatigue. Further
 studies are needed to better understand the pathogenesis of SS.

 OBJECTIVES

 The primary objective of this study is to enable the collection of longitudinal clinical and
 laboratory data and biologic specimens to identify pathogenetic mechanisms of SS by careful
 clinical phenotyping of SS patients and Sj(SqrRoot)(Delta)gren s-like conditions over time
 and collection of biologic samples for concurrent and future laboratory studies related to
 the pathogenesis of Sj(SqrRoot)(Delta)gren s syndrome. Another objective of the study is to
 identify biomarker candidates associated with the diagnosis, severity, prognosis, or organ
 involvement in SS.

 The protocol will enable the study of the genetic basis and the mechanistic aspects of
 immunologic and non-immunologic abnormalities of SS and their associations with various
 clinical phenotypes.

 ELIGIBILITY CRITERIA

 The study will enroll 300 subjects with Sj(SqrRoot)(Delta)gren s syndrome or
 Sj(SqrRoot)(Delta)gren s-like conditions. Subjects aged 16- years or older fulfilling
 European American Consensus Criteria for Primary or Secondary Sj(SqrRoot)(Delta)gren s
 syndrome are eligible for the study. Selected subjects with incomplete Sj(SqrRoot)(Delta)gren
 s syndrome or who are excluded from the European American criteria may also be eligible.
 Screening will be done on the Characterization of Diseases with Salivary Gland Involvement
 protocol (15-D-0051) prospectively or on the previous screening protocol (84-D-0056).

 DESCRIPTION OF THE STUDY

 This is a longitudinal observational study. All subjects will have at least three core
 evaluations (approximately biannually) during a 4-5 year period. Additional evaluations may
 be required if there is a significant change in the clinical condition of subjects likely
 related to SS or sicca syndrome or to provide additional research samples or clinical data
 for the pathogenesis studies. Clinical data will be collected through questionnaires,
 personal interviews, physical examination, laboratory testing and imaging studies. The core
 evaluation will include a complete medical history and physical examination and a complete
 oral and dry eye evaluation. Research studies include salivary scintigraphy for functional
 assessment of salivary gland function, testing of the autonomous nervous system and may
 include an ultrasound guided parotid core needle biopsy. Blood, saliva and biopsy samples
 will be stored and used for laboratory research studies aimed at the pathogenesis of
 Sj(SqrRoot)(Delta)gren s syndrome. Samples labeled with a code without any personal
 identifiers may be shared with researchers in and outside the NIH. DNA will be collected for
 genetic studies related to Sj(SqrRoot)(Delta)gren s syndrome and related conditions.
-  INCLUSION CRITERIA:

 1. Ability to sign informed consent form

 2. Fulfilling one the definitions below:

 1. Sj(SqrRoot)(Delta)gren s defined by European-American (EA) classification
 criteria for primary or secondary Sj(SqrRoot)(Delta)gren s syndrome (SS
 group)

 2. Excluded from the EA criteria because of a comorbid condition but otherwise
 fulfilling the European-American classification criteria (EA excluded SS
 group)

 3. Incomplete SS

 i. at least 2 of the EA criteria with a common manifestation of SS not included
 in these criteria (e.g., fatigue, vasculitis, arthritis, etc)

 ii. 2 or more common manifestations of SS which are not included in the EA
 criteria (e.g.,: fatigue, vasculitis, arthritis, autonomic dysfunction, etc ) and
 are not explained by other conditions

 EXCLUSION CRITERIA:

 1. Age <16 years

 2. inability or unwillingness to comply with follow up requirements

 3. Any medical or psychological/psychiatric condition or treatment that, in the
 opinion of the Principal Investigator, would exclude the subjects from the
 research studies (e.g., alternative explanation for subjects signs and symptoms)

 4. NIH employees who report directly to the principal investigator or who are a
 co-worker or relative of the principal investigator..