Axial sp a and its management

Spondyloarthritis (SpA)
3
Autoinflammatory disease entities with
overlapping clinical features:
Sacroiliiatis, spondylitis, peripheral
arthritis, enthesitis, dactylitis and uveitis
may be present
Associated with human leukocyte
antigen (HLA)-B27
Seronegative (absence of rheumatoid
factor)
All SpA subsets may evolve into ankylosing
spondylitis (AS)/radiographic SpA (r-SpA),
especially in HLA-B27 positive patients
5
Sieper J, Braun J. Clinician’s Manual on Axial Spondyloarthritis: Springer Healthcare Ltd.; 2014.

Good response to NSAIDs
Symptoms
Imaging
Lab
Patient‘s history
Inflammatory
back pain
ESR/CRP
Spondyloarthritis:
Characteristic Parameters Used for Diagnosis-I
4

Genetics
Predisposing/concomitant diseases
Infection* psoriasis Uveitis
*positive staining for Chlamydia in synovial membrane1
Spondyloarthritis-Characteristic
Parameters Used for Diagnosis II
1. Schumacher HR et al. Arthritis Rheum 1988; 31:937-46
Spondyloarthritis:
Characteristic Parameters Used for Diagnosis-II
HLA-B27
positive
family
history
Crohn‘s
5

Prevalence of SpA Equals That of Rheumatoid
Arthritis (RA) Across Most of the World
1. Sieper J, Braun J. Clinician’s Manual on Axial Spondyloarthritis: Springer Healthcare Ltd.; 2014.
2. Akkoc N. Curr Rheumatol Rep. 2008;10(5):371-378.
3. Dean LE, et al. Rheumatology (Oxford). 2014;53(4):650-657.
7
Worldwide, the prevalence of r-SpA (AS) is
about 0.1% to 1,4% and is higher in
northern countries1
SpA is at least as common as RA in most of
Europe2
In the US, the prevalence of r-SpA (AS) is
about 0.13%3
AmongAsian populations,China has the
highest prevalence of SpA which is more
common than RA2
In contrast, RA is more prevalent than SpA
in most of the rest of Asia, the Pacific
Region, and LatinAmerica2
Both rheumatic disorders are rare in Africa2
Prevalence of SpA and RA
Prevalence (%)
Country
12

SpA May Be Classified as Predominantly
Axial or Predominantly Peripheral
8
Spondyloarthritis
(SpA)
Axial Spndyloarthritis
(axSpA)
Non-radiographic
spondyloarthritis
(nr-axSpA)
Ankylosing
Spondylitis
(AS/r-SpA)
Radiographic stageNon-radiographic stage
Peripheral Spndyloarthritis
(pSpA)
Psoriatic
Arthritis
(PsA)
Reactive
Arthritis
Arthritis
with IBD
Undifferen
tiated SpA
Juvenile onset
spondyloarthritis

Inflammation in RA drives disabilitySeverity
0
Duration of Disease (Years)
5 10 15 20 25 30
Early Intermediate Late
© ACR
Kirwan JR. J Rheumatol. 2001;28:881-886; Scott DL. Rheumatology (Oxford). 2000;39:24-29.
Inflammation
Disability
Radiographs

No treatment
Paradigm shifts in the treatment of
rheumatoid arthritis
Smolen JS, et al. Arthritis Res Ther. 2008;10:208.
Recognition that:
• Destruction increases with time
• DMARD therapy retards damage
• Early DMARD start prevents accrual of
damage
• DMARD start before the occurrence of
destruction prevents damage
First
symptoms
Start of x-ray
changes
First visit to
rheumatologist
Time
Progression
Start of disease-modifying anti-rheumatic drug (DMARD) therapy
Late treatment start
‘Early’ treatment start
Ideal situation

Onset
Recognition that
• Damage increases with time
• Damage starts before diagnosis
• Biologic therapy may not retard damage
• Physical and social function decline
from the earliest phase
Paradigm shifts in the treatment of
axial spondyloarthritis
PhysicaldamageSocialdamage
Function
Social function
Ankylosis
Symptoms
Diagnosis Treatment

Spectrum of Axial SpA
1. Sieper J, van der Heijde D. Arthritis Rheum. 2013;65(3):543-551.
2. Sieper J, et al. Nature Reviews Disease Primers. 2015:15013.
12
 Initially, there is inflammation that is not detectable on X-ray but may be detectable on MRI (non-
radiographic[nr]-axSpA).1,2
 Later many patients develop structural changes that can be seen on X-ray (r-axSpA /AS).1,2
 Some patients also develop changes in the spine.1,2
 Of patients with axSpA, about 20% to 80% have nr-axSpA.The percentage of nr-axSpA decreases with
symptom duration.2

Progression of non-radiographic axial
spondyloarthritis to ankylosing spondylitis
– back pain duration
n=228
AS, ankylosing spondylitis; nr-axSpA, non-radiographic axial spondyloarthritis.Adapted from Poddubnyy D, et al. Ann Rheum Dis 2012;71:1998–2001.
32.7
47.5 46.3
61.1
68.0 71.4
67.3
52.5 53.7
38.9
32.0 28.6
0
10
20
30
40
50
60
70
80
90
100
Up to 1
year
(n=55)
>1–≤3
years
(n=40)
>3–≤6
years
(n=41)
>6–≤9
years
(n=18)
>9–≤12
years
(n=25)
>12 years
(n=49)
Patients(%)
nr-axSpA
AS

Burden of disease in pre-radiographic
axial SpA and established AS is similar
1.Rudwaleit, M et al. Arthritis Rheum 2004; 50:S211. Data from German Spondyloarthritis inception cohort = GESPIC
Rudwaleit et al. submitted
6
0
1
2
3
4
5
BASDAI Pain BASFI BASMI
AS 5-10 yr (n=117)
AS <5 yr (n=119)
Axial uSpA <5 yr (n=226)

Prospective data on patients diagnosed with AS
Delay in diagnosis is associated with
worse outcomes…
Aggarwal R and Malaviya AN. Clin Rheumatol 2009:28;327–331.
N=70; early diagnosis: ≤5.9 years delay; late diagnosis: >5.9 years delay.
Clinical feature Early diagnosis Late diagnosis p value
BASDAI 2.7 (S.D 1.7) 3.7 (S.D 1.8) 0.035
BASFI 2.5 (S.D 2.1) 3.8 (S.D 2.4) 0.033
BASMI 1.5 (S.D 2.2) 3.3 (S.D 2.7) 0.012
Age at first symptom 29.8 years (S.D9.3) 35.0 years(S.D 9.5) 0.030
Male 32/35 27/35 N.S

Khan MA. Ann Rheum Dis. 2002;61(suppl III):iii3-iii7.
0
20
40
60
80
100
0 10 20 30 40 50 60
CumulativePercentages
Age (y)
Males: complaints started Females: complaints started
Males: diagnosis made Females: diagnosis made
Symptom – diagnosis delay in AS

Axial SpA Epidemiology
Sieper J, Braun J. Clinician’s Manual on Axial Spondyloarthritis: Springer Healthcare Ltd.; 2014. 17
Symptoms of axSpA usually begin in the third decade of life
r-SpA (AS) is approximately twice as common in men than in women.
nr-axSpA, however, is more common in women than in men.

Inflammatory Back Pain Is the Central
Manifestation of Axial SpA
Pain and/or stiffness of the back, predominantly lower back and pelvis
Defined clinically and not by laboratory parameters
−Chronic back pain (>3 months duration) starting at an age <45 years
−Morning stiffness of the back >30 min
−Awakening in the second half of the night because of back pain
−Improvement of pain and stiffness by exercise but not by rest
8

Inflammatory Back Pain According to Various
Criteria
Calin et al.1 Rudwaleit et al.2 IBP Experts (ASAS)3
• Age of onset <40 years
• Insidious onset of pain
• Duration >3 months
• Association with
morning stiffness
• Improvement
with exercise
• Morning stiffness
>30 minutes
• Improvement in back
pain with exercise but
not with rest
• Awakening with back
pain during the second
half of the night
• Alternating buttock
pain
• Age of onset <40 years
• Insidious onset of pain
• Improvement
with exercise
• No improvement
with rest
• Pain at night (with
improvement upon
getting up)
IBP if 4 out of 5 are present IBP if 2 out of 4 are present IBP if 4 out of 5 are present
ASAS, Assessment of SpondyloArthritis International Society;
IBP, inflammatory back pain.
1. Calin A, et al. JAMA 1977;237:2613–2614.
2. Rudwaleit M, et al. Arthritis Rheum 2006;54:569–568.
3. Sieper J, et al. Ann Rheum Dis 2009;68:784–788.

