Sjögren's Syndrome
Clinical, Pathogenetic & Aspects
Athanasios G. Tzioufas, MD
Dept. of Pathophysiolo
gy
Medical School
National University of
Athens Greece
Alexandria, 1st ELAR, April 2013
Sjögren's Syndrome - Autoimmune Epithelitis
Female disease
♀/♂ : 9/1
Common
0.5-1% of adult females
4th -5th decade of life
Slowly progressive
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 11-2021-3031-4041-5051-6061-7071-80
81-90
AGE
% O
F P
AT
IEN
TS
At diagnosisAt diagnosisOnset Onset
Pavlidis et al, J Rheumatol 1998; 2, 9:5
Sjögren's Syndrome - Autoimmune Epithelitis
Center of autoimmune disordersalone (primary)with other (secondary)
Wide clinical spectrumorgan-specificsystemicneoplasia
Prototype autoimmune diseasehumoralcellular
Association of Sjögren's syndrome with other
autoimmune rheumatic diseases
Sjögren's syndrome - Immunopathology
Lymphocytic infiltration of the affected epithelial tissues
Autoantibodies-immune complex mediated disease
Autoantibodies to cellular autoantigens Autoantibodies to cellular autoantigens in pSS by IVTT and RIAin pSS by IVTT and RIA
Autoantibody to: PercentRo 60 66Ro 52 49La 57Calreticulin 20Carbonic anhydrase II 11M3R 11VAMP-2 4a-fodrin 4U1RNP 2Nucleolin 0Calpastatin 0NPY 0Tzioufas et al Arthritis Rheum 58 :S791, 2008
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
Sjögren's Syndrome – Autoimmune
Epithelitis Autoimmune Phenomena:
LesionActivated infiltrating cellsB cells T cells
helper/memoryLFA.1/HLA-DR+
Dendritic cells in advanced lesions
Activated epitheliumHLA-DRc-mycproinflammatory cytokineslymphoid chemokinesco-stimulatory/adhesion moleculesautoantigens 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
EPITHELIUMEPITHELIUMEndocrine
StressStress
Autoimmune Epithelitis
EXOSOMES
DC
DC
Ag-Release
T
T
TT
T
T
T
TT
Ag-Presentation
BB
B B
BB
EPITHELIUMEPITHELIUMPersistent Virus
Genetic Make-up
CD40
APOPTOSIS
Fas
FasL
B7
T
B
Cytokines/Chemokines
ICAM.1
CKreceptor
EPITHELIUMEPITHELIUMLa/SSB
La/SSBMHC-II
MHC-II
Sjögren's Syndrome - Autoimmune Epithelitis
Glandular manifestationsSalivary 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
reddevoid of epitheliumcracked “crocodile skin”
multiple cariesearly loss
Sjögren's Syndrome – Autoimmune Epithelitis
Sjögren's Syndrome - Autoimmune Epithelitis
Glandular manifestationsSalivary 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
reddevoid of epitheliumcracked “crocodile skin”
multiple cariesearly loss
Sjögren's syndrome – Autoimmune Epithelitis
Sjögren's Syndrome - Autoimmune Epithelitis
Glandular manifestationsSalivary 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
reddevoid of epitheliumcracked “crocodile skin”
multiple cariesearly loss
Sjögren's Syndrome – Autoimmune Epithelitis
Parotid gland enlargement
Sjögren's Syndrome - Autoimmune Epithelitis
Glandular manifestationsSalivary 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
reddevoid of epitheliumcracked “crocodile skin”
multiple cariesearly loss
Sjögren's Syndrome – Autoimmune Epithelitis
Salivary flow:
Parotid
Whole
Stimulated
Unstimulated (≤1.5ml/15min)
Sjögren's Syndrome – Autoimmune
EpithelitisSalivary gland biopsy
Chilsom focus score(≥ 1 foci/4mm2 )
Sjögren's Syndrome - Autoimmune Epithelitis
Glandular manifestationsLacrimal Gland Involvement
Subjective:
Objective:
Foreign body sensation
Lack of tearing “sticky”
eyelids
Conjunctival injection
Lacrimal gland enlargement (rare)
Keratoconjuctivitis sicca
“gritty”
“sandy”
Sjögren's Syndrome - Autoimmune Epithelitis
Schirmer's test (≤5mm/5min)
Rose-Bengal staining (≥4: van Bijsterveld’s scoring system)
(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 EpithelitisThe American-European Consensus Group classification criteria
Subjective
III. Ocular signs (positive result in at least one of the following tests)
Schirmer’s I testRose-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 flowParotid sialographySalivary scintigraphy
VI. Autoantibodies: Ro(SSA) and/or La(SSB)
Vitali C et al., Ann Rheum Dis. 2002;61:554
Sjögren's Syndrome - Autoimmune EpithelitisThe American-European Consensus Group classification criteria
Objective
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 EpithelitisThe American-European Consensus Group classification criteria
