Conventional and biologic

therapy in spondyloarthritis-
can stop both inflammation
and new bone formation?

Chung-Tei Chou, M. D. (周昌德)

Professor of Medicine (Yang-ming University)
Division of Allergy-Immunology-Rheumatology,
Veterans General Hospital Taipei, Taiwan
Dear Donkey

Please go slowly
and we are friends.
Please not let me
falling down
because I am
already at the age
of osteoporosis
Spondylopathy
Pre-axial
Ankylosing
SpA
Spondylitis
Psoriatic
Juvenile Uveitis
Arthritis
SpA

Undifferentiated
Arthritis SpA
Sacroiliitis
associated
with Crohn’s
disease / UC
Reactive arthritis
Reiter syndrome

© Muhammad Asim Khan

The concept of Spondyloarthritis
Spondylarthropathies (SpA)

Sub‐group Clinical presentation

Ankylosing spondylitis Axial involvement

Psoriatic arthritis Peripheral articular involvement

Reactive arthritis Enthesopathy

IBD related arthritis Extra‐articular features

Undifferentiated SpA
Ankylosing ＆ Psoriatic spondylitis
• Acute inflammation
• Chronic inflammation
• Bone destruction
• Bone formation
• Syndesmophyte
• Ankylosis
General Features of SpA

Inflammatory back pain

Peripheral arthritis, usually asymmetric
Enthesitis
Dactylitis
– Less common than enthesitis
– More common in PsA
Uveitis
– Usually acute, anterior, unilateral, and recurrent
ACR2009
Psoriasis vulgaris ( plaque type )
 Prevalence of IBP… in back pain

IBP = Inflammatory back pain

MBP = Mechanical back pain

15%

85%

Rudwaleit M, et al. Ann Rheum Dis 2004;63:535‐43

 Prevalence of IBP in spondyloarthritis

Sub-group Prevalence of axial involvement Ref. #

Inflammatory bowel disease 5 to 12% 1

20 to 40% 1, 3
Psoriatic arthritis
up to 78% 3, 4

Ankylosing spondylitis 100% (?) 5

Spondyloarthritis (ESSG study) 75% 6

1. Moll JMH. Clin Rheum Dis 1985;11:87‐111

2. Gladman DD, et al. Q J Med 1987;238:127‐41
3. Veale D, et al. Br J Rheumatol 1994;33:133‐8
4. Richtlin CT. Rheumatology 4th, ed. 2008;1183‐8
5. Reveille J. Rheumatology, 4th ed. 2008:1109‐18
6. Dougados M, et al. Arthritis Rheum 1991;34:1218‐27
 Inflammatory back pain (IBP)
• Traditional definition • New proposal
At least four of the following At least two of the following
– Morning stiffness – Morning stiffness
lasting longer than 30
– Improvement with minutes
exercise – Improvement with
– Insidious onset exercise but not by
– Persistence for ≥ 3 rest
months – Awakening with pain
– Younger than 40 years in the 2nd half of the
night
at onset
Calin A. JAMA 1977;237:2613
– Alternating buttock
pain
Rudwaleit M, et al. Arthritis
Rheum 2006;54:569
Final set of classification criteria for axial SpA selected by the ASAS
Concept of pre-radiographic axial SpA

Sieper et al ATLAS

Pre- radiological stage Radiological stage

(axial undiff. SpA)

Mod.New
Mod. NewYork Criteria1984
YorkCriteria 1984

Back pain Back pain Back pain

Radiological
Sacroiliiits Syndesmophytes

Time (years)
 Paramount importance of synovial tissue
Macrophage

LL SL bone erosion
MQ MQ
IL1 TNFα >> IL1 TNFα
MMP MMP

Proinflammaroty cytokines
Degradiation of cartilage and
bone

15
higher expression of MMP-3 in AS
than OA in the synovial LL, and
more prominent CD68+ cells
observed in AS than OA in the
synovial SL.
These results suggest that MMP-3
and CD68 cells may play an
important role in the
pathogenesis of synovial
inflammation in AS.

