1. Sjögren's Syndrome Clinical, Pathogenetic & Aspects
Dept. of Pathophysiology
Medical School
National University of Athens
Greece
Sjögren's Syndrome Clinical, Pathogenetic & Aspects
Athanasios G. Tzioufas, MD
Alexandria, 1st ELAR, April 2013

2. Sjögren's Syndrome - Autoimmune Epithelitis
Female disease
♀/♂ : 9/1
Common
0.5-1% of adult females
4th -5th decade of life
Slowly progressive

3. Sjögren's Syndrome - Autoimmune Epithelitis
The frequency distributions of ages at onset of symptoms & at diagnosis of primary Sjögren's syndrome 5 10 15 20 25 30 35 40 45
1-10
11-20
21-30
31-40
41-50
51-60
61-70
71-80
81-90
AGE
% OF PATIENTS
At diagnosis
Onset
Pavlidis et al, J Rheumatol 1998; 2, 9:5

4. Sjögren's Syndrome - Autoimmune Epithelitis
Center of autoimmune disorders
alone (primary)
with other (secondary)
Wide clinical spectrum
organ-specific
systemic
neoplasia
Prototype autoimmune disease
humoral
cellular

5. Association of Sjögren's syndrome with other autoimmune rheumatic diseases

6. Sjögren's syndrome - Immunopathology
Lymphocytic infiltration of the affected epithelial tissues
Autoantibodies-immune complex mediated disease

7. Autoantibodies to cellular autoantigens in pSS by IVTT and RIA
Autoantibody to:
Percent
Ro 60 66
Ro 52 49 La 57
Calreticulin 20
Carbonic anhydrase II 11
M3R
VAMP-2 4
a-fodrin
U1RNP 2
Nucleolin
Calpastatin
NPY
Τα αυτοαντισώματα έναντι ενός Ro/SSA και La/SSB απαντώνται κυρίως σε ασθενείς με σύνδρομο Sjögren, αλλά και σε ασθενείς με συστηματικό ερυθηματώδη λύκο και σπανιότερα σε ασθενείς με ρευματοειδή αρθρίτιδα και αδιαφοροποίητο αυτοάνοσο νόσημα. Οι πρωτεΐνες Ro/SSA και La/SSB ανευρίσκονται μαζί στα κυτταροπλασματικά ριβουνοκλεοπρωτεϊνικά σύμπλοκα Ro/La RNP. H απόκριση έναντι La/SSB θεωρείται ειδική για το σύνδρομο Sjögren.
Tzioufas et al Arthritis Rheum 58 :S791, 2008

8. Sjögren's Syndrome – Autoimmune Epithelitis Antibodies to Ro and La cellular antigens
Ro (SSA)
Unknown Function
La (SSB): transcription factor
Initiation and termination of RNA-polymerase III transcription
Gottlieb E et al., EMBO J., 1989; 8:841
Maraia RJ, Proc Natl Acad Sci USA, 1996; 93:3383
Maturation of pre-tRNAs and other RNA-polymerase III transcripts
Fan H et al., Mol Cell Biol 1998; 18:3201

9. Sjögren's Syndrome – Autoimmune Epithelitis Autoimmune Phenomena: Lesion
Activated infiltrating cells
B cells
T cells
helper/memory
LFA.1/HLA-DR+
Dendritic cells in advanced lesions
Activated epithelium
HLA-DR
c-myc
proinflammatory cytokines
lymphoid chemokines
co-stimulatory/adhesion molecules
autoantigens
Labial Minor SG
Skopouli et al, J Rheumatol. 1991, Yiannopoulos et al J Clin Immunol, 1992 Manoussakis et al Arthritis Rheum, 1999, Tzioufas et al J Autoimmunity, 1999, Xanthou et al, Clin Exp Immunol. 1999, Xanthou et al Arthritis Rheum, 2001

