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What is new in the pathogenesis and diagnosis of Sjögren's syndrome
Sandhya Pulukool, MDAssociate ProfessorDepartment of RheumatologyChristian Medical College and Hospital, Vellore
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DIAGNOSIS
ACR/EULAR classification criteria for primary Sjögren's syndrome 2016
5 criteria itemsWeighted scoreSCORE of ≥4
Shiboski CH et al Ann Rheum Dis. 2016
Item Weight
Focus score of ≥1 foci/4 mm2 3
Anti-SSA/Ro positive 3
Ocular Staining Score ≥5 (or van Bijsterveld score ≥4) in at least 1 eye 1
Schirmer’s test ≤5 mm/5 minutes in at least 1 eye 1
Unstimulated whole saliva flow rate ≤0.1 ml/minute 1
Validated in a separate cohortSensitivity-96% (92–98%) and specificity-95%(92–97%)against clinician-expert–classificationAgreement (k) with AECG criteria (0.91) ACR criteria (0.82)
International Sjogren’s Syndrome Criteria Working Group
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DIAGNOSIS
ACR/EULAR classification criteria for primary Sjögren's syndrome 2016
Inclusion criteria
Any patient with at least 1 symptom of ocular or oral dryness defined as a positive response to at least 1 of the following
1) Daily , persistent, troublesome dry eyes for >3 months?2) Recurrent sensation of sand or gravel in the eyes?3) Use tear substitutes > 3 times a day? 4) Daily feeling of dry mouth for >3 months5) Drink liquids to aid in swallowing dry food?
OR
Suspicion of SS from the ESSDAI questionnaire (at least 1 domain with a positive item)
Exclusion criteriaHepatitis C infection (confirmation by PCR) preexisting lymphoma is allowable
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Relevance of Minor Salivary Gland Biopsy
• FS ≥3 positive predictive value of 16% for lymphoma
• FS of <3 associated with a negative predictive value of 98%
Risselada AP Ann Rheum Dis (2014) The Netherlands
• GC-like structures in upto 25% of pSS• GC formation is associated with higher FS, RF, anti-SSA and SSB
positivity Risselada AP Semin Arthritis Rheum. (2013) The Netherlands
FS-focus score GC-germinal center
DIAGNOSIS
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DIAGNOSIS
Serology
Antibodies against carbamylated proteins
20% pSSAssociated with IgG, IgM, RF, β2-microglobulin9.2-fold higher odds of GC
Anti-TRIM38
10% pSSAssociated with anti-Ro60,anti-Ro52, anti-La, RF, and IgFocus scores of ≥3.0
Brith Bergum, Ann Rheum Dis. (2016) Norway
Wolska N, Arthritis Rheumatol (2016) US
Anti-Muscarinic3 Receptor
Meta –analysis-11 studiesPooled diagnostic OR 13.00 ( 6.00-26.00)Sensitivity-0.43 (95% CI, 0.28-0.58)Specificity 0.95 (95%CI, 0.91-0.97)
Deng C PLoS One (2015)
Salivary anti-M3RSensitivity- 0.44 Specificity -0.8855.81% SSMore in younger patientsHigh Ig Jayakanthan K Clin Rheumatol (2016) India
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DIAGNOSIS
Ultrasound and Sjögren's syndrome
• Meta –analysis• 37 studies and 33 ultrasonographic scoring systems• High risk of bias • Significant heterogeneity
• Sensitivity 0.69 (95%CI: 0.67-0.71)• Specificity 0.92 (95%CI: 0.91-0.93)• Diagnostic odds ratio 33.89 (95%CI: 20.75-55.35)• Low quality of studies-no judgement possible
K Delli Oral Dis (2015)
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PATHOGENESIS
Sjögren's syndrome - Lupus of mucosa
Nocturne, G. & Mariette, X. Nat. Rev. Rheumatol (2013)
Virus/ Endogenous nucleic acid
TLR /Cytosolic RNA/DNA sensors
pDCTypeI IFNα
BAFF
B cells
Th1,NK cellType II IFNγ
TFH
IL21
Th17IL17
Genetics &Epigenetics
TLR-Toll like receptorpDC- plasmacytoid dendritic cellsBAFF :B-cell activating factor
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PATHOGENESIS
Long Interspersed Nuclear Element 1 (L1) Retroelements triggers type I IFN pathway
Levels of L1 messenger RNA transcripts were increased in MSG tissue of SS
Transcript expression correlated with the expression of type I IFN
Mavragani CP Arthritis Rheumatol (2016) Greece, US
RNATLR7/8 9 cGAS
RIG-1
IFN α
DNA
ERV/LINE-1
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PATHOGENESIS
Epstein-Barr virus infection causes disease-specific autoreactive B cell activation in ectopic lymphoid structures of SS
GC Bcell
TFH cell
EBV reactivation in perifollicular plasma cells that produce anti-Ro52 antibodies
anti-Ro 52/anti-La 48 anti-EBV antibodies but not ACPAs
Croia C Arthritis Rheumatol. (2014) UK
Active EBV infection associated with ELS in salivary glands
SCID mice
Serum
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PATHOGENESIS
Interferon (IFN) expression correlates with key phenotypic features
Hall JC Arthritis Rheumatol (2015) US
• Three distinct patterns of IFN in salivary gland• type I-predominant, type II-predominant, and type I/II mixed
• High IFN activity associated with• abnormal sialometry, • leukopenia• hyperglobulinemia • high-titer ANA • anti-SSA, and • high focus score
