Evaluation of the Role of the Autonomic Nervous System in Sj(SqrRoot)(Delta)Gren s Syndrome

Sj(SqrRoot)(Delta)gren s syndrome (SjS) is a systemic exocrinopathy that affects as high as 5
percent of the population. It is manifested predominantly as dry eyes, dry mouth, and
fatigue. The exocrinopathy can be encountered alone (primary SjS) in approximately one half
of the patients or in the presence of another autoimmune disorder such as rheumatoid
arthritis, systemic lupus erythematosus, or systemic sclerosis (secondary SjS). The most
widely accepted classification for SjS is the American-European consensus classification
criteria for SjS.(Vitali, Bombardieri et al. 2002)

Current understanding about the pathogenesis of SjS stems from the assumption that the
autoimmune destruction of the exocrine glands leads to their hypofunction and symptoms of
dryness. The existing evidence however does not fully support this assumption and cannot
explain the underlying pathogenic mechanisms of SjS for the following reasons: 1) Discordance
between severely affected function and abundance of histologically normal and ex vivo
functional salivary glands; 2) at least 20% of patients have no evidence of systemic
autoimmunity; 3) Animal models of SjS develop glandular dysfunction long before they develop
autoimmunity; 4) Dryness and related symptoms respond poorly to immunosuppressive, including
newer biologics, but fairly well to secretagogues such as pilocarpine. 5) No pathogenic
antibodies or target epitopes have been identified to date to unify the pathogenesis of the
syndrome.

All exocrine glands are innervated by the autonomic nervous system (ANS) and dysautonomia can
mimic the phenotype of SjS, particularly cardinal manifestations, such as xerostomia and
xerophthalmia. Thus we hypothesize that ANS dysfunction is central to the pathogenesis of SjS
and propose to systematically study the ANS function in our cohort of patients with primary
SjS compared with normative data from age and sex-matched controls. This protocol calls for a
comprehensive evaluation of autonomic function, using physiological, neuropharmacologic,
neurochemical, and imaging approaches, to identify consistent distinctive patterns of ANS
involvement in SjS and thereby improve the diagnosis and understanding of pathophysiologic
mechanisms of SjS.

- INCLUSION CRITERIA:

1. Diagnosis of primary Sjogren s syndrome based on American-European Consensus
Group Sjogren s syndrome classification criteria or healthy volunteers.

2. Both genders and all minorities.

3. Age at entry at least 18 and less than 65 years.

EXCLUSION CRITERIA:

1. Current use of medications known to significantly influence the activity of the
sympathetic or parasympathetic nervous system if they cannot be held safely at the
time of ANS testing

2. Known co-existing diagnosis of ANS dysfunction (for healthy volunteers)

3. Medications-requiring diabetes mellitus

4. Diabetic autonomic neuropathy

5. Vitamin B12, folate deficiency, requiring replacement

6. Hepatic failure (AST or ALT greater than 1.5 x upper limit of normal)

7. Renal failure (GFR less than 30 ml/min, as estimated by the MDRD)

8. Congestive heart failure (Class II-IV)

9. Refractory ventricular arrhythmias

10. Symptomatic coronary heart disease

11. Previously established diagnosis of sinus node dysfunction

12. Severe anemia (Hgb less than 8)

13. Psychosis

14. Pregnant or lactating women

15. A candidate subject is excluded if, in the judgment of the Principal Investigator,
protocol participation would place the subject at substantially increased acute
medical risk.

16. Not able to provide informed consent

Medications: A candidate subject is excluded if clinical considerations require that the
subject continue treatment with a drug likely to interfere with the scientific results i.e.
a tricyclic antidepressant or fludrocortisone. Subjects with known or suspected allergy or
hypersensitivity to any test drug are excluded from receiving that drug. Subjects who must
take medications daily in the following categories are excluded: tricyclic antidepressants,
beta blockers, barbiturates, if they cannot be safely held during testing. Subjects unable
to discontinue nicotine or alcohol temporarily are excluded. Subjects are not to
discontinue any medications before the subject or the subject s physician discusses this
with the Principal Investigator, Dr. Nikolov, or the Associate Investigator, Dr. Goldstein.
If it is decided that discontinuing medications would be unsafe, then the subject is
excluded from the study. Subjects must discontinue use of alcohol and tobacco throughout
the period of testing in the protocol.

Herbal Medicines and Dietary Supplements: Certain herbal medicines or dietary supplements
are known or suspected to interfere with the experimental results, and such herbal
medicines or dietary supplements must be discontinued before enrollment in the study. For
many herbal medicines or dietary supplements, the mechanisms of action and therefore the
possible effects on the experimental results are unknown. In cases where the subjects wish
to continue their herbal medicines or dietary supplements while on study, and search of the
available medical literature fails to identify effects that are known or expected to
interfere with the experimental results, then the subjects may participate.