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Transcript
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 Syndromeis 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 autoantibodies. 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 4. Stimulation of gland water nutrients hormones 3. Stimulation of blood vessel water mucin protein 3. Cortical Outflow Tracts and HPA 1. Ocular or oral surface irritation Nerves on mucosal Afferent nerves 2. Midbrain of central nervous system Lacrimatory or salivatory nuclei 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 lymphocytes Focal lymphocytic infiltrates in the glands Gland dysfunction •Autoantibodies (anti-muscarinic antibody) Cytokines (type I IFN, g-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 Foci of lymphs Sjogren’s Normal 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 3. When the homing receptor encounters vascular adhesive molecules, the lymphocyte enters tissue. CD4+ Blood 2. Lymphs migrate through blood to tissues. B cell 1. T- and B-cells have surface “homing receptors” when generated in node or marrow. 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. Environmental Factor (virus-such as EBV) (apoptotic fragment) Innate (Toll receptor) Type I IFN Genetic Genetic Genetic Genetic Factors Factors Factors Factors (including (including (includingsex) sex) sex) (HLA-DR) (HLA-DR) (HLA-DR) (HLA-DR) Autoantibodies Immune system Immune complex Acquired Immune system (HLA-DR) T/B-cells Disease Manifestations Time period of years Ref. 32-33 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 Dry eyes and dry mouth Nerve pain 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.” Neuroplasticity in Pain Processing1-3 100 Pain Sensation 80 Hyperalgesia3 Cytokines alter pain perception 60 40 Pain state Allodynia 20 0 innocuous noxious Stimulus Intensity 1. Woolf CJ, Salter MW. Science. 2000;288:1765-1768. 2. Basbaum AI, Jessell TM. The perception of pain. In: Kandel ER, et al, eds. Principles of Neural Science. 4th ed. 2000:479. 3. Cervero F, Laird JMA. Pain. 1996;68:13-23. Normal The Pain Roadmap: Peripheral and Central Nervous System Landmarks • The neural processing of pain involves the: – peripheral nervous system – spinal cord (central nervous system) – brain (central nervous system) Central Nervous System Brain image courtesy of ATI Peripheral Nervous System Brain Regions that May Modulate Pain and 1-4 and Mouth: Central Amplification ofEmotion Pain from Eyes Regions Found on Functional MRI Both Somatosensory Cortex Pain Insular Cortex Prefrontal Cortex Thalamus Hippocampus 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 [email protected] The Body’s 2 Distinct But Interconnected Immune Systems ACQUIRED INNATE HLA-DR4–dependent: HLA-DR–independent: T cells respond to peptide antigens and generate Dendritic cells respond to specific structures found on bacteria and apoptotic memory cells Products (Toll receptors) Lymphyocytes Dendritic Cells (Type 2 interferon signature) (Type 1 interferon signature) Beutler B et al. Blood Cells Mol Dis. 1998;24:216-230.