강직성 척추염의 치료 경희대학교 의과대학 류마티스 내과 이상훈

Ankylosing spondylitis 1. Introduction Enteropathic Ankylosing spondylitis Undifferentiated SpA Psoriasis associated Urethritis or diarrhea associated 2

척추관절염 – spondyloarthritis 1. Introduction 척추관절염 – spondyloarthritis Spondyloarthritis-main manifestations 1. Axial involvement/spinal inflammation 2. Peripheral arthritis 3. Peripheral enthesitis Spondyloarthritis subtypes 1. Ankylosing spondylitis (AS) 2. Undifferentiated SpA 3. Reactive SpA 4. Psoriatic arthritis 5. SpA associated with chronic inflammatory bowel disease AS 3

TNF-alpha TGF-beta IL-1beta Soluble TNF receptor IL-6 IL-17 IFN-gamma 1. Introduction TNF-alpha IL-1beta IL-6 IL-17 IFN-gamma TGF-beta Soluble TNF receptor

1. Introduction

1. Introduction

1. Introduction

1. Introduction

Erosion  remodeling  bone formation 1. Introduction Erosion  remodeling  bone formation 9

History of Spondyloarthritis 1. Introduction History of Spondyloarthritis In 1957, “ rheumatoid spondylitis”  but RF (-) In 1961, Rome criteria In 1966, New York criteria In 1974, Moll et al introduced the concept of ‘seronegative spondyloarthropathy” In 1984, Modified New York criteria In 1990 Amor et al “European spondylarthropathy study group”

1. Introduction Part of a skeleton dating from 3500 BC, clearly showing bony bridging, but with minimal preservation of the sacroiliac joints. (With permission from Dastugue J. L'Anthropologie 1976; 80: 625–653.)

1. Introduction 2-3년 5-6년 10-15년

The goal of treatment - 염증의 조절 (골미란의 억제) - 강직의 억제 (석회화, 인대의 골경화 억제) 1. Introduction The goal of treatment - 염증의 조절 (골미란의 억제) - 강직의 억제 (석회화, 인대의 골경화 억제) - 항염증제 (nonsteroidal antiimflammatory drugs) - 종양괴사인자 차단제 (TNF-alpha blocker) 13

The management of ankylosing spondylitis 1. Introduction The management of ankylosing spondylitis Physiotherapy Medical Tx Surgical Tx Axial involv. Hip arthroplasty Corrective osteotomy of spine Increase of spinal mobility Pph involv. 14

1. Introduction 15

NSAIDs (non steroidal antiinflammatory drugs) - work rather well in patients with AS (70-80%) - good response to NSAIDs has even been identified as a diagnostic sign for spondyloarthritides - non-responsiveness to the NSAIDs might identify those with a poor prognosis ** continuous dosing with NSAIDs rather than the usual on-demand prescription decelerates radiographic progression over 2 years 16

Song et al, Arthritis Rheum, 2008, 58:929-938. 2. NSAIDS Song et al, Arthritis Rheum, 2008, 58:929-938. 17

Predictive factors for the longterm outcome of spondyloarthropathies 2. NSAIDS Predictive factors for the longterm outcome of spondyloarthropathies * 328 patients with spondyloarthropathy Hip arthritis – odds ratio 23 Sausage-like finger or toe – OR 8 Poor efficacy of NSAIDs – OR 7 High ESR (> 30 mm/h) – OR7 Limitation in range of motion of the lumbar spine – OR 7 Oligoarthritis – OR 4 Onset less than 16 years of age – OR 3 Amor, J Rheumatol, 1994, 21:1883-1887. 18

5% LR product 200 >90% Predominant axial SpA Chronic Low Back Pain 2. NSAIDS Chronic Low Back Pain 5% Inflammatory back pain LR 3.1 Heel pain (enthesitis) LR 3.4 Peripheral arthritis LR 4.0 dactylitis LR 4.5 Acute anterior uveitis LR 7.3 Pos.family history LR 6.4 LR product 200 Good response to NSAIDs LR 5.1 Elevated acute phase reactants LR 2.5 HLA B27 LR 9.0 MRI LR 9.0 X-rays sacroiliitis grade 3 LR 10.0 >90% Predominant axial SpA Amor, Rev Rhum Engl Ed, 1995, 62:10-15. 19

