1. SJOGREN’S SYNDROME: Theory to Practice in San Diego Robert I. Fox, M.D., Ph.D. Carla M. Fox, RN Scripps Memorial Hospital Scripps/XiMED Medical Center La Jolla, California USA robertfoxmd@mac.com

2. Take home lesson 1: 1)There are no FDA approved drugs for the systemic manifestations of Sjogren’s Syndrome. 2) Therefore, expert opinion must be used to choose therapies based on literature. 3)These recommendations are summarized in my new chapters with Alan Baer in UpToDate

3. Take home lesson-2 1.Steroids work 2.Long term steroids have complications 3.The definition of a rheumatologist is how to get a patient off steroids

4. Take home lesson-3 DMARDs -MTX, LEF, AZA similar to RA or SLE Immune suppressants-Mycophenolic acid, cyclosporin A, and Rapamycin

5. Old drugs in new ways Cytotoxics-cyclophosphamide with new lower dose regimens Anticoagulants and treat co-morbid conditions such as cardiovascular or thrombosis

6. The most challenging issues for SS therapy-1 1.Neurologic Manifestations—including peripheral neuropathy, ganglionopathy, and central nervous involvement. 2. Lymphadenopathy and lymphoma

7. The most challenging issues for SS therapy-2 3. IgG4 Related Disease Spectrum 4. Infections mimicking or occurring in SS

8. Fatigue and cognitive loss-3 Recognize depression Recognize sleep disorders Recognize autonomic neuropathy (POTS) Remember large number of patients needed to show efficacy of anti-depressants statistically due to placebo effect

9. Fatigue and cognitive loss-4 Our therapies are poor Need for new disease models and better therapy Recognize placebo effect in anecdotal report

10. Our future approach I have left to discussion period our collaborations with: Ramachandran (Salk) regarding phantom pain and neurochemistry of "veto" neurons Beutler (Scripps) and innate immune mechanisms of fatigue (post viral model) Oldstone (Scripps) for fatigue of multiple sclerosis and mouse viral model (LDL and cyclo-oxygenases)(Receptys)

11. Current critical issue in the patient with intractable eye symptoms The dissociation between ocular symptoms and objective findings: The patient with severe discomfort or complaints-- but relatively mild objective ocular surface a) meibomian gland dysfunction (blepharitis) b) irritant or allergic effects to preserved tears or ocular meds

12. New Concept in patient where ocular symptoms are out of proportion to symptoms (pioneered by Rosenthal et al at Harvard Cornea Unit in the post-Lasik patient) Central pain syndrome: "phantom pain" a loss of corneal nerve density and up-regulation of central pain processing (conforcal microscopy of cornea and fMRI of brain)

13. Systemic Extraglandular Manifestations Steroids work… but-- –The definition of a rheumatologist is how to taper steroids. Anti-malarials (HCQ, Quinacrine) DMARDs-MTX, Leflunomide, Mycophenolic Acid Biologics

14. Hydroxychloroquine Current debate about "efficacy" --we use it when we are dealing with increased ESR, rash, or arthritis. Current debate is about "fatigue" only. Efficacy in SLE was convincingly shown in "withdrawal studies," and those need to be done in SS patients. Issue of cost/benefit of OCR monitor and total dose vs. daily dose based on weight.

15. Biologics studied in SS (that show some promise) Anti-CD20 (rituximab)* –most widely used in SS and Europe for SS although FDA approved. Belimumab (BAFF)- has been disappointing in SS in terms of patient's self assessment. Abatacept (CD40 L)-Phase II safety good— improved ESSDAI, but no control arm.

16. Rituximab* Most widely used biologic in SS (ACR 2013 abstracts) in French and Scandanavian registries. Used in response to extraglandular manifestations such as persistent glandular swelling, pneumonitis, mixed cryoglobulinemia. New "black box" to rule out hepatitis B. *Not approved by FDA.

17. Other challenging problems Lymphoma-- MALT or diffuse lymphoma, or just an atypical lymphoid reaction. Interstitial pneumonitis and nephritis-- huge issues in sample variation during biopsy.

18. Persistent parotid gland swelling (after rule out of infection and lymphoma, steroids and rituximab)

19. Lymphocytic Interstitial Pneumonitis (LIP) Bi-basilar on CXR Prominent Cystic on CAT Lymphocytes on biopsy

20. SUMMARY - 1 1.Symptoms of ocular and oral symptoms are often greatly out of proportion to objective findings. 2. This may be due to augmentation of "central pain" pathways.

