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Sjögren's_syndrome~_Role_for_Cevimeline
1. Sjogren’s Syndrome: Evolving Concepts of Treatment based on Pathogenesis Robert I. Fox, M.D., Ph.D. Scripps Memorial Hospital and Research Institute La Jolla, California USA [email_address]
2. Acknowledgements Carla Fox, R.N. Clinical Coordinator and Medical Editor Scripps Memorial Hospital and Research Foundation Karin Tatsumoto, M.D. Daiichi Sankyo Tokyo, Japan
9. Historical 1892 - Mickulicz describes KCS (but term too vague-did not distinguish TBC and lymphoma) 1933 - Sjogren (distinguished from Vitamin D deficiency) 1953 - Morgan and Castleman- NEJM CPC 1956 - Bloch, Buchanan, Wohl, Bunim- Medicine defined the disease as we know it today 1980’s - Criteria consensus established for Sjogren’s 1990 - Organized therapeutic trials based on rational understanding of pathogenesis
10. New International Criteria - 1 1. Ocular Symptoms 2. Oral Symptoms 3. Salivary gland function (flow rate by flow rate, scan, or sialography) AND 4. Histopathology (focus score > 1) 5. Autoantibody to SS-A or SS-B
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12. There is good agreement about diagnosis for the patient with florid symptoms of keratoconjunctivitis sicca (KCS), parotid swelling, and high titer ANA with SS-A/SS-B. What is Sjogren’s?
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18. 1. Assess for (true) disability - medical/legal, especially if they are seeking disability benefits (although rare to find organic brain syndrome, the results are used to help patients alter their lifestyle) 2. Assess for depression- (duloxetene/milnicaprin or pregabalin approved therapy for fibromyalgia in US). Tricycyclics unlikely to be tolerated due to dryness 3. Assess decreased “executive function” (i.e., multi-tasking) often exacerbated by stress < modafalin-Provigil > We have found brief neuro-psychometric testing helpful to guide therapy:
20. Pathogenesis of Sjogren’s: the major misunderstanding The salivary and lacrimal glands are not fully destroyed. In fact, only 50% of the acini and ducts are destroyed. The residual ducts are not functioning due to the release of cytokines and metalloproteinases.
21. In Sjogren’s syndrome, many acini and ducts are spared Sjogren’s Normal Lymphocytic infiltrate Areas of “lazy” gland
22. The key question is: Why do the residual acini/ducts not function optimally? The glands and neural innervation are present. and… How does this relate to symptoms, pathogenesis and therapy?
23. When patients describe irritation of eyes or mouth… they are describing increased friction as the lid transverses the globe, or the tongue moves over the buccal mucosa.
24. Normally the upper eyelid glides over the globe on a coating called the tear film composed of water, protein, mucins orbit eyelid tear film
25. When the tear film is inadequate, the upper lid sticks to the surface of the orbit and actually pulls off the surface layer of the ocular surface. orbit eyelid Tear film The Sjogren’s patient is describing increased friction as the upper lid moves over the globe
26. 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.
29. To understand the symptoms of SS and the role of cevimeline… We must first review the concept of the functional circuit that governs tear and saliva.
30. Normal tearing or salivation secretion requires a functional unit 1. mucosal surface 4. gland Central Nervous System 3. blood vessel afferents efferents 2. lacrimatory or salivatory nuclei in midbrain water mucin protein water nutrients hormones cortical input
34. Muscarinic Receptor Actions a) M1 receptor : neuroprotective and anti-apoptotic properties for neurons b) M2 receptor : (found on cardiac tissues) c) M3 receptor : secretory function of gland
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36. Early in the clinical trials of cevimeline in Alzheimer’s Increased salivation was noted as a side effect, leading to its trials in Sjogren’s syndrome.
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40. Cevimeline is a neurotransmitter that mimics acetylcholine. and binds to Receptors of Muscarinic Type 1 and 3 M1 nerve cevimeline gland M1 M1 receptor mediates glandular resistance to “shock” and facilitate regrowth M1
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42. Drugs such as Aricept or Excelon currently approved for Alzheimer’s work to improve memory by inhibiting acetylcholine esterase and thus, increasing Ach in the gap ACh Acetyl cholinesterase
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45. Muscarinic Receptors There are at least 5 receptors (M1-M5), but we will concentrate on M1 and M3 mAChR that are found on the salivary gland. The muscarinic receptors are members of the super family of G-protein coupled receptors.
46. Binding of Cevimeline to Muscarinic Receptors CHO-K cells were transfected with different human muscarinic receptors with emphasis on M1, M2, and M3
56. 7. Sjogren’s syndrome serves as an interesting prototype disease to study the interaction of immune and neural function at a site accessible to biopsy. SUMMARY - 4