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