16
 Axial SPA=+
 Non‐radiologic SPA + Low back pain with normal sacroiliac joint

 Radiologic SPA (AS) AS with hip arthritis and total hip replacement
 Clinical relevant biomarkers in AS
Brunn J. Nat Rev Rheumatol 2012:8:8‐10

(1) Inflammation
CRP, IL6, VEGF
(2) Bone & cartilage destruction
MMP3, Cathepsin K,
(3) New bone formation
Scleostin, DKK1, bone alkaline phosphate
Primary goal in management of AS
 Inflammation
 Structure change

 Mobility

 Function
Goals of Treatment in AS
 Symptomatic control  Disease control
 Reduce pain &  rapid and sustained
stiffness control of inflammation
 Improvement of spinal
mobility and function
 Prevention of
structural damage
 Prevention of disability
 Remission
 healing
 Conventional vs Biologics
 NSAIDs  Anti-TNF
 DMARDs  Infliximab

 SSZ  Etanercept

 MTX  Adalimumab

 Corticosteroids  Golimumab

 Immunosuppressives
 Radiation
 Bisphosphonates
 Thalidomide
COX1/COX1 COX1/COX2 COX2/COX2
 Volteran • Mobic • Celebrex
 Naproxan • Nimed • Arcroxia
 Sulindac • Lonin
 Indomethacin • Relifex
(Acemet)
 Surgem

 Ketoprofen
 26

*Amor B, et al. Rev Rheum Engl Ed 1995;62:10-5

**Van der Heijde, et al. Arthritis Rheum 2005;52:1205-15
29
 31

Infliximab (5mg/kg) 0, 2, 6 weeks

8pts, 3AS, 1USPA, 4PSA
Results: at week 12
↓ SLL hyperplasia
↓ CD 53+ Synoviocytes
↓ Vascularity
↓ VACM-1
↓ PMN, CD68 + M
↓ CD4 T cells
Baeten D, Arthritis Res 2001;44:186
 32

1. Abduntant synovial
expression of RANKL &
OPG in SPA
2. Decreased RANKL
expression in patients
with good response to
TNFαblockade
Romen‐Sanchez C et al, Clin Rheumatol 2008:27:1429
(1) 2 weeks after infliximab, the combination of ESR, CRP and
platelet count distinguish responders from non‐responder
(81.3% sensitivity vs 72.7% specificity)
(2) Serum IL1α
R vs NonR at week 6 (sensitivity 84.9%,
Specificity 53.8%)
 Monoclonal Antibodies
 Soluble TNF receptors
Normal Neutralization
interaction of cytokines
Inflammator Monoclonal
cytokine antibody
Cytokine
receptor Soluble receptor
Inflammatory
signal No signal

Company Confidential
Presentation Title
© 200X Abbott Date
Generic Infliximab Adalimumab Etanercept Certolizumab Golimumab
Name

Trade Name Remicade Humira Enbrel Cimzia Simponi

Dosing Q6W-8W Q2W BIW Q4W Q4W

Dose 3-5 mg/kg 40mg 25mg 400mg 50mg

Routes I.V S.C S.C S.C S.C

Company Centocor Abbott Wyeth UCB ( Euro) Centocor

Mab Chimera Human Humanized, Human

Fab, Peg.

FDA Approved Approved Approved Approved Approved

1998
Company Confidential
Presentation Title
© 200X Abbott Date
 36

 Etanercept ( Enbral 恩博）

作用快、皮下注射 2次/星期
 Adalimumab (Humira 復邁）
皮下注射 1 次/ 2星期
 Infliximab ( Remicade)
血管注射 1次/ 1-2個月
 Golimumab
皮下注射 1 次/ 1個月
 37

1) 作用快(2星期 ‐1個月)
2) 作用強
3) 可有效抑制骨關節磨損破壞及關節變形
4) 可減少關節破壞所需要之外科手術(包括人工
關節)
 Indication of biological agents in
spondyloarthropathy
Uncontrolled
• AS axial & peripheral arthritis
• Psoriasis
• PSA axial & peripheral arthritis
• Uveitis
• Enthesopathy, dactylitis
• Crohn’s disease
• Reactive arthritis
• USPA
 40

Antibodies to infliximab and adalimumab are

related to reduced clinical response in AS
Infliximab: Adalimumab:
Percentage of patients fulfilling ASAS-20 Percentage of patients fulfilling ASAS-20
response criteria at week 54 response criteria at week 24

100 100

ASAS 20 response (%)

ASAS 20 response (%)

