1. Sjögren’s Syndrome
From Pathogenetic Mechanisms
to Target Therapies
Dott. Claudio Vitali
U.O. Medicina Interna
e Sezione di Reumatologia
Ospedale di Piombino, ASL 6 Livorno

2. Sjögren’s Syndrome - Definition
• Sjögren's syndrome (SS) is defined as an autoimmune
disease of the exocrine glands, involving in particular the
salivary and lacrimal glands.
• It may occur alone (primary SS), or in association with a
variety of connective tissue diseases and autoimmune
disorders (secondary SS).
• The spectrum of presentation of the disorder is very broad,
ranging from the local consequences of exocrine gland
dysfunction to major, life-threatening systemic
complications such as vasculitis, and renal or lung
involvement.

4. Sjögren’s Syndrome
Updating on Pathogenenesis

5. Autoimmune Epithelitis
EPITHELIUM
EPITHELIUM
EPITHELIUM
Persistent Virus La/SSB
MHC-II
FasL
Genetic Make-up CK
ICAM.1 receptor
Fas CD40
MHC-II
B7
EXOSOMES
Cytokines/
APOPTOSIS Chemokines
Ag-Release Ag-Presentation

6. Sjögren’s Syndrome
Updating on Pathogenenesis
3. Role of Epithelial Cells

8. Updating on Pathogenesis
1. Role of T-cells
The lymphoid tissue infiltrates in SS contain T cells, B
cells and plasma cells, with a predominance of primed
CD4+(CD45RO+) T cells in early-stage disease.
SGECs have the capability to function as antigen-
presenting cells and co-stimulate the infiltrating the
CD4+ T cells.
Proinflammatory cytokines, produced by CD4+ T cells
(and also by dendritic cells and macrophages), such as
IFN-γ and TNF-α seem to enhance the activation status
of SGECs in a positive feedback loop.

9. T-cells infiltrating Salivary Gland Tissue
E/E staining TCR+ cells
TGFβ+ cells Treg cells

10. B-cells in SS
No more than 20% of lymphocytic infiltrates in target
organs during the early phases of the disease.
Expanded in later phases of the disease.
Highly represented when GC structures are present.
Predominantly mature B-cell and MZ B-cell phenotypes.
Responsible of auto-Ab and IC production.
Possible oligoclonal-monoclonal selection.

12. Other B-cell Subsetting and Functions
B cells serve as Ag-presenting cells for autoAg-specific T
lymphocytes.
Effector (e) B cells, according to the Ag presented, may
produce two distinct pattern of cytokines:
Be-1 cells produce IFN-γ and IL-12 (Th1 phenotype).
Be-2 cells produce IL-4 and IL-13 (Th2 phenotype).
Regulatory B cells (Breg) produce IL-10 and TGFβ-1,
suppressing immune response and enhancing tolerance.

13. B-cell functions in SS
IC, mainly those containing locally produced anti-Ro/SSA
and nucleoprotein may activate dendritic cells and other
cell types via Fc-γ receptor, Toll-like receptor or B cell
receptors (BCRs).
This continuous stimulation seems to play a key role in
the oligoclonal-monoclonal selection and expansion of
RF-expressing MZ-like B cells.

14. Sjögren's Syndrome
(Autoimmune Epithelitis)
Does the syndrome evolve?
Exocrinopathy Systemic Disease Lymphoma
Poly-, oligo-, monoclonal
B cell activation
Polyclonal Monoclonal
B cell activation B cell activation

15. Sjögren's Syndrome
Autoimmune Epithelitis
Low risk for
lymphoma or death
Type-
Type-II
Type-
Type-I High risk group
Low C4
Palpable purpura

16. The Spectrum of Clinical Manifestations in SS
Glandular involvement Anti-muscarinic antibodies
Autoantibody-, IC-, or
Dry mouth vasculitis-related features
Dry eye Arthritis
Dry skin Epithelial involvement Glomerulonephritis
Dry vagina Xerotrachea Skin vasculitis
Bronchiolitis Raynaud’s phenomenon
Cholangitis Cytopenias
Renal tubular acidosis Peripheral neuropathy
Atrophic gastritis CNS involvement (?)
Lymphocyte infiltration
and proliferation
Interstitial nephritis B-cell
Interstitial pneumonitis hyperactivity
Autoimmune hepatitis
Lymph node/spleen enlargement
MALT lymphoma