ASAS Classification Criteria for Axial
Spondyloarthritis (AS)
Sensitivity: 79.5%, Specificity: 83.3%; n=975.
ASAS, Assessment of SpondyloArthritis
International Society; CRP, C reactive protein;
HLA, human leukocyte antigen; NSAIDs, non-steroidal
anti-inflammatory drugs; SpA, spondyloarthritis.
Adapted from Rudwaleit M, et al. Ann Rheum Dis 2011;70:25–30.
SpA Features
• Inflammatory back pain
• Arthritis
• Enthesitis (heel)
• Uveitis
• Dactylitis
• Psoriasis
• Crohn’s/ulcerative colitis
• Good response to NSAIDs
• Family history for SpA
• HLA-B27
• Elevated CRP

In patients with peripheral symptoms ONLY
Arthritis or enthesitis or dactylitis plus
OR
≥1 SpA feature
• Uveitis
• Psoriasis
• Crohn’s disease/ulcerative colitis
• Preceding infection
• HLA-B27
• Sacroiliitis on imaging
≥2 other SpA features
• Arthritis
• Enthesitis
• Dactylitis
• IBP ever
• Family history for SpA
ASAS Classification Criteria for Peripheral
Spondyloarthritis
Sensitivity: 79.5%, Specificity: 83.3%; n=975.
ASAS, Assessment of SpondyloArthritis International Society;
CRP, C reactive protein; HLA, human leukocyte antigen; IBP, inflammatory back pain; SpA, spondyloarthritis.
Adapted from Rudwaleit M, et al. Ann Rheum Dis 2011;70:25–30.

Clinical Utility of the Clinical Parameters of SpA
Rudwaleit M, van der Heijde D, Khan MA, Braun J, Sieper J. Ann
Rheum Dis 2004;63:535-543
Sensitivity Specificity +LR
Inflammatory back pain (updated information) 80% 72% 2.9
Enthesitis (heel pain) 37 % 89% 3.4
Peripheral arthritis 40 90 4.0
Dactylitis 18 96 4.5
Acute anterior uveitis 22 97 7.3
Positive family history for AS, AAU, IBD, ReA 32 95 6.4
Psoriasis 10 96 2.5
Inflammatory bowel disease 4 99 4.0
Good response to NSAIDs 77 85 5.1
acute phase reactants 50 80 2.5
HLA-B27 (updated information) Variable Variable 11
MRI (STIR) sacroiliitis (updated information) Variable Variable 11

Role of HLA B27
Dougados et al Lancet 2011; 377: 2127–37

Role of HLA B27 & Genetics of SpA
 In >90% of cases of r-SpA (AS) the
susceptibility is genetically determined
 Strongest link is with HLA-B27
 90–95% of pa tients with ankylosing
spondylitis are positive for HLA B27
 The risk of this disease developing is as
high as about 5% in HLA B27-positive
individuals
 The risk is substantially higher in HLA B27-
positive relatives of patients
 However, most HLA B27-positive
individuals remain healthy.
 Other genetic determinant include:
− The interleukin (IL)-23 receptor involved in the
T-helper cell 17 (Th-17) pathway
− Endoplasmic reticulum aminopeptidase-1
(ERAP-1) involved in peptide processing and
potentially linked with HLA-B27 in the process
of antigen presentation
92.5
85
60
50
0
10
20
30
40
50
60
70
80
90
100
Percent HLA-B27+
IBD = Inflammatory bowel disease
r-SpA/
(AS)
nr-axSpA r-SpA (AS)
with psoriasis
or IBD
Peripheral
SpAPrevalenceofHLA-B27(%)

2
3
1 4
The Hypothesized Roles of HLA-B27 in Axial SpA
Sieper J, et al. Nature Reviews Disease Primers. 2015:15013. 25
Four proposed mechanisms:
1. Presentation of autoantigens
by HLA-B27 that activates
autoreactive cytotoxicT cells
2. Formation of HLA-B27
homodimers that can activate
natural killer cells and T cells
3. Misfolding of HLA-B27 results
in intracellular stress and
production of
proinflammatory cytokines
such as IL-23
4. HLA-B27 may affect the
microbiome in the intestinal
tract which in turn may
modulate acquired immunity

Pathogenesis
26
The interaction of HLA-B27 with
different forms of stress
(mechanical, intracellular, or
microbial) triggers an
autoinflammatory immune
response1,2
This results in production of
proinflammatory cytokines
including tumour necrosis factor
(TNF), interleukin (IL)-23, and IL-17
and activation of various leukocytes1
The primary target is the
bone/cartilage interface2
Osteoclasts (green arrows) infiltrate at the bone–
cartilage interface in patient with r-SpA (AS)
15

The Sequence of Structural Damage in axSpA
27
In addition to inflammation, axSpA is
also characterized by abnormal bone
formation1
May occur in the following sequence1
−First, inflammation causes osteitis
−Next, the damaged area is filled with
(fibrous) repair tissue
−Finally, the repair tissue is ossified resulting
in abnormal bone formation
The exact link between inflammation
and bone formation is unclear2
1 2 3
16

Burden of Disease and Progression
of Axial SpA
17

Burden of Disease:
The Impact of Axial SpA on Quality of Life
2. Chorus AM, et al. Ann Rheum Dis. 2003.
3. Kotsis K, et al. Expert Rev Pharmacoecon Outcomes Res. 2014;14(6):857-872.
29
Quality of life refers to the impact of a disease on a patient’s daily life and
includes physical, social, psychological, and occupational well-being.1
The quality of life of patients with axSpA is worse than that of the general
population.1
Overall, the impact of axSpA on the quality of life is similar to that of
rheumatoid arthritis.1,2
Pain, stiffness, and fatigue can greatly limit daily activities, ability to work,
and social interactions of patients with axSpA.1,2 In particular, the impact
on working ability can be substantial.3
Disease activity is the strongest predictor of quality of life.3

Characteristics and Impact of Early Axial SpA:
The DESIR Cohort
30
* Either definite SIJ damage on pelvic x-ray examination according to the modified New York criteria8 or inflammatory lesion on MRI as defined in the Methods section.
† Presence of both structural damageof the SIJs on pelvic x-ray analysis and MRI inflammatory changes in the SIJs.
‡ Presence of structural damage of the SIJs on pelvic x-ray analysis without MRI inflammatory changes.
§ Presence of MRI inflammatory changes in the SIJs without structural damage on pelvic x-ray analysis.
¶Presence of HLA-B27 plus two clinical features of SpA.
ASAS, Assessment of Spondyloarthritis International Society; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing SpondylitisFunction Index; BASMI,
Bath Ankylosing SpondylitisMetrology Index; CRP, C-reactive protein; SF36, Short Form 36 Health Survey Questionnaire; SIJ, sacroiliac joint; SpA, spondyloarthritis.
ASAS Criteria for axSpA*
Imaging Clinical¶
X-ray+/MRI+
(r-SpA /AS)†
X-ray+/MRI-
(r-SpA/AS)‡
X-ray-/MRI+
(nr-axSpA)§
X-ray-/MRI-
CRP > 6mg/L
X-ray-/MRI-
CRP ≤ 6mg/L
Number 126 47 89 32 138
Age (years) 29 31 32 31 33
Disease duration (Months) 19 19 18 17 19
Female (%) 36 47 44 66 56
HLA-B27 Positive (%) 80 62 71 100 100
BASDAI 40 41 43 57 42
CRP (mg/L) 11 16 10 16 2.7
BASFI 27 32 29 45 26
BASMI 2.5 2.5 2.2 2.4 2.1
Mental SF36 41 42 41 40 40
Physical SF36 42 40 40 34 41
Molto A, et al. Ann Rheum Dis. 2015;74(4):746-751.

