3-4. Korean Initiative of primary Sjogrens Syndrome(KISS)

Report
Korean Initiative of primary Sjogren’s Syndrome
(KISS): Establishment of a prospective cohort
for primary Sjogren’s syndrome in Korea
19/SEP/2014
가톨릭대학교 서울성모병원 류마티스내과
곽승기
류마티스내과가 하는 일은?
자가면역질환과 근골격계 질환의 진료 및 연구
자가면역질환(autoimmune disease)이란?
Autoantibody 혹은 autoreactive T cell을 증명할 수 있는 질환
류마티스내과 영역의 자가면역질환
류마티스관절염(Rheumatoid Arthritis, RA)
전신홍반루푸스(Systemic Lupus Erythematosus, SLE)
---쇼그렌 증후군
Why Sjogren’s Syndrome Research?
Unmet need of Sjogren’s syndrome
진단기준이 정립되어 있지 않다.
질병활성도 평가방법 부재
치료법 부재 (FDA승인 받은 약제로 pilocarpine이 유일함)
진단기준(분류기준)의 변천사
1965
2002
1) Medicine (Baltimore) 1965;44:187–231.
2) Philadelphia: WB Saunders; 1971.
3) Oral Surg Oral Med Oral Pathol 1975;39:875–85
4) Japan: Japanese Ministry of Health; 1977.
5) Allergy 1981;36:139–53.
6) Scand J Rheumatol Suppl 1986;61:26–7.
7) Scand J Rheumatol Suppl 1986;61:22–5.
8) Arthritis Rheum 1986;29:577–85.
9) Arthritis Rheum 1993;36:340–7.
10) Rheumatology (Oxford) 2000;24:421–8.
11) Ann Rheum Dis 2002;61:554–8.
“Absence of a gold standard diagnostic test”
2013년도 보건의료 연구개발사업- 희귀질환 중개연구센터 구두평가
대한민국 쇼그렌 증후군
코호트 구축과 테라그노시스 개발
가톨릭대학교 의과대학
박성환
쇼그렌 증후군 중개연구센터
Contents
1. General review of Sjogren’s syndrome (SS)
2. Previous works on Sjogren’s syndrome (SS)
3. Korean initiative of primary Sjogren’s syndrome (KISS)
Historical outline
• 1930, Henrik Samuel Conrad Sjogren
- Swedish ophthalmologist
(1899~1986)
- describe the clinical and histological components of the
syndrome
- “A general disease” as a nosologic entity
• Various labels of Sjoren's syndrome
- Gougerot-Houwer-Sjogren syndrome
- Mikulicz-Sjogren syndrome
- ophthalmo-rhino-stomato-xerosis syndrome
- mucoserous dyssecretosis
- keratitis sicca
What is Sjogren’s syndrome (SS)?
•
A slowly progressive, inflammatory autoimmune disease affecting primarily the
exocrine glands
•
Lymphocyte infiltrates replace functional epithelium, leading to decreased
exocrine secretions (exocrinopathy) like dry eye, dry mouth
•
Female preponderance (9:1)
•
Approximate prevalence: 0.1 – 3 %
•
Characteristic autoantibodies, anti-Ro(SS-A) and anti-La(SS-B)
쇼그렌증후군 환자 침샘조직
정상인 침샘조직
x100
x100
Etiology and Pathogenesis
unknown
Etiology and Pathogenesis
Genetic factor
Environmental
factor
Immunologic
factor
Etiology and Pathogenesis
- Effector T cell activation
- B cell activation
- Cytokine activation (type 1 interferon, IL-1, IL-6, TNF-α, IL-21, IL-23, BAFF---)
- Apoptosis of acinar epithelial cells
- Viral infection
- Epithelial cell activation - autoimmune epithelialitis
-
Two models for the pathogenesis of SS
Immune Destructive Vs Immune Inhibited
Kelley’s Textbook of Rheumatology, 9th Edition 2013
Two models for the pathogenesis of SS
Immune Destructive Vs Immune Inhibited
Kelley’s Textbook of Rheumatology, 9th Edition 2013
Clinical manifestation
Prevalence at
diagnosis (%)
Prevalence at
10-year-follow-up (%)
Xerostomia
90
92
Dry eyes
95
95
Parotid gland enlargement
49
53
Arthralgias/arthritis
70
75
Raynaud’s phenomenon
41
48
Pulmonary involvement
23
29
Interstitial nephritis
7
9
Glomerulonephritis
0.4
2
Liver involvement
4
4
Peripheral neuropathy
1
2
Myositis
1
1
Central nervous system disease
0
0
Lymphoma
2
4
Glandular disease
Extraglandular disease
Classification or diagnostic criteria
1965
2002
1) Medicine (Baltimore) 1965;44:187–231.