10. Autoimmune Epithelitis
Endocrine
Stress
EPITHELIUM
EPITHELIUM
Persistent Virus
Genetic Make-up
EPITHELIUM
La/SSB
La/SSB
MHC-II
EXOSOMES
FasL
Cytokines/
Chemokines
ICAM.1 CK
receptor
Fas
CD40
MHC-II B7
APOPTOSIS B
Ag-Presentation T B DC
Ag-Release T

11. Sjögren's Syndrome - Autoimmune Epithelitis Glandular manifestations Salivary Gland Involvement
difficulty with chewing, swallowing
excessive fluid use
Subjective:
Objective:
Dry mouth
Intermittent parotid gland enlargement
Dry oral mucosa – mouth ulcers
Tongue
Teeth
Parotid gland enlargement
Tests
red
devoid of epithelium
cracked “crocodile skin”
multiple caries
early loss

12. Sjögren's Syndrome – Autoimmune Epithelitis

13. Sjögren's Syndrome - Autoimmune Epithelitis Glandular manifestations Salivary Gland Involvement
difficulty with chewing, swallowing
excessive fluid use
Subjective:
Objective:
Dry mouth
Intermittent parotid gland enlargement
Dry oral mucosa – mouth ulcers
Tongue
Teeth
Parotid gland enlargement
Tests
red
devoid of epithelium
cracked “crocodile skin”
multiple caries
early loss

14. Sjögren's syndrome – Autoimmune Epithelitis

15. Sjögren's Syndrome - Autoimmune Epithelitis Glandular manifestations Salivary Gland Involvement
difficulty with chewing, swallowing
excessive fluid use
Subjective:
Objective:
Dry mouth
Intermittent parotid gland enlargement
Dry oral mucosa – mouth ulcers
Tongue
Teeth
Parotid gland enlargement
Tests
red
devoid of epithelium
cracked “crocodile skin”
multiple caries
early loss

16. Sjögren's Syndrome – Autoimmune Epithelitis
Parotid gland enlargement

17. Sjögren's Syndrome - Autoimmune Epithelitis Glandular manifestations Salivary Gland Involvement
difficulty with chewing, swallowing
excessive fluid use
Subjective:
Objective:
Dry mouth
Intermittent parotid gland enlargement
Dry oral mucosa – mouth ulcers
Tongue
Teeth
Parotid gland enlargement
Tests
red
devoid of epithelium
cracked “crocodile skin”
multiple caries
early loss

18. Sjögren's Syndrome – Autoimmune Epithelitis
Salivary flow:
Parotid
Whole
Stimulated
Unstimulated (≤1.5ml/15min)

19. Sjögren's Syndrome – Autoimmune Epithelitis
Salivary gland biopsy
Chilsom focus score
(≥ 1 foci/4mm2 )

20. Sjögren's Syndrome - Autoimmune Epithelitis Glandular manifestations Lacrimal Gland Involvement
“gritty”
“sandy”
Foreign body sensation
Lack of tearing  “sticky” eyelids
Conjunctival injection
Lacrimal gland enlargement (rare)
Keratoconjuctivitis sicca
Subjective:
Objective:

21. Sjögren's Syndrome - Autoimmune Epithelitis
Schirmer's test (≤5mm/5min)
Rose-Bengal staining
(≥4: van Bijsterveld’s scoring system)

22. Sjögren's Syndrome - Autoimmune Epithelitis The American-European Consensus Group classification criteria Subjective
(Positive = a positive response to at least one of the three following questions)
I. Ocular symptoms:
Have you had daily, persistent, troublesome dry eyes for more than 3 months?
Do you have a recurrent sensation of sand or gravel in the eyes?
Do you use tear substitutes more than three times a day?
II. Oral symptoms:
Have you had a daily feeling of dry mouth for more than 3 months?
Have you had recurrently or persistently swollen salivary gland as an adult?
Do you frequently drink liquids to aid in swallowing dry food?
Vitali C et al., Ann Rheum Dis. 2002;61:554