Characteristics and Impact of nr-axSpA and r-SpA
(AS): The GESPIC and Herne Cohorts
German Spondyloarthritis Inception Cohort GESPIC1 Herne-Cohort2
nr-axSpA
≤ 5 years
r-SpA (AS)
≤ 5 years
All r-SpA (AS) nr-axSpA r-SpA (AS)
N=226 N=119 N=236 N=44 N=56
Age (years) 36.1 36.1 35.6 39.1 41.2
HLA-B27+ (%) 74.7 73.1 82.2 86.4 89.1
Female (%) 57.1‡ 34.5 36.0 68.2* 23.2
BASDAI (0–10) 3.9 4.0 4.0 3.6 4.3
Total pain (0–10) 4.8 4.8 5.0 4.0 5.0
BASFI (0–10) 2.5‡ 3.1 3.1 1.5 2.9
Patients global (0–10) 4.9 5.0 5.0 4.0 4.6
AbnormalCRP (%) 29.8†‡ 49.6† 51.9† 29.5#* 69.1#
2031
‡p<0.05 vs r-SpA (AS) ≤ 5 years; *p<0.05 vs r-SpA (AS)
†AbnormalCRP defined as >6 mg/litre
#AbnormalCRP defined as ≥5 mg/litre
r-SpA, radiographic SpA; AS, ankylosing spondylitis; BASDAI, Bath ankylosing spondylitis disease activity index; BASFI,
Bath ankylosing spondylitis functional index; nr-axSpA, non-radiographic axial spondyloarthritis.
1. Rudwaleit M, et al. Arthritis Rheum. 2009;60(3):717-727.
2. Kiltz U, et al. Arthritis Care Res (Hoboken). 2012;64(9):1415-1422.

Burden of Disease in nr-axSpA and in r-SpA (AS)
Rudwaleit M, et al. Arthritis Rheum. 2009;60(3):717-727. 32
Function (BASFI) and spinal mobility (BASMI) were significantly better in
patients with nr-axSpA than in patients with r-SpA (AS)
In contrast, general pain, pain at night, and fatigue were equally high in
patients with nr-axSpA and those with r-SpA (AS)
3.9
5.1
3.1
2
4
4.8
3.1
1.9
3.9
4.8
2.5
1.1
0
1
2
3
4
5
6
BASDAI Pain BASFI BASMI
Score
r-SpA (AS) >5 years (n=117)
r-SpA (AS) 5 years (n=119)
Patients with nr-axSpA 5 years (n=226)
Clinical scores in relation to disease duration
21
r-SpA, radiographicSpA; AS, ankylosing spondylitis; BASDAI,BathAnkylosing Spondylitis Disease Activity
Index; BASFI, Bath Ankylosing Spondylitis Functional Index; BASMI, Bath Ankylosing Spondylitis Metrology
Index; nr-axSpA, non-radiographic axial spondyloarthritis.

22
Natural History of Axial SpA
33Dougados, M. Personal communication..

23
Clinical
Features of Spa
34FDA Arthritis Advisory Committee Meeting. Regulatory considerations for the potential novel indication axial spondyloarthritis. 2013.

24
Clinical
Features of Spa
Sacroiliitis on
Imaging

25
Clinical
Features of Spa
Radiographic
Sacroiliitis
MRI Sacroiliitis

26
Clinical
Features of Spa
PROGRESSION
RESOLUTION
RESOLUTION
STABILITY
Radiographic
Sacroiliitis
MRI Sacroiliitis

After 2 years about 12% of patients with nr-axSpA progressed to r-SpA (AS)
In addition, a small proportion (< 3%) of patients with r-SpA (AS) regressed,
with radiographic sacroiliitis no longer detectable after 2 years
Progression of Axial SpA: The GESPIC Cohort
Poddubnyy D, et al. Ann Rheum Dis. 2011;70(8):1369-1374. 38
Radiographic
sacroiliitisat2years
Baseline Radiographic Sacroiliitis
Yes No
Yes 112 11 (11.6%)
No 3 (< 3%) 84
27

Predictors of Radiographic Progression
2. Poddubnyy D, et al. Ann Rheum Dis. 2011;70(8):1369-1374.
39
Male sex
Smoking
Syndesmophytes at first presentation
High degree of sacroiliitis on MRI
High levels of C-reactive protein (>6mg/L)
Manual work
28

41
Diagnosing Axial SpA: A Historic Perspective
BC 1900 1930s 1990s1984 2009
Modified
NY criteria
X-Ray Imaging MRI
Clinical
1. Feldtkeller E, et al. Rheumatol Int. 2003;23(1):1-5.
3. van der Linden S, Valkenburg HA, Cats A. Arthritis Rheum. 1984;27(4):361-368.
4. Rudwaleit M, et al. Ann Rheum Dis. 2009;68(6):777-783.

42
New ASAS Classification Criteria for Axial SpA
In patients with ≥ 3 months back pain and age at onset < 45 years
Sacroiliitis on imaging*
+
≥ 1 SpA feature
HLA-B27
+
≥ 2 other SpA features
SpA features:
 Inflammatory back pain (IBP)
 Arthritis
 Enthesitis (heel)
 Uveitis
 Dactylitis
 Psoriasis
 Crohn’s/colitis
 Good response to NSAIDs
 Family history for SpA
 HLA-B27
 ElevatedCRP
*Sacroillitis on imaging
 Active (acute) inflammation on MRI
highly suggestive of sacroiliitis
associated with SpA
 Definite radiographic sacroiliitis
according to the modified NewYork
criteria
These criteria were used in 649 patients with back pain
 Overall: Sensitivity 82.9%, Specificity 84.4%
 Imaging criteria only: Sensitivity 66.2%, Specificity 97.3%
 Clinical criteria only: Sensitivity 56.6%, Specificity 83.3%
Rudwaleit M, et al. Ann Rheum Dis. 2009;68(6):777-783.

43
Imaging Criteria for nr-axSpA and r-SpA (AS)
nr-axSpA r-SpA (AS)
Inflammation associated with sacroiliitis is
detected by MRI but not by plain
radiograph (X-ray)
 Definite subchondral bone marrow
edema/osteitis
– Either one signal (lesion) present on at
least two slices
– Or more than one signal on a single slice
Definite radiographic sacroiliitis
 Grade 2 bilaterally or grade 3 or
higher unilaterally on plain
radiograph
Sacroiliitis grade 3 bilaterally
Bone marrow edema

Diagnostic Approach to Patients With Suspected
Axial SpA
44Sieper J, et al. Nature Reviews Disease Primers. 2015:15013.

There Is a Substantial Delay in the Diagnosis
of r-SpA (AS) After Onset of Symptoms
Diagnosis of r-SpA (AS) is
delayed by 5 to 10 years
Due to low awareness of r-
SpA (AS) by non-
rheumatologists
Could be improved through
education and through
effective screening for
inflammatory back pain
Earlier diagnosis of axSpA can
provide patients with
effective interventions

ASAS Recommendations for Recognizing Axial
SpA in Primary Care
Poddubnyy D, et al. Ann Rheum Dis. 2015;74(8):1483-1487. 46
Patients with chronic back pain (duration ≥3 months) with back pain onset
before 45 years of age should be referred to a rheumatologist if at least one of
the following parameters is present:
 Inflammatory back pain*
 HLA-B27 positivity
 Sacroiliitis on imaging ( X-ray or MRI)†
 Peripheral manifestations (in particular arthritis, enthesitis and/or dactylitis)‡
 Extra-articular manifestation (psoriasis, inflammatory bowel disease and/or
uveitis)‡
 Positive family history for spondyloarthritis‡
 Good response to non-steroidal anti-inflammatory drugs‡
 Elevated acute phase reactants§
* Any set of criteria, preferably ASAS definition of inflammatory back pain: at least four out of five parameters present: (1) age at onset ≤40 years; (2) insidious onset; (3) improvement with exercise; (4) no
improvement with rest; and (5) pain at night (with improvement upon getting up).
† Only if imaging available, not recommended as a routine screening parameter.
‡ According to the definition applied in the classification criteria for axial spondyloarthritis: Arthritis: past or present active synovitis diagnosed by a physician; Enthesitis (heel): past or present
spontaneous pain or tenderness at examination of the site of the insertion of the Achilles tendon or plantar fascia at the calcaneus. Dactylitis: past or present dactylitis, diagnosed by a physician. Extra-
articular manifestation: past or present psoriasis, inflammatory bowel disease and/or uveitis anterior, confirmed by a physician. Good response to non-steroidal anti-inflammatory drugs (NSAIDs): 24–48
h after a full dose of a NSAID the back pain is not present any more or is much better. Family history of SpA: presence in first-degree (mother, father, sisters, brothers, children) or second-degree
(maternal and paternal grandparents, aunts, uncles, nieces and nephews) relatives of any of the following: (1) ankylosing spondylitis; (2) psoriasis; (3) acute uveitis; (4) reactive arthritis; and (5)
inflammatory bowel disease.
§ C-reactive protein serum concentration or erythrocyte sedimentation rate above upper normal limit after exclusion of other causes for elevation.

