biological-targeted treatments in gca & takayasu arteritis · gca and takayasu arteritis = same...

Biological-targeted treatments

in GCA & Takayasu arteritis

Maxime Samson

Department of Internal Medicine and Clinical Immunology, Dijon University Hospital

INSERM U1098, FHU Increase, University of Burgundy

9th international congress of Internal Medicine

Athens (9-11th March 2017)

Disclosures

Symposium ROCHE CHUGAÏ

Invitation to congressesROCHE CHUGAÏACTELIONLFBABBVIEGSK

GCA and Takayasu arteritis = same disease?

1 – Grayson PC et al. Ann Rheum Dis. 2012

Same histopathologyStrong similarities in the distribution of arterial disease 1

GCA and Takayasu arteritis = same disease?

GCA 2• age > 50• 10-20/105 people > 50 years /year• Caucasian people +++ • easy assessment of disease activity:

• symptoms• CRP, ESR, fibrinogen

TAK 3• age < 40• 1 – 3 / million / year• Asian countries (Japan) • difficult assessment of disease activity:

• imaging• scores

Same histopathologyStrong similarities in the distribution of arterial disease 1

1 – Grayson PC et al. Ann Rheum Dis. 20122 – Salvarani C et al. Lancet 2008

3 – Seyahi E. et al. Curr Opin Rheumatol 2017

GCA and TAK = same disease?

GCA 2• age > 50 (peak: 70-80)• sex ratio (F/H) ≈ 3• 10-20/105 people > 50 years /year

• Caucasian people +++ • Rare in Arabic and Asian countries

• easy assessment of disease activity: • symptoms• CRP, ESR, fibrinogen

TAK 3• age < 40 years• Sex ratio (F/H) = 5-12 • 1 – 3 / million / year

• Asian countries (Japan) • Turkey (northwestern)

• difficult assessment of disease activity:

• imaging• scores

1 – Grayson PC et al. Ann Rheum Dis. 20122 – Salvarani C et al. Lancet 2008

3 – Seyahi E. et al. Curr Opin Rheumatol 2017

Glucocorticoids remain the first-line treatment of GCA and TAK

Same histopathologyStrong similarities in the distribution of arterial disease 1

GC-sparing drugs in GCA

Azathioprine: 32 patients, AZA after remission, negative 1

Dapsone: toxicity (agranulocytosis) 2

Hydroxychloroquine: 74 patients, negative 3

1 – De Silva M et al Ann Rheum Dis 19862 – Liozon F et al. Eur J Intern Med 19933 – Sailler L et al. ACR Atlanta 2009

Azathioprine 1

Dapsone 2

Hydroxychloroquine 3

Methotrexate

7.5 to 20 mg/week, during 12 - 24 months 4,5,6

Meta-analysis 7

Reduction in the risk of relapse

Mild GC-sparing effect

1 – De Silva M et al Ann Rheum Dis 19862 – Liozon F et al. Eur J Intern Med 19933 – Sailler L et al. ACR Atlanta 2009

4 – Spiera RF et al. Clin Exp Rheumatol 20015 – Jover JA et al. Ann Intern Med 20016 – Hoffman G et al Arthritis Rheum 20027 – Mahr A et al. Arthritis Rheum 2007

GC-sparing drugs in GCA

GC-sparing drugs in TAK

Misra DP et al. Autoimmunity Reviews 2017

NA: not available↑ improvement

↓ worsening→← no change

GC-sparing drugs in TAK

Misra DP et al. Autoimmunity Reviews 2017

NA: not available↑ improvement

↓ worsening→← no change

What is the place of biologics in the treatment

of GCA and TAK?

When?

Usually after failure of tapering GC despite the use of IS

At diagnosis?

What biologic?

