1. SJOGREN’S SYNDROME: Theory to Practice
Robert I. Fox, M.D., Ph.D.
Scripps Memorial Hospital
Scripps/XiM Medical Center
La Jolla, California USA

2. Goals-1:
There are no FDA approved drugs for the systemic manifestations of Sjogren’s syndrome
Therefore, expert opinion must be used to choose therapies based on literature
These recommendations are summarized in my new chapter in UpToDate

3. Goals-2
3. The existing treatment borrows from RA and SLE in the use of DMARDs, as well as interstitial pneumonitis and lymphoma
4. The most widely used biologic is rituximab, although not approved by FDA.
5. The question is when to use DMARD or Biologic Agent

4. Goals-3 The most challenging issues for therapy
6. Neurologic Manifestations—including peripheral neuropathy, ganglionopathy, and central nervous involvement 7. Fatigue and cognitive loss 8. Lympho-proliferative swelling and possible lymphoma

5. All slides are available and can be downloaded from my website using your desktop computer robertfoxmd.com (although these may not be accessed by iPhone due to our web security) 5

6. “Old” Consensus Criteria, 2002 called the American-European Consensus Group Criteria (AECG)
Evidence of a systemic autoimmune cause for the dryness--
Positive anti-Ro (SS-A or SS-B antibody)
Positive minor salivary gland biopsy (focus score >1)
A new consensus criteria is being developed
with slightly different features
It will be called the SICCA-AECG criteria

7. ESSDAI- European SS Activity Index (to assess if therapy working)
Weighted domains to give a total score— the Sjogren’s equivalent to ACR-50 for RA.
The validated ESSDAI activity score has
been the accepted outcome measure of
FDA clinical trials.
Clinical significance is 3.5 units of change

8. Systemic Manifestations
Steroids work but have side effects.
DMARDs to taper or replace steroids.
Hydroxychloroquine
Methotrexate, Azathioprine
Mycophenolic acid mofetil
We are interested in Sirolimus (rapamycin)

9. Biologics Studied in SS
Anti-CD20 (rituximab)* –most widely used in SS although FDA approved
Belimumab (BAFF)-has been disappointing in SS
Abatacept (CD40 L)-Phase II safety good—improved ESSDAI but no control arm
TNF antagonists shown not useful

10. Rituximab Most widely used biologic in SS (ACR 2013 abstracts).
Used in response to extraglandular manifestations such as persistent glandular swelling, pneumonitis, mixed cryoglobulinemia.
Not approved by FDA.

11. EYE DRYNESS results in the clinical appearance of keratoconjunctivitis sicca (KCS) characteristic of Sjogren’s Syndrome
Artificial tears
Punctal occlusion
Ocular lubricants
Treat blepharitis first
Topical cyclosporin
Topical “soft” steroids
often
Used if not able totolerate
Restsis alone

12. Systemic Ocular Often need DMARDs
Topical or intra-ocular steroids
Recurrent uveitis –may get by with azathioprine or cell cept
Retinal vasculitis-may need rituxan or cyclophosphamide
Watch out for ocular herpetic lesions

13. Rash distinct from SLE (erythema annulare) the “old” subacute SLE which is negative for complement staining

14. Therapy of skin lesions
Hydroxychloroquine for E. annulare
or methotrexate if psoriaform
Vasculitis (usually small vessel) may need methotrexate
Vasculitis of mixed cryoglobulinemia responds to rituximab (indication approved by FDA)
Mono-neuritis multiplex (medium vessel) may also require cyclophosphamide

15. Arthritis distinct from RA (Jaccoud’s like or erosive OA)
Hydroxychloroquine, Methotrexate, Rituximab
(less successful with azathioprine or leflunomide limited by leukopenia)

16. Parotid swelling (after rule out infection and lymphoma, steroids and rituximab)

17. Lymphocytic Interstitial Pneumonitis
Bi-basilar on CXR
Prominent Cystic on CAT
Lymphocytes on biopsy

18. Lung involvement (after rule out TBC, MAI, Lymphoma)
Interstitial pneumonitis—steroid and
Mycophenolic acid; have avoided MTX due to MTX lung
Rituximab

19. Transverse Myelitis Neuromyelitis Optica
DeVic’s Syndrome:
Transverse Myelitis Neuromyelitis Optica
After rule out infection, treatments with cytoxan and or rituximab.
Maintenance with azathioprine
May need to treat like multiple sclerosis—new options approved

