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SpA non-radiografica: fase precoce di spondilite anchilosante o altro?

Ignazio Olivieri

Rheumatology Department of Lucania, S. Carlo Hospital of Potenza and Madonna delle Grazie Hospital of Matera

Disclosures

Consulting fees, research or institutional support and educational grants from: Abbott, Bristol Meyer Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Roche

Juvenile SpA

Reactive arthritis

Arthritis associated with

Ulcerative colitis and Crohn’s disease

Psoriatic Arthritis

Undifferentiated SpA

Acute anterior uveitis

Ankylosing Spondylitis

The spondyloarthritis complex

Historical Look at Classification Criteria for Axial SpA

Modified New York Criteria for AS1

1984

Sacroiliitis (x-ray) (required) Plus 1 below: IBP/stiffness >3 months Limitation of Lumbar spine motion Limitation of chest expansion

1 van der Linden et al. Arthritis Rheum. 1984 Apr;27(4):361-8.

Juvenile SpA

Reactive arthritis

Arthritis associated with

Ulcerative colitis and Crohn’s disease

Psoriatic Arthritis

Undifferentiated SpA

Acute anterior uveitis

Ankylosing Spondylitis

The spondyloarthritis complex

Historical Look at Classification Criteria for Axial SpA

Modified New York Criteria for AS1

1984

Amor Classification Criteria for Spondyloarthritis2

1990

1 van der Linden et al. Arthritis Rheum. 1984 Apr;27(4):361-8. 2Amor et al. Rev Rhum Mal Osteoartic.1990 Feb;57(2):85-9.

Sacroiliitis (x-ray) (required) Plus 1 below: Inflammatory LBP/stiffness >3 months Limitation of Lumbar spine motion Limitation of chest expansion

Scoring ≥6/23 points Examples: Good response to NSAIDs Expanded pain description Articular & Extra-articular manifestations Genetic Background (HLA-B27, family hx) Sacroiliitis (x-ray)

Historical Look at Classification Criteria for Axial SpA

Modified New York Criteria for AS1

1984

Amor Classification Criteria for Spondyloarthritis2

European Spondyloarthropathy Study Group (ESSG) Criteria3

1991 1990

1van der Linden et al. Arthritis Rheum. 1984 Apr;27(4):361-8. 2Amor et al. Rev Rhum Mal Osteoartic.1990 Feb;57(2):85-9. 3Dougados et al, Arthritis Rheum. 1991 Oct;34(10):1218-27.

IBP or Synovitis (required) Plus 1 below: Enthesitis Family hx Psoriasis, CD, or UC Preceding infection Buttock pain Sacroiliitis (x-ray) No HLA-B27

Sacroiliitis (x-ray) (required) Plus 1 below: Inflammatory LBP/stiffness >3 months Limitation of Lumbar spine motion Limitation of chest expansion

Scoring ≥6/23 points Examples: Good response to NSAIDs Expanded pain description Articular & Extra-articular manifestations Genetic Background (HLA-B27, family hx) Sacroiliitis (x-ray)

Historical Look at Classification Criteria for Axial SpA

Modified New York Criteria for AS1

1984

Amor Classification Criteria for Spondyloarthritis2

European Spondyloarthropathy Study Group (ESSG) Criteria3

1991 1990

van der Linden et al. Arthritis Rheum. 1984 Apr;27(4):361-8. Amor et al. Rev Rhum Mal Osteoartic.1990 Feb;57(2):85-9. Dougados et al, Arthritis Rheum. 1991 Oct;34(10):1218-27. Rudwaleit M et al. Ann Rheum Dis 2009;68 777-83

Sacroiliitis (x-ray) (required) Plus 1 below: Inflammatory LBP/stiffness >3 months Limitation of Lumbar spine motion Limitation of chest expansion

Scoring ≥6/23 points Examples: Good response to NSAIDs Expanded pain description Articular & Extra-articular manifestations Genetic Background (HLA-B27, family hx) Sacroiliitis (x-ray)

IBP or Synovitis (required) Plus 1 below: Enthesitis Family hx Psoriasis, CD, or UC Preceding infection Buttock pain Sacroiliitis (x-ray) No HLA-B27

Assessment of SpondyloArthritis (ASAS) Criteria for Axial Spondyloarthritis4

2009

Sacroiliitis (X-ray or MRI) Plus ≥1 SpA feature or HLA-B27 Plus ≥2 SpA features

Duration of symptoms (years)

Back pain Back pain Radiographic

sacroiliitis

Back pain

Syndesmophytes

Non-radiographic stage (axial undifferentiated

SpA)

Radiographic stage

Modified New York Criteria 1984

Rudwaleit M, et al. Arthritis Rheum. 2005;52:1000-8.

MRI sacroiliitis

Ankylosing Spondylitis

13

Definition of Positive MRI-SI Joint

ASAS handbook, Ann Rheum Dis 2009;68 (Suppl II) (with permission) 13

14

Age at First Symptoms and at First Diagnosis in Ankylosing Spondylitis Patients

1Feldtkeller et al. Current Opinion in Rheum 2000;12:239-247 (with permission).