Education
Exercise
Physical Therapy
Rehabilitation
Patient
Associations
Self Help Groups
NSAIDs
AXIAL DISEASE
PERIPHERAL
DISEASE
TNF Blockade
Sulfasalazine
Local Corticosteroids
A
N
A
L
G
E
S
I
C
S
S
U
R
G
E
R
Y
ASAS/EULAR Recommendations for
Management of Spondyloarthritis
ASAS, Assessment of SpondyloArthritis International Society; EULAR, European League Against Rheumatism; NSAIDs, non-steroidal anti-inflammatory drugs.
Adapted from Zochling J, et al. Ann Rheum Dis 2006;65:442–452.

ASAS/EULAR Recommendations for
Management of Spondyloarthritis
Exercises and rehabilitation have proven (short-
term) efficacy
Education is of key importance!
Prognosis and Expectation
Motivation
Prevention of “Damage”
ASAS, Assessment of SpondyloArthritis International Society; EULAR, European League Against Rheumatism.
Adapted from Zochling J, et al. Ann Rheum Dis 2006;65:442–452.
Education
Exercise
Physical Therapy
Rehabilitation
Patient
Associations
Self Help Groups
S
U
R
G
E
R
Y

Local GC
Slow-acting drugs (SSZ, pamidronate)
Physical therapy
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GC, glucocorticoid; IBD, inflammatory bowel
disease; NSAID, nonsteroidal anti-inflammatory drugs; SSZ, sulfasalazine; TNFi, tumor necrosis factor inhibitors.
Adapted from Ward MM, et al. Arthritis Rheum 2016;68:282–298.
Active AS
NSAIDs
Systemic glucocorticoids
TNFi
Alternative TNFi
Consider if peripheral arthritis or TNFi contraindications
Local GC Consider if ≤2 joints; use infrequently
Avoid achilles, patellar, quadriceps
Monitor validated AS disease activity measure, and CRP or ESR regularly
Unsupervised back exercises, formal group or individual self-management education, fall evaluation/counselling
Remains active
TNFi contraindication
Remains active
Recurrent iritis
IBD
Isolated sacroiliitis
Peripheral arthritis
Enthesitis
Conditionally recommend against
Strongly recommend
Conditionally recommend
Strongly recommend against
Qualifier
Local GC
Use TNFi monoclonals
Use infliximab or adalimumab
No preferred drug
Non-TNFi biologicNo preferred drug
Use continuously
Consider if peripheral flare,
pregnancy, IBD flare
Active over passive
Land-based over aquatic
ACR/SAA/SPARTAN Treatment Recommendations in
Ankylosing Spondylitis (2)

Adapted from Ward MM, et al. Arthritis Rheum 2016;68:282–298.
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GC, glucocorticoid; IBD, inflammatory bowel disease;
NSAID, nonsteroidal anti-inflammatory drugs; SSZ, sulfasalazine; TNFi, tumor necrosis factor inhibitors.
Strongly recommend
Conditionally recommend
Strongly recommend against
Qualifier
Conditionally recommend against
Stable AS
AS and:
Physical therapy
Hip arthoplasty
Treatment by ophthalmologist
NSAIDs Use on-demand
TNFi alone (monotherapy)
TNFi alone (monotherapy)
Monitor validated AS disease activity measure, and CRP or ESR regularly
Unsupervised back exercises, formal group or individual self-management education, fall evaluation/counselling
At home topical GC
Use infliximab or adalimumab
over etanercept
NSAIDs & TNFi
Elective spine osteotomy
Slow-acting drugs & TNFi
No preferred NSAID
Consider specialized centre
Advanced hip arthritis
Severe kyphosis
Acute iritis
IBD
Recurrent iritis
Use TNF monoclonals over etanercept
ACR/SAA/SPARTAN Treatment Recommendations in
Ankylosing Spondylitis (3)

52
Treatment Algorithm for Axial SpA
Sieper J, et al. Nature Reviews Disease Primers. 2015:15013.
BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; SI, sacroiliac; TNF, tumor necrosis factor.

2010 Updated ASAS Recommendations for Use
of Anti-TNF Agents in Patients With Axial SpA
Van der Heijde D, et al. Ann Rheum Dis 2011;70:905–908. 53
ASAS,The Assessment of SpondyloArthritis international Society; BASDAI,
Bath Ankylosing Spondylitis DiseaseActivity Index; DMARD, disease-
modifying anti-rheumatic drug; nr-axSpA, non-radiographic axial SpA; SpA,
spondyloarthritis
Importantly, all patients who fulfil theASAS axial SpA criteria, including patients with nr-axSpA, can be
treated with anti-TNF agents according to these recommendations.
ASAS, The Assessment of SpondyloArthritis international Society; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; DMARD,
disease-modifying anti-rheumatic drug; nr-axSpA, non-radiographic axial SpA; SpA, spondyloarthritis

Continuous use of Non-steroidal Anti-inflammatory Drugs
Reverts the Effects of Inflammation on Radiographic
Progression in Ankylosing Spondylitis
0.8
1.7
0.9
0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Low CRP High CRP
DifferencebetweenthemodifiedStoke
AnkylosingSpondylitisSpineScoreat
month0andmonth24
On Demand Continuous
CRP, C reactive protein.
Adapted from Kroon F, et al. Ann Rheum Dis 2012;71:1623-9
P=0.62 P=0.003

Conventional Disease-modifying Anti-rheumatic Drugs are
Largely Not Effective for the Treatment of Patients with
Ankylosing Spondylitis
BASDAI, Bath ankylosing spondylitis disease activity index; sc, subcutaneous.
1. Adapted from Haibel H, et al. Ann Rheum Dis 2005;64:124–126.
2. Adapted from Haibel H, et al. Ann Rheum Dis 2007;66:419–421.

Conventional Disease-modifying Anti-rheumatic Drugs are
Largely Not Effective for the Treatment of Patients with
BASDAI, Bath ankylosing spondylitis disease activity index.
Adapted from Braun J, et al. Ann Rheum Dis 2006;65:1147–1153.

Overview of TNF inhibitor Biologics
TNF inhibitor treatment is recommended in patients with persistently high
disease activity despite conventional treatments1
LT-α, lymphotoxin-α; mAb, monoclonal antibody; PEG, polyethylene glycol.
1. Zochling J, et al. Ann Rheum Dis 2006;65:442–452.
2. Remicade EU SmPC. 3. Humira EU SmPC.
4. Simponi EU SmPC. 5. Enbrel EU SmPC.
Infliximab2 Adalimumab3 Golimumab4 Etanercept5
Class Chimeric
monoclonal
antibody
Human
monoclonal
antibody
Human
monoclonal
antibody
Human soluble
receptor TNF-i
Construct Chimeric mAb Recombinant
human mAb
Recombinant
human mAb
Recombinant
fusion protein
Binding target TNF-α TNF-α TNF-α
TNF-α and
LT-α
Half-life 8.0–9.5 days 14 days 12±3 days 70 hours

Anti-TNF Agents for Axial SpA
2. Dougados M, et al. Arthritis Res Ther. 2014;16(6):481.
3. Mathieu S, et al.. Rheumatology. 2013;52(1):204-209.
4. Braun J, et al. Ann Rheum Dis. 2011;70(6):896-904.
5. van der Heijde D, et al. Arthritis Rheum. 2005;52(2):582-591.
58
Rapidly improve symptoms1
NormalizeCRP1
Reduce inflammation in the
sacroiliac joints and in the
spine1
Reduce the need for NSAIDs2,3
Various anti-TNF agents have
similar efficacy1,4-8
Effective in r-SpA (AS) and in
nr-axSpA1
Have little or no impact on new
bone formation/spondylosis1
*Defined using ASAS response criteria 40 (ie, 40% improvement from baseline).
†Different studies, no head-to-head comparisons.
Response to treatment at 24 weeks*†1,4-8
6. Davis JC, et al. Ann Rheum Dis. 2005;64(11):1557-1562.
7. van der Heijde D, et al. Arthritis Rheum. 2006;54(7):2136-214.
8. Inman RD, et al. Arthritis Rheum. 2008;58(11):3402-3412.
9. Cimzia SPC, 2014.