Anti-TNF-α agents

Anti-IL-6R (tocilizumab)

Other biologics: abatacept, ustekinumab

Anti-TNF-α drugs in GCA

TNF-α

Hernandez-Rodriguez J et al. Rheumatology (Oxford) 2004

Anti-TNF-α drugs in GCA

TNF-α

Hernandez-Rodriguez J et al. Rheumatology (Oxford) 2004Samson M et al. Ann Rheum Dis 2013

Anti-TNF-α drugs in GCA

Infliximab 1

44 patients

Infliximab (n=28)

Placebo (n=16)

GC discontinuation before W24Infliximab or placebo:

- W0, W2, W6 - and every 8 weeks

1 – Hoffman G et al. Ann Intern Med 2007

Anti-TNF-α drugs in GCA

Infliximab 1

Etanercept 2

ETA (n=8) vs. PLA (n=9)

25 mg twice a week from inclusion to 12 months

Primary endpoint = % of patients with a controlled disease without prednisone at month 12

PLA = 22%

ETA = 50%

1 – Hoffman G et al. Ann Intern Med 20072 – Martinez-Taboada VM et al. Ann Rheum Dis 2008

NS

Anti-TNF-α drugs in GCA

Infliximab 1

Etanercept 2

Adalimumab 3

70 patients

Adalimumab (n=34)

Placebo (n=36)

1 – Hoffman G et al. Ann Intern Med 20072 – Martinez-Taboada VM et al. Ann Rheum Dis 20083 – Seror R et al. Ann Rheum Dis 2013

ADA/PLA

P = 0.51

Anti-TNF-α drugs in TAK

Usually after failure of tapering GC despite the use of IS

No randomized controlled studies

Anti-TNF-α drugs in TAK

Review of TAK patients treated with anti-TNF-α agents 1

120 patients in 20 observational studies

Infliximab (n=109)

Etanercept (n=17); adalimumab (n=9)

Responders = 80%

GC tapering or discontinuation = 40%

Relapses = 37%

1 – Clifford A et al. Curr Opin Rheumatol 2013

Anti-TNF-α drugs in TAK

French Takayasu Network 1

49 patients TAK patients treated with biologics

35 treated with anti TNF-α agents

Infliximab = 28

Etanercept = 6

Adalmimumab = 1

1 – Mekinian A et al. Circulation 2015

Anti-TNF-α drugs in TAK

French Takayasu Network 1

49 patients TAK patients treated with biologics

35 treated with anti TNF-α agents

Complete response = NIH scale <2 and prednisone <10 mg/d

3 months: 35%

6 months: 61%

12 months: 74%

40% of switch to another biologic

1 – Mekinian A et al. Circulation 2015

Anti-TNF-α drugs in TAK

French Takayasu Network 1

Relapse-free survival at 3 years (Andersen-Gill)

1 – Mekinian A et al. Circulation 2015

Biologics = 91%

DMARDS = 59%

P = 0.009

Biologics

DMARDS

Biologics were associated with

DMARDs (MTX++)in 76% of cases

Anti-TNF-α in GCA and TAKTake-home messages

GCA

No effect:

1 - to prevent relapse2 - to spare GC

TAK

Probably effective to prevent relapse(s) and spare GC

BUT no randomized controlled

trial

1 – Samson M et al. Rev Rhum 2017

GCA pathogenesis

1 – Samson M et al. Rev Rhum 2017

GCA pathogenesis

1 – Samson M et al. Rev Rhum 2017

GCA pathogenesis

1 – Samson M et al. Rev Rhum 2017

GCA pathogenesis

1 – Samson M et al. Rev Rhum 2017

GCA pathogenesis

1 – Samson M et al. Rev Rhum 2017

TAK pathogenesis

↑ IL-6 in vascular lesions 2

↑ IL-6 in the serum 3 1 – Samson M et al. Rev Med Int 20162 – Saadoun D et al. Arthritis Rheumatol 2015

3 - Park MC et al. Rheumatology (Oxford) 2006

1 - Villiger PM et al. Lancet 2016

First randomized controlled trial 1

Monocentric (2011-2014)

30 GCA patients:

23 new onset GCA

7 relapsing GCA

2 arms:

Prednisone + TCZ (8mg/Kg/4 weeks during 52 weeks) (n=20)

Prednisone + placebo (n=10)

Tocilizumab in GCA(Villiger PM et al. Lancet 2016)

