Annual Rheumatology & Therapeutics Review for...

Annual Rheumatology &

Therapeutics Review for

Organizations & Societies

Spondyloarthritis and

Biologics: Update on

Ankylosing Spondylitis &

Psoriatic Arthritis—

Guidelines and Management

Spondyloarthritis

• A family of related diseases that cause inflammation in spine, peripheral joints, and tendon/ligament insertion sites (enthesium)

• Spondyloarthritis includes:

– Psoriatic arthritis

– Ankylosing spondylitis

– Undifferentiated spondyloarthritis

• (axial spondyloarthritis, peripheral spondyloarthritis)

– Reactive arthritis

– Inflammatory bowel disease associated arthritis

Differences Between Psoriatic Arthritis (PsA)

and Rheumatoid Arthritis (RA)

• PsA is an inflammatory joint disease with marked

phenotypic diversity

– Musculoskeletal features

– Cutaneous

– Gastrointestinal

– Ocular manifestations

• Comorbidities

– Obesity

– Type 2 diabetes

– Hypertension

– Cardiovascular disease

– Mortality

Important Characteristics of PsA

• Psoriasis precedes inflammatory joint disease in 70 to

85 % of patients

• Equally common in men and women

• Reported prevalence of inflammatory joint manifestations

among patients with psoriatic skin lesions varies widely

– 6.25% (2000 US study) to 48% (2002 Swedish study)

– Estimated at 20-30%

• Worldwide prevalence of PsA .03 to 1 %

• Familial and genetic considerations

Synovio-entheseal complex (SEC) Concept

• Subchondral bone

inflammation and

resorption

• Periosteal new

bone formation

Bone

Enthesitis

Enthesitis

McGonagle D. Arthritis Rheum 1999. 42:1080-1086; Tan AL, et al. Rheumatology 2006;45:1294–7

Psoriasis and PsA: Shared Pathways

• Infiltrating leukocytes and their cytokine products may

be similar in the skin and in the inflamed joint

Image taken from AbbVie Presentation AHD-5019B.

Nograles KE, et al. Nat Clin Pract Rheumatol. 2009;5:83-91.

Link Between Psoriasis and PsA

• PsA is initiated by immune response that may arise in the skin or possibly the process of skin and joint involvement may be triggered by an overlapping mechanism

Chiu YG. Psoriasis Forum. 2012; 18(2): 48-56

Role of Osteoclast Precursors

• Circulating osteoclast precursors (OCPs) have been shown to be elevated in PsA.

• OCPs drop rapidly after anti-TNF Rx

• 25% of patients with psoriasis had elevated OCPs and 50 % of these developed PsA in 3 yrs

• Cell based assay difficult

The New Axial and Peripheral

Spondyloarthropathy Criteria

In patients with ≥3 months back pain

and age at onset <45 years

Sacroiliitis on imaging* plus ≥1 SpA feature†

HLA-B27 plus

≥2 other SpA features OR

van der Heijde D et al. ACR 2009, Philadelphia #1790; Rudwaleit M, et al.

Ann Rheum Dis 2009; 68:770; Rudwaleit M, et al. Ann Rheum Dis 2009; 68:777.

ASAS Classification Criteria for Axial Spondyloarthritis

(SpA) and Update of TNFi Treatment Recommendations

• *Sacroiliitis on imaging – Active (acute) inflammation on

MRI highly suggestive of sacroiliitis associated with SpA or definite radiographic sacroiliitis, according to mod NY criteria

• †SpA features – Inflammatory back pain

– Arthritis

– Enthesitis (heel)

– Uveitis

– Dactylitis

– Psoriasis

– Crohn‘s/colitis

– Good response to NSAIDs

– Family history for SpA

– HLA-B27

– Elevated CRP

ASAS Classification Criteria for Peripheral SpA

• ≥1 classic SpA feature:

– Uveitis

– Psoriasis

– Colitis

– Preceding infection

– HLA-B27

– Sacroiliitis by imaging*

• Definite radiographic sacroiliitis

• Active (acute) inflammation on MRI

• ≥ 2 other SpA features:

– Arthritis

– Enthesitis

– Dactylitis

– History of inflammatory

back pain

– Positive family history

or

Arthritis, Enthesitis, or Dactylitis, plus:

Rudwaleit M, et al. Presented at: 2009 ACR Annual Scientific Meeting; October 17-21, 2009; Philadelphia, PA. Abstract 1793.

Psoriatic Arthritis

CASPAR Criteria for PsA

Established Inflammatory Articular Disease (joint, spine, or entheseal) with 3 or more of:

1. Psoriasis

(a) Current (2 pts) Psoriatic skin or scalp disease as judged by a physician

(b) Hx A history of psoriasis that may be obtained from patient,

family doctor, dermatologist or rheumatologist

(c) Family Hx A history of psoriasis in a first or second degree relative

according to patient report

2. Psoriatic Nail Changes

Typical psoriatic nail dystrophy including onycholysis, pitting

and hyperkeratosis observed on current physical

examination

3. A negative test for RF By any method except latex, preferably by ELISA or

nephelometry, according to local laboratory reference range

4. Dactylitis (a) Current Swelling of an entire digit

(b) Hx A history of dactylitis recorded by a rheumatologist

5. Radiographic evidence of

juxta-articular new bone

formation

Ill-defined ossification near joint margins (but excluding

osteophyte formation) on plain radiographs of hand or foot

Taylor WJ, et al. Arthritis Rheum 54: 2665-2673, 2006

Psoriatic Arthritis: Epidemiology

• Reported incidence of PsA varies from 3.4 to 8 per

100,000 population

• Present in about 20%-30% of patients with psoriasis

• Occurs in about equal numbers in both sexes

• Mean onset of symptoms: between ages 30 and 50

Characteristics of PsA (MRI)

Dactylitis Enthesitis Linked to Bone Marrow Edema

McGonagle D et al. EULAR 2007. Barcelona; Eshed I et al. Ann Rheum Dis. 2007; 66:1553-1559. Ritchlin C et al. J Clin Invest. 2003;111:824.

