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

곽 승 기

류마티스내과가 하는 일은?

자가면역질환 과 근골격계 질환의 진료 및 연구

자가면역질환(autoimmune disease)이란?

Autoantibody 혹은 autoreactive T cell 을 증명할 수 있는 질환

류마티스내과 영역의 자가면역질환

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류마티스관절염 (Rheumatoid Arthritis, RA)

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전신홍반루푸스 (Systemic Lupus Erythematosus, SLE)

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쇼그렌 증후군

Why Sjogren’s Syndrome Research?

Unmet need of Sjogren’s syndrome

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진단기준이 정립되어 있지 않다 .

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질병활성도 평가방법 부재

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치료법 부재 (FDA 승인 받은 약제로 pilocarpine 이 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 박 성 환 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, 9 th Edition 2013

Two models for the pathogenesis of SS

Immune Destructive Vs Immune Inhibited

Kelley’s Textbook of Rheumatology, 9 th Edition 2013

Clinical manifestation

Prevalence at diagnosis (%) Prevalence at 10-year-follow-up (%) Glandular disease

Xerostomia Dry eyes Parotid gland enlargement

Extraglandular disease

Arthralgias/arthritis Raynaud’s phenomenon Pulmonary involvement Interstitial nephritis Glomerulonephritis Liver involvement Peripheral neuropathy Myositis Central nervous system disease Lymphoma 90 95 49 1 1 0 2 70 41 23 7 0.4

4 92 95 53 2 1 0 4 75 48 29 9 2 4

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 Only objective measures!

2 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 연구센터

왜

필요한가?!

연구배경 현 진단 기준의 국내 적합성 미확립 : 미국/유럽 류마티스 학회에서 제시한 classification criteria에 준하여 진단 2012 개정 국제 분류 기 준 미국 류마티스 학 회 분류 기준

1) 정확한 기준이 모호한 상태

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질병 활성도를 반영하는 정확한 진단 마커 필요

1984 Janpnese I 1986 Greek 1986 California 1993 EU I 1996 EU II 1997 Japanese II 1999 Japanese III

국내 쇼그렌 증후군 연구센터

왜

필요한가?!

연구배경 명확한 원인,병리기전이 밝혀지지 않음  병인 표적 치료제 부재 대증요법으로 치료 병인을 근본적으로 조 절할 수 있는 치료법 필 요함 질병활성도 평가기준 미흡

Sjogren’s syndrome Research

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Basic research

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Translational research

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Clinical research

연구를 위하여 무엇이 필요할까?

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표적장기의 조직 혹은 cell line – salivary gland tissue

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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 Th17 cell Regulatory T cells 1986 Th1/Th2

J Immunol

. 1986;136:2348-57

J Immunol

. 1986;136:2348-57

Nat Immunol

. 2005;6:1123-32

Nat Immunol

. 2005;6:1133-41

Th1/Th2 paradigm period

RA is Th17 mediated disease

2011 2005 2003 Th17 cell Regulatory T cells

RA seemed to be Th1 mediated disease

1986 Th1/Th2 concept

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

, 5 th 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

Objective Institutes Subject Follow up No. participa nts Sampling SICCA (2004- enrollment closed)

1) 2) Clinical data and biospecimens Develop standardized classification criteria 6 international research group Suspicious / diagnosed SS patients 2years from enrollment Only patients with objective(+)

UKPSSR (2009-2012)

For high quality clinical research 32 hospitals in UK pSS patients fulfilling AECG criteria 2594 500 1) Blood – serum, RNA, DNA 1) 2) 3) 4) Blood- serum, plasma, DNA, PBMC Saliva – whole, parotid Tears, conjunctival cells LSG 410

ASSESS (2006-2009)

To identify predictors of systemic complications and lymphoma in pSS 15 centers in France pSS patients fulfilling AECG criteria Annual f/u for 5yrs

Introduction (III)

Korean Initiative of primary Sjogren’s Syndrome (KISS ) Objective: 1) Clinical data + Biospecimen 2) Develop Theragnosis (Therapy + Diagnosis)

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Clinical data

– Clinical manifestation – Disease indices •

Biomarker and therapeutic target

– Saliva sample – Blood sample – Salivary gland sample

Methods

– 1. Organization and funding source

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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  Wonkwang University Hospital  Chonnam National University Hospital  Jeju National University Hospital  Chungnam National University Hospital   Keimyung University Dongsan Center , Daegu Catholic University Medical Center  Gyeongsang National University Hospital

Methods

– 2. Data collection

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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)

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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)

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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

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Saliva

– Total Cell – RNA – Total cell - DNA – Supernatant – Oral bacteria •

Peripheral blood

– PBMC-RNA – Whole blood-DNA – Serum – Plasma •

Sal ivary gland

– RNA extraction for microarray or RNA sequencing

Varibles Demographics Fullfillment of classification criteria Disease activity index - ESSDAI Disease damage index - SSDDI Patient reported outcomes – XI,ESSPRI, EQ5D,OSDI Laboratory data Autonomic dysfunction - Heart rate variability test Past medications Current medications Eye exam Sampling

Saliva Blood Salivary gland tissue (optional)

Initial

v v v v v v v v v v

Annual follow up

v v v v v v v v v v

Results

– 1. Enroll status (by Sep 5 th 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 Total Number Number (%), mean ± SD (range) 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 97 97 95 87 87 87 87 85 81 99 93 99 95 95 96 96 95 94 93 85 85 97 80 99 (100%) 57 (61.3%) 52 ± 10.89 (26-73) 22.46 ± 2.71 (17.3-32.3) 93 (97.9%) 2.86 ± 3.67 (0-19.2) 95 (97.9%) 74 (77.9%) 48 (47.5%) 15 (17.2%) 12 (13.8%) 7 (8.0%) 71 (83.5%) 0.034 ± 0.061 (0-0.4) 84 (87.5%) 51 (53.1%) 66 (69.5%) 63 (67.0 %) 5.15 ± 1.71 (1.0-9.7) 4.20 ± 4.36 (0-20) 2.55 ± 1.01 (0-5) 35.6± 9.07 (14-55) 36.6 ± 23.97 (0-93)

Research plans

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Natural history of the disease

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Agreement of the 2002 AECG criteria and 2012 ACR criteria

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Clinical validities of disease activity indices in Korean patients

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Biomarker and therapeutic target