Pathogenesis of Sjogren’s Syndrome:

1. Pathogenesis ofSjogren’s Syndrome: Translating Basic Sciencefrom “Bench to Bedside”

2. Sjogren’s Syndrome • Increased mortality risk, particularly due to lympho-proliferative complications • Quality of life- equated with moderate angina • “Disability” predominantly due to fatigue and cognitive • “Limitations”: • dry eyes (limits work- especially computer) • dry mouth (limits sleep and social interactions around eating) • Out of pocket expense of artificial tears and dental decay

3. Background-1 • Sjogren’s syndrome represents the interface of: • Immune and exocrine secretory functions (dryness) • Immune and neural function (neuropathy/cognitive) • Immune and hypothalamic-adrenal axis (autonomic) • d) Autoimmune proliferation and lymphoma • e) Lupus-like features of vasculitis and immune complex

4. Background-2The Danger Signal When we get “flu symptoms” of arthralgia, fatigue, cognitive dysfunction— it is a result of the cytokines/neurotransmitters released by the innate immune system. When these reactions persist due to a vicious cycle perpetuated in genetically predisposed individual by the acquired immune system, the result is autoimmune disease.

5. Pathogenesis: Take Home Lessons-1 • Innate and Acquired Immune Systems are targets for current therapy—including TNF, BAFF and IL-6 inhibitors, steroids, traditional DMARD’s and new oral agents (Jak and syk inhibitors). • Functional circuit that controls immune and neural function comprises the new “frontier” for therapy from fibromyalgia to depression. The functional circuit is the link between cytokines and symptoms.

6. Take Home Lesson - 2The two arms of the immune system mutually interactin the initiation and perpetuation of Sjogren’s Syndrome Acquired System Innate System  (Adaptive, immediate) - HLA independent  Dendritic cells  Cytokines-particularly  Type I interferon  Interferon-gamma  BAFF, IL-6, IL-17  Complement, CRP Sensors of the innate system  Toll receptors (TLR)-pathogen motifs  DAMP (damage recognition patterns)-apoptosis  RIG-1 (retinoid inducible genes)  NOD/Card receptors-more than in colitis •  (HLA-DR)-memory • Traditional T-cell and • B-cell and their cytokines • HLA-DR association • with autoantibody • production • Target of drugs such as • DMARDs and certain • biologics

7. Take Home Lesson 3:The Functional Circuit(Cytokines are not enough) Control of tears or saliva flow are complex processes that involve both afferent nerve pathways that go to the midbrain and efferent nervesthat modulate glandular function. The midbrain signals are influenced by the cortical outflow and the hypothalamic axis.

8. Normal tearing or salivation secretion requires a functional unit water mucin protein • Ocular or oral surface • irritation 5. Stimulation of gland Nerves on mucosal water nutrients hormones 3. Cortical Outflow Tracts and HPA Afferent nerves 2. Midbrain of central nervous system Lacrimatory or salivatory nuclei 4. Stimulation of blood vessel

9. In Sjogren’s syndrome, the release of Ach and VIP by efferent nerves to the glands --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 • Gland dysfunction • Autoantibodies • (anti-muscarinic antibody) • Cytokines (type I IFN, g-IFN) • Metalloproteinases • (outside-inside signaling molecules) lymphocytes Focal lymphocytic infiltrates in the glands

10. 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 Normal Sjogren’s

11. In Sjogren’s syndrome The residual glandular cells are paralyzed by the local immune reaction. Even though the acini/ducts are 50% present, their innervations and their receptors for neurotransmitters are present.

12. 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.

13. We need to keep in mind that the gland is not destroyed but appears “paralyzed”,the release of cytokines hasled to dysfunction

14. This may help us understanda) the functional circuit analogy may also apply to neuropathic pain(poor correlation with nerve biopsy)b) symptoms of dry eyes and dry mouth that do not correlate with either tear or saliva flow measurements

15. Or Fibromyalgia(Central Sensitization)where symptoms of fatigue and cognitive (executive) function do not correlate with our acute phase reactants or MRI scans

16. Take home Clinical Lessons • When we see a dry eye, when do we need to immediately refer to Ophthalmology? • What are the warning signs for lymphoma when we see a swollen parotid gland? • What should we do with the patient who has symptoms of neuropathy or fatigue?

17. 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

18. For Routine Dry Eye • Do not use preserved tears more than 4 times a day • Learn to mix and match • No Lasik surgery and care with blepharoplasty (exposure keratitis) • Use of lubricants at night and lid scrubs in AM • Restasis may be useful • Punctal Occlusion • Lotemax (a soft steroid) may be used together with Restasis for 2 wks

19. But be on the look out for conditions that require immediate Ophthalmologic EvaluationCorneal Abrasion (fluorescein)

20. Ulcerative keratitis(in patient given broad spectrum antibiotic plus anesthetic)

21. Scleritis (vasculitis)

22. Non-ulcerative keratitis Herpetic keratitis (slit lamp-fluorescein) dendrites

23. What are the particular oral needs of the SS patient A dry mouth is not necessarily a painful mouth • Yeast infection in the mouth is erythematous candidiasis-esp. on hard palate and buccal recesses • look for angular cheilitis and erythema under the dentures • Fissured tongue and loss of papilla • Poor correlation between symptoms and flow rates

