CONCURRENT SYMPOSIUM- SPONDYLOARTHRITIS - Recent advances in the management of Axial SpA - Dr Nigil...

Axial Spondyloarthritis2016 Treatment Update

Nigil Haroon MD, PhD, DM

Asst. Professor of Medicine and RheumatologyUniversity of Toronto

Clinician Scientist and Attending PhysicianUniversity Health Network, Toronto

University of Toronto

Nigil Haroon. University of Toronto

Disclosures

• Consultant for Amgen, Abbvie, Celgene, Janssen, MSD, Novartis, UCB.

• Work Supported By CIHR Krembil Foundation TGTW Foundation


Cardiovascular mortality is increased in

A. Rheumatoid ArthritisB. Ankylosing SpondylitisC. Both A & B


Objectives

• Pathogenic Basis for Treatment Options in AxSpA

• Window of opportunity in AS treatment

• Interleukin 17A inhibition in AS

• Discuss 2016 update of ASAS/EULAR Recommendations


Prevalence trend: AS in Ontario

N=6,930

N=24,976

Haroon NN et al. BMJ Open 2014


Incidence rate increases significantly in Females between 2000:2005

Haroon NN et al. BMJ Open 2014


Goals of AxSpA Treatment

Baraliakos et al. Arthritis Research & Therapy 2008, 10:R104


Goals of AxSpA Treatment

Inflammation

New Bone Formation

Functional Capacity

Vascular Morbidity

Vascular Mortality

Haroon NN, et al. Annals of Internal Medicine: 2014


AS: Vascular Mortality

Haroon NN, et al. Annals of Internal Medicine: 2014

Favours ASFavours Controls

0

Cardio-V Mortality

Cerebro-V Mortality

HR: 1.35; 1.07-1.70

HR: 1.60; 1.17-2.20

1 2

35%

60%


STIR +: Inflammation T cells HypertrophicChondrocytes

Inflammatory Infiltrate (T, Fib, Mac)

CalcificationNew Bone

In situ hybridization TNFα mRNA in cellular infiltrate

Inflammatory Infiltrates in SI Joints

Braun J et al. Arthritis Rheum. 1995 Apr;38(4):499-505.

Bollow et al. Ann Rheum Dis 2000;59:135–140


IL-17+ve cells increased in SpA

Appel et al. Arthritis Research & Therapy 2011, 13:R95


Remains active

TNFi

TNFi Contraindication

Active AS

Remains active

Isolated sacroiliitis

Peripheral arthritis

Enthesitis

Monitor validated AS-Specific Disease Activity Measure, CRP, or ESR regularly

LEGENDStrongly recommendConditionally recommendConditionally recommend againstStrongly recommend againstQualifier

NSAIDsUse continuously if active

No preferred drug

No preferred drug

PhysicalTherapy Land-based over aquatic

Active over passive

Alternative TNFi

Local GC

Local GC Consider if ≤2 joints; use infrequently

Local GC Avoid Achilles, patellar, quadriceps

Non-TNFi biologic

Slow-Acting Drugs (SSZ, pamidronate)

Consider if peripheral joint disease or TNFi contraindcations

Systemic glucocorticoidsConsider if peripheral flare, pregnancy, IBD flare

use infliximab or adalimumab

Recurrent iritis

IBDuse TNFi monoclonals

Unsupervised back exercises, formal group or individual self-management education, fall evaluation/counseling


Delays in starting treatment has significant consequences in the management of AS

A. TrueB. False


Window of Opportunity


Davis JC Jr. et al. Arthritis Rheum 2003;48:3230-6; van der Heijde D et al. Arthritis Rheum 2005;52:582-91; van der Heijde D et al. Arthritis Rheum 2006;54:2136-46; Humira Product Monograph, Abbott Laboratories Ltd., 2009; Inman RD et al. Arthritis Rheum 2008;58(11):3402-12.

