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

2. All slides are available on my website robertfoxmd.com2

3. Typical features of dry eyes, dry mouth and swollen glands

4. The Dryness is the result of Lymphocytic Lacrimal and Salivary Glands
Foci of lymphs
Sjogren’s
Normal

5. Diagnosis of Sjogren’s Syndrome

6. 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)

7. 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)

8. Ocular Manifestations
In Sjogren’s syndrome patients

9. Normally the upper eyelid glides over the globe on a coating called the tear film composed of water, protein, mucins
eyelid
orbit
tear film

10. 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.
eyelid
orbit
Tear film

11. Dryness results in the clinical appearance of keratoconjunctivitis sicca (KCS) characteristic of Sjogren’s syndrome

12. But be on the look out for conditions that require immediate Ophthalmologic Evaluation Corneal Abrasion (fluorescein)

13. Ulcerative keratitis (caused by physician who gave broad spectrum topical antibiotic plus topical anesthetic)

14. Scleritis (vasculitis)

15. Important to Recognize
Herpetic keratitis
(slit lamp-fluorescein)
dendrites

16. That may occur in Sjogren’s syndrome patients
Other Eye Conditions
That may occur in Sjogren’s syndrome patients

17. UVEITIS – Symptoms - 1 --anterior, intermediate, posterior--
Painful red eye – the pain can range from mild aching to intense discomfort,
and focusing the eye makes the pain worse.
The eye can feel tender or bruised.
Blurred or cloudy vision – this may come after other symptoms.
Sensitivity to light (photophobia)

18. UVEITIS Symptoms - 2
Loss of peripheral vision (ability to see objects at the side of field of vision).
A pupil shaped differently or that
doesn't get smaller when reacting to
light.
Marked or new floaters – shadows,
webs, dots or veils that move across
the field of vision.

19. TREATMENT OF UVEITIS Oral and injected steroids Methotrexate
Cyclosporine
Rule out infectious causes and
“mimics.”

20. Oral Manifestations Difficulty swallowing or talking
Increased dental cavities
Increased oral candidiasis
Increased laryngo-tracheal reflux

21. Severe Xerostomia with dry tongue
Angular
Cheilitis
(yeast)

22. Sjogren’s Syndrome- Cervical Dental Caries

23. Extraglandular Manifestations
May be similar to SLE patients
May be distinct from SLE patients
SS patients are frequently incorrectly
Diagnosed as SLE or RA

24. Rash distinct from SLE (erythema annulare)

25. High Risk of Lymphoma

26. Interstitial nephritis
Renal tubular acidosis
Hypokalemia and periodic paralysis-may be induced by herbal remedies
Glomerulonephritis uncommon except in mixed cryoglobulinemia or amyloid

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

28. Pulmonary Manifestations
NSIP-nonspecific interstitial pneumonitis
Different from the more common pericarditis or pleurisy of SLE
Watch for pulmonary arterial hypertension in your population (more frequent in Asians than in Caucasions)

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

30. Sjogren’s Syndrome – with Parotid Enlargement and Lymphoma
MRI not used much for diagnosis of SS itself but of value in investigating causes of persistent salivary gland swelling. However with the increasing availability of scanners, and emerging evidence from Berlin [Vogl et al]and Japan [Izumi et al], we may see this non-invasive technique being used more frequently for diagnostic purposes

31. Neuropathy-one of the most difficult problems
Peripheral neuropathy
Autonomic Neuropathy
Mononeuritis Multiplex
Stroke including thrombosis and anti-cardiolipin
Meningo-Encephalitis

32. The most difficult “benign” symptoms are “neurologic”
Fatigue –make sure no elevated ESR, and no abnormal thyroid, orcortisol
Impaired cognition (executive
function)—distinguished from
depression or encephalitis

33. Consensus Criteria, 2002 also called the American-European Consensus Group Criteria (AECG)
Symptoms of Dryness plus
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)

34. 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.

35. 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)

36. Treatment of DRY EYE Benign Symptoms-1
Artificial tears and lubricants
Punctal occlusion with plugs or cautery
Do not use preserved tears more than 4x/day
Topical cyclosporin (Restasis)
Topical Xiidra (Liftegrast, LFA-1)

37. Recognition of Blepharitis
Common cause of ocular irritation,
Mimicking Sjogren patients:
Seborrheic dermatitis or rosacea
Infection: Staph or pseudomonas
Meiobian gland dysfunction
When Meibomian gland
are plugged, then toxins
can cause punctate
Keratopathy-
This is called Thygeson’s
Punctate keratopathy

38. Treatment of Blepharitis
Lid scrubs with warm water and diluted baby shamphoo
May require antibiotics such as doxycycline
New techniques such as Lipiflow to ”unclog” the glands

39. DRY EYE Therapy (Special needs in operating room)
Special needs in operating room (low humidity and high risk corneal abrasion)
Avoid Lasik eye surgery
Look for “lid lag” and exposure zone keratopathy, especially if history thyroid disease.

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

41. 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)

42. 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 (robertfoxmd.com).

43. 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)

44. Biologics Previously Studied in SS
Anti-CD20 (rituximab)* –glandular swelling, extraglandular renal and lung , mixed cryoglobulinemia
BAFF (Blys)-ACR 2017 abstracts has been disappointing
Abatacept (CD40 L)-ACR 2017

45. 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.

46. 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.

47. 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

48. SS Related Health Care Costs-
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%.
Dry Mouth can lead to tooth loss and malnutrition

49. 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.

50. 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).

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

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

53. 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

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

55. Thank you for your time and attention
Cảm ơn bạn đã dành thời gian và sự chú ý của bạn

57. Sjogren’s Syndrome The View from San Diego

58. Our Clinical Hospital in La Jolla, California

59. The Research Institute
at Summer Solstice