pathology of sjogen disease

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

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

5. Sjögren's Syndrome - Autoimmune Epithelitis
The frequency distributions of ages at onset of symptoms
& at diagnosis of primary Sjögren's syndrome
0
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
%OFPATIENTS
At diagnosisAt diagnosis
OnsetOnset
Pavlidis et al, J Rheumatol 1998; 2, 9:5

6. 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

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

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

9. Autoantibodies to cellular autoantigens in pSSAutoantibodies to cellular autoantigens in pSS
by IVTT and RIAby IVTT and RIA
Autoantibody to: Percent
Ro 60 66
Ro 52 49
La 57
Calreticulin 20
Carbonic anhydrase II 11
M3R 11
VAMP-2 4
a-fodrin 4
U1RNP 2
Nucleolin 0
Calpastatin 0
NPY 0
Tzioufas et al Arthritis Rheum 58 :S791, 2008

10. 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
Sjögren's Syndrome – Autoimmune Epithelitis
Antibodies to Ro and La cellular antigens

11. 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
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
Labial Minor SG

12. EPITHELIUMEPITHELIUM
Endocrine
StressStress
Autoimmune Epithelitis
EXOSOMES
DC
DC
Ag-Release
T
T
T
T
T
T
T
T
T
Ag-Presentation
B
B
B
B
BB
EPITHELIUMEPITHELIUM
Persistent Virus
Genetic Make-up
CD40
APOPTOSIS
Fas
Fas
L
B7
T
B
Cytokines/
Chemokines
ICAM.1
CK
recepto
r
EPITHELIUMEPITHELIUM
La/SSB
La/SSB
MHC-II
MHC-II

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

16. Sjögren's syndrome – Autoimmune Epithelitis

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

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

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

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

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

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

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

24. (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
Sjögren's Syndrome - Autoimmune Epithelitis
The American-European Consensus Group classification criteria
Subjective

25. 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)
Sjögren's Syndrome - Autoimmune Epithelitis
The American-European Consensus Group classification criteria
Objective

26. 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
Sjögren's Syndrome - Autoimmune Epithelitis
The American-European Consensus Group classification criteria

27. 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
Sjögren's Syndrome - Autoimmune Epithelitis
The American-European Consensus Group classification criteria

28. Primary Sjögren's Syndrome-systemic manifestations
Clinical manifestations at diagnosis & end of follow-up
(261 patients)
Skopouli et al., Semin Arthritis Rheum 2000; 29: 296
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 4
Renal involvement
interstitial 7 9
glomerulonephritis 0.4 2
Peripheral Neuropathy 1 2
Lymphoproliferative disorders 2 4

29. Primary Sjögren's Syndrome-systemic manifestations
Clinical manifestations at diagnosis & end of follow-up
(261 patients)
Skopouli et al., Semin Arthritis Rheum 2000; 29: 296
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 4
Renal involvement
interstitial 7 9
glomerulonephritis 0.4 2
Peripheral Neuropathy 1 2
Lymphoproliferative disorders 2 4

30. Sjögren’s Syndrome
Epithelial involvement – Clinical evidence
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
Labial Minor SG
Kidney Liver
Lung

31. Primary Sjögren's Syndrome-systemic manifestations
Clinical manifestations at diagnosis & end of follow-up
(261 patients)
Skopouli et al., Semin Arthritis Rheum 2000; 29: 296
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 4
Renal involvement
interstitial 7 9
glomerulonephritis 0.4 2
Peripheral Neuropathy 1 2
Lymphoproliferative disorders 2 4

32. Clinical spectrum of primary Sjögren's syndrome

33. 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 or
Eye & salivary gland
tests
Serology
If any positive

34. 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

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

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

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

38. Sjögren's Syndrome – conventional
DMARDs
Sicca Manifestations
Immunomodulation:
Methotrexate
(Clin Exp Rheumatol 1996, 4:555)
Azathioprine
(J Rheumatol 1998; 25:896-899)
Nandrolone decanoate
(Clin Exp Rheumatol 1988, 6:53)
Cyclosporine A
(Ann Rheum Dis 1986, 45:732)

39. Sjögren's Syndrome – Biologic therapies
Sicca Manifestations
Immunomodulation:
Anti-TNF a
Mariette et al. Arthritis Rheum. 2004 Apr;50(4):1270-6,
Sankar et al.Arthritis Rheum. 2004 Jul;50(7):2240-5.
IFN-a
Cummins et al. Arthritis Rheum. 2003 Aug 15;49(4):585-93.
Anti-CD20
Meijer et al.Arthritis Rheum. 2010 Apr;62(4):960-8.

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

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

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

44. 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

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

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

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

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