Treatments for PsA

1. Data drawn from AS trials (applied as surrogate for PsA spondylitis)

Kavanaugh A et al. Systematic Review of Treatments for Psoriatic Arthritis. J Rheum. 2006;33(7):1417-21.

Peripheral

Arthritis

Skin and Nail

Disease Axial Disease 1 Dactylitis

Enthes

itis

NSAIDs ■ ■ ■ ■

Intra-articular

steroids ■

Topicals ■

Physiotherapy ■

Psoralen

UVA/UVB ■

Oral DMARDs ■ ■

Biologics ■ ■ ■ ■ ■

GRAPPA PsA Rx Recommendations

Ritchlin, CT, et al. Ann Rheum Dis. 2009;68:1387–94.

Peripheral

arthritis

Skin and nail

diseases

Axial

disease Dactylitis Enthesitis

Initiate therapy:

NSAID

IA steroids

DMARD

(MTX, CsA,

SSZ, LEF)

Biologics

(anti-TNF)

Initiate therapy:

Topicals

PUVA/UVB

Systemics

(MTX, CsA, etc)

Biologics

(anti-TNF, etc)

Initiate therapy:

NSAID

PT

Biologics

(anti-TNF)

Initiate therapy:

NSAID

Injection

Biologics

(anti-TNF)

Initiate therapy:

NSAID

PT

Biologics

(anti-TNF)

Reassess response to therapy and toxicity

Historical Data on MTX use in PSA

Study Duration Treatment # pts Results

1984 Willkens 3mo MTX vs Placebo 37

Improved

Physician

Global Only

1995 Spadaro 12 mo MYX vs Cyclosp 35 No def benefit

2005

Fraser 12 mo

MTX + placebo or

Cyclo in non-resp 72 No def benefit

2008

Scarpa 6 mo Early PSA 35

Definite

Improvement

NOR-DMARD

Lie

6 mo

Observational Compared RA to PSA 430 Similar results

MTX in PsA: RESPOND Trial

• Open label, 16 week trial of MTX 15-20 mg/week

vs. MTX plus infliximab

Baranauskaite et al., Ann Rheum Dis 2012;71:541.

115 subjects

randomized

57 assigned to

IFX + MTX

58 assigned to

MTX alone

47 completed study

through week 16

47 completed study

through week 16

4 withdrew consent

prior to treatment 10 discontinued

• 7 – Aes

• 1 – lost to follow up

• 2 – noncompliance

7 discontinued

• 2 – Aes

• 3 – noncompliance

• 2 – protocol eligibility

RESPOND Results


• Greater response to infliximab, however MTX effective

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

ACR20 ACR50 ACR70 DAS28

Remission

MTX

MTX + INF

Response at Week 16

RESPOND Skin Results


Outcome IFX + MTX (%) MTX (%) p value

PASI 50 100 80.0 0.0059

PASI 75 97.1 54.3 <0.0001

PASI 90 70.6 28.6 <0.01

MTX in Psoriatic Arthritis (MIPA) Trial

• Inclusion

– Synovitis in ≥ 1 joint

– Psoriasis skin/nails

• Exclusion

– Other arthropathies

– Recent steroids/DMARDS

– Contra-indications to MTX

• Intervention

– Methotrexate

(target 15mg/wk)

– Matching placebo

• Primary outcome

– Psoriatic Arthritis Response

Criteria

• Secondary outcomes

– Patient Global Assessments

– Assessor Global Assessments

– HAQ & Pain

– Tender & Swollen Joint

Counts

– ESR & CRP

– Composite Measures (ACR20)

Kingsley et al., Rheumatology 2012;51:1368.

Hypothesis: Methotrexate improves disease activity and function in

psoriatic arthritis

Design: 6-month RCT comparing methotrexate with placebo

MIPA Flowchart

Screened

462

Randomized

221

Not Entered

241

Ineligible: 148

- Previous methotrexate: 69

- Inactive arthritis: 47

- Concomitant disease: 21

- Diagnostic uncertainty: 11

Non-consent: 93

Allocated to Active

109

Allocated to Placebo

112

Follow Up

Lost to followed up (23)

- Adverse Events: 4

- Worse disease: 7

- Patient choice: 12

Discontinued Intervention (12)

- Adverse Events: 3

- Worse disease: 7

- Patient choice: 2

Follow Up

Lost to followed up (21)

- Adverse Events: 5

- Worse disease: 3

- Patient choice: 13

Discontinued Intervention (14)

- Adverse Events: 4

- Worse disease: 7

- Patient choice: 3

Analysed

Intention to Treat: 109 (100%)

Valid Complaint Completer: 67 (61%)

Excluded from analysis: (7)

Analysed

Intention to Treat: 112 (100%)

Valid Complaint Completer: 61 (54%)

Excluded from analysis: (16) Kingsley et al., Rheumatology 2012;51:1368.

Initial

NS

NS

NS

NS

3 months 6 months

Initial 3 months 6 months

Methotrexate Placebo



Swollen Joint Count

ESR HAQ

Tender Joint Count12

10

8

6

4

2

17

151311

9

75

1.5

1.3

1.1

0.9

0.7

0.5

25

20

15

10

MIPA Results

• Joint Counts, ESR and HAQ


MIPA Trial Caveats

• Small numbers of patients with high dropout

rate – may have been inadequately powered

• Target dose of MTX was 15 mg/week – too low?