Inhibition of osteoblastic acitivity 2. NSAIDS Inhibition of osteoblastic acitivity * 40 patients with spondyloarthropathy, 1976 - retrospective study - 1) continuous phenylbutazone 2) intermittent 3) no medication  continuous phenylbutazone retarded of ossification of the lumbar vertebral column Boersma JW, Scand J Rheumatol, 1976, 5:60-64. 20

2. NSAIDS Zhang X, J Clin Invest, 2002, 109:1405-1415. 21

2. NSAIDS Zhang X, J Clin Invest, 2002, 109:1405-1415. 22

Retarding of radiographic progression 2. NSAIDS Retarding of radiographic progression - 215 AS patients - randomized, double-blind clinical trial - celebrex, ketoprophen, placebo - 2 years, prospective study Wanders A, Arthritis Rheum, 2005, 52:1776-1765. 23

Wanders A, Arthritis Rheum, 2005, 52:1776-1765. 2. NSAIDS Wanders A, Arthritis Rheum, 2005, 52:1776-1765. 24

Wanders A, Arthritis Rheum, 2005, 52:1776-1765. 2. NSAIDS 22% 45% Wanders A, Arthritis Rheum, 2005, 52:1776-1765. 26

Cardiovascular adverse effect? 2. NSAIDS Cardiovascular adverse effect? Cannon CP, Lancet, 2006, 368:675-684. 27

DMARDs - Sulfasalazine: !!? pph arthritis 에서 효과가 인정 - Methotraxate: !? HACA 억제 위해 infliximab 투여시 사용 인정 - Leflunomide: ?? pph arthritis 에서의 효과 미미, 데이터 부족 28

Multicenter, double-blind, placebo-controlled Study 3. DMARDS Sulfasalazine study SpA Pts : 619 264: AS 221: PsA 134: ReA Multicenter, double-blind, placebo-controlled Study Clegg DO, Arthritis Rheum, 1999, 42:2325-2329. 29

3. DMARDS Sulfasalazine study 5-aminosalicylate sulfapyridine 30

Taggart A, Arthritis Rheum, 1996, 39:1400-1405. 3. DMARDS Sulfasalazine study Taggart A, Arthritis Rheum, 1996, 39:1400-1405. 31

;; small dosage in MTX (7.5 mg or 10 mg / week) 3. DMARDS MTX study - meta-analysis - 116 Pts, 3 RCT  BASDAI, BASFI, HAQ-S, Physician and Patients global assessment ; no benefit ;; small dosage in MTX (7.5 mg or 10 mg / week) Chen J, Cochrane Databse Syst Rev, 2006, 118: CD004525. 32

Maksymowych WP, Arthritis Rheum, 2002, 46: 766-773. 3. DMARDS Pamidronate Maksymowych WP, Arthritis Rheum, 2002, 46: 766-773. Grover R, Ann Rheum Dis, 2006, 65: 688-689. 33

TNF-alpha blockers - effectiveness : best - inflammation control but bone formation? - flare of uveitis? - TB risk 34

4. TNF-alpha blockers TNF-alpha Francois RJ, Neure L, Sieper J, Braun J. Immunohistologic examination of open sacroiliac biopsies of patients with ankylosing spondylitis Ann Rheum Dis. 2005 Oct 25

Tumor necrosis factor-alpha (TNF-alpha) 4. TNF-alpha blockers Tumor necrosis factor-alpha (TNF-alpha) Identified in 1970s by Lloyd Old et al., as a serum factor that caused necrosis of some murine tumors In the 1980s, studies into the role of TNF-alpha intensified TNF alpha is a multifunctional pro-inflammatory mediator a) induction of further cytokine production b) activation or expression of adhesion molecules c) growth stimulation 36

Tumor necrosis factor-alpha (TNF-alpha) 4. TNF-alpha blockers Tumor necrosis factor-alpha (TNF-alpha) Two forms of TNF-alpha 1) membrane-bound: 26kDa 2) soluble TNF-alpha: 17kDa 37

4. TNF-alpha blockers TNF-alpha receptor TRAF2 Apoptosis TRADD NFkB Share structural similarity in extra-cellular domain Intracellular domain differences Different signaling pathway 38