• Focus score highest in type II-predominant IFN(IFNγ)
•High IFNγ:IFNα ratio predictive of SS-lymphoma cut-off values > 22.3 specificity of 87.5% and sensitivity of 88.9%
Nezos A J Autoimmun (2015) Greece
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PATHOGENESIS
Single-cell analysis of glandular T cell receptors in SS
• TCR repertoire in CD4+ memory T cells from SG and PB of 10 pSS by PCR
• Degree of clonal expansion increased in SG versus PB
• Expanded clones from SG had sequence similarity of CDR3 both within and among SS patients
• Antigenic selection of T cells and shared antigen recognition
• Extent of SG clonal expansion correlated with reduced saliva production and increased SG fibrosis
JCI Insight. 2016 US
APC
TH
Activated TH
T cell clones with identical TCR
VariableRegion
ConstantRegion
HypervariableRegion CDR3
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PATHOGENESIS
Th17 cell play a critical role in the development of Sjogren’s syndrome
Lin X Ann Rheum Dis. (2015) Hong Kong
No SG dysfunction
IL-17 KO C57BL/6 Wild C57BL/6
Adoptive transfer ofTh17 cells
Serum autoantibody production Tissue destructionIncreased Th17 cells
Cervical LN andLymphocytic foci in inflammed SG
Salivary gland
Antigen immunisation
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PATHOGENESIS
LighTs off ! New Villians in SS Unaffected Haskett, J Immunol. (2016), UK
Lymphotoxin/LIGHT Signaling Axis- lymphoid organisation and immune cell recruitment
Lymphotoxin β receptor
Baminercept (Blocks the Lymphotoxin β receptor ) Negative results of Baminercept trial??
PD programmed death 1ICOS Inducible T-cell COStimulator
Two PD1 hi ICOS hi effector subsets PD1 hi Il21 Th1 phenotypePD1 hi Il10 eTreg phenotype
PD1- naive conventional T cells
NOD mice model
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PATHOGENESIS
RBMS3 a novel susceptibility gene associated with female pSS
Hum Genet. 2016 Taiwan
•GWAS in Han Chinese population•RBMS3(P = 4.89 × 10-5)
•Modulating acinar apoptosis and TGF-β
signaling in target exocrine system
Gene associated to germinal centre formationcase-only candidate gene study SNPs in CCL11 (eotaxin)
Reksten TR, Ann Rheum Dis. 2014, Norway
Germline variation of TNFAIP3 in SS-associated lymphomaOR- 2.7 UK 3.12(French) Nocturne J Ann Rheum Dis. 2016 UK ,France
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PATHOGENESIS
Epigenetics• Hypomethylation of interferon (IFN)-regulated genes in all three tissues --blood, B cells, T cells, MSG
•Hypomethylation of IFN-regulated genes• Seropositive patients• Correlated with increased gene expression
• Genes--Inflammatory genes and immune-cell markers and genes of GWAS
• Methylation status of the top five differentially methylated genes inversely correlated with focus score and with ocular staining score
Imgenberg-Kreuz J Ann Rheum Dis. 2016 Sweden
Cole M B et al Arthritis Rheumatol. (2016) US
Miceli-Richard C et al Ann Rheum Dis.(2016) France
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• Less diversity in pSS• Microbial dysbiosis independent of
hyposalivation Siddiqui H ,J Oral Microbiol 2016 ,Norway
Ann Rheum Dis (2015) Abstract,India
Szymula A ,Clin Immunol. (2014) US• A peptide from the von Willebrand factor type
A domain protein (vWFA) from the oral microbe Capnocytphaga ochracea
• Activates Ro60 reactive T cells and induce autoantibody responses against Ro60
• Firmicutes ,Streptococcus , Capnocytophaga , and Veillonella enriched
• Pseudomonas, Synergistetes and Spirochaetes depleted
Salivary microbiome –cause or effect
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Desiccating stressScopolaminelow humidity
Antibiotics
C57BL/6 mice
environmental mouse model of dry eye
Gut dysbiosis
Increased IFNγ, dec IL-13 in conjunctiva
Worsens ocular inflammation
SS ocular and systemic disease was inversely correlated with microbial diversity
SS mice with gut dysbiosis DON’T CRY
de Paiva Sci Rep 2016,USA
• Decrease in Clostridium • Increase in Enterobacter,
Escherichia/ Shigella, and Pseudomonas
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PATHOGENESIS
Sjögren's syndrome - Lupus of mucosa
EBV-Virus/ Endogenous nucleic acid-LINE 1
TLR /Cytosolic RNA/DNA sensors
pDCTypeI IFNα
BAFF
B cells
Th1,NK cellType II IFNγ
TFH
IL21
Th17IL17
Genetics-TNFAIP3, RBMS3, CCL11 Epigenetics-Hypomethylation-IFN Microbiome-salivary, gut
T
T
T
T
T
T
T
DC
BB
New T cell subsetsCD4+PD HI
Increased clonality of SG T cell –antigen driven
High IFNγ:IFNα
CCL11
Lymphoma
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Regarding new ACR/EULAR criteria for Sjogrens syndrome, which is false
1)OSS≥32)5 Criteria items3)Weighted score4)Score ≥ 4
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Thanks
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