Sjögren’s SyndromeFrom Pathogenetic Mechanisms

to Target Therapiesto Target Therapies

Dott. Claudio VitaliU.O. Medicina Interna

e Sezione di Reumatologia

Ospedale di Piombino, ASL 6 Livorno

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

• 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.

Sjögren’s Syndrome

Updating on Pathogenenesis

EPITHELIUMEPITHELIUM

Autoimmune Epithelitis

EXOSOMES

EPITHELIUMEPITHELIUMPersistent Virus

Genetic Make-up

CD40Fas

FasL

B7

Cytokines/

ICAM.1CKreceptor

EPITHELIUMEPITHELIUM

La/SSBMHC-II

MHC-II

Ag-Release Ag-Presentation

APOPTOSISCytokines/Chemokines

Sjögren’s Syndrome

Updating on Pathogenenesis3. Role of Epithelial Cells

Updating on Pathogenesis1. 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.

T-cells infiltrating Salivary Gland Tissue

E/E staining TCR+ cells

TGFβ+ cells Treg cells

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.� 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.

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.

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.

Sjögren's Syndrome

(Autoimmune Epithelitis)

Does the syndrome evolve?

LymphomaLymphomaSystemic DiseaseSystemic DiseaseExocrinopathyExocrinopathy

Polyclonal

B cell activation

Monoclonal

B cell activation

Poly-, oligo-, monoclonal

B cell activation

Sjögren's Syndrome Autoimmune Epithelitis

TypeType--IIII

Low risk for lymphoma or death

TypeType--II

Low C4Palpable purpura

High risk group

The Spectrum of Clinical Manifestations in SS

Glandular involvementDry mouthDry eyeDry skinDry vagina

Epithelial involvementXerotracheaBronchiolitisCholangitisRenal tubular acidosisAtrophic gastritis

Autoantibody-, IC-, or vasculitis-related featuresArthritisGlomerulonephritisSkin vasculitisRaynaud’s phenomenonCytopeniasPeripheral neuropathyCNS involvement (?)

Anti-muscarinic antibodies

Atrophic gastritis

Lymphocyte infiltrationand proliferationInterstitial nephritisInterstitial pneumonitisAutoimmune hepatitis

Lymph node/spleen enlargementMALT lymphoma

CNS involvement (?)

B-cell hyperactivity

Sjögren’s SyndromeSjögren’s Syndrome

News in Therapeutic Approach

New and possible therapeutic approaches in primary SS using biological agents

B-cell-targeted therapies• Rituximab (chimeric anti-CD20)• Ocrelizumab (humanized anti-CD20)• Epratuzumab (anti-CD22)• Belimumab (anti-BAFF)

Cytokine-targeted therapies• Infliximab (anti-TNF)• Etanercept (anti-TNF)• Tocilizumab (anti-IL6r)• Anti-IL10• Belimumab (anti-BAFF)

T-cell-targeted therapies• Efalizumab (anti-CD11a)• Alefacept (anti-CD2)• Abatacept (anti-CD80/86)

• Anti-IL10• Anti-IL17• Anti-IFNα

Complement-targeted therapies• Eculizumab (anti-C5a/C5b-9)

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 ResponseMariette et al. [2] 103 RCT No response

Etanercept Sankar et al. [3] 28 RCT No responseZandbelt et al. [4] 15 Open-label No response

Epratuzumab Steinfeld et al. [5] 16 Phase I/II ResponseEpratuzumab Steinfeld et al. [5] 16 Phase I/II Response

1. Arthritis Rheum 2001; 44: 2371–52. Arthritis Rheum 2004; 50: 1270–63. Arthritis Rheum 2004; 50: 2240–54. J Rheumatol 2004; 31: 96-1015. Arthritis Res Ther 2006; 8: R129

CD20 Expression on B cells

AntiCD20-mediated

B cell depletion

Rituximab in SS: Acquired Experience (I)Authors/

Year Type of Study

N° of Patients Mean ageM/F ratio

RTX Schedule

Pre-treatment

Pijepe et al./2005 Open-label

8 with early SS7 with SS+MALT

46.3 yrs1/14

4 infusions375 mg/m2 yes

Gottenberg et al./ 2005* Retrospective

4 with SS2 with SS+NHL

57.5 yrs0/6

4 infusions375 mg/m2 yes/no

Devauchelle-Pensec et al/ Open-label 16 with SS

54.8 yrs2/14

2 infusions375 mg/m2 no

2007Open-label prospective

16 with SS 2/14 375 mg/m no

Seror et al./2007* Retrospective

11 with SS5 with SS+NHL

54.3 yrs0/16

4 infusions375 mg/m2 yes

Case Reports/ 2003-2008

_ 6 with SS4 with SS+NHL(MALT)

