Overview of Sjogren’s Syndrome: Robert I. Fox, MD., Ph.D. Scripps Memorial and Ximed La Jolla, CA

It is a great honor to provide an overview for our distinguished experts Dr. Stephen Cohen--Eye Dr. Avu Wu--Mouth Dr. Daniel Sauder--Skin Dr. Fisher--Sleep Dr. Nichols--GI Dr. Wallace--Lupus Dr. Cohen--New Drugs

Goals 1. Emphasize that evaluation of Sjogren’s is different from a disorder like Rheumatoid Arthritis 2. Recognize that Sjogren’s patient has symptoms that often do not correlate closely with laboratory abnormalities 3. In development of future therapy, we have to take a broader point of view to understand the basis of Sjogren’s symptoms

Sjogren’s Syndrome- is important to recognize and treat but receives little attention even from the American College of Rheumatology “Quality of life”- patients equated the impact of dryness in Sjogren’s on their life a) at same level of limitation as patients with moderate angina b) they are willing to give up 2 years of life!!! to not have this condition

Factors not generally considered or measured with lab tests “Disability” is most commonly due to fatigue and cognitive impairment “Limitations” on daily activities: dry eyes (limits work- especially computer) dry mouth (limits sleep and social interactions around eating) extra-glandular manifestations, particularly neurologic “Expense of artificial tears and dental decay

Typical Clinical Features of dry eyes, dry mouth and swollen glands

Dryness results in the clinical appearance of keratoconjunctivitis sicca (KCS) characteristic of Sjogren’s syndrome The upper lid literally sticks to the surface epithelial surface and pulls surface mucin layers off. The Rose Bengal dye retention is like “rain water pooling in a street pothole” This test can be done at bedside and allows “triage” and rapid referral of patients to Ophthalmology

Severe Xerostomia with dry tongue

Sjogren’s Syndrome- Cervical Dental Caries

In Sjogren’s syndrome: there is often a poor correlation between how the patient feels and the laboratory tests. This frustrates both patients and doctors.

The labs and the symptoms: Take Home Lessons-1 We measure blood counts, sedimentation rates and auto- antibodies. This gives an idea of the “activity” of the immune system based on lymphocyte hormones. However, these lab tests do not often correlate well with the patient’s symptoms.

The key to understanding this imbalance of labs and symptoms Recognition that lymphocyte hormones (which is what we are really measuring indirectly through our lab tests) influence: the nerve’s function to activate glandular secretion the nerve’s ability to transmit sensations of pain or discomfort

The Functional Circuit The functional circuit refers to the “nerve” input from eye and mouth to the central nervous system. In other words, the threshold for sensing “pain or dryness” may differ in individual patients.

Normal tearing or salivation secretion requires a functional unit Nerves on mucosal 4. Stimulation of gland 2. Midbrain of central nervous system 3. Stimulation of blood vessel Afferent nerves 3. Cortical Outflow Tracts and HPA Lacrimatory or salivatory nuclei water mucin protein water nutrients hormones 1.Ocular or oral surface irritation

In Sjogren’s syndrome, the release of neural transmitters --and the response of the glands to neural transmitters-- are impaired by lymphocytes that enter the gland and release inflammatory factors ocular and oral dryness Focal lymphocytic infiltrates in the glands lymphocytes Gland dysfunction Autoantibodies (anti-muscarinic antibody)  Cytokines (type I IFN,  -IFN) Metalloproteinases (outside-inside signaling molecules)

In Sjogren’s, only 50% of the acini and ducts are destroyed. Despite their retention of neural innervation, the residual glands do not function as a result of the inflammatory environment Sjogren’s Normal Foci of lymphs

Thus, the interesting question is: Why are the residual glandular elements not working? This fundamental question of how immune and neural systems interact will be the “holy grail” of neuroscience for the next decade.

In addition to the symptoms SS has lymphoproliferative properties— it lies on the border between autoimmunity and lymphoma.

Sjogren’s Syndrome – with parotid enlargement indicates lymphoproliferative tendency

The normal salivary gland is not a lymph node. Why are there lymphocytes in the salivary gland?