Anti-TNFs in AS: ASAS20 at 24 Weeks%

pat

ient

s

p<0.001

GolimumabEtanercept Adalimumab

p<0.001p<0.0001 p<0.001

Infliximab

p<0.001


31.3

18.812.5 15.0

77.8

61.155.6 60.0

0

20

40

60

80

100

ASAS 20 ASAS 50 Part. Remission BASDAI 50

Placebo Infliximab

Barkham N, et al. Arthritis Rheum. 2009;60:946-954.

P=0.006P=0.012 P=0.009 P=0.006

Perc

enta

ge o

f Pat

ient

sEfficacy of Infliximab in B27+ Patients

With MRI+ Early Sacroiliitis

Week 16


BASDAI50 response – Wk12

>=40% 20-40% 10-20% <10%

Vastesaeger N et al.Ann Rheum Dis 70:973, 2011.

Nigil Haroon. University of Toronto Alper M van Sijl et al. Ann Rheum Dis 2015;74:119-123

TNFi and progression of subclinical atherosclerosis in AS


TNFi and progression of subclinical atherosclerosis in AS

No-TNFi TNFI Rx0.59

0.60.610.620.630.640.650.660.670.680.69

PrePost

Correlation of ΔBASDAI & cIMTR = 0.308 (p=0.013)

CAROTID IMT


Spinal Fusion in AS &Window of Opportunity


Wide Variability in Progression of SpA

0 10 20 30 40 50 60 70 80 90 10005

1015202530354045

Δ m

SASS

S

Cumulative Probability Plot

© NIGIL HAROON


Predictors of Progression

Inflammation

Damage

Smoking

p < 0.001

p < 0.001

P = 0.002

Haroon N et al. Arthritis Rheum 2013


Spondyloarthritis

Inflammation

New Bone Formation

Inflammation New Bone Formation

Inflammation New Bone Formation


ASDAS and Progression of Spinal Fusion

< 1.3 1.3-2.1 2.1-3.5 >3.50

0.5

1

1.5

2

2.5

3

3.5

Rate

of m

SASS

S Pr

ogre

ssio

n (u

nits

/2yr

s)

Baseline ASDAS

Ramiro S. ARD. 2014

Inflammation and New Bone Formation

Baraliakos et al. Arthritis Research & Therapy 2008, 10:R104


It is important to continue NSAIDs even if patients are doing well on TNF inhibitors

A.TrueB.False


Mean daily dose of celecoxib: 243 mg in the continuous-

treatment group and 201 mg in the on-demand group.

Mean difference: 42 mg (P 0.0001).

Nigil Haroon. University of TorontoJoachim Sieper et al. Ann Rheum Dis doi:10.1136/annrheumdis-2015-207897

ENRADAS Study

Continuous GroupN=85

Continuous GroupN=62

On Demand GroupN=60

Baseline

2yr FU

NSAIDS continous group vs On Demand

On Demand GroupN=82

Effects of NSAIDs on RAdiographic Damage in Ankylosing Spondylitis

Nigil Haroon. University of Toronto Joachim Sieper et al. Ann Rheum Dis doi:10.1136/annrheumdis-2015-207897

ENRADAS: NSAID Index

Mean daily dose: 112mg

Mean daily dose: 66mg


Cumulative probability plot of X-ray Progression


ACR Abstract # 758. Sieper et al.

CONCLUSION

NSAIDs have no disease modifying effect

IMPLICATIONS

NSAIDs should be used for symptom modification in ASIf patients are stable on TNFi, NSAID continuation is