P<0.001 p=0.012

50 50

0 0
No anti-infliximab Anti-infliximab No anti-adalimumab Anti-adalimumab
antibodies antibodies detected antibodies antibodies detected
ASAS: ankylosing spondylitis assessment scale
Adapted from de Vries MK et al. Ann Rheum Dis. 2007;66:1252–1254.
Adapted from de Vries, et al. Ann Rheum Dis. 2009;68:1787–1788.
ARTHRITIS & RHEUMATISM
Vol. 60, No. 4, April 2009, pp 946–954
DOI 10.1002/art.24408
© 2009, American College of Rheumatology
 PAIN (V)
 FUNCTION (V)
 SPINAL MOBILITY (V)
 Quality of life (V)
 ↓ESR, ↓CRP (V)
 Persistence (V)
 MRI (V)
 Syndesmophyte (?)
 ATLAS

ASAS20 ASAS40 ASAS 5/6 ASAS Partial Remission

100

80
Responders (%)

60

40

20

0
0 12 24 52 104 156
Weeks of adalimumab exposure
N= 310 298 282 261 234
Ns for ASAS 5/6 = 309, 297, 281, 260, and 232, respectively
Observed data
van der Heijde, et al. SAT0273
 Anti‐TNF‐α therapy in enthesitis

• Short‐term of randomized trail (12, 24 weeks)

showed significant improvement of AS with
enthsitis
• Open‐label Rhapsody trial showed 122 of 173
AS had resolution of plantar fasciitis after
adalimumab
 Anti‐TNF‐a therapy in uveitis

• All 3 TNF‐a inhibitors reduced the frequency

of uveitis flares
• Adalimumab=Infliximab> etanercept
 Clinical efficacy of etanercept
Multicentre, open‐labeled study of Etanercept in
the treatment of patients with ankylosing
spondylitis in Taiwanese
2006‐2007
16 centers, 23 sites, 46 AS patients
Etanercept 25mg Biw x 3 months
Efficacy: primary endpoint – ASAS 20
secondary endpoint – ASAS 50,
ASAS 70, BASFI, BASDAI, global
assessment
 Table Summary of ASAS response over time

(Respons Week2 Week4 Week8 Week12

e)
ASAS 20 71.7% 87.0% 87.0% 91.3%

ASAS 50 34.8% 58.7% 63.0% 71.7%

ASAS 70 13.0% 28.3% 37.0% 45.7%

Partial 13.0% 30.4% 41.7% 49.3%

Remission
Mod Rheumatol 2010 (accepted)
 Table Summary of the changes on major
outcome measure
Evaluation Outcome measures Baseline 12 weeks P-value

Patient global
73.72±16.50 24.17±23.72 <0.0001
assessment
ASAS Back pain 72.65±16.88 21.50±23.33 <0.0001
component
BASFI 57.80±24.87 20.45±21.40 <0.0001
Inflammation 67.34±22.53 22.07±21.57 <0.0001
Acute-phase CRP level (mg/dl) 2.82±3.21 0.51±2.65 <0.0001
reactant ESR (mm/hour) 35.73±23.13 7.76±7.95 <0.0001
Modified Schober test
2.11±2.76 2.58±3.42 0.0079
Spinal mobility (cm)
measure Chest expansion (cm) 2.77±1.69 3.56±1.82 0.0004
Occiput-to wall (cm) 6.59±7.14 5.32±6.65 0.0006
BASDAI 68.18±16.54 21.60±20.44 <0.0001
 Conclusion

• Better clinical response of anti‐TNFa therapy was

observed in Chinese than in Caucasian with AS

• The long‐term efficacy in Chinese is unknown

• Optimal dosage and relapse rate after stop of

anti‐TNFa agent in Chinese needs to be identified
僵直性脊椎炎病患使用Humira之人
數及時間
 Results Comparison of clinical and laboratory
data in AS patients before and after 12 weeks of
adalimumab treatment

Baseline First M 2nd M 3rd M P

BASDAI 8.08 ±0.92 4.61±0.75 3.85±0.60 3.10±0.52 <0.0001

BASFI 3.35±2.13 2.05±1.47 <0.0001

VAS 7.85±1.20 3.555±1.03 <0.0001

ESR 45.78±21.90 12.33±15.08 9.74±11.70 8.14±10.87 <0.0001

CRP 3.232±2.19 0.58±0.65 0.47±0.49 0.46±0.40 <0.0001

Do we need to treat ankylosing spondylitis patients with “
total spinal ankylosis” with TNF α blockers
 Effect of TNF blockers on new bone formation ‐‐
AS
• Although TNF blockade also strongly suppresses
signs and symptoms in SpA, clinical trials have thus
far failed to show any inhibitory effects on new bone
formation and ankylosis.