Infliximab: a chimeric antibody (25% mouse derived, 75% human protein) 4. TNF-alpha blockers Infliximab: a chimeric antibody (25% mouse derived, 75% human protein) 75kd, 55kd

Development of fully humanized monoclonal antibody 4. TNF-alpha blockers Development of fully humanized monoclonal antibody 40

Mechanism of Action infliximab 4. TNF-alpha blockers Mechanism of Action infliximab Each molecule is able to bind to two molecules of TNF-alpha Forms a relatively stable complex Binds to soluble and membrane bound TNF Such cells lyse in vitro complement mediated, in vivo different mechanism No binding TNF-beta (lymphotoxin alpha) 41

4. TNF-alpha blockers 42

The History of Anti-TNF alpha blocker 4. TNF-alpha blockers The History of Anti-TNF alpha blocker 1994 : infliximab for RA, Lancet 1997: etanercept for RA, NEJM 1998: infliximab for Crohn’s disease 1998 : Enbrel was the first anti-TNF drug and was approved by the US. FDA 1999: 54-week results on infliximab at EULAR. Lancet 1999: Remicade was the second TNF inhibitor to be approved by the US. FDA 2000: infliximab, open label, monocentre study, 3 loading infusion for AS 2001: etanercept for AS, Arthritis &Rheumatism 2002: Humira was approved

Mechanism of Action Etanercept 4. TNF-alpha blockers Mechanism of Action Etanercept Binds with TNF alpha and beta Binding is reversible Dissociated TNF remains bioactive 44

4. TNF-alpha blockers TNF-a is expressed on the cell membrane and then hydrolyzed to release the soluble form, which forms homotrimers. TNF-b (LT-a) has no cell membrane attachment domain but can form either membrane-anchored heterotrimers with LT-b or soluble homotrimers. Receptor binding specificities are indicated.

4. TNF-alpha blockers

Prevent radiologic progression by TNF-alpha blocker 4. TNF-alpha blockers Prevent radiologic progression by TNF-alpha blocker Van der Heijde D, Arthritis Rheum, 2008, 58: 1324-1331. 47

Van der Heijde D, Arthritis Rheum, 2008, 58: 1324-1331. 4. TNF-alpha blockers 70% Van der Heijde D, Arthritis Rheum, 2008, 58: 1324-1331. 48

Adverse Events Reporting System (AERS) database of FDA 4. TNF-alpha blockers TB risk? Adverse Events Reporting System (AERS) database of FDA 1998~2003 IFM: 248 cases ETN: 39 cases Wallis RS, Arthritis Rheum, 2008, 58: 947-952. 49

Wallis RS, Arthritis Rheum, 2008, 58: 947-952. 4. TNF-alpha blockers TB risk? Wallis RS, Arthritis Rheum, 2008, 58: 947-952. 50

Registry-Based Study; - prior to January 1, 2006, databases 4. TNF-alpha blockers Uveitis ? Registry-Based Study; - prior to January 1, 2006, databases - 43 cases a/w etanercept, 14 a/w infliximab, 2 a/w adalimumab - etanercept >> infliximab (p < 0.001) or adalimumab (p < 0.01) - underlying disease ; exclude  etanercept: 20 cases, infliximab: 4, adalimumab: 2 cases - etanercept >> infliximab (p < 0.001) Lim LL, Arthritis Rheum, 2007, 56: 3248-3252. 51

Lim LL, Arthritis Rheum, 2007, 56: 3248-3252. 4. TNF-alpha blockers Uveitis ? Lim LL, Arthritis Rheum, 2007, 56: 3248-3252. 52

Braun J, Arthritis Rheum, 2005, 52: 2447-2451. 4. TNF-alpha blockers Uveitis ? Braun J, Arthritis Rheum, 2005, 52: 2447-2451. 53

? Ankylosing spondylitis Rheumatoid arthritis Functional loss 5. Conclusion Ankylosing spondylitis Rheumatoid arthritis Functional loss Functional loss TNF-alpha blockers NSAIDS ? inflammation Bone formation inflammation Bone destruction 54

경청해 주셔서 감사합니다. 55