Anti-TNF Agents Can Be Effective for Extra-
Articular Manifestations of SpA*
2. Gorman JD, et al. N Engl J Med. 2002;346(18):1349-1356.
3. van der Heijde D, et al. Rheumatology. 2013;52(2):321-325.
4. Aydin SZ, et al. Rheumatology. 2010.
5. Tam L-S, et al. Rheumatology. 2014;53(6):1108-1119
59
May reduce flares of uveitis1
Some are effective for inflammatory bowel disease (IBD)1;
etanercept, however, does not have efficacy in IBD1
Anti-TNFs are effective for psoriasis1
May be effective for enthesitis2-4
In addition, anti-TNF therapy may reduce the increased cardiovascular risk of patients
with r-SpA (AS) or other types of inflammatory arthritis5

Rapid Clinical Response Observed as Early as 2 Weeks with
Etanercept in Ankylosing Spondylitis
ASDAS, ankylosing spondylitis disease activity score; SSZ, sulfasalazine.
Adapted from van der Heijde D, et al. Rheumatology 2012;51:1894–1905.
• From as early as week 2 of etanercept treatment onwards, improvements in mean ASDAS scores
were significantly greater vs sulfasalazine
• The improvement in ASDAS from baseline was significantly greater from week 2 with
etanercept vs sulfasalazine (32.9 vs 9.2%, P <0.001)
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
0 4 8 12 16
Week
* *
*
* *
MeanASDASscore
Etanercept SSZ

OLE Study of 12-week Randomized Controlled Trial:
Clinical Outcomes for up to 5 Years in Ankylosing Spondylitis
Patients
ASAS, Assessment of SpondyloArthritis international Society;
OLE, open-label extension.
Adapted from Martín-Mola EI, et al. Clin Exp Rheumatol 2010;28:238–245.
The ASAS20, ASAS40, and ASAS5/6
responses to etanercept were sustained
over time
ASAS20 ASAS5/6
100
80
60
40
20
0
Patients(%)
Weeks
0 24 48 72 96 120 144 168 192 216 240 264
Start of current study
ASAS40
100
80
60
40
20
0
Patients(%)
Weeks
0 24 48 72 96 120 144 168 192 216 240 264
100
80
60
40
20
0
Patients(%)
Weeks
0 24 48 72 96 120 144 168 192 216 240 264
Last observation carried forward
Observed

Baraliakos et al: Measures in Advanced Ankylosing
Spondylitis Over 7 Years
• Etanercept achieves sustained efficacy in all of the applied AS efficacy measures
• 62% of patients completed the 7-year treatment period
• 31.3% of the completers were in ASAS partial remission and 43.8% showed an ASDAS inactive disease status
by year 7
• 68.8% of etanercept patients achieved BASDAI <3 and maintained ASDAS moderate disease activity at
year 7
ASAS, Assessment of SpondyloArthritis International Society; ASDAS, ankylosing spondylitis disease activity score;
BASDAI, Bath ankylosing spondylitis disease activity index; BASFI, Bath ankylosing spondylitis functional index;
BASMI, Bath ankylosing spondylitis metrology index; CRP, C reactive protein.
Adapted from Baraliakos X, et al. Arth Res Ther 2013;15:R67.
Age (years) 36.3 ± 7.5
Disease duration 13 ± 7.7
BASDAI (0–10) 6.3 ± 0.9
BASFI (0–10) 5.3 ± 1.9
BASMI (0–10) 3.9 ± 2.2
CRP (mg/l) 20.8 ± 17.7
ASDAS units 3.9 ± 0.7
Baseline characteristics of study completers
7
6
5
4
3
2
1
0
0 1 2 3 4 5 6 7
Year
Scorepoints
Course of related clinical parameters
BASDAI
ASDAS
BASFI
BASMI

Effect of Etanercept on Heel Enthesitis in Spondyloarthritis
-18.79
-28.14
-34.15
-37.59
-11.6 -12.02
-10.53
-11.58
-40
-30
-20
-10
0
Etanercept Placebo
PGA, patient’s global assessment.
Adapted from Dougados M, et al. Ann Rheum Dis 2010;69:1430–1435.
Week 2 Week 4 Week 8 Week 12
P=0.013
P=0.007
PGADiseaseActivity
P=0.433
P=0.84

Impact of TNF inhibitors on Radiographic Progression in
334 mNY AS patients (excl. bamboo spine)
Spinal X-rays every ±2 yrs
Confounders: age, age at onset of axial
symptoms, duration of disease, HLA–B27 status,
sex, and smoking burden.
mSASSS, modified Stoke ankylosing spondylitis
spine score.
Adapted from Haroon N, et al. Arthritis Rheum 2013;65:2645–2654.
5
4
3
2
1
<2.1 2.1–2.4 >3.9
Start TNF inhibitor after
10 years of disease
duration
P=0.044
P=0.03
P=0.04
Proportion of disease duration exposed to TNFα inhibitor (%)
Meanrateofradiographicprogression
2.0
1.5
1.0
0.5
0.0
<25 25–50 >50
Cumulative probability
RateofmSASSprogression
12.0
8.0
6.0
4.0
0.0
20
10.0
2.0
0 40 60 80 100
Gap between radiographs (years)
DeltamSASSS
6
2.4–3.9
Patients who started TNF inhibitors
within 10 years of disease onset
Patients who started TNF inhibitors
after 10 years of disease onset
Patients taking TNF
inhibitors
Patients not taking TNF
inhibitors

The Efficacy of TNFα Blockers in Patients with
Ankylosing Spondylitis: A Meta-analysis
The use of concomitant non-steroidal antirheumatic drugs was allowed. ASAS40, Assessment of SpondyloArthritis
international Society 40% improvement; BASDAI, Bath ankylosing spondylitis disease activity index;
RE, random effects; TNF, tumour necrosis factor.
Adapted from Callhoff J, et al. Ann Rheum Dis 2015;74:1241–1248.
Change in BASDAI
• TNFα blockers improve disease activity and physical function clinically relevant for patients with
AS and nr-axSpA
• The BASFI effect size was 0.67
• ASAS40 response (OR 4.7)
Adalimumab
Adalimumab
Certolizumab 200 mg
Certolizumab 400 mg
Etanercept
Infliximab
Adalimumab
Adalimumab
Etanercept
Etanercept 25 mg 2x weekly
Etanercept 50 mg weekly
Etanercept
Etanercept
Golimumab
Infliximab
Infliximab
Infliximab
0.88 (0.63, 1.12)
0.65 (0.20, 1.09)
0.88 (0.27, 1.49)
0.84 (0.60, 1.07)
1.01 (0.55, 1.48)
0.75 (0.28, 1.21)
1.07 (0.82, 1.32)
0.99 (0.54, 1.44)
0.74 (0.31, 1.16)
1.05 (0.61, 1.48)
0.94 (0.21, 1.67)
0.74 (0.29, 1.19)
1.30 (0.99, 1.60)
1.75 (1.20, 2.31)
1.52 (0.54, 2.50)
0.73 (0.07, 1.39)
1.34 (1.05, 1.62)
0.00 0.50 1.00 1.50 2.00 2.40
1.00 (0.87, 1.13)
Favours TNF blockerFavours control
Standardized mean difference (95% CI)Treatment