Part of the cause of Sjogren’s is that lymphocytes “home” to the glands 1. T- and B-cells have surface “homing receptors” when generated in node or marrow. CD4+ B cell Blood 3. When the homing receptor encounters vascular adhesive molecules, the lymphocyte enters tissue. 2. Lymphs migrate through blood to tissues.

Time course of autoimmune response * 1. Genetic factors predispose to Sjogren’s 2. Environmental factor such as a viral infection leads to autoantibody. 2. Antibodies precede disease. 3. Presence of antibody does not mean disease. Genetic Factors (including sex) (HLA-DR) Genetic Factors (including sex) (HLA-DR) Genetic Factors (including sex) (HLA-DR) Genetic Factors (including sex) (HLA-DR) Auto- antibodies Acquired Immune system (HLA-DR) T/B-cells Disease Manifestations Time period of years Innate Immune system (Toll receptor) Genetic Factors (including sex) (HLA-DR) Environmental Factor (virus-such as EBV ) (apoptotic fragment) Type I IFN Immune complex Ref

Overview of Symptoms When we get “flu symptoms” of joint pain, fatigue, foggy thinking— it is a result of the lymphocyte hormones released by the immune system. When these reactions persist in genetically predisposed individual by the immune system, the result is autoimmune disease.

Summary-1 Sjogren’s syndrome represents the interface of: a)Immune and exocrine secretory functions (dryness) b)Immune and neural function (neuropathy/cognitive) c)Immune and hypothalamic-adrenal axis (endocrine) d) Autoimmune proliferation and lymphoma e) Lupus-like features of vasculitis and immune complex

Summary-2 1.Extraglandular manifestations are determined by lymphocyte homing to tissues-- factors that govern their retention in tissues and their apoptosis. 2.Factors governing their clonal expansion and lympho-proliferation lead to lymphoma-derived from B-cells themselves, T-cells, and dendritic cells.

Summary -2 Why is SS predominantly in women X-chromosome location of Toll receptor; X-linked genes for apoptosis; X-linked genes for transcription promoter of pro-inflammatory loci including NF-K; X-linked control of metalloproteinase release under hormonal regulation.

Treatment of Sjogren’s in 2012: Opportunities and Challenges a)Treatment of Dry Eyes and Mouth b)Treatment of Extraglandular Manifestations-- Lupus like symptoms-arthralgia, rash Neuropathy (central and peripheral) Cognitive and myalgia (fibromyalgia) Lymphoproliferative

Thank you for coming I will now take questions Or if there is time, I can describe a bit about how we are approaching this problem of functional circuit in association with colleagues at Scripps and Salk

Neuropathy Poor correlation between symptoms and objective findings: –Eye pain- does not correlate with tear flow; –Mouth pain-not correlate with saliva; –Peripheral neuropathy-not correlate with nerve biopsy; –Cognitive-not correlate with acute phase reactants.

Fibromyalgia: The elephant in the Room Fatigue Cognitive Nerve pain Dry eyes and dry mouth

As rheumatologists We will need to learn a new vocabulary about the perception of pain and how it is modulated by cytokines. The key term is the “plasticity” of the nervous system. How the perception of pain is modulated by cytokines of the “stress axis.”

Cytokines alter pain perception

Brain Regions that May Modulate Pain and Emotion 1-4 Prefrontal Cortex Hippocampus Insular Cortex Thalamus Somatosensory Cortex Both Pain Central Amplification of Pain from Eyes and Mouth: Regions Found on Functional MRI

Thank you for your time and attention I would be happy to entertain any questions now or later. The slides are available to you for your use at

The Body’s 2 Distinct But Interconnected Immune Systems ACQUIRED Lymphyocytes (Type 2 interferon signature) Beutler B et al. Blood Cells Mol Dis. 1998;24: HLA-DR4–dependent: T cells respond to peptide antigens and generate memory cells INNATE Dendritic Cells (Type 1 interferon signature) HLA-DR–independent: Dendritic cells respond to specific structures found on bacteria and apoptotic Products (Toll receptors)