The Pathogenesis and Natural History of Sjogren s Syndrome

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..