23. Sjögren's Syndrome - Autoimmune Epithelitis The American-European Consensus Group classification criteria Objective
III. Ocular signs (positive result in at least one of the following tests)
Schirmer’s I test
Rose-Bengal score or another ocular dye score
IV. Histopathology 
focus score ≥1
V.  Salivary gland involvement (positive result in at least one of the following tests)
Unstimulated salivary flow
Parotid sialography
Salivary scintigraphy
VI. Autoantibodies:
Ro(SSA) and/or La(SSB)
Vitali C et al., Ann Rheum Dis. 2002;61:554

24. Sjögren's Syndrome - Autoimmune Epithelitis The American-European Consensus Group classification criteria
Rules for classification:
Definitive primary SS
presence of any four of the six items
in patients without any potentially associated disease
Secondary SS
item‑1 or item‑2 plus any two from items 3, 4, 5
in patients with a potentially associated disease
(another connective tissue disease)
Vitali C et al., Ann Rheum Dis. 2002;61:554

25. Sjögren's Syndrome - Autoimmune Epithelitis The American-European Consensus Group classification criteria
Exclusion criteria:
prior head and neck irradiation
pre-existing lymphoma
acquired immunodeficiency disease (AIDS)
hepatitis C infection
sarcoidosis
graft‑versus‑host disease
sialoadenosis
drugs (neuroleptic, anti‑depressant, anti‑hypertensive, parasympatholytic)
Vitali C et al., Ann Rheum Dis. 2002;61:554

26. Primary Sjögren's Syndrome-systemic manifestations Clinical manifestations at diagnosis & end of follow-up (261 patients)
Diagnosis
End of follow-up
patients (%)
Arthralgia/arthritis 70 75
Raynaud’s phenomenon 41 48
Purpura 10 11
Pulmonary involvement
(small airway disease) 19 23
Primary biliary cirrhosis 4
Renal involvement
interstitial 7 9
glomerulonephritis
0.4 2
Peripheral Neuropathy 1
Lymphoproliferative disorders
Skopouli et al., Semin Arthritis Rheum 2000; 29: 296

27. Primary Sjögren's Syndrome-systemic manifestations Clinical manifestations at diagnosis & end of follow-up (261 patients)
Diagnosis
End of follow-up
patients (%)
Arthralgia/arthritis 70 75
Raynaud’s phenomenon 41 48
Purpura 10 11
Pulmonary involvement
(small airway disease) 19 23
Primary biliary cirrhosis 4
Renal involvement
interstitial 7 9
glomerulonephritis
0.4 2
Peripheral Neuropathy 1
Lymphoproliferative disorders
Skopouli et al., Semin Arthritis Rheum 2000; 29: 296

28. Sjögren’s Syndrome Epithelial involvement – Clinical evidence
Labial Minor SG
Kidney
Liver
Lung
Systemic Manifestations
Frequency (%)
Pulmonary involvement
small airway disease 23
Renal involvement
interstitial 9
Liver involvement
billiary cirrhosis 4
Skopouli et al., Semin Arthritis Rheum 2000
Moutsopoulos HM. Clin Immunol Immunopathol. 1994 28

29. Primary Sjögren's Syndrome-systemic manifestations Clinical manifestations at diagnosis & end of follow-up (261 patients)
Diagnosis
End of follow-up
patients (%)
Arthralgia/arthritis 70 75
Raynaud’s phenomenon 41 48
Purpura 10 11
Pulmonary involvement
(small airway disease) 19 23
Primary biliary cirrhosis 4
Renal involvement
interstitial 7 9
glomerulonephritis
0.4 2
Peripheral Neuropathy 1
Lymphoproliferative disorders
Skopouli et al., Semin Arthritis Rheum 2000; 29: 296

30. Clinical spectrum of primary Sjögren's syndrome

31. Sjögren's Syndrome - Autoimmune Epithelitis Algorithm for the diagnosis
If positive
Sjögren's Syndrome
Dry mouth
Dry eyes
Salivary gland enlargement
Raynaud’s phenomenon
Purpura
Renal tubular acidosis or
Eye & salivary gland tests
Serology
If any positive

