Sj gren s syndrome clinical pathogenetic aspects
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National University of Athens Greece. Dept. of Pathophysiology Medical School. Sjögren's Syndrome Clinical, Pathogenetic & Aspects. Athanasios G. Tzioufas, MD. Alexandria, 1 st ELAR, April 2013. Sjögren's Syndrome - Autoimmune Epithelitis. Female disease ♀ / ♂ : 9/1 Common

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Sj gren s syndrome clinical pathogenetic aspects

National University of Athens

Greece

Dept. of Pathophysiology

Medical School

Sjögren's SyndromeClinical, Pathogenetic & Aspects

Athanasios G. Tzioufas, MD

Alexandria, 1st ELAR, April 2013


Sj gren s syndrome autoimmune epithelitis
Sjögren's Syndrome - Autoimmune Epithelitis

  • Female disease

    • ♀/♂ : 9/1

  • Common

    • 0.5-1% of adult females

  • 4th -5th decade of life

  • Slowly progressive


Sj gren s syndrome autoimmune epithelitis1

45

40

At diagnosis

35

Onset

30

25

% OF PATIENTS

20

15

10

5

0

1-10

11-20

21-30

31-40

41-50

51-60

61-70

71-80

81-90

AGE

Sjögren's Syndrome - Autoimmune Epithelitis

The frequency distributions of ages at onset of symptoms & at diagnosis of primary Sjögren's syndrome

Pavlidis et al, J Rheumatol 1998; 2, 9:5


Sj gren s syndrome autoimmune epithelitis2
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



Sj gren s syndrome immunopathology
Sjögren's syndrome - Immunopathology rheumatic diseases

  • Lymphocytic infiltration of the affected epithelial tissues

  • Autoantibodies-immune complex mediated disease


Sj gren s syndrome clinical pathogenetic aspects

Autoantibodies rheumatic diseasesto cellular autoantigens in pSS by IVTT and RIA

Tzioufas et al Arthritis Rheum 58 :S791, 2008


Sj gren s syndrome clinical pathogenetic aspects

Sjögren's Syndrome – Autoimmune Epithelitis rheumatic diseasesAntibodies 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


Sj gren s syndrome autoimmune epithelitis autoimmune phenomena lesion

Labial Minor SG rheumatic diseases

Sjögren's Syndrome – Autoimmune EpithelitisAutoimmune 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


Autoimmune epithelitis

Stress rheumatic diseases

La/SSB

Endocrine

La/SSB

MHC-II

FasL

CK

receptor

ICAM.1

Fas

CD40

MHC-II

B7

EXOSOMES

APOPTOSIS

Cytokines/

Chemokines

T

T

T

T

T

T

T

T

T

T

DC

DC

Ag-Presentation

Ag-Release

B

B

B

B

B

B

B

Autoimmune Epithelitis

EPITHELIUM

EPITHELIUM

EPITHELIUM

Persistent Virus

Genetic Make-up


Sj gren s syndrome autoimmune epithelitis glandular manifestations salivary gland involvement

red rheumatic diseases

devoid of epithelium

cracked “crocodile skin”

multiple caries

early loss

Sjögren's Syndrome - Autoimmune EpithelitisGlandular manifestationsSalivary Gland Involvement

  • Dry mouth

  • Intermittent parotid gland enlargement

  • Dry oral mucosa – mouth ulcers

  • Tongue

  • Teeth

  • Parotid gland enlargement

  • Tests

difficulty with chewing, swallowing

excessive fluid use

  • Subjective:

  • Objective:



Sj gren s syndrome autoimmune epithelitis glandular manifestations salivary gland involvement1

red rheumatic diseases

devoid of epithelium

cracked “crocodile skin”

multiple caries

early loss

Sjögren's Syndrome - Autoimmune EpithelitisGlandular manifestationsSalivary Gland Involvement

  • Dry mouth

  • Intermittent parotid gland enlargement

  • Dry oral mucosa – mouth ulcers

  • Tongue

  • Teeth

  • Parotid gland enlargement

  • Tests

difficulty with chewing, swallowing

excessive fluid use

  • Subjective:

  • Objective:



Sj gren s syndrome autoimmune epithelitis glandular manifestations salivary gland involvement2

red rheumatic diseases

devoid of epithelium

cracked “crocodile skin”

multiple caries

early loss

Sjögren's Syndrome - Autoimmune EpithelitisGlandular manifestationsSalivary Gland Involvement

  • Dry mouth

  • Intermittent parotid gland enlargement

  • Dry oral mucosa – mouth ulcers

  • Tongue

  • Teeth

  • Parotid gland enlargement

  • Tests

difficulty with chewing, swallowing

excessive fluid use

  • Subjective:

  • Objective:


Sj gren s syndrome autoimmune epithelitis5
Sjögren's Syndrome – Autoimmune Epithelitis rheumatic diseases

Parotid gland enlargement


Sj gren s syndrome autoimmune epithelitis glandular manifestations salivary gland involvement3

red rheumatic diseases

devoid of epithelium

cracked “crocodile skin”

multiple caries

early loss

Sjögren's Syndrome - Autoimmune EpithelitisGlandular manifestationsSalivary Gland Involvement

  • Dry mouth

  • Intermittent parotid gland enlargement

  • Dry oral mucosa – mouth ulcers

  • Tongue

  • Teeth

  • Parotid gland enlargement

  • Tests

difficulty with chewing, swallowing

excessive fluid use

  • Subjective:

  • Objective:


Sj gren s syndrome autoimmune epithelitis6

Salivary flow: rheumatic diseases

Parotid

Whole

Sjögren's Syndrome – Autoimmune Epithelitis

Stimulated

Unstimulated (≤1.5ml/15min)


Sj gren s syndrome autoimmune epithelitis7
Sjögren's Syndrome – Autoimmune Epithelitis rheumatic diseases

Salivary gland biopsy

Chilsom focus score

(≥ 1 foci/4mm2 )


Sj gren s syndrome autoimmune epithelitis glandular manifestations lacrimal gland involvement
Sjögren's Syndrome - Autoimmune Epithelitis rheumatic diseasesGlandular manifestationsLacrimal Gland Involvement

  • Subjective:

  • Objective:

“gritty”

“sandy”

  • Foreign body sensation

  • Lack of tearing  “sticky” eyelids

  • Conjunctival injection

  • Lacrimal gland enlargement (rare)

  • Keratoconjuctivitis sicca


Sj gren s syndrome autoimmune epithelitis8
Sjögren's Syndrome - rheumatic diseasesAutoimmune Epithelitis

Schirmer's test (≤5mm/5min)

Rose-Bengal staining

(≥4: van Bijsterveld’s scoring system)


Sj gren s syndrome clinical pathogenetic aspects

Sjögren's Syndrome - Autoimmune Epithelitis rheumatic diseasesThe American-European Consensus Group classification criteriaSubjective

(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


Sj gren s syndrome clinical pathogenetic aspects

Sjögren's Syndrome - Autoimmune Epithelitis rheumatic diseasesThe American-European Consensus Group classification criteriaObjective

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


Sj gren s syndrome clinical pathogenetic aspects

Sjögren's Syndrome - Autoimmune Epithelitis rheumatic diseasesThe 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


Sj gren s syndrome clinical pathogenetic aspects

Sjögren's Syndrome - Autoimmune Epithelitis rheumatic diseasesThe 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


Sj gren s syndrome clinical pathogenetic aspects
Primary Sjögren's Syndrome-systemic manifestations rheumatic diseasesClinical manifestations at diagnosis & end of follow-up(261 patients)

Skopouli et al., Semin Arthritis Rheum 2000; 29: 296


Sj gren s syndrome clinical pathogenetic aspects
Primary Sjögren's Syndrome-systemic manifestations rheumatic diseasesClinical manifestations at diagnosis & end of follow-up(261 patients)