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

21. SUMMARY-1 The American European Consensus criteria:
Subjective symptoms of dryness
Objective evidence of autoimmune process such as a positive antibody to SS-A or RF
Positive minor salivary gland biopsy

22. SUMMARY-3 Additional Differential Diagnosis include: Celiac disease
Hepatitis C and HIV
Sarcoidosis, IgG4-related disease
Tuberculosis, Syphilis, and Leprosy
Fibromyalgia with incidental autoantibodies

23. SUMMARY-5 Recognize systemic (extraglandular) sites
Rule out infections and begin treatment with DMARDs to spare steroids.
DMARDs similar to use in SLE.
Hydroxychloroquine
Methotrexate, Azathioprine, mycophenolic acid

24. SUMMARY-7
Our treatment of fatigue in SS remains unsatisfactory, and represents a great therapeutic challenge for the next decade.
Later, we can discuss our approach to this problem in collaboration with Salk Institute and our research institute.

25. Thank you for your time and attention

26. We are still missing key targets in the pathogenesis of fatigue and the adrenal-hypothalmic axis.
In both SS and SLE, we can lower the cytokine
with biologics, but the patient still feels little
improvement.
This will be the focus of future direction for
therapy.

27. Information on website
Benign manifestations include:
Dry and painful eyes
Dry and painful mouth
Myalgias, arthralgia, fatigue
Impaired cognition (executive
function)— trying to distinguish
“fibromyalgia” from “depression”

28. Differential Diagnosis of SS-3
The antibody to Ro (SS-A) or La (SS-B) do not fulfill criteria for SLE.
Many older patients labeled with mild SLE actually have SS.
Many patients in Hematology clinic with mixed cryoglobulinemia, hemolytic anemia or ITP actually have SS.

29. Is Sjogren’s just SLE with 4/5 SLE Criteria?
Different antibody profile (anti-SSA/B)
are not criteria for SLE;
SS is more organ specific –
(salivary/lacrimal gland)
and more lymphoproliferative.

30. Why is Sjogren’s not just SLE with 4/5 Criteria?
Interstitial pneumonitis (not pleurisy), interstitial nephritis (not glomerulonephritis)
Higher frequency of lymphoma
Genome Screens support this with Homing receptors found in SS but not SLE (CXCR5)

32. Summary-1
Functional circuit needs to be considered when assessing “benign” symptoms of corneal or oral pain.
Symptoms of oral/ocular pain do not correlate with markers of systemic inflammation (ESR/CRP) because the events are contained within the brainstem and cortex.

33. 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.

34. Dry and Painful Mouth-1
If you thought that Dentists did not care about SS,
then wait until you see their Dental Care Plans --
The answer to all problems is a $25,000 tooth
implant.

35. Dry and Painful Mouth-2 Must treat underlying oral candida (which is
erythematous spots on roof of mouth) before anything
will work.
Candida often lurks under dentures–
Patients would rather run naked through clinic
than remove a denture.

36. Dry and Painful Mouth-3 Angular cheilitis the most obvious hint.
Treatment of oral candida is a slow process
involving multiple steps.
Use website for education.

39. We are also looking at additional targets of interest
Chemokines and their receptors (CCR) on vascular cells and lymphocytes
TLR receptors: SLAC-15 that links Toll receptor and type 1 IFN
Methylation modulators and siRNA
Neural mediator circuits:
Receptors on cornea--substance P (TRPV1), VIP and CGRP pain receptors
TRPM8, TRPA1, and CGRP in trigeminal ganglion neurons
Trigeminal ganglion neurons- MCP-1, MIP-2,
CCR and CCL at the blood brain barrier

40. CCR and Blood Brain Barrier

41. Activation of microglial cells through mTor/AKT
The tsp-null mouse allows us to look at the interaction of peripheral inflammation and microglial cells
Activation of microglial cells through mTor/AKT
In absence of thrombospondin, constitutive activation of Th17 and IFN-g activates microglial cells
Nociceptive (pain) pathway occurs through smad3 and non-smad pathways that involve mTor/AKT pathways in cranial nerve V

42. Thank you for inviting us.
Robert I. Fox, M.D., Ph.D.