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

2. Learning Objectives: By the end of the session, the participant will be able to: the participants should be able to:
Define the European criteria for
diagnosis of Sjogren’s Syndrome (SS)
Symptoms of dry eyes and mouth
Objective evidence of autoimmunity:
(either a SS-A/SS-B or a positive lip biopsy)

3. Learning Objectives List 2 glandular manifestations of SS.
Dryness of eyes or mouth
Lymphoproliferation or lymphoma of lacrimal or salivary glands
involvement with SS presentations.

4. Learning Objectives
Describe at least 4 sites of extraglandular involvement in Sjogren’s syndrome Skin-vasculitis Lungs-interstitial pneumonitis or BALT Kidneys-interstitial nephritis Neurologic-peripheral or central

5. Learning Objectives
Identify at least 3 differential diagnoses that are difficult to distinguish from Sjogren’s Syndrome. SLE—altho they often co-exist, there are differences IgG4-related disease. This is a newly defined comples of diseases Idiopathic Neurologic disorders with an incidental SS-A

6. All slides are available on my website robertfoxmd.com6

7. SS has “benign” and “systemic”
Background-1
SS has “benign” and “systemic”
manifestations.

8. Background-2 Benign manifestations include: Dry and painful eyes
Dry and painful mouth
Myalgias, fatigue
Impaired cognition (executive
function)— trying to distinguish
“fibromyalgia” from “depression”

9. SS Related Health Care Costs-1:
Dry or painful eyes are now most
common cause of visits to
Ophthalmologists in U.S. and Japan.
Lost productivity (over $160 billion/year just
for dry eyes (especially in computer users
where decreased blink rate is 90%.

10. Sjogren’s symptoms are so debilitating, that patients would:
equate SS with impact similar to
moderate angina.
trade 2 years of “life expectancy”
to not have SS symptoms.

11. SS-Related Health Care Costs-2:
Direct healthcare costs in Great Britain (NHS)
are second only to RA, and exceed SLE.
RA £2693
(not including TNFs)
pSS £2188
(not including OTC cost of
artificial tears or dental costs)
Age Matched NHS Controls £849

12. SS-Related Health Care Costs-3:
Despite these costs of health care,
patient and physician dissatisfaction
with clinical outcomes
is higher in pSS
than in SLE or RA.

13. Diagnosis of Sjogren’s Syndrome

14. The European-American Consensus Criteria, 2002
Symptoms of dry eyes and dry mouth
Inability to eat a dry cracker without water.
Water needed at bedside at night.
Objective signs of dry eyes and dry mouth
(Schirmer’s test, tear break up)
(Saliva flow)

15. Consensus Criteria, 2002 also 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)

16. Most important “child” of AECC was the ESSDAI (European Sjogren’s Syndrome Activity Index) which includes 16 domains of activity score including glandular and extraglandular activity
The ESSDAI ranges from 1-130
Practically, the range is 1-41
A clinically meaningful change is 3.5 units
Constitutional
Skin
Lung, Renal
Neurologic

17. ESSDAI- European SS Activity Index
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.

18. You need to be aware
There is a recently proposed criteria called the SICCA criteria (described below).
The sudden introduction of a new criteria has led to confusion in practice and research.
The SICCA criteria will need to be modified, and committees are now at work to form a new consensus criteria.

19. SICCA Preliminary Criteria (Shiboski, 2012)
Requires 2 out of 3 criteria:
Positive Anti-SS A/B or ANA >320;
Ocular Staining Score >3;
Positive labial gland biopsy: focus
score >1.

20. There is about an 82% overlap between the SICCA criteria and the AECC criteria

21. Does it matter?
Our outcome measure ESSDAI was based on old AECC criteria.
Literature search and prognosis are all based on old AECC criteria.
The 5 published studies comparing both systems indicate IT DOES make a difference.

22. Clinical Manifestations
Benign glandular dryness
Systemic -- extraglandular

23. Clinical Key Points : Dry Mouth

24. literally sticks to the
EYE DRYNESS results in the clinical appearance of keratoconjunctivitis sicca (KCS) characteristic of Sjogren’s Syndrome
The upper lid
literally sticks to the
Epithelial surface
and pulls surface
mucin layers off.
The Rose Bengal
dye retention test
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

25. Rash distinct from SLE (erythema annulare)

26. Arthritis distinct from RA

27. High Risk of Lymphoma

28. Differential Diagnosis of SS-1
SLE-- many similarities to SS
RA, Scleroderma, Dermatomyositis-- called secondary Sjogren’s
Primary biliary cirrhosis
Fibromyalgia with incidental positive ANA

29. Differential Diagnosis of SS-2
Hepatitis C
HIV (AIDS)
Tuberculosis
Leprosy
Syphilis
Lymphoma with positive ANA
IgG4-Related Diseases-evolving spectrum

30. 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.

31. 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.