2) Philadelphia: WB Saunders; 1971.
3) Oral Surg Oral Med Oral Pathol 1975;39:875–85
4) Japan: Japanese Ministry of Health; 1977.
5) Allergy 1981;36:139–53.
6) Scand J Rheumatol Suppl 1986;61:26–7.
7) Scand J Rheumatol Suppl 1986;61:22–5.
8) Arthritis Rheum 1986;29:577–85.
9) Arthritis Rheum 1993;36:340–7.
10) Rheumatology (Oxford) 2000;24:421–8.
11) Ann Rheum Dis 2002;61:554–8.
“Absence of a gold standard diagnostic test”
2002 American-European Consensus Group
criteria
Subjective
Objective
Classification criteria for Sjogren’s syndrome: a revised version of the
European criteria proposed by the American-European Consensus Group.
[Ann Rheum Dis 2002;61:554–8.]
2012 ACR criteria
1. Positive serum anti-SSA/Ro and/or anti-SSB/La or (positive
rheumatoid factor and ANA titer 1:320)
2. Labial salivary gland biopsy exhibiting focal lymphocytic
sialadenitis with a focus score ≥1 focus/4 mm2
Only objective measures!
3. Keratoconjunctivitis sicca with ocular staining score (using
lissamine green and fluorescein) ≥3 (assuming that
individual is not currently using daily eye drops for
glaucoma and has not had corneal surgery or cosmetic
eyelid surgery in the last 5 years)
Arthritis Care Res (Hoboken). 2012 Apr;64(4):475-87.
At least 2 of the following 3 objective features
국내 쇼그렌 증후군 연구센터왜 필요한가?!
현 진단 기준의 국내 적합성 미확립
: 미국/유럽 류마티스 학회에서 제시한 classification criteria에 준하여 진단
2002
진단 기준이 지속적으로 개정되고
있음
개정 국제 분류 기
준
2012
미국 류마티스 학
회 분류 기준
1) 정확한 기준이 모호한 상태
1971~1980
1981~1990
1991~2001
2012필요
2002 진단 마커
 질병 활성도를
반영하는
정확한
1984 Janpnese I
1975-76 Copenhagen
2) 국내 적합성
미검증1993 EU I
1986 Greek
1986 California
1996 EU II
1997 Japanese II
1999 Japanese III
연구배경
국내 쇼그렌 증후군 연구센터왜 필요한가?!
명확한 원인,병리기전이 밝혀지지 않음
병인 표적 치료제 부재
대증요법으로 치료
병인을 근본적으로 조
절할 수 있는 치료법 필
요함
질병활성도 평가기준 미흡
연구배경
Sjogren’s syndrome Research
Basic research
Translational research
Clinical research
연구를 위하여 무엇이 필요할까?