The Efficacy of TNFα Blockers in Patients with
Non-radiographic Axial Spondyloarthritis: A Meta-analysis
Adapted from Callhoff J, et al. Ann Rheum Dis 2015;74:1241–1248.
Change in BASDAI
ASAS40 response
Treatment Standardized mean difference (95% CI)
Treatment
Adalimumab
Adalimumab
Certolizumab 200 mg
Certolizumab 400 mg
Etanercept
Infliximab
0.76 (0.16, 1.36)
0.48 (0.19, 0.77)
0.98 (0.47, 1.49)
1.01 (0.50, 1.51)
0.35 (0.08, 0.62)
1.26 (0.58, 1.94)
0.73 (0.44, 1.01)
0.00 0.50 1.00 1.50 2.00
Standardized mean difference
Favours TNF blockerFavours control
1.000.50 5.0 20.00
Odds ratio (log scale)
3.62 (2.45, 5.34)
6.00 (1.46, 24.69)
2.56 (1.32, 4.94)
4.67 (1.40, 15.53)
4.81 (1.43, 16.23)
3.25 (1.60, 6.62)
8.40 (1.93, 36.62)Adalimumab
Adalimumab
Certolizumab 400 mg
Infliximab
Certolizumab 200 mg
Etanercept
Odds ratio (95% CI)
The use of concomitant non-steroidal antirheumatic drugs was allowed. ASAS40, Assessment of SpondyloArthritis
international Society 40% improvement; BASDAI, Bath ankylosing spondylitis disease activity index;
RE, random effects; TNF, tumour necrosis factor.

Long-term Efficacy of Etanercept Treatment in Patients with
nr-axSpA or AS: Long-term Results of the ESTHER Trial
All differences between ASand nr-axSpA were not statistically significant. AS, ankylosing spondylitis; ASAS40, Assessment of SpondyloArthritis international
Society 40% improvement; BASDAI, Bath ankylosing spondylitis disease activity index; BASFI, Bath Ankylosing Spondylitis Functional Index;
CRP, C-reactive protein; nr-axSpA, non-radiographic axial spondyloarthritis .
Poddubnyy D, et al. Ann Rheum Dis 2015;74(Suppl2):267.
Screening Year 4 Year 5 Year 6
BASDAI
AS 5.3 (1.0) 1.9 (1.8) 1.6 (1.4) 1.8 (1.6)
nr-axSpA 5.5 (1.3) 1.8 (1.3) 1.7 (1.3) 1.5 (1.2)
BASFI
AS 3.9 (1.9) 1.4 (1.5) 1.3 (1.3) 1.3 (1.3)
nr-axSpA 4.3 (2.3) 1.2 (1.3) 1.2 (1.4) 1.1 (1.3)
CRP (mg/L)
AS 11.9 (17.0) 1.6 (1.6) 2.1 (2.3) 3.4 (3.7)
nr-axSpA 9.2 (13.1) 2.6 (4.1) 0.9 (0.7) 1.7 (2.3)
ASAS40
AS - 82.4% 88.2% 80%
nr-axSpA - 70.6% 76.5% 82.4%
ASAS partial
remission
AS - 64.7% 70.6% 53.3%
nr-axSpA - 47.1% 47.1% 64.7%
BASDAI50
AS - 76.5% 88.2% 86.7%
nr-axSpA - 70.6% 76.5% 82.4%
• There was a sustained and similar clinical response in patients with nr-axSpA and AS treated with
etanercept over 6 years

Clinical and Imaging Efficacy of Etanercept in nr-axSpA: The EMBARK Study, a
Randomized, Double-blind, Placebo-controlled Trial
68
M. Dougados1, D. van der Heijde2, J. Sieper3, J. Braun4, W.P. Maksymowych5, G. Citera6,
R. Pedersen7, R. Bonin7, J. Bukowski7,A. Koenig7, B.Vlahos7, D. Alvarez7
1Paris-Descartes Univ., Cochin Hospital, Paris, France; 2Leiden Univ. Med. Center, Leiden, The
Netherlands; 3Charité - Universitätsmedizin Berlin, Berlin, Germany; 4Rheumazentrum Ruhrgebiet,
Herne, Germany; 5Univ. of Alberta, Edmonton, Canada; 6Consultorios Reumatológicos Pampa,
Buenos Aires, Argentina; 7Pfizer Inc, Collegeville, PA, United States
Dougados M, et al. Arthritis Rheumatol. 2014;66(8):2091-2102.

Etanercept
50 mg QW*
Placebo*
EMBARK: Study Design
69
Etanercept 50 mg QW*
Primary endpoint:
ASAS40 at week 12
Period 1:
Double blind
Period 2:
Open label
R
Safety
Screening BL 12842 16 104 10824
*Patients continued to receive background NSAIDs prescribed at a stable, optimal anti-inflammatory doses.

EMBARK: Main Inclusion/Exclusion Criteria
70
Inclusion criteria
≥18<50 years of age
axSpA (defined by ASAS criteria)
Symptom duration of 3 months5 years
BASDAI score ≥4 despite current NSAID use
Failed ≥2 NSAIDs (including current one)
Exclusion criteria
Radiological sacroiliitis grades 3-4 unilaterally or
grade ≥2 bilaterally (defined by modified NY criteria for r-SpA (AS),
as determined by central imaging reader)
Prior biologic use (except for IBD, >6 months before BL)

15.2
20.0
28.6
33.3
3.8
14.8 15.7 14.8
0
10
20
30
40
50
0 2 4 6 8 10 12
PatientsachievingASAS40(%)
Weeks
Etanercept (n=105) Placebo (n=108)
EMBARK: Proportion of Patients Achieving
ASAS40 Response (0-12 Weeks)
Dougados M, et al. Arthritis Rheumatol. 2014;66(8):2091-2102. 71
Primary
endpoint†
†
*
*P<0.05; †P<0.01

EMBARK: ASAS 40 Response at Week 12 in Patients
With or Without Extra-Articular Manifestations
Dougados M, et al. Arthritis Rheumatol. 2014;66(8):2091-2102. 72
Etanercept was effective in patients with nr-axSpA who had enthesitis or
uveitis at baseline
Subgroup Etanercept Placebo PValue Odds Ratio
(95% CI)
Enthesitis at baseline
No 13/34 (38.2) 6/31 (19.4)
0.903
2.6 (0.8, 8.0)
Yes 21/71 (29.6) 10/77 (13.0) 2.8 (1.2, 6.5)
History of uveitis at baseline
No 30/98 (30.6) 16/98 (16.3)
0.078
2.3 (1.1, 4.5)
Yes 5/8 (62.5) 0/9 (0) NE

EMBARK: Proportion of Patients Achieving
ASAS40 Response (0-48 Weeks) (mITT, LOCF)
73
15.2
20.0
28.6
33.3
42
44
47.0
55.0
52.0
3.8
14.8 15.7 14.8
38.1
51.4
52.4
53.3
53.3
0
10
20
30
40
50
60
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48
PatientsachievingASAS40(%)
Week
Etanercept (n=105) Placebo/ETN (n=108)
†
*
†
Open-label ETN
Maksymowych WP, et al. Ann Rheum Dis. 2015.
*P<0.05; †P<0.01
mITT, Modified intention-to-treat; LOCF, Last observation carried forward

EMBARK: Mean Change from Baseline - SPARCC
MRI SI Scores (mITT, LOCF)
60
-4.6
-5.8
-1.13
-4.1
-6
-5
-4
-3
-2
-1
0
ImprovementfrombaselineSPARCC
score
Etanercept Placebo
Baseline scores 7.9 7.0
Week 12 Week 48
Maksymowych WP, et al. Ann Rheum Dis. 2015.
mITT, Modified intention-to-treat; LOCF, Last observation carried forward

48 WEEKS
BME
Erosions
Backfill
T1W STIRBASELINE
STIR
EMBARK: Example 1 of MRI Images at Baseline
and at 48 Weeks
Maksymowych WP, et al. American College of Rheumatology 2014, Abstract #43334. 75
At baseline there
are erosions and
bone marrow
edema (BME)
At 48 weeks the
erosions are less
apparent, there is
backfill, and the
BME has subsided

48 WEEKS
BME
Erosions
Backfill
48 WEEKS
T1W STIRBASELINE
BME
Erosion
Backfill
T1W
EMBARK: Example 2 of MRI Images at Baseline
and at 48 Weeks
Maksymowych WP, et al. American College of Rheumatology 2014, Abstract #43334. 76
At baseline there
are erosions and
bone marrow
edema (BME)
At 48 weeks there is
backfill and the
BME has subsided

69.8
308
561
0
100
200
300
400
500
600
General population
TNF inhibitor-naïve AS patients
TNF inhibitor-treated AS patients
MeanincidenceofTB
per100,000PY
Incidence Rates of TB in Korea
Higher Incidence of Tuberculosis is Observed in
Korean Ankylosing Spondylitis Patients Treated
with TNF blockers
AS, ankylosing spondylitis; PY, patient-years; TB, tuberculosis.
Adapted from Kim EM, et al. J Rheumatol 2011;38:2218–2230.