21. Additional Differential Diagnosis includes: Celiac disease Hepatitis C and HIV Sarcoidosis, IgG4-related disease Tuberculosis, Syphilis, and Leprosy Fibromyalgia with incidental autoantibodies SUMMARY - 2

22. SUMMARY - 3 Our treatment of fatigue in SS remains unsatisfactory, and represents a great therapeutic challenge for the next decade. The pathways may be similar to PTSD, and animal models indicate new pathways such as prostaglandins-- the mouse viral model.

23. Thank you for your time and attention

24. Acknowledgement-Scripps Bruce Beutler and Ari Theofilopoulos Role of innate system in fatigue Mike Oldstone and Frank Chishari Mechanism of fatigue in MS and role of cyclooxygenases and sphingosines

26. Acknowledgments Salk V. Ramachandran and Sarah Stone Role of phantom pain and veto neurons Role of Vth cranial nerves neurokines

28. Cognitive: Executive Function Loss Also found in multiple sclerosis The elephant in the Room Fatigue Cognitive Nerve pain Dry eyes and dry mouth

29. The concept of pain plasticity is well known to psychologists (we collaborate with V. Ramachandran at Salk Institute) The concept of “phantom pain” will be important later as we deal with "brain fog" or "neuropathy."

30. To estimate the role of "central pain,” we use the method of Rosenthal et al at Harvard Cornea Clinic for patients with severe pain after Lasik cornea surgery 1. We score the pain level (1-10) and then use ophthaine to anesthetize the eye-- then rescore the pain. 2. Early in disease, the ophthaine completely reverses pain, but later in course, a much lower decrease.

32. Moulton et*. Al used fMRI in SS patients with chronic ocular pain using fMRI of nociceptive pain have been studied Cortical regions that activate with ocular pain signal at “benign stimuli levels” occur only in chronic SS patients with severe pain *Moulton EA, Becerra L, Rosenthal P, Borsook D. An Approach to Localizing Corneal Pain Representation in Human Primary Somatosensory Cortex. PloS one 2012;7:e44643.

33. Emotional stressors potential the role of cytokines in pain pathways Emotional Physiological Similar pattern of Fos-ir in cortical neurons in response to distinct stressors

34. Thrombospondin (-/-) mouse model of SS 4 wks. Lacrimal gland biopsies The mouse has ANA+, SS-A+ TSP null can not activate TGF-  In absence TGF-  continuous Th-17 TGF-  and cytokine activation stimulates mTor/AKT WT Tsp-/- 24 wks

35. The tsp-null mouse allows us to look at the interaction of peripheral inflammation and microglial cells-1 Activation of microglial cells through mTor/AKT. In absence of thrombospondin, constitutive activation of Th17 and IFN-  activates microglial cells.

36. At the level of the Vth nerve (Tsp -/- mouse) Microglial cells translate inflammatory signals that go to nociceptive cortex WT TSP (-/-) mTor and AKT activated in response to “lower stimuli” in the tsp (-/-) mouse

37. Don’t miss other causes of ocular pain Topical or intra-ocular steroids in uveitis. Recurrent uveitis–- may need azathioprine or mycophenolic acid. Retinal vasculitis-- may need rituximab or cyclophosphamide. Watch out for ocular herpetic lesions. Make sure not a fungal or embolic lesion.

38. Other sites of systemic involvement

39. Lymphocytic Interstitial Nephritis (steroids, mycophenolic acid, rituximab)

40. Lung involvement Rule out TBC, infections including MAI, and lymphoma. Interstitial pneumonitis– Steroid and Mycophenolic acid; -- Have avoided MTX due to MTX lung Rituximab useful, but rarely will exacerbate

41. Lung and Renal Involvement: (basis for treatment) We like initial steroids and tapered steroids with mycophenolic acid or perhaps rituximab. We saw many UIP/DIP and interstitial nephritis biopsy samples at Stanford (Carrington and Dorfman in our Pathology Department) At the same time, mycophenolate was developed there for our transplant program.

42. Lymphoma or Pseudolymphoma Stanford was a lymphoma center. We also developed rituximab at Stanford (Levy lab). and it had low toxicity A lot of Levy post docs founded IDEC across street from Scripps. One of first uses of Rituxan was a member of the Scripps family. Ask me how we arrived at 375mg/m2 dosing.