24. Burning Mouth Syndrome • Mouth symptoms are out of proportion to the objective dryness • May be a localized form of neuropathy • This may respond to a mouth rinse with (klonepin .5 mg in 2ml mylanta) for 2 minutes bid • May be due to oral yeast infection

25. Severe Xerostomia with dry tongue

26. What are the particular needs at time of dental visit • Frequent hygiene visits • Avoid full veneers that cover caries • Avoid “amateur” tooth whiteners (at malls) • Use of fluoride topically and by tray • Use of MI Paste by Oral Hygienist • Avoid Sugar and acidic beverages

27. Sjogren’s Syndrome- Cervical Dental Caries

28. SS has lymphoproliferative properties—it lies on the border between autoimmunity andlymphoma.

29. Sjogren’s Syndrome – with parotid enlargement indicates lymphoproliferative tendency

30. Risk factors for lymphoma • Germinal centers on minor salivary gland biopsy • Low complement C4 • MGUS (esp. IgM-K with RF activity) and mixed cryoglobulin • The T-cells and dendritic cells drive B-cell clonal expansion, particularly driven by BAFF, until a B-cell clone escapes to become a lymphoma. Germinal Centers in Minor SG Biopsy

31. In patients with persistent parotid swelling despite a brief trial of steroids/antibiotics, • particularly unilaterally for over 6 wks or recur when taper steroids • Enlarged cervical node next to parotid • B-symptoms such as fever and weight loss • Low threshold for needle biopsy to rule out lymphoma

32. Since over 60% of these lymphomas are MALT’s: • they may be very responsive to B-cell depletion (Rituxan) as is published • we still favor Cytoxan plus Rituxan in MALT’s • If your oncologist wants to give CVP-R, go very light on the vincristine due to increased susceptibility of neuropathy

33. Extraglandular Manifestations of Sjogren’s Syndrome Is Sjogren’s syndrome just SLE with 4 criteria? It is best to think of SLE as a disease mediated by antibody and immune complex damage It is best to think of Sjogren’s as a disease mediated by cell infiltration into tissues There is a great deal of overlap, but also differences SSS SS SLE

34. Sjogren’s vs. SLE—extraglandular • The rash of leukocytoclastic vasculitis vs. hyper-globulemic purpura • The lung manifestations of pleurisy vs. interstitial pneumonitis • The renal manifestations of glomeruloneprhtis vs. interstitial nephritis • The increased risk of lymphoma

35. However, SS and SLE are more similar than dissimilar • The genetics of SS are remarkably similar to a subset of SLE (i.e.. HLA-DR3) • The pattern of auto-antibodies are similar, including SS-A in SLE patients • Most importantly, the response to therapies are similar

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

37. Our most difficult problems • Neuropathy—peripheral and central; • Chronic fatigue and vague cognitive impairment; • Lymphoproliferation; • Accelerated cardiovascular complications.

38. 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.

39. 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.”

40. Cytokines alter pain perception

42. Brain Regions that May Modulate Pain and Emotion1-4 Central Amplification of Pain from Eyes and Mouth: Regions Found on Functional MRI Both Pain Somatosensory Cortex Insular Cortex Prefrontal Cortex Thalamus Hippocampus

43. Fibromyalgia • We have found the combination of low dose cymbalta (30-60) plus Lyrica 75 most useful and best tolerated • More cymbalta and GI intolerance • More Lyrica and weight gain

44. Take Home Lesson 1 1. Topical therapy and ability to stimulate saliva or tears remains inadequate. 2. Treatment of extraglandular manifestations such as arthritis, rashes, hemolytic anemia, or lymphomas is rapidly improving. 3.The treatment of the neuro-endocrine manifestations (cognitive impairment and fatigue) remains inadequate.

45. 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 RobertFoxMD@mac.com

47. Treatment of Sjogren’s in 2010:Opportunities and Challenges • Treatment of Dry Eyes and Mouth • Treatment of Extraglandular Manifestations-- • Lupus like symptoms-arthralgia, rash • Neuropathy (central and peripheral) • Cognitive and myalgia (fibromyalgia) • Lymphoproliferative

48. Take Home Points-1 • Topical therapy of dry eyes and dry mouth: new targets include water transport, mucins, and topical small molecules such as jak 3. • Dry mouth symptoms may be “burning” mouth and require treatment as a local neuropathy.

49. Take Home Point-2 • Poor correlation of symptoms and objective findings of both dryness and neuropathic symptoms. • This poor correlation is the greatest challenge since it involves cortical perception of discomfort • The neuro-endocrine circuit in Sjogren’s may provide insight into “fibromyalgia”

50. Take home points-3 • Systemic Manifestations for lupus like symptoms DMARDs Hydroxychloroquine Methotrexate Leflunomide Small molecules-Jak3 and Jak ½ Filomodulin (MS approved) Biologic Agents Anti-CD20 rituximab and new variants Anti-BAFF (Benlysta) Anti-CD22 (Eprumazab) Taci-Ig and ICOS Homing receptors