Duration of symptoms (years)

Back pain Back pain Radiographic

sacroiliitis

Back pain

Syndesmophytes

Non-radiographic stage (axial undifferentiated

SpA)

Radiographic stage

Modified New York Criteria 1984

Rudwaleit M, et al. Arthritis Rheum. 2005;52:1000-8.

MRI sacroiliitis

Ankylosing Spondylitis

Duration of symptoms (years)

Back pain Back pain Radiographic

sacroiliitis

Back pain

Syndesmophytes

Non-radiographic stage (axial undifferentiated

SpA)

Radiographic stage

Modified New York Criteria 1984

Rudwaleit M, et al. Arthritis Rheum. 2005;52:1000-8.

MRI sacroiliitis

Axial spondyloarthritis

Predominantly Axial SpA

Ankylosing Spondylitis

Non-radiographic axial SpA

Predominantly Peripheral SpA

Reactive arthritis

Psoriatic Arthritis

Arthritis with inflammatory bowel disease

Undifferentiated SpA

Concept of Spondyloarthritides (SpA)

Disease course of axial spondyloarthritis

New Nomenclature (1)

Spondyloarthritis

Axial Peripheral

SIJ structural damage (plain pelvic X-Rays)

Yes No

Ankylosing Spondylitis Axial non radiographic spondyloarthritis

Axial radiographic Spondyloarthritis (1) Claudepierre P.et al. Joint Bone Spine 2012,79:534-5

Disease course of axial spondyloarthritis

Labelling of biologics in axial SpA

• 2004 → 2012: Ankylosing Spondylitis • 2012 → ongoing:

[ Ankylosing Spondylitis] OR Axial non-radiographic spondyloarthritis

and - SIJ inflammation at MRI OR Abnormal CRP axial spondyloarthritis with at least one of the following: - Presence of SIJ structural damage at pelvic X-Rays - Presence of SIJ inflammation at MRI or Abnormal CRP

57,1 54 54,6

68,2

47,6

0102030405060708090

100

GESPIC* Haibel ABILITY-I Kiltz ASASValidation

%

Percent Female in Non-Radiographic Axial SpA Cohorts

Rudwaleit. Arthritis Rheum. 2009:60(3)717–727. Haibel et al. Arthritis Rheum 2008;58(7):1981-91. Sieper et al. ACR 2011. Tues2486A. 4Kiltz et al. EULAR 2011 FRI 0529. Rudwaleit et al.Ann Rheum Dis 2009;68:777-783.

Female sex generally >50% of nr-axSpA cohort

*GESPIC combines patients with primarily axial and primarily peripheral symptoms

2 3 4

5

1

Disease course of axial spondyloarthritis

Structural damage in axial Spondyloarthritis

* Dougados M. et al. Joint Bone Spine 2011;78:598-603

Disease course of axial spondyloarthritis

Cross sectional analysis of familial SpA*

40%

70%

86%

<10n = 99

10-19n = 110

≥20 n = 120

Rad

iogr

aphi

c

Sacr

oilii

tis (%

)

Disease duration (years)

*Saïd-Nahal R, … Amor B, Dougados M, Breban M. Arthritis Rheum 2000;43:1356-1365

Disease course of axial spondyloarthritis

Baseline radiographic sacroiliitis

Yes no

112 11 3 84

11.6%

The GESPIC cohort

yes

no

2 ye

ar

Rad

iogr

aphi

c sa

croi

liitis

(115) (95) 2.6%

Disease course of axial spondyloarthritis

Baseline radiographic sacroiliitis

Yes no

116 16 7 310

yes

no

2 ye

ar

Rad

iogr

aphi

c sa

croi

liitis

(123) (326) 5.7%

4.9%

0-2 years1-2 2-9 years1,3-7 ≥10 years1,5

% progression 8-12% 20-45% 36-59%

Progression from non-radiographic axial SpA to AS: Longitudinal Studies

1Sampaio-Barros et al, J Rheumatol 2010; 37:1195-9. 2Poddubnyy et al, Ann Rheum Dis 2011; 70: 1369-74. 3Schattenkirchner et al, Clin Rheumnatol 1987; 6 (Suppl 2): 83-6. 4Sany et al. Arthritis Rheum 1980;23(2):258-9. 5Mau et al. J Rheumatol. 1988;15:1109–14. 6Oostveen et

al, J Rheumatol 1999; 26:1953-8. 7Bennett et al. Arthritis Rheum 2008; 58(11):3413-18.

Includes² only patients age ≥17

• Variable methodology and disease definitions were used in the studies reported • Most studies included report mixed axial and peripheral disease at baseline

• No study used ASAS criteria for axial SpA • Reported range represents data from different sources, study N range 23-119

32

Hypothetical Development of Radiographic Sacroiliitis in Patients With Axial SpA

0

20

40

60

80

100

2 5 10 20

Axi

al S

pA (%

)

Time (years)

Radiographic Non-radiographic

Chronic back pain

Disease course of axial spondyloarthritis

Natural history of the disease

Clinical features of Spa

CDER, FDA 2013. Regulatory considerations for the potential novel indication axial spondyloarthritis. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM366488.pdf. Accessed 20 February 2014.