32. Sjögren's syndrome – treatment. Progress of the last decade
Understanding of the natural history
Insights into pathogenetic mechanisms
New biologics-experience from other diseases
Outcome measures

33. Sjögren’s Syndrome Therapy
Collaboration
Rheumatology
Ophthalmology
Oral medicine – Dentistry
Other medical specialties

34. Current treatments for dry mouth
Thanou-Stavraki and James, 2008

35. Current and experimental treatments for dry eyes
Thanou-Stavraki and James, 2008

36. Sjögren's Syndrome – conventional DMARDs Sicca Manifestations
Immunomodulation:
Methotrexate
(Clin Exp Rheumatol 1996, 4:555)
Azathioprine
(J Rheumatol 1998; 25: )
Nandrolone decanoate
(Clin Exp Rheumatol 1988, 6:53)
Cyclosporine A
(Ann Rheum Dis 1986, 45:732)

37. Sjögren's Syndrome – Biologic therapies Sicca Manifestations
Immunomodulation:
Anti-TNF a
Mariette et al. Arthritis Rheum Apr;50(4):1270-6,
Sankar et al.Arthritis Rheum Jul;50(7):
IFN-a
Cummins et al. Arthritis Rheum Aug 15;49(4):
Anti-CD20
Meijer et al.Arthritis Rheum Apr;62(4):960-8.

38. JAMA, July 28, 2010—Vol 304, No. 4 38

40. Treatment of Sjögren's syndrome
Empirical
Symptomatic
Therapeutic regimens used successfully in other systemic diseases (particularly SLE and RA)
Lack of control trials

41. Sicca features Xerostomia Xerophthalmia Other sicca features
FIRST STEP
Topical therapies
Saliva substitutes
(1+/B)
Preservative-free artificial tears
(1++/B)
Topical measures
(4/D)
Topical ocular vit. A/glycols
(2+/B)
Topical 0.05% Cyclosporine A
(1++/B)
SECOND STEP
Systemic therapies
N-acetylcysteine
(1+/B)
N-acetylcysteine*
(4/D)
Pilocarpine
Cevimeline
(1++/A)
Pilocarpine
Cevimeline
(1++/A)
Pilocarpine
(1++/B)
Plug insertion
(1+/B)
* For ENT sicca features

42. Sjögren's Syndrome -Therapy Parenchymal organ involvement
Lungs, Kidneys, Liver
Slow process
Usually does not lead to organ failure
Skopouli et al., Semin Arthritis Rheum. 2000, 29:296
Lack of controlled therapeutic trials
Corticosteroids ineffective-dangerous?
Anecdotal reports with azathioprine, MMF, IVIG

43. Sjögren's Syndrome -Therapy Systemic Vasculitis
Corticosteroids
Cyclophosphamide
Plasmapheresis
IVIg
Others

44. Extraglandular involvement
Joint
Pulmonary
Renal
Vasculitic
Neurological
Life-threatening
Arthralgia
Arthritis
Bronchial
Interstitial
Tubular
Glomerular
CNS
Multineuritis
Polyneuropathy
Ataxic neuronop
HCQ
NSAIDs
Inhaled tx
Cortic.
Bic/K replac. MP
Cortic.
IVIG
HCQ
CYC
Cortic.
CYC
RTX
Pex
Aza
RTX
MTX
MPA/CyA
PA/Aza
Pex
RTX
RTX
RTX
First-line therapy
Second-line therapy
Third-line therapy
Refractory cases

45. Treatment options-Summary
Sicca manifestations
Dry eyes
topical 0.05% cyclosporine (twice daily)
severe refractory ocular dryness
May add topical NSAIDs
Dry mouth
Pilocarpine
Cevimeline
Systemic manifestations
No clear benefits from
HCQ GC
Other immunosuppressive
RTX is promising for some situations
Vasculitis
Glomerulonephritis
Arthritis

46. Collaborators-Dept of Pathophysiology-UOA
E Kapsogeorgou
M Manoussakis
F Skopouli
M Voulgarelis
HM Moutsopoulos