17. Sjögren’s Syndrome
News in Therapeutic Approach

18. New and possible therapeutic approaches in
primary SS using biological agents
B-cell-targeted therapies Cytokine-targeted therapies
• Rituximab (chimeric anti-CD20) • Infliximab (anti-TNF)
• Ocrelizumab (humanized anti-CD20) • Etanercept (anti-TNF)
• Epratuzumab (anti-CD22) • Tocilizumab (anti-IL6r)
• Belimumab (anti-BAFF) • Anti-IL10
• Anti-IL17
T-cell-targeted therapies • Anti-IFNα
• Efalizumab (anti-CD11a)
• Alefacept (anti-CD2) Complement-targeted therapies
• Abatacept (anti-CD80/86) • Eculizumab (anti-C5a/C5b-9)

19. Therapeutic role of biological agents in SS: reported studies
Biological agent Authors No of Pts. Study design Efficacy
Infliximab Steinfeld et al. [1] 16 Open-label Response
Mariette et al. [2] 103 RCT No response
Etanercept Sankar et al. [3] 28 RCT No response
Zandbelt et al. [4] 15 Open-label No response
Epratuzumab Steinfeld et al. [5] 16 Phase I/II Response
1. Arthritis Rheum 2001; 44: 2371–5
2. Arthritis Rheum 2004; 50: 1270–6
3. Arthritis Rheum 2004; 50: 2240–5
4. J Rheumatol 2004; 31: 96-101
5. Arthritis Res Ther 2006; 8: R129

20. CD20 Expression on B cells

21. AntiCD20-
mediated
B cell
depletion

22. Rituximab in SS: Acquired Experience (I)
Authors/ N° of Patients Mean age RTX Pre-
Year Type of Study M/F ratio Schedule treatment
Pijepe et al./ 8 with early SS 46.3 yrs 4 infusions
2005 Open-label 7 with SS+MALT 1/14 375 mg/m2 yes
Gottenberg et 4 with SS 57.5 yrs 4 infusions
al./ 2005* Retrospective 2 with SS+NHL 0/6 375 mg/m2 yes/no
Devauchelle- 54.8 yrs 2 infusions
Pensec et al/ Open-label 16 with SS 2/14 375 mg/m2 no
2007 prospective
Seror et al./ 11 with SS 54.3 yrs 4 infusions
2007* Retrospective 5 with SS+NHL 0/16 375 mg/m2 yes
Case Reports/ _ 6 with SS 55.0 yrs 4 infusions
2003-2008 4 with SS+NHL 0/10 375 mg/m2 NA data
(MALT) 1 pts+CHOP
Dass et al./ 17 with SS 51.0 yrs 1 gr day 1 and
2008 Pilot RCT 8 RTX / 9 Placebo 0/17 15 yes
* Two patients in both series. Total N° of treated pts 69

23. Rituximab in SS: Acquired Experience (II)
Authors/ Systemic Subjective Objective Lymphoma Lab
Years manifestations sicca sicca efficacy evaluation
Pijepe et al./ Improvement of Improvement Slight Good IgM RF
2005 fatigue, arthralgia, in dry mouth increase in response in decrease
physical function stimulated SF 6/7 pts B-cell
in early phase depletion
Gottenberg et Improvement of Good IgM RF
al./ 2005* systemic Improvement No Changes response in decrease
manifestations in 3/6 1/2 B-cell
in 5/6 depletion
Devauchelle- Improvement of Significant No case with IgM RF
Pensec et al/ fatigue, arthralgia, improvement No Changes LNH decrease
2007 arthritis, DA, QoL of VAS for included B-cell
dryness depletion
Seror et al./ Improvement of 5/11 had Improvenent Good IgM RF
2007* systemic improved of ocular response in decrease
manifestations VAS for changes in 4/5 pts B-cell
In 9/11 dryness 2/11 depletion
Dass et al./ No case with IgM RF
2008 Improvement of No enough No changes LNH decrease
fatigue, SF-36 data included B-cell
depletion