not warranted


OASIS data: mSASSS rate (p=ns)*

infliximab OASIS OASIS meeting study criteria)0

0.2

0.4

0.6

0.8

1

1.2

1.4

Infliximab*

Etanercept OASIS OASIS meeting study criteria)0

0.2

0.4

0.6

0.8

1

1.2

1.4

Etanercept*

.91 .951.27

.9 1.01.2

van der Heijde D et al., Arthritis Rheum 2008;58: 1324-31

van der Heijde D et al., Arth Res Ther 2008;58: 1324-31

van der Heijde D et al., Arthritis Rheum 2008;58: 3063-70

Adalimumab OASIS OASIS meeting study criteria)0

0.2

0.4

0.6

0.8

1

1.2

Adalimumab*

.81.0 .9

Credit: Lianne Gensler


Study Centers

United States

Toronto



CohortN: 334 Patients

HLA-B2783.4%

Males77%

Mean Age: 40.7 ± 13.8 years

Mean disease duration: 16.4 ± 12.8 yearsMean age of onset: 24.2 ± 9.9 years

Progressors

Non-Progressors


Early use of TNF-inhibitors reduces rate of radiographic progression

N=120N=42N=39

OR: 0.36; CI:0.15-0.91; p=0.03



Best results when TNF-inhibitors started within 10 years of disease onset

60%

20%



The Effect of TNF Inhibition on Radiographic Progression inAnkylosing Spondylitis: An Observational Cohort Study of

374 Patients. Maksymowych WP. et al.

• FOllow-up Research Cohort in AS (FORCAST)• 374 patients with AS from Northern Alberta• Mean FU of 3.1 years

ABSTRACT NUMBER: 975

Std Rx(n=147)

TNFi(n=227)


The Effect of TNF Inhibition on Radiographic Progression inAnkylosing Spondylitis: An Observational Cohort Study of

374 Patients. Maksymowych WP. et al.

ABSTRACT NUMBER: 975

Significant variables in multiple propensity analysis

Coefficient 95% CI p

Baseline mSASSS 0.018 0.003 – 0.032 0.015

Baseline ASDAS 0.24 0.031 – 0.45 0.024

Time between disease onset and anti-TNF start:

No anti-TNF Ref

<5 years -1.41 -2.56 – -0.25 0.017

5-10 years -0.34 -1.30 – 0.62 0.49

>10 years -0.17 -0.70 – 0.36 0.53

Maksymowych et al. ACR 2015


TNFi + High Dose NSAIDs decrease risk of progression in AS

Gensler L. et al. ACR 2016


Secukinumab Significantly Improves Signs and Symptoms of Active Ankylosing Spondylitis: 52-

Week Data From MEASURE 2, a Randomised, Double-Blind, Placebo-Controlled Phase 3 Trial With

Subcutaneous Loading and Maintenance Dosing

J. Sieper1, J. Braun2, X. Baraliakos2, D. Baeten3, M. Dougados4,

P. Emery5, A. Deodhar6, C. Wei7, B. Porter8, M. Andersson9,

S. Mpofu9, H. Richards9

1Charité University Medicine Berlin, Berlin, Germany; 2Rheumazentrum Ruhrgebiet, Herne, Germany; 3Academic Medical Centre, Amsterdam, The Netherlands; 4Université Paris René

Descartes and Hôpital Cochin, Paris, France; 5University of Leeds, Leeds, UK; 6Oregon Health & Science University, Portland, USA; 7Chung Shan Medical University Hospital,

Taichung, Taiwan; 8Novartis Pharmaceuticals Corporation, East Hanover, USA; 9Novartis Pharma AG, Basel, Switzerland

MED/COSas/0002


MEASURE 2: Study Design

Randomisation was stratified according to whether subjects were anti–TNF-naïve or had previous intolerance or inadequate response to anti-TNF therapy. BL, baseline; i.v., intravenous; q4wk, every 4 weeks; PBO, placebo; R, randomisation; s.c., subcutaneous; TNF, tumour necrosis factor; Wk, Week.- MED/COSas/0002

TreatmentLoading

PrimaryEndpoint

Secukinumab 75 mg s.c.Wk 4 and q4wk

Secukinumab75 mg s.c. BL, Wks 1, 2, 3

Secukinumab 150 mg s.c. Wk 4 and q4wk

Secukinumab150 mg s.c.BL, Wks 1, 2, 3

PBO s.c. BL, Wks1, 2, 3

PBO s.c. Wks 4, 8, 12



1 8 12 163 4Week 2BL

FinalInjection Wk 256

FinalAssessment/

Wk 260/Wk 268

R1:1:1

R1:1

46

N=72

N=73

N=74


Rapid Improvements in ASAS20 Response Through Week 16 (Primary Endpoint)