• Mean joint count ~5 – to few to identify

response?

• Very high placebo response

Does MTX really work in PSA ?

Can we even tell from the available data?


59

38

11 15

4 0

0

10

20

30

40

50

60

70

80

90

100

ACR 20 ACR 50 ACR 70

Perc

en

t o

f P

ati

en

ts

P.001 for all endpoints

Etanercept Placebo

PsA: Etanercept Phase III Endpoints

Mease P. et al. Arthritis Rheum 2004; Jul;50(7):2264-72

With MTX Without MTX

*P.001

19 13

62 58

0

10

20

30

40

50

60

70

80

90

100

Pe

rce

nt

of

Pa

tie

nts

* *

Placebo Etanercept

PsA: Etanercept Phase III +/- MTX

Mease P. et al. Arthritis Rheum 2004; Jul;50(7):2264-72

PsA: Adalimumab Phase III

14

58

15

57

4

36

6

39

1

20

1

23

0

10

20

30

40

50

60

ACR20

ACR50

ACR70

All results

P<0.001 placebo

vs adalimumab

Perc

en

tag

e o

f P

ati

en

ts

Week 12 Week 24

n=162 n=162 n=151 n=151

Placebo Adalimumab

40 mg eow

Placebo Adalimumab

40 mg eow

Mease P. et al. Arthritis Rheum 2008; 67:Suppl_3 iii2-iii25

PsA: Adalimumab Phase III PASI

15

72

12

75

4

49

1

59

0

30

0

42

0

10

20

30

40

50

60

70

80

PASI 50 PASI 75 PASI 90

Perc

en

tag

e o

f P

ati

en

ts

Week 12 Week 24

n=69 n=69 n=69 n=69

All results

P<0.001 placebo

vs adalimumab Placebo Adalimumab

40 mg eow

Placebo Adalimumab

40 mg eow

Mease P. et al. Arthritis Rheum 2008; 67:Suppl_3 iii2-iii25

16% 11%

54% 58%

0

20

40

60

80

100

Week 14 Week 24 Pro

po

rtio

n o

f S

ub

jects

Ach

ievin

g A

CR

20

p < 0.001 p < 0.001

Primary Endpoint Major Secondary Endpoint

PsA: Infliximab Phase III ACR20

Placebo Infliximab

Antoni C, et al. Ann Rheum Dis. 2005;64:ii14-ii17.

Pe

rce

nt A

CR

20

Re

sp

on

de

rs

100

75

50

25

0 Week

Pbo/Inf

Inf/Inf

94 86 73 70 62 54 50 46 38 30 22 18 16 14 10 6 2 0

Placebo/Infliximab Infliximab in study extension

Infliximab/Infliximab

PsA: Infliximab Extension

• Methods: Pts randomized to inflix 5 mg/kg every 8 wks through week 46

– Open-label extension gave inflix 5 mg/kg at wks 54, 62, 70, 78, 86, 94

– Open arrows = placebo infusions; filled arrows = infliximab infusions

• Conclusions: Infliximab therapy through week 94 resulted in sustained improvement in joint/skin

sx, and inhibited radiographic progression

Antoni CE et al. J Rheum. 2008. 35:869–76

2.3% 1.1%

63.9% 60.2%

0

20

40

60

80

100

Week 14 Week 24

Pro

po

rtio

n o

f S

ub

jects

Ach

ievin

g P

AS

I 75

p < 0.001 p < 0.001

Major Secondary

Endpoint

Placebo Infliximab

PsA: Infliximab Phase III PASI


37.2% 33.7% 35.0%

20.4% 22.2%

42.0%

0

20

40

60

80

100

Baseline Week 14 Week 24

Pro

po

rtio

n o

f S

ub

jects

wit

h E

nth

eso

path

y

p = 0.016 p = 0.002

Placebo Infliximab

PsA: Infliximab Phase III Enthesitis


32 30

41

11 18

40

0

20

40

60

80

100


Placebo Infliximab

Nu

mb

er

of

Su

bje

cts

p = 0.025 p < 0.001

PsA: Infliximab Phase III Dactylitis


4

51 32

66

0102030405060708090

100

Week 24 Week 104

ACR 20 ACR 50

ACR 70

n=140 n=70 n=61

GLM 50 mg

PBO

Pati

en

ts (

%)

Pati

en

ts (

%)

Pati

en

ts (

%) *p<0.001 vs PBO

*

*

*

n=105

Enthesitis score†

Week 24 Week 104

*

Week 24 Week 104

12

72

52

91

0102030405060708090

100

n=113 n=146 n=70 n=61

19

44 1 31

0

20

40

60

80

100

Week 24 Week 104

n=140 n=70 n=61 n=105

-13

40 46

61

-20

0

20

40

60

80

Week 24 Week 104

PsA: Golimumab Phase III Controlled and OL

Kavanaugh et al. Arthritis Rheum 2009; Sep;68(9):1387-94. Kavanaugh et al. Arthritis Rheum 2012; 64(5):625-39.

Kavanaugh A et al. Ann Rheum Dis. 2011; 70:399.

1

72

56

69

0

20

40

60

80

100

Week 24 Week 104

Pati

en

ts (

%)

GLM 50 mg

PBO

*p<0.001 vs PBO

*

n=102

n=73 n=66 n=43

PASI 75

PsA: Golimumab PASI 75 Response

Noh JW, et al EULAR 2010, OP0025. Cantini F, et al. Biologics: Targets and Therapy, 2013; 7:1-6 .

Kavanaugh et al. Arthritis Rheum 2012; 64(5):625-39.