Etanercept

Infliximab

Adalimumab
Inefficacy, anti‐infliximab antibody in
SPA
1. After infliximab
29% detect antibody after one year injection‐ low responder
2. After adalimmumab
For AS, 31% had antibody after 6 M injection‐ low responder
For RA, 13% had antibody (related with MTX concomitantly
use)
3. After etanercept
No antibody detectable
By Irene van der Horst , Netherlands, 2011, IGAS meeting
 LORHEN: Drug survival in RA is better
with etanercept
1.0
Risk of continuing on therapy (%)

70 62.5 0.9
60 53.6
49.1
0.8

Survival
50
40
0.7
30
*
20 0.6
Etanercept
10 0.5 Adalimumab
0 Infliximab
ETN ADA INF 0.4
0 6 12 18 24 30 36
Survival at 3 years
Time
(months)
*p<0.027 vs. other treatment groups

Adapted from Marchesoni A, et al. Ann NY Acad Sci 2009;1173:837‐46 56

 RATIO: Risk of TB in RA + AS patients treated with
TNFi agents
Time from onset of last anti TNF treatment and first symptoms of tuberculosis
according to the last anti TNF received
70% Total
60%
Cumulative frequency of

50%
tuberculosis

40%
Infliximab
30%
Adalimumab
20%

10%
Etanercept
0%
0 6 12 18 24 30 36 42 48 54 60
Time from onset of last anti TNF treatment (months)
 The risk of TB is higher for patients receiving infliximab or adalimumab than those
receiving etanercept
Adapted from Tubach F, et al . Arthritis Rheum 2009;60:1884–1894
 如何選擇不同之生物製劑
• (1) 藥物之副作用
• (2) 藥物使用之方便性
• (3) 藥物維持之穩定性
• (4) 病患之前是否有感染病 (如 結核等)
 Approach to the AS patients who
fails a TNFα antagonist
(1) Back pain due to degenerative or
mechanical factors
‐‐ Spinal compression fractures
‐‐ Spondylolithiasis, disc herniation
‐‐ Spinal stenosis, myelopathy
(2) Back pain due to infection
(3) Back pain due to malignancy
(4) Back pain due to psychiatry or
fibromyalgia
Ritchlin CT, Best Practice & Research Clin Rheumatol 2010:24:683
Anti-TNFα for syndesmophyte
 New therapy in AS
• Anti IL17
• Anti IL6R
• Usterkinumab
• Abatacept
• Rituximab
• Anti‐BMP
• Anakinra
 Possible biologics in PsA
• Anti‐IL15 Curr Opin Pharmacol. 2004

• Rituximab Ann Rheum Dis. 2010;69(Suppl 3):116.

• Apremilast (oral phosphodiesterase‐4

inhibitor) Arthritis Rheum 2009;60(10):S471.

• Tocilizumab
• Janus kinase (JAK inhibitor)
• Denosumab (RANK ligand inhibitor)
 抗腫瘤壞死因子 風險管理
1) 感染 (結核或潛在結核)
結核菌皮下試驗(PPD) >5 or >10mm
γ干擾素(Quantiferon)
Positive intermediate
Negative
2) B型肝炎
B肝帶原，且HBV DNA 高 需治療
抗B肝核心體抗體(Anti‐HBC)陽性

64
 生物製劑何時退場
1) 進場容易，退場難
2) 目前無一定之規範
3) 逐漸減藥或注射時間拉長
4) 個人經驗
5) 國外之經驗，停藥後復發率仍高

65
 高價之生物製劑:
台灣未來是否有低價之生物製劑市場?
1) 大陸
國外進口，恩利(台灣恩博)$375/一次注射
國內生產，益塞普$64.5/一次
2) 台灣
國外，恩博$150/一次注射
國內，仍未上市(效果及安全性未知)
3) 韓國
三星

66
 結論
生物製劑治療之原則與優點
The early, the better 早鳥有蟲吃
One stone, 3 birds 一石三鳥(作用快，作用強，
作用久)

67
Captain
Chou

Was
almost
“dead” in
the
Dead Sea