Sj

1
Sjögren's SyndromeClinical, 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

Pavlidis et al, J Rheumatol 1998 2, 95
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 11
VAMP-2 4
a-fodrin 4
U1RNP 2
Nucleolin 0
Calpastatin 0
NPY 0
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 8841
• Maraia RJ, Proc Natl Acad Sci USA, 1996 933383
• Maturation of pre-tRNAs and other RNA-polymerase
  III transcripts
• Fan H et al., Mol Cell Biol 1998 183201

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

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
EPITHELIUM
EPITHELIUM
EPITHELIUM Persistent Virus Genetic Make-up
11
Sjögren's Syndrome - Autoimmune
EpithelitisGlandular manifestationsSalivary
Gland Involvement
difficulty with chewing, swallowing excessive
fluid use

• Dry mouth
• Intermittent parotid gland enlargement
• Dry oral mucosa mouth ulcers
• Tongue
• Teeth
• Parotid gland enlargement
• Tests

• Subjective
• Objective

12
Sjögren's Syndrome Autoimmune Epithelitis
13
Sjögren's Syndrome - Autoimmune
EpithelitisGlandular manifestationsSalivary
Gland Involvement
difficulty with chewing, swallowing excessive
fluid use

• Dry mouth
• Intermittent parotid gland enlargement
• Dry oral mucosa mouth ulcers
• Tongue
• Teeth
• Parotid gland enlargement
• Tests

• Subjective
• Objective

14
Sjögren's syndrome Autoimmune Epithelitis
15
Sjögren's Syndrome - Autoimmune
EpithelitisGlandular manifestationsSalivary
Gland Involvement
difficulty with chewing, swallowing excessive
fluid use

• Dry mouth
• Intermittent parotid gland enlargement
• Dry oral mucosa mouth ulcers
• Tongue
• Teeth
• Parotid gland enlargement
• Tests

• Subjective
• Objective

16
Sjögren's Syndrome Autoimmune Epithelitis
Parotid gland enlargement
17
Sjögren's Syndrome - Autoimmune
EpithelitisGlandular manifestationsSalivary
Gland Involvement
difficulty with chewing, swallowing excessive
fluid use

• Dry mouth
• Intermittent parotid gland enlargement
• Dry oral mucosa mouth ulcers
• Tongue
• Teeth
• Parotid gland enlargement
• Tests

• Subjective
• Objective

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
EpithelitisGlandular manifestationsLacrimal
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 Bijstervelds
scoring system)
22

Sjögren's Syndrome - Autoimmune EpithelitisThe
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. 200261554

23

Sjögren's Syndrome - Autoimmune EpithelitisThe
American-European Consensus Group classification
criteriaObjective

• III. Ocular signs (positive result in at least
  one of the following tests)
• Schirmers 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. 200261554

24

Sjögren's Syndrome - Autoimmune EpithelitisThe
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. 200261554

25

Sjögren's Syndrome - Autoimmune EpithelitisThe
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. 200261554

26
Primary Sjögren's Syndrome-systemic
manifestationsClinical manifestations at
diagnosis end of follow-up (261 patients)
Diagnosis End of follow-up
patients () patients ()
Arthralgia/arthritis 70 75
Raynauds 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
Skopouli et al., Semin Arthritis Rheum 2000 29
296
27
Primary Sjögren's Syndrome-systemic
manifestationsClinical manifestations at
diagnosis end of follow-up (261 patients)
Diagnosis End of follow-up
patients () patients ()
Arthralgia/arthritis 70 75
Raynauds 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
Skopouli et al., Semin Arthritis Rheum 2000 29
296
28
Sjögrens SyndromeEpithelial 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
29
Primary Sjögren's Syndrome-systemic
manifestationsClinical manifestations at
diagnosis end of follow-up (261 patients)
Diagnosis End of follow-up
patients () patients ()
Arthralgia/arthritis 70 75
Raynauds 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
Skopouli et al., Semin Arthritis Rheum 2000 29
296
30
Clinical spectrum of primary Sjögren's syndrome
31
Sjögren's Syndrome - Autoimmune
EpithelitisAlgorithm for the diagnosis
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
Sjögrens 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 DMARDsSicca
Manifestations

• Immunomodulation
• Methotrexate
• (Clin Exp Rheumatol
  1996, 4555)
• Azathioprine
• (J Rheumatol
  1998 25896-899)
• Nandrolone decanoate
• (Clin Exp Rheumatol 1988, 653)
• Cyclosporine A
• (Ann Rheum Dis 1986, 45732)

37
Sjögren's Syndrome Biologic therapiesSicca
Manifestations

• Immunomodulation
• Anti-TNF a
• Mariette et al. Arthritis Rheum.
  2004 Apr50(4)1270-6,
• Sankar et al.Arthritis Rheum. 2004
  Jul50(7)2240-5.
• IFN-a
• Cummins et al. Arthritis Rheum.
  2003 Aug 1549(4)585-93.
• Anti-CD20
• Meijer et al.Arthritis Rheum. 2010
  Apr62(4)960-8.

38
JAMA, July 28, 2010Vol 304, No. 4
39
(No Transcript)
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

• Topical therapies

• FIRST STEP

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)

• Systemic therapies

• 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
42
Sjögren's Syndrome -TherapyParenchymal organ
involvement

• Lungs, Kidneys, Liver
• Slow process
• Usually does not lead to organ failure
• Skopouli et al., Semin Arthritis Rheum. 2000,
  29296
• Lack of controlled therapeutic trials
• Corticosteroids ineffective-dangerous?
• Anecdotal reports with azathioprine, MMF, IVIG

43
Sjögren's Syndrome -TherapySystemic Vasculitis

• Corticosteroids
• Cyclophosphamide
• Plasmapheresis
• IVIg
• Others

44
Extraglandular involvement
Joint
Pulmonary
Renal
Vasculitic
Neurological
Life-threatening
Arthralgia
Arthritis
Interstitial
Tubular
Glomerular
CNS
Multineuritis
Polyneuropathy Ataxic neuronop
Bronchial
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

• 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

46
Collaborators-Dept of Pathophysiology-UOA

• E Kapsogeorgou
• M Manoussakis
• F Skopouli
• M Voulgarelis
• HM Moutsopoulos