24 24

58 64

0

10

20

30

40

50

60

70

ACR 20

ACR 70 ACR 50

CZP 200 mg Q2 weeks

PBO

Pa

tien

ts (

%)

Pa

tien

ts (

%)

Week 12 Week 24

11 13

36

44

05

101520253035404550

Week 12 Week 24

Pa

tie

nts

(%

)

3 4

25 28

0

5

10

15

20

25

30

Week 12 Week 24

CZP 400 mg Q4 weeks

52 56

25 28

13

24

P<0.001 both CZP

arms vs placebo.

PsA: Certolizumab Phase III

Mease et al. Ann Rheum Dis.2014 Jan;73(1):48-55

15

62

0

20

40

60

80

100

1

Pati

en

ts (

%)

Week 24

CZP 200 mg Q2 weeks

PBO

CZP 400 mg Q4 weeks

61

*P<0.001 CZP arms vs placebo.

PsA: Certolizumab PASI 75 Response

Mease P, et al. EULAR 2012

IMPACT: Infliximab in PsA –

Mean PASI Score at Week 98

PASI (Psoriasis Area and Severity Index) Score measured at baseline

and weeks 50 and 98 for 46 patients evaluated at baseline and week 98.


5.7

1.2 1.5

0

2

4

6

8 M

ean P

AS

A S

core

Antoni CE et al. J Rheum. 2008. 35:869–76

IMPACT 2 – Total vdH-Sharp Score in PsA:

Mean Change at Weeks 24 and 54

• In placebo-controlled trial, pts received infliximab at wks 16, 18 and 22, then every 8 wks

• All pts received infliximab from week 24

Change f

rom

Baselin

e in

Tota

l vdH

-S S

core

P<0.001 0.82

0.53

-0.7

-0.94 -1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

Week 24 Week 54

Placebo (n=100) Infliximab 5 mg/kg (n=100)

Van der Heijde D et al. Ann Rheum Dis. 2005; 64:ii61-ii64.

IMPACT 2 – Probability of Structural Change

Cumulative percentage

Change in tota

l m

od

ifie

d v

dH

-Score

-15

-10

Placebo Infliximab 5 mg/kg

-5

0

5

10

15

0 10 20 30 40 50 60 70 80 90 100

Probability Plot

Van der Heijde D et al. Ann Rheum Dis. 2005; 64:ii61-ii64.

Patients with 1 Dactylitis Digits or

Enthesopathy at Baseline and at Week 24

P<0.001

Patients with 1 Dactylitis Digits

P=0.002

Patients with Enthesopathy

Perc

enta

ge o

f P

atients

Placebo (n=100) Infliximab 5 mg/kg (n=100)

41

34 40

12

0

20

40

60

80

100

Baseline Week 24

35 37 42

20

0

20

40

60

80

100

Baseline Week 24

Antoni C, Krueger GG, de Vlam K et al. Ann Rheum Dis. 2005; Aug;64(8):1150-7

ADEPT Study Design

• Co-primary endpoints included ACR20 response at Week 12 and

mean change from baseline in mTSS for adalimumab at Week 48

vs. placebo at Week 24

Adalimumab 40 mg EOW

(n=151)

Randomized controlled trial (RCT) Open-label extension (OLE)

Adalimumab 40 mg EOW (n=285)

Placebo EOW (n=162)

Week

0 12 24 48 88

N=313*

EOW=every other week

*315 patients were initially randomized, although 2 patients did not receive study drug

Mease, PJ, et al. Arthritis Rheum. 2005; 52: 3279-3289; Gladman DD, et al. Arthritis Rheum. 2007; 56:476-488; Data on file, AbbVie Inc.

Adalimumab in PsA (ADEPT):

2-Year ACR and PASI Scores

Adalimumab during RCT / adalimumab long-term Placebo during RCT / adalimumab long-term

2-year extension study: 277 subjects from 313 originally enrolled in RCT

0

10

20

30

40

50

60

70

80

90

100

0 24 48 72 96 120 144

Weeks

Resp

on

ders

(%

)


0

10

20

30

40

50

60

70

80

90

100

0 24 48 72 96 120 144 Weeks

Resp

on

ders

(%

)


0

10

20

30

40

50

60

70

80

0 24 48 72 96 120 144 Weeks

Resp

on

ders

(%

)

ACR20 ACR50 ACR70

0

10

20

30

40

50

60

70

80

0 24 48 72 96 120 144 Weeks

Resp

on

ders

(%

)

ACR20 ACR50 ACR70

Mease P et al. Ann Rheum Dis 2009;68:702.

*P ≤ 0.001 adalimumab at wk 24 vs placebo

Open-label phase Double-blind phase

Adalimumab 40 mg QOW (n = 152)

Placebo (n = 144)

Adalimumab 40 mg QOW or QW (n = 128)

Adalimumab 40 mg QOW or QW (n = 134)

(rolled over from placebo)

*

Weeks

0.9 1.0

-0.1* 0.1

-0.50

0.00

0.50

1.00

1.50

24 48

Weeks Me

an

Ch

an

ge

in

mT

SS

Gladman et al. Arthritis Rheum. 2007;56: 476-488.

Mease PJ et al. Poster FRI0212 presented at EULAR, June 2005; Vienna, Austria.