32. 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)

33. Lymphoma and Type II mixed cryoglobulinemia

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

35. Transverse Myelitis Neuromyelitis Optica
DeVic’s Syndrome:
Transverse Myelitis Neuromyelitis Optica

36. Lymphocytic Interstitial Nephritis

37. Pathogenesis-1 Genetics Environmental Factors
Cytokines of innate and acquired immune system

38. Pathogenesis-2 only about 20%.
Concordance of SS among identical twins
only about 20%.
Thus, genetic sequence is not enough and
over 80% is epigenetic— environmental
factor or gene regulation.
Distinct histone acetylation pattern
upstream of key genes.

39. Pathogenesis-3 Novel miRNA, some with sequence similar
Large sequences of untranslated mRNA.
Novel miRNA, some with sequence similar
to EBV fragments.
Genetics in GWAS recently published and
only SS (not SLE) has homing receptor
(CXCR5) as a strong “hit.”

40. Pathogenesis-4 To briefly summarize PATHOGENESIS …
Acquired Immune System--
HLA DR and Associated T-cell directed B-cell antibodies;
IFN-g and IL-17 pathways
Innate immune system—
Type I IFN signature
NK like cells link acquired and innate

41. Time course of autoimmune response. 1
Time course of autoimmune response* Genetic factors predispose to Sjogren’s Environmental factors such as a viral infection may lead to formation of autoantibodies Antibodies precede disease (however, presence of antibody does not necessarily mean disease).
Innate
Immune system
(Toll receptor)
Environmental
Factor
(virus-such as EBV)
(apoptotic fragment)
Auto-
antibodies
Immune
complex
Type I IFN
Genetic
Factors
(including sex)
(HLA-DR)
Genetic
Factors
(including sex)
(HLA-DR)
Genetic
Factors
(including sex)
(HLA-DR)
Genetic
Factors
(including sex)
(HLA-DR)
Genetic
Factors
(including sex)
(HLA-DR)
Disease
Manifestations
Acquired
Immune system
(HLA-DR)
T/B-cells
* Time period of years

42. The main cytokine targets match those identified in genome wide screens*
HLA-DR (T-cell), CTLA and IFN-g
NF-K /IkB
Homing receptor (CXCR5)
Type I IFN –IRF5, STAT4, TLR3/7/9 and pkR (cytoplasmic
sensor)
B-cell activation –BLK, BAFF, IL12, and A20 (TNFAIP3)
* Most of these targets do not map to the encoded protein but to upstream sites of RNA transcription that are not translated (presumed epigenetic sites such as methylation)

43. Pathogenesis-5 Genome-Wide Association Parallels-- our studies on cytokine profiles
Strongest is HLA-DR and acquired immune system leading
to T-cell/B-cell production of autoantibody.
Next strongest are Innate Immune markers associated
with Type 1 IFN production.
As noted above, also find a homing receptor (CXCR5)
which goes with the tissue-specific homing receptors.
In SS patients with lymphoma, find A20 (member of
TNF superfamily) that suppresses NFK-b and B-cell
proliferation.

44. Treatment of DRY EYE Benign Symptoms-1
Artificial tears and lubricants
Punctal occlusion
Do not use preserved tears more than 4x/day
Topical cyclosporin (Restasis)
Recognize and treat blepharitis

45. DRY EYE Therapy-2
Special needs in operating room (low humidity and high risk corneal abrasion)
Avoid Lasik eye surgery
Look for “lid lag” and exposure zone keratopathy.

46. Treatment of DRY MOUTH-1
Artificial Saliva, mouth rinses and sprays
Secretagogues-pilocarpine and cevimeline
Fluoride to prevent caries
Treat oral candida (often under dentures)

47. Treatment of DRY MOUTH-2
Avoid medications with anti-cholinergic side effects (esp. over the counter medications at night) such as Benadryl or amitryptilline.
Keep nasal passages open to avoid mouth breathing.
Recognize gastric reflux at night (laryngo-tracheal reflux)

48. Patient Education
Time does not permit patient education at time of office visit.
Create and use an internet site for common questions about treatment.
Feel free to use information from my website for your patients.

49. 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)

50. Biologics Previously Studied in SS
Anti-CD20 (rituximab)* –glandular swelling, extraglandular renal and lung, mixed cryoglobulinemia
BAFF (Blys)-ACR 2012 abstracts has been disappointing
Abatacept (CD40 L)-ACR 2012

51. 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.

52. 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.

53. 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

54. SUMMARY-2 Differential Diagnosis
Although SLE is closely related to SS, there are distinct clinical and genetic factors.
Think of SLE as immune complex mediated and SS as aggressive lymphocytic infiltrates (including high risk of lymphoma).

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

56. SUMMARY-4 Formulate a plan of treatment for benign DRY EYE symptoms--
Use of artificial tears and lubricants
Punctal occlusion
Topical cyclosporin
Treat blepharitis

57. 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

58. SUMMARY-6 DMARD Therapy
Systemic symptoms-use of DMARDs
SLE like symptoms
Rashes including E. annulare and
Hyperglobulemic purpura
Lymphoma
Interstitial pneumonitis and nephritis

59. 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.

60. Thank you for your time and attention
شكرا لك على لطفك والاهتمام

62. 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.

63. 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.

64. 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.

65. 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.

66. 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.

69. 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

70. CCR and Blood Brain Barrier

71. 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

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