Biologics Have an Increased Risk of Tuberculosis and
Lymphoma Compared to Traditional Disease-modifying
Anti-rheumatic Drugs
DMARD vs Biologics in rheumatoid arthritis
*P<0.05; **Traditional DMARDs as referent.
†This data was not adjusted for rheumatoid arthritis disease activity.
Not a head-to-head comparison. Differences in baseline characteristics among patient groups may exist.
DMARDS, disease-modifying anti-rheumatic drugs; IRR, incidence rate ratio; NNH, number needs to harm; TB, tuberculosis.
Adapted from Chiu YM, et al. Int J Rheum Dis 2014;17(Suppl3):9–19.
Traditional DMARDs Biologic DMARDs IRR (95%CI)**
Rate/100000 Rate/100000
TB 546 1458 2.67*(2.12–3.34)
Lymphoma† 41 133 3.24*(1.37–7.06)
Serious
infection
2956 3068 1.04 (0.89–1.19)

Biphasic Emergence of Active Tuberculosis in
Rheumatoid Arthritis Patients Receiving TNF inhibitors
2006–2009 Taiwan VGH-TC
Age/sex
Duration of
RA (years)
Baseline
TST/QFT
INHP TNF inhibitor
Duration of TNF
inhibitor before TB
(months)
Concomitant medications
Location of active
tuberculosis
Anti-tuberculosis drug
sensitivity
1 66/F 8.5 TST+/QFT+ + Adalim. 2
methotrexate 15 mg/week
PSL 5 mg/day
Pulmonary
INH-R
RIF-S
2 54/F 10.6 TST+/QFT+ + Adalim. 3
methotrexate 12.5
mg/week
PSL 7.5 mg/day
Pulmonary INH-S
3 62/F 10.2 TST–/QFT+ – Adalim. 3
PSL 7.5 mg/day
Miliary INH-S
4 72/F 8.5 TST–/QFT– – Adalim. 3
PSL 5 mg/day
Pleura (Lt) INH-S
5 68/F 8.3 TST–/QFT– – Etaner. 20
PSL 5 mg/day
Miliary INH-S
6 44/F 9.2 TST–/QFT– – Etaner. 22
methotrexate
12.5 mg/week
PSL 5 mg/day
Pulmonary INH-S
7 55/M 8.4 TST–/QFT– – Adalim. 23
PSL 7.5 mg/day
Pleura (Lt) INH-S
8 40/F 12.2 TST–/QFT– – Etaner. 23
PSL 5 mg/day
Joint (5th MTP) NA
9 61/F 10.8 TST–/QFT– – Adalim. 24
PSL 5 mg/day
Pulmonary INH-S
Adalim, adalimumab; Etaner, etanercept; F, female; INHP, isoniazid prophylaxis; INH-R, resistant to isoniazid; INH-S, sensitive to isoniazid; Lt, left side;
M, male; MTP, metatarsophalangeal joint; NA, not applicable; QFT, QuantiFERON-G assay; RA, rheumatoid arthritis;
RIF-S, sensitive to rifampicin; PSL, prednisolone; TB, tuberculosis; TST, tuberculin skin test.
Adapted from Chen DY, et al. Ann Rheum Dis 2012;71:231–237.

Higher Incidence of Tuberculosis is Observed in
Korean Ankylosing Spondylitis Patients Treated
with TNF inhibitor Monoclonal Antibodies
Among patients with AS, soluble receptor TNF inhibitor treatment is associated
with a lower risk of TB infection compared with TNF inhibitor monoclonal antibody
treatment
AS, ankylosing spondylitis; PY, patient-years; TB, tuberculosis.
Adapted from Kim EM, et al. J Rheumatol 2011;38:2218–2230.
540
490
0
0
100
200
300
400
500
600
Infliximab-treated AS patients
Adalimumab-treated AS patients
Etanercept-treated AS patients
Incidence Rates of TB in Korea
MeanincidenceofTB
per100,000PY

TB infection decreased in RA patients using biologics
after LTBI risk management plan in Spain
IRR vs. general
Population
IRR vs. RA
with csDMARDs
Before RMP 19 5.8
After RMP 7 2.4
100% compliance 1.8 Undetermined
<100% compliance 13 4.8
Gomez-Reino JJ et al. Arthritis Rheum 2007;57:756–61.
IRR, incidence rate ratio; LTBI, latent TB infection; RA,
rheumatoid arthritis; RMP, risk management plan.

Interleukin-17/IL-23 pathway
Jethwa H et al. Clin and Exp immunology 2015;183:30-36.

IL-17 levels in AS and health Controls
Mei Y et al. Clin Rheumatol 2011;30: 269-273.

About Secukinumab
• Secukinumab is a human monoclonal antibody
that selectively neutralizes circulating IL-17A.
• Research shows that IL-17A plays an
important role in driving the body's immune
response in psoriasis and spondyloarthritis
conditions, including PsA and AS.
• Secukinumab is the first IL-17A inhibitor with
positive Phase III results for the treatment of
PsA and ankylosing spondylitis (AS).
Confidential. For Internal Use only

MEASURE 1 and MEASURE 2 studies
Efficacy and Safety at 16 and 52 weeks in AS

MEASURE 1 and MEASURE 2 studies:
Objective and Methods
Objective
• Assess the efficacy and safety of secukinumab in patients with active AS
Primary endpoint
• ASAS20 response at Week 16
Methods
• Patients were randomly assigned in a 1:1:1 ratio to 1 of 2 secukinumab groups or the
placebo group
• MEASURE 1: Patients received an IV loading infusion of secukinumab 10 mg/kg at
baseline and Weeks 2 and 4, followed by SC secukinumab 150 mg or 75 mg Q4W
starting at Week 8. Patients in the placebo group were treated according to the same
schedule of IV and SC doses
• MEASURE 2: Patients received SC secukinumab 150 mg or 75 mg or placebo at
baseline, Weeks 1, 2, and 3; and Q4W starting at Week 4
• At Week 16 in both studies, patients in the placebo group were randomly reassigned to
receive secukinumab 150 mg or 75 mg
Baeten, et al. N Engl J Med. 2015;373:2534-48.

MEASURE 1 and 2 studies: Efficacy
Response Rate Through Week 16
(PBO-controlled Phase) and
Through Week 52 Among
Patients Randomly Assigned to
Secukinumab or PBO at Baseline
in MEASURE 1 and MEASURE 2
Figure: Proportions of patients
with Assessment of
Spondyloarthritis International
Society 20 (ASAS20) responses
(improvement ≥20% and absolute
improvement ≥1 unit [on a 10-unit
scale] in ≥3 of the 4 main ASAS
domains, with no worsening by
≥20% in the remaining domain)
and the proportion with ASAS40
responses (improvement ≥40%
and absolute improvement ≥2
units [on a 10-unit scale] in ≥3 of
the 4 main ASAS domains, with no
worsening in the remaining
domain) in MEASURE 1 (Panels A
and B) and MEASURE 2 (Panels C
and D).
Baeten, et al. N Engl J Med. 2015;373:2534-48.

Cytokines activate
cells through JAK pathways
2
Cytokines
Inhibition of JAK Pathways May Modulate
Recruitment, Activation, and Effector Cell Function
JAK pathway signaling
induces production of further
pro-inflammatory signals
3
JAK JAK
STAT
P
STAT
P
STAT
P
STAT
P
STAT
Further recruitment and
activation of cells and effector
function occurs
4
Pro-inflammatory
cytokines recruit cells
1
Activated
Immune Cells
JAK: Janus Kinase; P: Phosphate; STAT: Signal Transducer and Activator of Transcription.
McInnes IB et al. Nat Clin Pract Rheumatol. 2005;1:31-39.