Adalimumab in PsA: (ADEPT): Mean Change From Baseline

in Modified Total Sharp Score (mTSS) at 48 Weeks

GO-REVEAL: ACR Response and Enthesitis Score (50 mg

dose): Placebo Controlled at Week 24 and OL at Week 104

4

51 32

66

0102030405060708090

100

Week 24 Week 104

ACR 20 ACR 50

ACR 70

n=140 n=70 n=61

GLM 50 mg

PBO

Pati

en

ts (

%)

Pati

en

ts (

%)

Pati

en

ts (

%) *p<0.001 vs PBO

*

*

*

n=105

Enthesitis score†

Week 24 Week 104

*

Week 24 Week 104

12

72

52

91

0102030405060708090

100

n=113 n=146 n=70 n=61

19

44 1 31

0

20

40

60

80

100

Week 24 Week 104

n=140 n=70 n=61 n=105

-13

40 46

61

-20

0

20

40

60

80

Week 24 Week 104

Kavanaugh A et al. Arthritis Rheum 2009;60:976, Kavanaugh et al. 64(5):625-39 Arthritis Rheum 2012.

Kavanaugh A et al. Ann Rheum Dis. 2011; 70 (Suppl 3):238.

RAPID- PSA: PASI 75 Response

15

62

0

20

40

60

80

100

1

Pati

en

ts (

%)

PASI 75

Week 24

CZP 200 mg Q2 weeks

PBO

CZP 400 mg Q4 weeks

61

* *

P<0.001 CZP arms vs placebo.

Mease P, et al. EULAR 2012 #512

Kavanaugh A et al. Arthritis Rheum 2009;60:976. Kavanaugh et al. Arthritis Rheum 2012; ;64(5):625-39.

GO-REVEAL: Mean Change From Baseline

In Total vdH-S Score Over Time

-0.4

-0.2

0

0.2

0.4

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Weeks

Mean C

hange F

rom

BL

GLM 100 mg (n=146)

GLM 50 mg (n=146)

PBO/PBO to 50 mg (n=113)

*

**

*p=0.011; **p=0.086

3 4

25 28

0

5

10

15

20

25

30

24 24

58 64

0

10

20

30

40

50

60

70

ACR 20

ACR 70 ACR 50

CZP 200 mg Q2 weeks

PBO

Pa

tien

ts (

%)

Pa

tie

nts

(%

)

*

Week 12 Week 24

11 13

36

44

05

101520253035404550

Week 12 Week 24

Pa

tien

ts (

%)

Week 12 Week 24

CZP 400 mg Q4 weeks

52 56

25 28

13

24



RAPID™-PSA: ACR Response At Weeks 12 and 24

RAPID- PSA: PASI 75 Response

15

62

0

20

40

60

80

100

1

Pati

en

ts (

%)

PASI 75

Week 24

CZP 200 mg Q2 weeks

PBO

CZP 400 mg Q4 weeks

61



IL-12 & IL-23 Differences: p40 Subunit is Common

IL - 23

IL-17

INF

IL -

12

IL - 12

p40 p35 p40

IL-12Rβ2 IL-12Rβ1

IL-23R

T cell membrane

IL-6

IL-22

Th1 cell proliferation Th17 cell proliferation

p19

IL-12Rβ1

Adapted from: Gutcher I, Becher B. J Clin Invest. 2007;117:1119-1127.

Ustekinumab in PsA

• PSUMMIT 1 – 615 pts with PsA despite DMARDs and/or NSAIDs

• PSUMMIT 2 – 312 pts with PsA despite DMARDs, NSAIDs, and/or TNFi’s (or intolerance/toxicity from TNFi)

– Intended as TNFi failure trial, but recruitment lagged

• Both included 3 arms:

– Placebo

– Ustekinumab 45 mg wks 0, 4, q12 wks

– Ustekinumab 90 mg wks 0, 4, q12 wks • Primary endpoints 24 weeks

PSUMMIT 1

11.0%

57.2%

62.4%

0%

10%

20%

30%

40%

50%

60%

70%

80%

PASI 75

PBO

UST 45 mg UST 90 mg

Response at Week 24

22.8%

8.7%

2.4%

42.4%

24.9%

12.2%

49.5%

27.9%

14.2%

0%

10%

20%

30%

40%

50%

60%

70%

80%


(pts with >3% BSA)

Kavanaugh A, et al. ACR 2012, L4.

PSUMMIT 2: Response at Week 24

PBO

UST 45 mg UST 90 mg

20.2%

6.7% 2.9%

* 43.7%

† 17.5%

6.8%

* 43.8%

* 22.9%

8.6%

0%

10%

20%

30%

40%

50%

60%

70%

80%


5.0%

51.3% 55.6%

0%

10%

20%

30%

40%

50%

60%

70%

80%

PASI 75 (pts with >3% BSA)

*P≤.001 vs placebo; †P<.05 vs placebo.

Ritchlin C, et al. ACR 2012, #2557

O

O

O

O

OO

O

S

N

NH

Apremilast

• Inhibits PDE 4 conversion of cAMP to AMP

• cAMP leads to dis-inhibition of PKA

• Results in inhibition of NFkB and stimulation of CREB

(Activates Transcription)

Role of PDE4

de Castro Barbosa, et al. BJPS 2011; 162:1674–1685

Apremilast PALACE Pivotal Trials

19

38

19

32

18

41

6

16

5

11 8

15

1 4

1 1 2 4

0

5

10

15

20

25

30

35

40

45

PBO +/- DMARDs(n=168)

Apremilast 30 mgBID +/- DMARDs

(n=168)



(n=162)



(n=167)

Pati

en

ts (

%)

Response at Week 16


Otezla® Package Insert

ACR20 Response Over 52 Weeks: PALACE 1, 2, 3 Apremilast 30 mg BID

0

10

20

30

40

50

60

70

PALACE 1

PALACE 2

PALACE 3

Study Week

16 24 40 52

55.0

63.0

52.6

Patients Receiving Apremilast From Baseline

Data as Observed

Pa

tie

nts

Ac

hie

vin

g a

n

AC

R20 R

esp

on

se (

%)

PALACE 1 (Responders/n) 64/150 73/145 80/140



Kavanaugh A, et al. EULAR 2013 [oral presentation]. Cutolo M. SIR 2013 [oral presentation].