0 4 8 12 160

20

40

60

80

100

28.4%

41.1%

61.1%

Secukinumab 150 mg s.c. (N = 72) Secukinumab 75 mg s.c. (N= 73)Placebo (N = 74)

*

*

†

*P < 0.0001; †P < 0.001; §P < 0.01; ‡P < 0.05 versus placebo (P-values at week 16 were adjusted for multiplicity of testing); NRI data presented through Week 16.ASAS, Assessment of Spondyloarthritis International Society criteria; NRI, nonresponder imputation.- MED/COSas/0002

1 2 3

Per

cent

age

of R

espo

nder

s

§

‡

§

† †

‡

†

Weeks

†

47


ASAS20 Response in Anti–TNF-Naïve and Anti–TNF-IR Subjects at Weeks 16 and 52

†P < 0.001; ‡P < 0.05 vs. placebo at Week 16.ASAS, Assessment of Spondyloarthritis International Society criteria; s.c., subcutaneous; IR, inadequate response; TNF, Tumour necrosis factor.Anti–TNF-IR subjects had an inadequate response to, or intolerance of anti-TNF therapy. Missing data were imputed as non-responses through Week 16 (NRI, non-responder imputation); Week 52 data are as observed - MED/COSas/0002.

anti–TNF-naïve anti–TNF-IR0

20

40

60

80

100

68.2

50.051.1

2531.124.1

Secukinumab 150 mg s.c. Secukinumab 75 mg s.c. PlaceboP

erce

ntag

e of

Re-

spon

ders

‡

†

N = 44 N = 45 N = 45 N = 28 N = 28 N = 29

anti–TNF-naïve anti–TNF-IR0

20

40

60

80

10082.1

59.171.4

47.4

Per

cent

age

of

Res

pond

ers

N = 45

N=28 N=28

N = 44 N = 28 N = 28

At Week 16

At Week 52

48


Crohn’s Disease Worsening with Secukinumab


IL17−/− Mice Suffer Worse Epithelial Injury and Enhanced Gut Permeability after DSS

Administration

Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability. Immunity 43, 2015, 727–738

Gut P

erm

eabi

lity

Nigil Haroon. University of TorontoImmunity 2008 28, 445-453DOI: (10.1016/j.immuni.2008.03.001)

Different Faces of Th17 Cells


Dysregulation of Occludin Cellular Localization in the Absence of IL-17A after DSS-Induced Injury


No Increased Risk of IBD Among Secukinumab-Treated Patients with Pso, PsA or AS: Data from 14 Phase 2 and Phase 3 Clinical Studies. Atul

A. Deodhar et al.

ACR 2016: ABSTRACT NUMBER: 962


Secukinumab Phase II Study

Xenofon Baraliakos et al. Ann Rheum Dis 2015


Distribution of MRI inflammatory and fatty lesions in VEs in subjects (N=10) treated with secukinumab from core study baseline to week 94.

Xenofon Baraliakos et al. Ann Rheum Dis doi:10.1136/annrheumdis-2015-207544

©2015 by BMJ Publishing Group Ltd and European League Against Rheumatism


2016 Update of the ASAS-EULAR Management Recommendations for AxSpA

Current practice is to start with TNFi

If TNFi therapy fails, switch to another TNFi or IL-17i


Summary


The Team

Zhenbo Zhang

Kelly Thickett

Hasan Abdullah

Kirby Yee Matthew He Jano Muralitharan

Vidya Ranganathan

P Rahman D Philpott B WoutersMike Zeng

Archita Srinath

CONCURRENT SYMPOSIUM- SPONDYLOARTHRITIS - Recent advances in the management of Axial SpA - Dr Nigil...

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