Tofacitinib is a JAK Inhibitor
Tofacitinib inhibits the autophosphorylation
and activation of JAK2
Cytokine binding to its cell surface receptor
leads to receptor polymerization1
1
JAKs cannot phosphorylate the
receptors that therefore cannot
dock STATs
2
JAKs cannot phosphorylate
STATs, which cannot dimerize and
move to the nucleus to activate
new gene transcription
3
JAK: Janus Kinase; STAT: Signal Transducer and Activator of Transcription.
1. Shuai K, Liu B. Nat Rev Immunol. 2003;3(11):900-911; 2. Jiang JK, et al. J Med Chem. 2008;51(24):8012-8018.
91
Gene transcription
JAK JAK
STAT
STAT
Tofacitinib
X

Tofacitinib in Patients with Ankylosing
Spondylitis: A Phase 2, 16-Week, Randomized,
Placebo-Controlled, Dose-Ranging Study
Désirée van der Heijde
Presented at ACR 2015, San Francisco
Désirée van der Heijde,1 Atul Deodhar,2 James C Wei,3 Edit Drescher,4 Dona Fleishaker,5
Thijs Hendrikx,6 David Li,6 Sujatha Menon,5 Keith S Kanik5
1Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands;
2Division of Arthritis & Rheumatic Diseases, Oregon Health & Science University, Portland, Oregon, USA;
3Division of Allergy, Immunology and Rheumatology, Chung Shan Medical University Hospital, Taichung, Taiwan;
4Csolnoky Ferenc Hospital, Veszprém, Hungary; 5Pfizer Inc, Groton, CT, USA; 6Pfizer Inc, Collegeville, PA, USA

 AS is a chronic, immune mediated systemic inflammatory disease of the
axial skeleton with a major impact on quality of life1
 Treatment goals focus on remission or low disease activity
● Current guidelines support anti-TNF treatments to achieve these aims2,3
 However, a limited number of drugs are available for AS
● Remission and / or low disease activity is not achievable for all patients with
current treatment options
 This was the first investigation of the effects of tofacitinib, an oral Janus
kinase inhibitor, in adult patients with active AS
Background
1. Inman RD. Chp 25 in: Goldman L, Schafer AI. Goldman’s Cecil Medicine 25th ed. 2016;
2. Ward MM, et al. Arthritis Rheumatol. 2015; DOI: 10.1002/art.39298; 3. Braun J, et al. Ann Rheum Dis. 2010; 70: 896-904.
AS, ankylosing spondylitis; SI, sacroiliac; TNF, tumor necrosis factor
93

 Inclusion criteria included:
● Age ≥18 years
● Fulfilling the modified New York criteria for AS
» radiographic sacroiliitis confirmed by a central reader
● Active disease based on
» BASDAI score ≥4
» back pain score ≥4
● Inadequate response / intolerance to prior NSAID therapy
 Exclusion criteria included:
● Treatment with other DMARDs (except those permitted below)
● Current or prior TNF inhibitor or biologic treatment
 Permitted concomitant medication:
● methotrexate, sulfasalazine, oral corticosteroids, injected
corticosteroids, topical and intra-rectal corticosteroids
Inclusion and exclusion criteria
94
AS, ankylosing spondylitis; BASDAI; Bath ankylosing spondylitis Disease Activity Index;
DMARD, disease modifying antirheumatic drug; NSAID, non-steroidal anti-inflammatory drug; TNF, tumor necrosis factor

Study design
95
 Patients randomized 1:1:1:1 for 12 weeks + 4 weeks follow-up off study
drug in this Phase 2, multicenter, randomized, double-blind, placebo-
controlled, dose-ranging study: NCT01786668
AS, ankylosing spondylitis; BID, twice daily; MRI, magnetic resonance imaging
Tofacitinib (CP-690,550) 5 mg BID
Day 1 Week 2 Week 4 Week 8 Week 12
Baseline MRI Treatment MRI
Week 16
EndofTreatment
Placebo
Followup
Randomization
Screening

Normal Approximation to ASAS20 at Week 12
(FAS, NRI/LOCF)-Observed Results
Placebo
N=51
Tofacitinib
2 mg BID
N=52
Tofacitinib
5 mg BID
N=52
Tofacitinib
10 mg BID
N=52
n 21 27 42 29
Difference from placebo (active-placebo)
Difference 10.75 39.59 14.59
SE 9.77 8.80 9.74
95% CI
(-8.41,
29.90)
(22.35,
56.83)
(-4.50,
33.69)
p-value 0.271 <0.001 0.134
41.18
51.92
80.77
55.77
0
20
40
60
80
100
Week 12
ASAS20ResponseRate(SE)(%)
Placebo Tofa 2 mg
Tofa 5 mg Tofa 10 mg
96
Table 14.2.1.2.1
NRI/LOCF: Non-Responder Imputation for dropouts; Last Observation Carried Forward for missing components; SE: Standard Error

Ankylosing Spondylitis Disease
Activity Score major improvement
97
*p<0.05
ASDAS, ankylosing spondylitis disease activity score; BID, twice daily; CRP, C-reactive protein; SE, standard error
*
Mean(SE)ASDASmajor
improvementresponserate,%
Mean (SD) baseline ASDAS 3.7 (0.8) 3.6 (0.8) 3.7 (0.9) 3.7 (0.8)

Bath Ankylosing Spondylitis Functional
Index Week 12 change from baseline
98
BASFI, Bath ankylosing spondylitis functional index; BID, twice daily; LS, least squares; SE, standard error
Mean (SD)
baseline BASFI
5.7 (2.3) 5.5 (1.9) 5.8 (2.2) 5.7 (2.4)

Axial SpA: Summary
• Axial SpA includes nr-axSpA and r-SpA (AS) and is characterized by
inflammation and abnormal bone formation in the axial skeleton1 and may
also manifest with peripheral tissue inflammation.2
• SpA is at least as common as RA in many countries3 and correlates with
the prevalence of HLA-B27.2
• nr-axSpA is the early manifestation of axial SpA when sacroiliitis can be
detected by MRI but before structural changes can be detected by x-ray.1
• The burden of disease in ax-SpA is high and is similar for nr-axSpA and r-
SpA (AS).4-6
• Elevated CRP7 and severe sacroiliitis8 are strong positive predictors of
sacroiliitis progression.
3. Akkoc N, et al. Curr Rheumatol Rep 2008;10:371–378.
5. Molto A, et al. Ann Rheum Dis. 2015;74(4):746-751.
6. Kiltz U et al. Arthritis Care Res 2012;64:1415–1422.
7. Poddubnyy D, et al. Ann Rheum Dis 2011;70:1369–1374.
8. Bennett A, et al. Arthritis Rheum 2008;58:3413–3418.

Axial SpA: Summary (continued)
2. Poddubnyy D, et al. Ann Rheum Dis. 2015;74(8):1483-1487.
3. Braun J, et al. Ann Rheum Dis. 2011;70(6):896-904.
4. Van der Heijde D, et al. Ann Rheum Dis 2011;70:905–908.
5. Mathieu S, et al. Rheumatology. 2013;52(1):204-209.
100
There is an unacceptably long delay between the onset of symptoms and
the diagnosis of r-SpA (AS) due to low awareness by non-rheumatologists.1
Diagnosis could be improved by screening for inflammatory back pain,
HLA-B27, sacroiliitis, and other SpA features in patients with chronic back
pain.1,2
Management of nr-axSpA and r-SpA (AS) should be comprehensive and
include non-pharmacological steps such as education, exercise and
physical therapy as well as pharmacological therapy such as NSAIDs,
analgesics, and anti-TNF agents.3
The various approvedAnti-TNF agents have shown similar efficacy in
axSpA2 and should be used in patients with high disease activity who have
not improved on NSAIDs.4
Anti-TNFs rapidly improve symptoms, normalize CRP, reduce
inflammation in the sacroiliac joint, reduce the need for NSAIDs, and are
effective in nr-axSpA and in r-SpA (AS).
Newer therapies show promise in management ofAxSpA

Axial sp a and its management

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