Cutolo M. ACR 2013 [oral presentation]. Edwards CJ, et al. ACR 2013 #311.

5.3

17.0

3.9

33.1

58.7

21.7

0

10

20

30

40

50

60

70

PASI 75 PASI 50 sPGA

Pa

tie

nts

ac

hie

vin

g r

es

po

ns

e (

%) Placebo

Apremilast 30 mg BID

LOCF, Full Analysis Set (N=844)

282 562 n = 282 562 282 562

ESTEEM: Apremilast Psoriasis

Reich K, et al. AAD 2013: Late breaker.

Apremilast Dose Escalation Schedule

Table 1: Dosage Titration Schedule

Otezla® Package Insert

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 &

thereafter

AM AM PM AM PM AM PM AM PM AM PM

10 mg 10 mg 10 mg 10 mg 20 mg 20 mg 20 mg 20 mg 30 mg 30 mg 30 mg

2.2 Dosage Adjustment in Patients with Severe Renal Impairment

T Cell Differentiation and Role of IL-17

Koenders M I et al. Ann Rheum Dis 2006;65:iii29-iii33

IL-23/STAT3

Th 1 IL-23

Th 17

Th 2

IFNγ

IL-4, IL-10

IL-17

TNFα

IL-6

IL-17F Th 0

IL-17

Fibroblast

Macrophage

Chondrocyte

Osteoblast

Inflammation

Cartilage damage

Bone erosion

Cytokines/chemokines

-IL-1,-6,-8

-TNFα

-LIF, GRO, MIP-1α

-GM-CSF

Destruction mediators

-MMPs

-Nitric oxide

-COX2

RANK

Osteoclastogenesis

IL-23

IL-15

Th 17

Cytokine Signaling in PsA (and SpA)

Miossec P Nature Reviews Drug Discovery;2012(11):263

Secukinumab Phase III PsA

• Human anti-interleukin 17A antibody

• 2 pivotal trials, 1 IV load, 1 all subcut.

– Doses 75 mg, 150 mg, 300 mg q4wks

• Primary endpoint 24 weeks

– Open label extension to 52 weeks

Secukinumab Phase III, IV Load

0

20

40

60

80

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Re

sp

on

de

rs (

%)

50.0%

17.3%

69.5%

66.9%

50.5% Secukinumab 10/mg/kg IV

150 mg subcut (n=202)

Secukinumab 10/mg/kg IV

75 mg subcut (n=202)

Placebo (n=202)

Week

Mease P, et al. ACR 2014, Boston, #953

Secukinumab Phase III, Subcut Only

54

35.0

20.0

51

35

21 29

18

6

15 7

1 0

20

40

60

80

100

ACR20 ACR50 ACR70

‡

‡

*

‡

*

SKB 300 mg SC (n=100)

SKB 150 mg SC (n=100)

SKB 75 mg SC (n=99)

PBO (n=98)

Response at Week 24

McInnes I, et al. ACR 2014, Boston, #L1

Secukinumab Additional Endpoints

• Significant improvements in psoriasis, dactylitis, enthesitis in both trials

• Inhibition of structural damage demonstrated in IV load trial

• Significant, but lower response in TNFi experienced patients

• Safety:

– SAE’s comparable to placebo

– SIE’s 2.9/100 pt-yr 150 mg, 2.6/100 pt-yr 75 mg, 1.4/100 pt-yr placebo (IV load trial)

Ankylosing Spondylitis

Ankylosing Spondylitis (AS) Progression

Little H, et al. Am J Med. 1976;60:279-285.

AS: Prevalence in Adults

Khan MA. Ann Intern Med. 2002;136:896-907; Akkoc N and Khan, MA. Arthritis Rheum 2005 Dec;52(12):4048-9

Ethnic Group

or Region Prevalence in General Population (%)

Eskimos (Alaska) 0.4

Sami (Finland) 1.8

Northern Norway 1.4

Mordovia 0.5

The Netherlands 0.2

Germany (Berlin) 0.55

Background: AS

• Common clinical features:

– Axial arthritis (eg, spondylitis, sacrolitis)

– Arthritis of “girdle joints” (shoulders, hips)

– Morning stiffness

– Fatigue

– Fever

– Weight loss

• Disease in many pts is progressive, may lead to disability

• Severe AS may be associated with CV disease, pulmonary fibrosis, or neurologic sequelae

Age at onset of

symptoms

Age at diagnosis

Age (yrs)

% o

f P

atients

n=1,396

From first symptoms to diagnosis: 5 - 10 yrs

0

20

40

60

80

100

0 10 20 30 40 50 60 70

920 males

476 females

Feldtkeller E, et al. Z Rheumatol. 1999;58:21-30; Feldtkeller E, et al. Rheumatol Int. 2003;23:61-6

Age at Onset of Symptoms and Age

at Diagnosis in AS – Data from German AS Society (DVMB)

Diagnostic Standard for AS:

Modified New York Criteria (1984)

• Clinical criteria:

– Low back pain and stiffness for more than 3 months.

Improvements occur with exercise but not with rest

– Limitation on motion of the lumbar spine (occuring in sagittal

and frontal planes)

– Limitation of chest expansion (relative to normal values)

• Radiological criterion:

– Sacroiliitis (grade ≥2 bilaterally or grade 3-4 unilaterally)

Definite AS: Radiologic criterion present plus 1 or more clinical criterion

Probable AS: 3 clinical criteria present or radiologic criterion present without

clinical criteria

van der Linden S et al. Arthritis Rheum. 1984;27:361-8.