Tocilizumab in GCA(Villiger PM et al. Lancet 2016)

Villiger PM et al. Lancet 2016

Prednisone regimen

Pre

dn

iso

ne (

mg

/Kg

/day) At inclusion = 1 mg/Kg/day

Rapid tapering: 0.1 mg/kg/wk (W0 - W8)

0.05 mg/Kg/wk (W8 - W12)

Then 1 mg/month until discontinuation

CS discontinuation at W36

Weeks

Villiger PM et al. Lancet 2016

Relapse-free survival at week 52

Tocilizumab in GCA(Villiger PM et al. Lancet 2016)

Tocilizumab

Placebo

P=0.0005

TOCILIZUMAB IN GCAGIACTA (Stone JH et al. ACR 2016)

251 patients: (47% new-onset GCA; 53% relapsing GCA)

Age > 50 years

ESR > 50 mm/hr (or CRP ≥ 24.5 mg/L)

Clinical signs of GCA or PMR

Proof of vasculitis:

Positive TAB

Evidence of large vessel vasculitis by angio-CT scan, angio-MRI, PET-CT

(not Doppler)

TOCILIZUMAB IN GCAGIACTA (Stone JH et al. ACR 2016)

% of sustained remission

(remission without relapse and deviation from the prednisone regimen)

Randomized double-blind

Dramatic efficacy of tocilizumab

TOCILIZUMAB IN GCAGIACTA (Stone JH et al. ACR 2016)

Safety

PLA+ 26 W

PLA + 52 W

TCZ / w TCZ / 2 w

≥ 1 AE 96% 92.2% 98% 95.9%

≥ 1 SAE 22% 25.5% 15% 14.3%

No deathsNo bowel perforation2 cancers (in placebo groups)

TOCILIZUMAB IN GCAGIACTA (Stone JH et al. ACR 2016)

TOCILIZUMAB IN GCAHORTOCI (Samson M et al. ACR 2016)

Phase 2 multicenter prospective open-label study

Follow-up = 52 weeks

20 newly diagnosed GCA patients

3/5 ACR criteria

AND proof of vasculitis:

Positive TAB

OR aortitis (angio-CT scan or 18FDG-PET scan)

Starting dosage = 0.7 mg/Kg/day Dosage at week 24 = 0.1 mg/Kg/day

Prednisone (e.g. for 60 Kg):Prednisone <10 mg/day at week 12GC discontinuation at week 48Cumulative dose = 2653 mg

4 infusions of IV tocilizumab (8 mg/Kg/4 weeks)

weeks

Tocilizumab

TOCILIZUMAB IN GCAHORTOCI (Samson M et al. ACR 2016)

Re

lap

se-f

ree

su

rviv

al1.0

0.8

0.6

0.4

0.2

0.0

TCZ

Weeks

75% at 6 months45% at 1 year

TOCILIZUMAB IN GCAHORTOCI (Samson M et al. ACR 2016)

Tocilizumab in TAK

1 – Koster MJ et al. Curr Opin Rheumatol 20162 – Goel R et al. Int J Rheum Dis 20133 – Xenidis T et al. Rheumatology (oxford) 2013

4 – Tombetti E et al. J Rheumatol 20135 – Bredemeier M et al. Clin Exp Rheumatol 2012

Observational cohorts 1

≈ 70 patients with TAK (often relapsing/refractory)

TCZ at 8 mg/Kg/4 weeks

o > 80% of clinical and laboratory improvement by 3 months

o < 20% of relapse during treatment

• clinical and angiographic signs of activity

• BUT normal acute phase reactants 2-5

Tocilizumab in TAK(Nakaoka Y et al. ACR 2016)

Double-blind randomized controlled trial

36 relapsing TAK patients randomized in 2 groups:

TCZ 162 mg/week SC

Placebo

Prednisone regimen: tapered by 10%/week from week 4

Primary endpoint: time to first relapse of TAK (Kerr’s criteria)

Tocilizumab in TAK(Nakaoka Y et al. ACR 2016)

P = 0.596

Tocilizumab

Placebo

Tocilizumab in GCA and TAKTake-home messages

GCA

2 positive RCT

Effective +++…

BUT probably not curative

Tocilizumab in GCA and TAKTake-home messages

GCA

2 positive RCT

Effective +++…

BUT probably not curative

TAK

1 small negative RCT

Effective?