표적장기의 조직 혹은 cell line – salivary gland tissue
동물모델 확립
Our results regarding Sjogren’s syndrome
(2009-2013)
- Th17 cell associated cytokines such as IL-21 and their implications in SS
- The role of T cell attracting chemokines in SS
- Establishment of animal model of SS
- Others
T cell development in thymus (positive or negative selection)
Priming of naïve T cells
Signal 3: cytokine stimulation
Siganl 2: costimulatory signal
Signal 1: Antigen stimulation with MHC-APC
Effector T cells
Naïve T cell
Memory T
cells
History of effector CD4+T cell discovery
2014
2005
2003
1986
Th1/Th2
J Immunol. 1986;136:2348-57
Th17 cell
Regulatory T cells
J Immunol. 1986;136:2348-57
Nat Immunol. 2005;6:1123-32
Nat Immunol. 2005;6:1133-41
RA is Th17 mediated disease
2011
Th1/Th2 paradigm period
2005
2003
RA seemed to be Th1 mediated disease
1986
Th1/Th2 concept
Th17 cell
Regulatory T cells
Annu. Rev. Immunol. 2008;26:57-79
Schematic representation of the osteoclastogenic potential of
IL-21 in the rheumatoid synovium
KWOK SK et al. Arthritis Rheum. 2012;64:740-51
Contents
1. General review of primary Sjogren’s syndrome (PSS)
2. Previous works on PSS
3. Korean initiative of primary Sjogren’s syndrome (KISS)
Introduction (I)
 Primary Sjogren’s syndrome (pSS) is a slowly progressvie, inflammatory
autoimmune disease affecting primarily exocrine glands.
Hochberg-Rheumatology, 5th Edition
 The prevalence and health economic impact of pSS are comparable with RA.
Rheumatology. 2011;50:32-9
 However, pSS research has been relatively poorly supported.
 The creation of a large cohort of clinically well-characterized pSS patients will
provide valuable resources to promote high-quality pSS research.
Introduction (II)
 There has not been a nation-wide registry for primary Sjogren’s syndrome
(pSS) in Korea in contrast to the existence of SICCA in US, UKPSSR in UK,
and ASSESS in France.
 Interests on this “Orphan” disease are increasing among researchers.
 The integrative data will facilitate clinical and basic research of pSS.
Sjogren’s syndrome Registries in the world
SICCA
(2004- enrollment closed)
Objective
1)
2)
Clinical data and
biospecimens
Develop standardized
classification criteria
UKPSSR
(2009-2012)
ASSESS
(2006-2009)
For high quality clinical
research
To identify predictors of
systemic complications and
lymphoma in pSS
Institutes
6 international research
group
32 hospitals in UK
15 centers in France
Subject
Suspicious / diagnosed SS
patients
pSS patients fulfilling AECG
criteria
pSS patients fulfilling AECG
criteria
Follow
up
2years from enrollment
Only patients with objective(+)
No.
participa
nts
2594
Sampling 1) Blood- serum, plasma,
2)
3)
4)
DNA, PBMC
Saliva – whole, parotid
Tears, conjunctival cells
LSG
Annual f/u for 5yrs
500
1) Blood – serum, RNA, DNA
410
Introduction (III)
Korean Initiative of primary Sjogren’s Syndrome (KISS)
Objective:
1) Clinical data + Biospecimen
2) Develop Theragnosis (Therapy + Diagnosis)
• Clinical data
– Clinical manifestation
– Disease indices
• Biomarker and therapeutic target
– Saliva sample
– Blood sample
– Salivary gland sample
Methods – 1. Organization and funding source
•
Organization
– Sjogren’s Syndrome Research Center (SSRC) located in Seoul St.
Mary’s hospital in Seoul, Korea
•
Funding source
– SSRC is supported by the Korean Ministry of Health and Welfare
from June 2013 to May 2019
•
This study is registered in the Clinical Research Information Service of
South Korea (Board Approval Number KCT 0001099)
•
Collaborators
References
 Seoul St Mary’s Hospital,
 Konkuk University Medical
Center,
 Hanyang University
Hospital for Rheumatic
Diseases,
 Soonchunhyang University
Seoul hospital
 Chungnam
National
University
Hospital
 Keimyung
University
Dongsan
Center,
 Daegu Catholic
University
Medical Center
 Wonkwang
University
Hospital
 Gyeongsang
National
University
Hospital
 Chonnam National
University Hospital
 Jeju National
University
Hospital
Methods – 2. Data collection
•
Patient enrollment
– Patients with age 19 or more
– who fulfill either 2002 AECG classification criteria or 2012 ACR
classification criteria for primary Sjogren’s syndrome
– who provide informed consent on the registration and sampling
•
Follow up
– Annually
•
Data sets
– Relevant variables were selected.