ASAS/EULAR Recommendations

for Management of AS (2005)

Education,

exercise,

physical

therapy,

rehabilitation,

patient

associations,

self-help

groups

NSAIDs

Peripheral

disease

Axial

disease

Sulfasalazine

TNF antagonists

A

n

a

l

g

e

s

i

c

s

Local corticosteroids

S

u

r

g

e

r

y

Zochling J et al. Ann Rheum Dis. 2006;65:442-452.

Efficacy of NSAIDs and Cox II Inhibitors

Pooled Effect Size* (95% CI)

Outcome NSAIDs Coxibs

Spinal pain 1.11 (0.96-1.26)

1.05 (0.88-1.22)

Peripheral joint pain 0.62 (0.26-0.97)

—

Function 0.62

(0.47-0.76) 0.63

(0.47-0.80)

Conclusion: NSAIDs improve spinal pain, peripheral joint pain, and function; Coxibs are equally effective, although effect on peripheral arthritis has not been investigated

*Compared with placebo, over 6 weeks

Zochling J et al. Ann Rheum Dis. 2006;65:423-432.

Efficacy of Sulfasalazine

(Cochrane Meta-Analysis)

Some Evidence of Benefit No Evidence of Benefit

• ESR

• Morning stiffness

• Peripheral arthritis (2 trials)

• Physical function

• Pain

• Spinal mobility

• Enthesitis

• Patient and physician global assessment

Conclusion: Patients with early disease, with higher levels of ESR, and peripheral arthritis may benefit

11 randomized controlled trials

Chen J, Liu C. Cochrane Database Syst Rev. 2005;(2):CD004800.

Response after 24 Weeks of TNF-alpha

Blocker Treatment in Ankylosing Spondylitis

0

10

20

30

40

50

60

Infliximab Placebo Etanercept Placebo Adalimumab Placebo

*Different studies, no head to head comparison

ASAS 40 ASAS 50 ASAS 40

%

van der Heijde et al, Arthritis Rheum 2005, 52: 582-91; Davis J et al, Arthritis Rheum. 2003, 48:3230-6;

van der Heijde et al, Arthritis Rheum 2006, 54:2136-46

Long-Term Efficacy of Etanercept

0

25

50

75

100

0 12 24 36 48 60 72 84 96

% R

es

po

nd

ers

Week

ASAS 20 ASAS 40

ASAS 5/6

RCT

(25 mg BIW etanercept)

Open Label

(25 mg BIW etanercept)

72-Week Open-Label Extension

Davis JC, et al. Ann Rheum Dis. 2005;64:1557-1562

Golimumab in AS: Week 104

• Purpose

– To assess GLM efficacy and safety at week 104

• Methods

– 356 pts randomized to GLM 50 mg, GLM 100 mg, PBO (1.8:1.8:1)

– Primary end point at week 14 with early escape possible at week 16

– Placebo pts crossed to GLM 50 mg at week 24

– Patients receiving GLM 50 mg could be dose-escalated to 100 mg during f/u

• Results (Week 104)

• Conclusion

– Clinical improvements noted at week 24 persisted to week 104

– No new safety signals

– Patients who early-escaped from GLM 50 mg to GLM 100 mg at week 14 had a diminished

response on all parameters, identifying a subset of patients who are TNF unresponsive?

Braun J et al. ACR 2009, Philadelphia #1259

GLM 50 GLM 100

n 90 118

ASAS 20 (%) 77 (86) 91 (77)

ASAS 40 (%) 74 (82) 71 (60)

Certolizumab in AS and Axial SpA

• RCT of pts meeting criteria for AS or non-radiographic axial SpA

(without sacroiliitis on plain radiographs)

• 325 pts treated for 12 weeks with placebo, 200 mg q2 wks,

or 400 mg q4 wks

• Equally effective in both classic AS and NR-axSpA

40

6

58.7

28.3

62.7

29.4

ASAS20 ASAS partialremission

PBO

CZP 200 mg Q2W

CZP 400 mg Q4W AS NR-AxSpA

% %

Landewé R, et al. ACR 2012, Washington, #777

20

40

60

80

100

0 20

40

60

80

100

0

Adalimumab in Axial SpA

• RCT of 195 pts meeting criteria for axial SpA

• Treatment with placebo vs. adalimumab 40 mg eow

0

10

20

3031 31

37

Placebo (N=94)

Adalimumab (N=91)

35

13

1915

6

ASAS20

% P

atie

nts

ASAS5/6 ASDASCII ASDAS MI BASDAI50

3

52

A

40

50

60

70

80

Sieper J, et al. Ann Rheum Dis 2012, online ahead of print.

Apremilast pilot in AS

Pathan E, et al. Ann Rheum Dis 2013;72:1475–80

START Study Design Pilot Study Investigating Co-primary Clinical and MRI Endpoints (N=38)

Placebo tablets BID

Follow-up

Apremilast tablets 10 mg BID, days 1-2

Apremilast tablets 20 mg BID, days 3-4

Apremilast tablets 30 mg BID, days 5-end

Active AS

patients

Random

ise

Screening 2 weeks Dose 12 weeks 4 weeks

85 57 29 15 8 1 113

Clinical assessments

Days

Imaging assessments

Treatment period

(days)

Mean

(S

E)

ab

so

lute

ch

an

ge

fro

m b

aselin

e i

n B

AS

DA

I

Apremilast Placebo

0.00

No

treatment

8 15 29 57 85 113

0.25

−0.25

−0.50

−0.75

−1.00

−1.25

−1.50

−1.75

−2.00

Apremilast Results

Pathan E, et al. Ann Rheum Dis 2013;72:1475–80

IL-6 in AS

Sieper J, et al. EULAR 2012, Berlin, #OP0166; Sieper J, et al. EULAR 2012, Berlin, #OP0169

