Sjögren's Syndrome Clinical, Pathogenetic & Aspects Athanasios G. Tzioufas, MD Dept. of...

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


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


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


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


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



Dry mouth



Tongue

Teeth


Tests

Subjective:

Objective:


swallowing

excessive fluid use



Sjögren's syndrome – Autoimmune Epithelitis



Dry mouth



Tongue

Teeth


Tests

Subjective:

Objective:


swallowing

excessive fluid use




Salivary flow:

Parotid

Whole

Stimulated

Unstimulated (≤1.5ml/15min)


EpithelitisSalivary gland biopsy

Chilsom focus score(≥ 1 foci/4mm2 )


Glandular manifestationsLacrimal Gland Involvement

Subjective:

Objective:

Foreign body sensation

Lack of tearing “sticky”

eyelids

Conjunctival injection

Lacrimal gland enlargement (rare)

Keratoconjuctivitis sicca

“gritty”

“sandy”


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)



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)



Exclusion criteria:

prior head and neck irradiationpre-existing lymphomaacquired immunodeficiency disease (AIDS)hepatitis C infectionsarcoidosisgraft‑versus‑host diseasesialoadenosisdrugs (neuroleptic, anti‑depressant, anti‑hypertensive, parasympatholytic)



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)


(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)


(1++/A)


(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

Sjögren's Syndrome Clinical, Pathogenetic & Aspects Athanasios G. Tzioufas, MD Dept. of...

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