Disease course of axial spondyloarthritis

Clinical features of Spa

Sacroiliitis on imaging

Natural history of the disease

CDER, FDA 2013. Regulatory considerations for the potential novel indication axial spondyloarthritis. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM366488.pdf. Accessed 20 February 2014.

Disease course of axial spondyloarthritis

Clinical features of Spa MRI

sacroiliitis

Radiographic sacroiliitis

Natural history of the disease

CDER, FDA 2013. Regulatory considerations for the potential novel indication axial spondyloarthritis. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM366488.pdf. Accessed 20 February 2014.

Disease course of axial spondyloarthritis

Clinical features of Spa

PROGRESSION

RESOLUTION

RESOLUTION

STABILITY

Natural history of the disease

Radiographic sacroiliitis

CDER, FDA 2013. Regulatory considerations for the potential novel indication axial spondyloarthritis. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM366488.pdf. Accessed 20 February 2014.

Disease course of axial spondyloarthritis

27,5 31,7 29,4

43,8

27,4

X-RAY +MRI +

n = 132

X-RAY +MRI -n = 55

X-RAY -MRI +n = 99

X-RAY -MRI -CRP +n = 33

X-RAY -MRI -CRP -

n = 154

BAS

FI (m

ean)

Imaging clinical

*Molto A…Dougados M. Ann Rheum Dis 2014, jan, Epub ahead of print

Validity of the ASAS criteria

Burden of the disease: BASFI*

Burden of disease in pre-radiographic axial SpA and established AS is similar

Rudwaleit M, et al. Arthritis Rheum. 2004;50:S211.

0

1

2

3

4

5

6

BASDAI Pain BASFI BASMI

AS 5-10 yrs. (n=120)AS <5 yrs. (n=105)Pre-radiogr. AS <5 yrs. (n=196)

ADALIMUMAB IN RHEUMATIC DISEASES

Sieper J, et al. Ann Rheum Dis 2013; 72:815-822

18 11

27

55

0

20

40

60

80

% p

atie

nts

baseline CRP * treatment

p=.03

Abnormal Normal 10/57 17/62 4/37 16/29

Baseline CRP

n/N:

% p

atie

nts

14 16

38 35

0

20

40

60

80 baseline sacroiliitis by MRI * treatment

p=.65

Positive Negative

7/51 17/45 7/45 16/46

Sacroiliitis on Baseline MRI

n/N:

Whole population * treatment

15

36

0

20

40

60

80

Placebo (n=94) Adalimumab (n=91)

% p

atie

nts

*

p<.001

Whole population

Efficacy (% ASAS40 response) Adalimumab in non-radiographic axial spondyloarthritis

Placebo

Adalimumab

111 65 46

0

15,2 20

28,6 33,3

41,4

44

0 3,8 14,8

15,7 14,8

38,5

51,9

0

10

20

30

40

50

60

0 2 4 6 8 10 12 14 16 18 20 22 24

Patie

nts (

%)

Weeks

ETN/ETN

PBO/ETN

Pfizer 1031 study – proportion of patients achieving ASAS40 response at week 12 and 24

*p<0.05; †p<0.01 vs placebo. ASAS, Assessment of SpondyloArthritis international Society; ETN, etanercept; LOCF, last observation carried forward; mITT, modified intention to treat; nr-axSpA, non-radiographic axial spondyloarthritis; NSAID, non-steroidal anti-inflammatory drug; PBO, placebo.

• In this population of patients with early, active nr-axSpA who had an inadequate response to ≥2 NSAIDs, ETN was more effective than PBO in decreasing disease activity

ASAS40 response at week 12 and 24 (mITT, LOCF)

Double blind Open label

*

* †

(n = 105)

(n = 108)

Dougados M, et al. Arth Rheum 2014;66:2091–2102.

15,4 15,4

44,9 43,5

49,3 54,3

0

20

40

60

80

Week 14 Week 24

Res

pons

e R

ate

(% P

atie

nts)

ASAS40 at Weeks 14 and 24

■ PBO ■ GLM 50 mg ■ GLM 100 mg

GO-RAISE Study In Ankylosing Spondylitis

50 mg golimumab every four weeks vs 100

mg golimumab every four weeks vs placebo

n= 78 138 140 Inman R et al. A&R 2008; 58:3402-12

* p<0.001 *

* *

*

GO-AHEAD Study

In non-radiographic axial spondyloarthritis

50 mg golimumab every four weeks vs placebo

Abstracts with data from GO-AHEAD are presented during the scientific sessions Posters THU0218 & THU0238 Abstract AB0757

Treatment of AS and nr-axSpA with Golimumab

CHMP positive opinion for

nr-axSpA indication received May 2015

Take home messages

CONCLUSIONS

Non-radiographic/Non-imaging axial

spondyloarthritis DOES EXIST The natural history of axial spondyloarthritis requires

further investigations Non-radiographic/Non-imaging axial

spondyloarthritis deserves to have access to all the therapies available for radiographic axial spondyloarthritis

Grazie per l’attenzione