• No significant response to IL-6 inhibition in two

separate trials:

– Tocilizumab– 99 pts 8 mg/kg IV q4 wks x 12 wks

– Sarilumab (human anti-IL6R) – 100 pts 150 mg/kg

subcut weekly x 12 wks

• No MRI improvement in sarilumab trial

• IL-6 doesn’t appear to be a viable target in AS

Secukinumab in AS

• Pilot study of secukinumab

(human anti-IL17A) in 30 pts with AS

– 2 mg/kg IV q3 wks x 2 doses

– Primary endpoint at week 6

Placebo

Secukinumab

80

60

40

20

0 ASAS20 ASAS40

Perc

ent

Respondin

g

61%

17%

30%

0%

100

Baeten D, et al. ACR 2010, #L7

Secukinumab Phase III AS

• Human anti-interleukin 17A antibody

• 2 pivotal trials, 1 IV load, 1 all subcut

– Doses 75 mg, 150 mg, q4wks

• Primary endpoint 16 weeks

– Open label extension to 52 weeks

Secukinumab in AS, IV Load

• Similar response in all subcut trial, except 75 mg dose somewhat

less effective

• Reduced efficacy in TNF experienced patients

• Safety profile similar to that seen in PsA

61 60

29

0

20

40

60

80*

42

33

13

0

20

40

60

80

*

*

% ASAS20 Response

Week 16

% ASAS40 Response

Week 16

Baeten D, et al. ACR 2014, Boston, #819

Are TNFi ‘Disease Modifying’ in AS?

• TNFi do not prevent

‘osteoproliferation’ in

established AS

• “Damage” in AS is both,

‘catabolic + anabolic’ (erosions

+ new bone formation)

• Could starting TNFi early

(in ‘nr axial SpA’ stage)

prevent osteoproliferation?

• Do they reduce rate of erosion

progression?

SPARTAN-GRAPPA Educational Symposium

0.9 0.9

0.8

1

0

0.2

0.4

0.6

0.8

1

1.2

Eta

nerc

ept

Inflixim

ab

Ada

limum

ab

OASIS

mSASSS Over 2 years Change in

Three separate trials, not head-to-head Van der Heijde et. Al. Arthritis Rheum. 2008 May;58(5):1324-31.

Van der Heijde et.al. Arthritis Rheum. 2008 Oct;58(10):3063-70.

Van der Heijde et al. Arthritis Res Ther. 2009;11(4):R127. Epub 2009 Aug 24

Do TNFi Slow Radiographic Progression in AS?

• Longitudinal cohort of 1600 patients with AS

• 368 with 2 radiographs at least 1.5 years apart (1.5−9 yrs) [mean = 2.8 yrs]

– Mean disease duration 16.5 years (±12.9 years), 75% male, 83% B27+

• Baseline ESR, baseline mSASSS & smoking associated with progression in MVA

TNFi protective against progression

• Reliability of propensity modelling?

• Adjustment for timing of xrays?

• Controlled for NSAID use?

Haroon N & Gensler LS et al, ACR 2012, Washington, #782

OR P value

Baseline ESR 1.02 0.07

Baseline

mSASSS 1.05 0.002

Smoking 1.1 0.01

TNFi use 0.38 0.01

Cannot Fully Withdraw TNFi Therapy in AS

0

1

2

3

4

5

6

7

Change f

rom

baselin

e

BASDAI BASFI BASMI

Infliximab withdrawal

Infliximab

readministration Weeks

Baraliakos X, et al. EULAR 2005, #FRI0222

Comcast Rx: Infliximab On-Demand

• 247 pts. randomized after loading to infliximab q6 wks vs. on-demand upon symptom recurrence

– On-demand group then randomized to MTX up to 12.5 mg vs. no MTX.

– Symptom recurrence determined via phone call

• ASAS 20 at 58 weeks 75% vs. 46%

• More infusions in continuous group

– MTX did not affect response or number of infusions

• More patients with infusion reactions in continuous treatment group (14.5% vs. 6.5%).

• MTX - no impact.

Breban M, et al. Arthritis Rheum 2008; 58:15–25

Possibility of Reducing TNFi Dose in AS

86.3 90.4

0

50

100

ETN 50 mg qweek ETN 50 mg qoweek

%

Noh JW, et al EULAR 2010, OP0025. Cantini F, et al. Biologics: Targets and Therapy, 2013; 7:1-6.

• Retrospective - etanercept could be stretched out as far as 25 mg

q12 days with maintenance of efficacy

• Prospective, open label trial from Italy - 78 pts in “clinical remission”

(BASDAI < 4, no acute phase reactants or extra-axial disease) on

etanercept 50 mg weekly were randomized to 50 mg q wk or eow

– Nearly all pts maintained response, in both groups

Conclusions

• PsA, AS and other spondyloarthropathies are

joint, enthesial, and skin inflammatory diseases

with distinctive clinical presentations and

extra-articular manifestations

• Traditional DMARDs may be effective for

peripheral disease, but no apparent effectiveness

in axial disease

• Current biologics may not slow progression,

but there is interest in targets that may

Conclusions (cont.)

• Anti-TNF agents have demonstrated efficacy for

treating multiple clinical domains of PsA, AS,

axial, and peripheral SpA

• Ongoing research is examining additional

targets, such as IL-17, for treating incomplete

responders to anti-TNF inhibitors

• The new axial and peripheral SpA criteria expand

the patient base for whom emerging therapies

will be assessed

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