1. 강직성 척추염의 치료
경희대학교 의과대학
류마티스 내과 이상훈

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

3. 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

4. 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

5. 1. Introduction

6. 1. Introduction

7. 1. Introduction

8. 1. Introduction

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

10. 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”

11. 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.)

12. 1. Introduction
2-3년
5-6년
10-15년

13. 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

14. 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

15. 1. Introduction 15

16. 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

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

18. 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: 18

19. 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 B LR 9.0
MRI LR 9.0
X-rays sacroiliitis grade LR 10.0
>90%
Predominant axial SpA
Amor, Rev Rhum Engl Ed, 1995, 62:10-15. 19

20. 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

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

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

23. 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: 23

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

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

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

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

29. 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: 29

30. 3. DMARDS
Sulfasalazine study
5-aminosalicylate
sulfapyridine 30

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

32. ;; 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: CD 32

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

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

35. 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 Oct 25

36. 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

37. 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

38. 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

39. 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

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

41. 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

42. 4. TNF-alpha blockers 42

43. 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

44. 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

45. 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.

46. 4. TNF-alpha blockers

47. 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: 47

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

49. 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: 49

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

51. 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: 51

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

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

54. ? 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

55. 경청해 주셔서 감사합니다. 55