24. Rituximab in SS: Acquired Experience (III)
Authors/ Immediate Delayed HACA Therapy
Years reaction reaction formation compliance Drop out
Pijepe et al./ 3 patients
2005 3/15 patients 3/15 patients 4/15 (2/4 doses) 1/15 pts
Gottenberg et
al./ 2005* 2/6 1*/6 No data 1 patient Not evaluated
(3/4 doses)
Devauchelle- All received
Pensec et al/ 10/16 4/16 No data complete 1/16 (incident
2007 doses lymphoma)
Seror et al./ All received
2007* 1/16 2*/16 1/8 complete No
doses
Dass et al./ 1 patient 1 patient
2008 4/8 1/8 No data (1/2 doses) (not computed)
•*Same patient in both series.
• HACA, human anti-chimeric antibodies

25. Personal Experience with Rituximab in SS
Result on
Result on SS LNH
Case Main clinical features Associated LNH features features
Woman RTA Large cell, Remission
54 y.o. Cutaneous amiloidosis nodal Not relevant after RTX
DD 25 yrs Chronic SGE +CHOP
Woman Lung interstitisl Improvement of
63 y.o. involvement, Low grade MALT lung involvement Remission
DD 18 yrs purpura, low C4, SGE, and purpura
peripheral neuropathy
Woman Overlap with limited Low grade MALT Remission of
68 y.o. scleroderma. with regional systemic features. Remission
DD 15 yrs Arthritis, purpura, SGE node involvement Relapse after 1 yrs
DD, disease duration
RTA, renal tubular acidosis
SGE, salivary gland enlargement

26. Sjögren’s Syndrome
Perspectives in Therapeutic Approach

27. Potential biological agents to be used in SS: reported studies
Biological agent Target Function Applications
Alefacept CD2 Block of the CD2/LFA-3 interaction Psoriasis
Inhibition of memory T-cells
Abatacept CD80/86 Block of CD80/86-CD28 interaction RA
Inhibition of costimulatory mechanisms
between APC and T-cell
Belimumab BAFF Block of the BAFF action RA & SLE
Down-regulation of B-cell (phase II)
proliferation and pSS (phase II)
survival
Tocilizumab IL6R Block the IL6-IL6R interaction RA
B-N10 IL10 Block the IL10 action SLE

28. BAFF/Blys
(B-cell activating factor)
Member of TNF superfamily
Produced in situ by infiltrating T-cells and macrophages,
and probably by resident epithelial and mesenchimal
cells.
Key signal to infiltrating B cells for
- proliferation
- survival
- organization in GC
- autoantibody production
- oligo-/monoclonal selection.
Possible target for therapy.

32. Main Issues
High priority for trials of B cell depletion therapy in patient with type I
primary SS.
Anti-BAFF therapy seems to be an interesting option to B cell depleting
therapy.
Combining B cell depletion with anti-BAFF therapy may have synergistic
effects.

33. Summary (I)
At this stage not enough data is available to settle RTX place
in the tratment of SS.
We are currently awaiting results from RCT on this topic
Data from trial and and cases accumulated so far show that
RTX in SS is relatively safe, but serum sickness like reactions
are not infrequent
RTX has not been able to demonstrate convincing efficacy on
objective glandular function related to SS, but is promising
regarding effects on systemic features, SS-associated NHL,
and fatigue.
The drug is effective in depleting B cells from peripheral blood
and the treatment is linked with decreased levels of RF
Isaksen K, Jonssson R, Omdal R. Scand J Immunol 2008; 68: 554-64

34. Summary (II)
A fundamental problem with interpreting and designing studies
on SS is related to the lack of a common scoring system for
disease severity and activity.
This leads to substantial methodological weakness when tryng
to compare and evaluate the different studies.
Isaksen K, Jonssson R, Omdal R. Scand J Immunol 2008; 68: 554-64

35. Sjögren’s Syndrome
Need for Outcome Measures

36. The Italian Job

38. The EULAR Initiative

39. EULAR Project on the Definition
of Activity Criteria for SS
Steering Committee
Hendrika Bootsma, NL
Simon Bowman, UK
Jacques-Eric Gottenberg, France
Xavier Mariette, France
Philippe Ravaud, France (Epidemiologist)
Raphaele Seror, France (Fellow)
Elke Theander, Sweden
Athanasios Tzioufas, Greece
Claudio Vitali, Italy (Chairman)

40. “Dichotomy” of clinical
manifestations
Main symptomatic Systemic
features features
Dryness Synovitis, vasculitis,
Fatigue pulmonary, PNS, CNS,
Pain renal, hematological, etc
Disabling but benign Severe
All About 1/3
Evaluated by patient Evaluated by clinician
ESSPRI ESSDAI

41. Grazie per l’attenzione!