– 1 coordinator who interviews patient, manages CRF, acquires
samples and enters data into web-based database
Variables (I)
•
Demographic data
: including education, marital status, socioeconomic status,
reproductive history
•
Classification criteria
: 2002 AECG / 2012 ACR classification criteria
•
•
•
Extraglandular manifestations
Disease activity index : ESSDAI
Disease damage index : SSDDI
•
Questionnaire
– Xerostomia Inventory: assessing oral symptom
– ESSPRI: assessing pSS specific symptom
– OSDI: assessing eye symptom
– EQ-5D: QoL
Variables (II)
•
Laboratory data
– CBC, BC, UA
– Autoantibody profile
– Chest
•
Autonomic dysfunction : Heart Rate Variability
•
Medication (past and current)
– DMARD, biologics, NSAID, antioxidant…
•
Eye exam
– Schirmer’s test, BUT, ocular staining score, Corneal damage
Methods – 3. Sample collection
•
Saliva
– Total Cell – RNA
– Total cell - DNA
– Supernatant
– Oral bacteria
•
Peripheral blood
– PBMC-RNA
– Whole blood-DNA
– Serum
– Plasma
•
Salivary gland
– RNA extraction for microarray or RNA sequencing
Varibles
Initial
Annual
follow up
Demographics
v
Fullfillment of classification criteria
v
Disease activity index - ESSDAI
v
v
Disease damage index - SSDDI
v
v
Patient reported outcomes – XI,ESSPRI, EQ5D,OSDI
v
v
Laboratory data
v
v
Autonomic dysfunction - Heart rate variability test
v
Past medications
v
Current medications
v
v
Eye exam
v
v
Sampling
Saliva
v
Blood
v
Salivary gland tissue (optional)
v
v
Results – 1. Enroll status (by Sep 5th 2014)
128 patients screened
2 withdrew consent
1 follow up loss
5 unmet classification criteria
101 patients enrolled
9 refused sampling
78 patients completed
blood and saliva
sampling
9 patients completed
only blood sampling
5 patients completed
only saliva sampling
Results – 2. Baseline characteristics
Table 1. Baseline Characteristics at enrollment
Demographic features
Gender (female)
Menopause
Age (yr)
BMI (kg/m2)
Smoking status: Non smoker
Clinical features
Disease duration (yrs)
Fulfillment of 2002 AECG criteria
Fulfillment of 2012 ACR criteria
Presence of extraglandular manifestation
Arthralgia/arthritis
Raynaud's phenomenon
Cutaneous involvement
Neurologic involvement
Schirmer test ≤ 5mm/5min
Unstimulated salivary flow rate (mL/min)
Autoantibodies
Anti Ro positivity
Anti La positivity
Rheumatoid factor positivity
ANA positivity (≥1:320)
Disease-specific indices
ESSPRI
ESSDAI
SSDDI
Patient reported outcomes
Xerostomia inventory
OSDI, score
Total
Number
Number (%),
mean ± SD (range)
99
93
99
95
95
99 (100%)
57 (61.3%)
52 ± 10.89 (26-73)
22.46 ± 2.71 (17.3-32.3)
93 (97.9%)
97
97
95
2.86 ± 3.67 (0-19.2)
95 (97.9%)
74 (77.9%)
87
87
87
87
85
81
48
15
12
7
71
0.034 ±
(47.5%)
(17.2%)
(13.8%)
(8.0%)
(83.5%)
0.061 (0-0.4)
96
96
95
94
84 (87.5%)
51 (53.1%)
66 (69.5%)
63 (67.0 %)
93
85
85
5.15 ± 1.71 (1.0-9.7)
4.20 ± 4.36 (0-20)
2.55 ± 1.01 (0-5)
97
80
35.6± 9.07 (14-55)
36.6 ± 23.97 (0-93)
Research plans
• Natural history of the disease
• Agreement of the 2002 AECG criteria and 2012 ACR criteria
• Clinical validities of disease activity indices in Korean patients
• Biomarker and therapeutic target

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