Tocilizumab in GCA and TAKTake-home messages

GCA

2 positive RCT

Effective +++…

BUT probably not curative

TAK

1 small negative RCT

Effective?

These patients are difficult to monitor

AbataceptInhibition of T cell activation

CTLA4-Ig (abatacept)

Multicenter randomized controlled trial

GCA (ACR criteria)

New-onset diseases

OR relapsing GCA

Abatacept in GCALangford CA et al (Arthritis and Rheum 2017)

Prednisone (40-60 mg/d), then taperedAbatacept (10mg/kg) at D1, D15, D29 & W8

Remission at W12? No

Yes

Abatacept(10 mg/kg/28 days)

Placebo(every 28 days)

Stop GC at W28

Remission Relapse

Continuation until 12 months

Stop abatacept/placebo

Follow up until W24 after stopping abatacept/placebo

Randomization

Abatacept in GCALangford CA et al (Arthritis and Rheum 2017)

Months

Re

lap

se-f

ree

su

rviv

al (

%)

41 randomized patients (44% relapsing GCA)

abatacept

placebo

Survival without relapse at 12 months:Abatacept = 48%Placebo = 31%

P = 0.049

Abatacept in GCALangford CA et al (Arthritis and Rheum 2017)

Months

Re

lap

se-f

ree

su

rviv

al (

%)

26 randomized patients (4 newly diagnosed, all in placebo group)

abatacept

placebo

Survival without relapse at 12 months:Abatacept = 22%Placebo = 40%

P = 0.853

Abatacept in TAKLangford CA et al (Arthritis and Rheum 2017)

Abatacept in GCA and TAKTake-home messages

GCA

1 positive RCT

Moderate effect

TAK

1 negative RCT

No effect

Ustekinumab

anti p40 (IL-12/23)(ustekinumab)

Bensson et al Nat Biotech 2011

↓ Th1 ↓ Th17

25 patients with refractory GCA

Ustekinumab 90 mg SC at W0, W4 and every 12 weeks

Follow-up = 15 months

Efficacy and good safety profile

Decrease in the dose of GC: 15 to 5 mg/day (P=0.002)

Without new relapse

11 AE

2 relapses after stopping ustekinumab in 3 patients

Ustekinumab(Conway R et al. Ann Rheum Dis. 2016; ACR 2015 - 2016 )

Anakinra (IL-1Ra) GCA: 3 cases 1 & an ongoing trial (NCT02902731)

Rituximab (anti-CD20) GCA: 2 cases 2,3

TAK: 8 cases 4-7

Other biologics

1 - Ly K et al. Joint Bone Spine 20142 - Mayrbaeurl B et al. Clin Rheumatol 20073 – Bhatia A et al. Ann Rheum Dis 20054 – Hoyer BF et al. Ann Rheum Dis 2012

5 – Galarza C et al. Clin Rev Allergy Immunol 20086 – Ernts D et al. Case Repo Rheumatol 20127 – Caltran E et al. Clin Rheumatol 2014

Conclusion

1 – Glucocorticoids remain the cornerstone of the

treatment of GCA and TAK

2 – Conventional IS drugs (MTX +++) are still useful to

treat relapsing or corticodependent patients

Conclusion

GCA

EffectiveTocilizumab +++

Abatacept

Not effectiveAnti TNF-α

Need for more dataUstekinumab

Anakinra

TAK

Effective?Anti-TNF-α

Not effective? (more data needed)

Tocilizumab

Not effectiveAbatacept

Conclusion

GCA

EffectiveTocilizumab +++

Abatacept

Not effectiveAnti TNF-α

Need for more dataUstekinumab

Anakinra

Thank you for your attention

DijonINSERM U 1098

Immunoregulation and Immunopathology

BarcelonaVasculitis Research Unit - IDIBAPS

Hospital Clínic, University of Barcelona