Exclusion criteria:
prior head and neck irradiationpre-existing lymphomaacquired immunodeficiency disease (AIDS)hepatitis C infectionsarcoidosisgraft‑versus‑host diseasesialoadenosisdrugs (neuroleptic, anti‑depressant, anti‑hypertensive, parasympatholytic)
Vitali C et al., Ann Rheum Dis. 2002;61:554
Sjögren's Syndrome - Autoimmune EpithelitisThe American-European Consensus Group classification criteria
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 75Raynaud’s phenomenon 41 48Purpura 10 11Pulmonary involvement
(small airway disease) 19 23Primary biliary cirrhosis 4 4Renal involvement
interstitial 7 9glomerulonephritis 0.4 2
Peripheral Neuropathy 1 2Lymphoproliferative disorders 2 4
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 75Raynaud’s phenomenon 41 48Purpura 10 11Pulmonary involvement
(small airway disease) 19 23Primary biliary cirrhosis 4 4Renal involvement
interstitial 7 9glomerulonephritis 0.4 2
Peripheral Neuropathy 1 2Lymphoproliferative disorders 2 4
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 2000Moutsopoulos HM. Clin Immunol Immunopathol. 1994
Labial Minor SG
Kidney Liver
Lung
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 75Raynaud’s phenomenon 41 48Purpura 10 11Pulmonary involvement
(small airway disease) 19 23Primary biliary cirrhosis 4 4Renal involvement
interstitial 7 9glomerulonephritis 0.4 2
Peripheral Neuropathy 1 2Lymphoproliferative disorders 2 4
Clinical spectrum of primary Sjögren's syndrome
Sjögren's Syndrome - Autoimmune
Epithelitis
Algorithm for the diagnosis
If positive
Sjögren's Syndrome
Dry mouthDry eyes
Salivary gland enlargement
Raynaud’s phenomenon PurpuraRenal tubular acidosis
or or
Eye & salivary gland tests
Serology
If any positive
Sjögren's syndrome – treatment. Progress of the last decade
Understanding of the natural historyInsights into pathogenetic mechanismsNew biologics-experience from other diseasesOutcome measures
Sjögren’s Syndrome
Therapy
Collaboration
Rheumatology
Ophthalmology
Oral medicine – Dentistry
Other medical specialties
Current treatments for dry mouth
Thanou-Stavraki and James, 2008
Current and experimental treatments for dry eyes
Thanou-Stavraki and James, 2008
Sjögren's Syndrome – conventional
DMARDs
Sicca ManifestationsImmunomodulation:
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)
Sjögren's Syndrome – Biologic
therapies
Sicca ManifestationsImmunomodulation:
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-CD20Meijer et al.Arthritis Rheum. 2010 Apr;62(4):960-8.
JAMA, July 28, 2010—Vol 304, No. 4
Treatment of Sjögren's syndrome
Empirical
Symptomatic
Therapeutic regimens used successfully in other systemic diseases (particularly SLE and RA)
Lack of control trials
Sicca features
Xerostomia
Saliva substitutes(1+/B)
Saliva substitutes(1+/B)
N-acetylcysteine(1+/B)
N-acetylcysteine(1+/B)
PilocarpineCevimeline
(1++/A)
PilocarpineCevimeline
(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)
PilocarpineCevimeline
(1++/A)
PilocarpineCevimeline
(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
Sjögren's Syndrome -Therapy
Parenchymal organ involvement
Lungs, Kidneys, Liver
Slow process
Usually does not lead to organ failureSkopouli et al., Semin Arthritis Rheum. 2000, 29:296
Lack of controlled therapeutic trials
Corticosteroids ineffective-dangerous?
Anecdotal reports with azathioprine, MMF, IVIG
Sjögren's Syndrome -Therapy
Systemic Vasculitis
Corticosteroids
Cyclophosphamide
Plasmapheresis
IVIg
Others
Joint Pulmonary Renal Vasculitic Neurological Life-threatening
Arthralgia Arthritis Bronchial Interstitial Tubular Glomerular CNS Multineuritis PolyneuropathyAtaxic 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
Treatment options-Summary
Systemic manifestationsNo clear benefits from
HCQGCOther immunosuppressiveRTX is promising for some situations
VasculitisGlomerulonephritisArthritis
Sicca manifestationsDry eyes
topical 0.05% cyclosporine (twice daily) severe refractory ocular dryness
May add topical NSAIDs
Dry mouthPilocarpine Cevimeline
Collaborators-Dept of Pathophysiology-UOA
E KapsogeorgouM ManoussakisF SkopouliM VoulgarelisHM Moutsopoulos