Skopouli et al., Semin Arthritis Rheum 2000; 29: 296


Sj gren s syndrome epithelial involvement clinical evidence

  • Lung rheumatic diseases

  • Labial Minor SG

  • Liver

  • Kidney

Sjögren’s SyndromeEpithelial involvement – Clinical evidence

Skopouli et al., Semin Arthritis Rheum 2000

Moutsopoulos HM. Clin Immunol Immunopathol. 1994


Sj gren s syndrome clinical pathogenetic aspects
Primary Sjögren's Syndrome-systemic manifestations rheumatic diseasesClinical manifestations at diagnosis & end of follow-up(261 patients)

Skopouli et al., Semin Arthritis Rheum 2000; 29: 296


Clinical spectrum of primary sj gren s syndrome
Clinical spectrum of primary rheumatic diseasesSjögren's syndrome


Sj gren s syndrome autoimmune epithelitis algorithm for the diagnosis

Dry mouth rheumatic diseases

Dry eyes

Salivary gland enlargement

Raynaud’s phenomenon

Purpura

Renal tubular acidosis

or

or

If any positive

Eye & salivary gland tests

Serology

If positive

Sjögren's Syndrome

Sjögren's Syndrome - Autoimmune EpithelitisAlgorithm for the diagnosis


Sj gren s syndrome treatment progress of the last decade
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


Sj gren s syndrome therapy
Sjögren’s Syndrome decade Therapy

  • Collaboration

    • Rheumatology

    • Ophthalmology

    • Oral medicine – Dentistry

    • Other medical specialties


Current treatments for dry mouth
Current treatments for dry mouth decade

Thanou-Stavraki and James, 2008


Current and experimental treatments for dry eyes
Current and experimental treatments for dry eyes decade

Thanou-Stavraki and James, 2008


Sj gren s syndrome conventional dmards sicca manifestations
Sjögren's Syndrome – conventional DMARDs decade 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)


Sj gren s syndrome biologic therapies sicca manifestations
Sjögren's Syndrome – Biologic therapies decade 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.



Treatment of sj gren s syndrome
Treatment of Sjögren's syndrome decade

Empirical

Symptomatic

Therapeutic regimens used successfully in other systemic diseases (particularly SLE and RA)

Lack of control trials


Sj gren s syndrome clinical pathogenetic aspects

Sicca features decade

Xerostomia

Xerophthalmia

Other sicca features

Topicaltherapies

FIRST STEP

Saliva substitutes

(1+/B)

Preservative-free artificial tears

(1++/B)

Topicalmeasures

(4/D)

Topical ocular vit. A/glycols

(2+/B)

Topical 0.05% Cyclosporine A

(1++/B)

Systemictherapies

SECOND STEP

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


Sj gren s syndrome therapy parenchymal organ involvement
Sjögren's Syndrome -Therapy decade 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


Sj gren s syndrome therapy systemic vasculitis
Sjögren's Syndrome -Therapy decade Systemic Vasculitis

  • Corticosteroids

  • Cyclophosphamide

  • Plasmapheresis

  • IVIg

  • Others


Sj gren s syndrome clinical pathogenetic aspects

Extraglandular involvement decade

Joint

Pulmonary

Renal

Vasculitic

Neurological

Life-threatening

Arthralgia

Arthritis

Interstitial

Tubular

Glomerular

CNS

Multineuritis

Polyneuropathy

Ataxic neuronop

Bronchial

HCQ

NSAIDs

Inhaledtx

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


Treatment options summary

Systemic manifestations decade

No clear benefits from

HCQ

GC

Other immunosuppressive

RTX is promising for some situations

Vasculitis

Glomerulonephritis

Arthritis

Sicca manifestations

Dry eyes

topical0.05%cyclosporine (twicedaily)

severe refractory ocular dryness

May add topical NSAIDs

Dry mouth

Pilocarpine

Cevimeline

Treatment options-Summary


Collaborators dept of pathophysiology uoa
Collaborators-Dept of Pathophysiology-UOA decade

  • E Kapsogeorgou

  • M Manoussakis

  • F Skopouli

  • M Voulgarelis

  • HM Moutsopoulos