Sjögren’s Syndrome
From Pathogenetic Mechanisms
     to Target Therapies

         Dott. Claudio Vitali
       U.O. Medici...
Sjögren’s Syndrome - Definition
• Sjögren's syndrome (SS) is defined as an autoimmune
  disease of the exocrine glands, in...
Sjögren’s Syndrome

Updating on Pathogenenesis
Autoimmune Epithelitis

                        EPITHELIUM
                        EPITHELIUM
                         EPI...
Sjögren’s Syndrome

Updating on Pathogenenesis
    3. Role of Epithelial Cells
Updating on Pathogenesis
                 1. Role of T-cells
The lymphoid tissue infiltrates in SS contain T cells, B
cell...
T-cells infiltrating Salivary Gland Tissue
          E/E staining                TCR+ cells




          TGFβ+ cells     ...
B-cells in SS
No more than 20% of lymphocytic infiltrates in target
organs during the early phases of the disease.

Expand...
Other B-cell Subsetting and Functions
B cells serve as Ag-presenting cells for autoAg-specific T
lymphocytes.

Effector (e...
B-cell functions in SS

IC, mainly those containing locally produced anti-Ro/SSA
and nucleoprotein may activate dendritic ...
Sjögren's Syndrome
             (Autoimmune Epithelitis)
              Does the syndrome evolve?


Exocrinopathy          ...
Sjögren's Syndrome
Autoimmune Epithelitis
                       Low risk for
                    lymphoma or death
 Type-...
The Spectrum of Clinical Manifestations in SS
Glandular involvement         Anti-muscarinic antibodies
                   ...
Sjögren’s Syndrome

News in Therapeutic Approach
New and possible therapeutic approaches in
      primary SS using biological agents

B-cell-targeted therapies            ...
Therapeutic role of biological agents in SS: reported studies

Biological agent Authors                   No of Pts.   Stu...
CD20 Expression on B cells
AntiCD20-
mediated
  B cell
depletion
Rituximab in SS: Acquired Experience (I)
    Authors/                          N° of Patients     Mean age          RTX   ...
Rituximab in SS: Acquired Experience (II)
   Authors/           Systemic             Subjective       Objective      Lymph...
Rituximab in SS: Acquired Experience (III)
   Authors/       Immediate        Delayed         HACA        Therapy
    Year...
Personal Experience with Rituximab in SS
                                                                                 ...
Sjögren’s Syndrome

Perspectives in Therapeutic Approach
Potential biological agents to be used in SS: reported studies


Biological agent   Target    Function                    ...
BAFF/Blys
           (B-cell activating factor)
Member of TNF superfamily

Produced in situ by infiltrating T-cells and ma...
Main Issues

  High priority for trials of B cell depletion therapy in patient with type I
  primary SS.
  Anti-BAFF thera...
Summary (I)
At this stage not enough data is available to settle RTX place
in the tratment of SS.

We are currently awaiti...
Summary (II)

A fundamental problem with interpreting and designing studies
on SS is related to the lack of a common scori...
Sjögren’s Syndrome

Need for Outcome Measures
The Italian Job
The EULAR Initiative
EULAR Project on the Definition
   of Activity Criteria for SS
        Steering Committee

Hendrika Bootsma, NL
Simon Bowm...
“Dichotomy” of clinical
           manifestations
Main symptomatic             Systemic
    features                 featu...
Grazie per l’attenzione!
Vitali Claudio Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità Compa
Vitali Claudio Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità Compa
Vitali Claudio Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità Compa
Vitali Claudio Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità Compa
Vitali Claudio Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità Compa
Vitali Claudio Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità Compa
Vitali Claudio Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità Compa
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Vitali Claudio Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità Compa

  1. 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. 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.
  3. 3. Sjögren’s Syndrome Updating on Pathogenenesis
  4. 4. 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
  5. 5. Sjögren’s Syndrome Updating on Pathogenenesis 3. Role of Epithelial Cells
  6. 6. 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.
  7. 7. T-cells infiltrating Salivary Gland Tissue E/E staining TCR+ cells TGFβ+ cells Treg cells
  8. 8. 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.
  9. 9. 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.
  10. 10. 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.
  11. 11. 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
  12. 12. Sjögren's Syndrome Autoimmune Epithelitis Low risk for lymphoma or death Type- Type-II Type- Type-I High risk group Low C4 Palpable purpura
  13. 13. 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
  14. 14. Sjögren’s Syndrome News in Therapeutic Approach
  15. 15. 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)
  16. 16. 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
  17. 17. CD20 Expression on B cells
  18. 18. AntiCD20- mediated B cell depletion
  19. 19. 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
  20. 20. 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
  21. 21. 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
  22. 22. 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
  23. 23. Sjögren’s Syndrome Perspectives in Therapeutic Approach
  24. 24. 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
  25. 25. 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.
  26. 26. 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.
  27. 27. 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
  28. 28. 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
  29. 29. Sjögren’s Syndrome Need for Outcome Measures
  30. 30. The Italian Job
  31. 31. The EULAR Initiative
  32. 32. 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)
  33. 33. “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
  34. 34. Grazie per l’attenzione!

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