55.0 yrs0/10

4 infusions375 mg/m2

1 pts+CHOP NA data

Dass et al./2008 Pilot RCT

17 with SS8 RTX / 9 Placebo

51.0 yrs0/17

1 gr day 1 and 15 yes

* Two patients in both series. Total N° of treated pts 69

Rituximab in SS: Acquired Experience (II)Authors/

YearsSystemic

manifestationsSubjective

siccaObjective

siccaLymphoma

efficacyLab

evaluation

Pijepe et al./2005

Improvement of fatigue, arthralgia, physical function

Improvement in dry mouth

Slight increase in

stimulated SF in early phase

Good response in

6/7 pts

IgM RF decrease

B-cell depletion

Gottenberg et al./ 2005*

Improvement of systemic

manifestationsin 5/6

Improvement in 3/6

No ChangesGood

response in 1/2

IgM RF decrease

B-cell depletion

Devauchelle- Improvement of Significant No case with IgM RF Devauchelle-Pensec et al/2007

Improvement of fatigue, arthralgia, arthritis, DA, QoL

Significantimprovement

of VAS for dryness

No ChangesNo case with

LNH included

IgM RF decrease

B-cell depletion

Seror et al./2007*

Improvement of systemic

manifestationsIn 9/11

5/11 had improved VAS for dryness

Improvenent of ocular

changes in 2/11

Good response in

4/5 pts

IgM RF decrease

B-cell depletion

Dass et al./2008 Improvement of

fatigue, SF-36No enough

dataNo changes

No case with LNH

included

IgM RF decrease

B-cell depletion

Rituximab in SS: Acquired Experience (III)

Authors/Years

Immediate reaction

Delayed reaction

HACA formation

Therapycompliance Drop out

Pijepe et al./2005 3/15 patients 3/15 patients 4/15

3 patients(2/4 doses) 1/15 pts

Gottenberg et al./ 2005* 2/6 1*/6 No data 1 patient

(3/4 doses)Not evaluated

Devauchelle-Pensec et al/

All receivedPensec et al/2007

10/16 4/16 No data complete doses

1/16 (incident lymphoma)

Seror et al./2007* 1/16 2*/16 1/8

All receivedcomplete

dosesNo

Dass et al./2008 4/8 1/8 No data

1 patient(1/2 doses)

1 patient (not computed)

•*Same patient in both series.• HACA, human anti-chimeric antibodies

Personal Experience with Rituximab in SS

Case Main clinical features Associated LNHResult on SS

features

Result on LNH

features

Woman54 y.o.DD 25 yrs

RTACutaneous amiloidosisChronic SGE

Large cell,nodal Not relevant

Remissionafter RTX+CHOP

Woman 63 y.o.DD 18 yrs

Lung interstitisl involvement,purpura, low C4, SGE,

Low grade MALTImprovement of lung involvementand purpura

RemissionDD 18 yrs purpura, low C4, SGE,

peripheral neuropathyand purpura

Woman68 y.o.DD 15 yrs

Overlap with limited scleroderma.Arthritis, purpura, SGE

Low grade MALT with regional node involvement

Remission of systemic features.Relapse after 1 yrs

Remission

DD, disease durationRTA, renal tubular acidosisSGE, salivary gland enlargement

Sjögren’s SyndromeSjögren’s Syndrome

Perspectives in Therapeutic Approach

Potential biological agents to be used in SS: reported studies

Biological agent Target Function Applications

Alefacept CD2 Block of the CD2/LFA-3 interaction PsoriasisInhibition of memory T-cells

Abatacept CD80/86 Block of CD80/86-CD28 interaction RAInhibition of costimulatory mechanismsbetween 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

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.

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.

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 infrequentare 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

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.to compare and evaluate the different studies.

Isaksen K, Jonssson R, Omdal R. Scand J Immunol 2008; 68: 554-64

Sjögren’s SyndromeSjögren’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, NLSimon Bowman, UKJacques-Eric Gottenberg, FranceJacques-Eric Gottenberg, FranceXavier Mariette, FrancePhilippe Ravaud, France (Epidemiologist)Raphaele Seror, France (Fellow)Elke Theander, SwedenAthanasios Tzioufas, GreeceClaudio Vitali, Italy (Chairman)

“Dichotomy” of clinical manifestations

Main symptomatic features

Systemic features

DrynessFatigue

Synovitis, vasculitis, pulmonary, PNS, CNS, Fatigue

Pain pulmonary, PNS, CNS,

renal, hematological, etc

Disabling but benign Severe

All About 1/3

Evaluated by patientESSPRI

Evaluated by clinicianESSDAI

Grazie per l’attenzione!