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CRMO

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Il razionale di una scelta
terapeutica
Fabrizio De Benedetti
UOC Reumatologia
Ospedale Pediatrico Bambino Gesù
Chronic Recurrent Multifocal
Osteomyelitis (CRMO)
 Rare childhood disorder
 It presents with bone pain, fever and
multifocal osteolytic bone lesions
 It is usually sporadic but there is
evidence of a genetic component
 Etiology and pathogenesis are unknown
OSTEOCLAST
NUCLEI
BONE MATRIX
CRMO: bone scan - whole body MRI
proIL-1b
IL-1b
Interleukin-1 drives chronic multifocal osteomyelitis
(CMO) in mice
(Cassel SL et al PNASS 2014 – Lukens JR et al PNAS 2014)
CMO mice: autosomal recessive – Mutation in Pstpip2
- Increased production of proinflammatory cytokines
- bone inflammation and destruction
Interleukin-1 drives chronic multifocal osteomyelitis
(CMO) in mice
(Cassel SL et al PNASS 2014 – Lukens JR et al PNAS 2014)
CMO mice: autosomal recessive – Mutation in Pstpip2
- IL-1R-/- mice and IL-1b -/-mice are protected from
disease
• Evidence from murine models in CRMO
• Role of IL-1 in genetic CRMO (Majeed syndrome)
• Evidence for inflammasome activation in CRMO
Majeed syndrome
•
•
•
•
Chronic recurrent multifocal osteomyelitis
Mycrocytic congenital dyserythropoiesis
Recurrent fever
Neutrophilic dermatosis
• Caused by mutation in LPIN2
–
–
–
–
Phosphatase involved in glycerolipid biosynthesis
Transcription coactivators of lipid metabolism genes
Possible role in oxidative stress
Possible role in chromosomal missegregation
Majeed syndrome
Prompt response of inflammatory markers and of
bone lesions to IL-1 inhibition
Herlin T et al, Ann Rheum Dis 2013
Etanercept
Anakinra
Canakinumab
• Evidence from murine models in CRMO
• Role of IL-1 in genetic CRMO (Majeed syndrome)
• Evidence for inflammasome activation in CRMO
Inflammasome and IL-1b in CRMO
• Increased expression of inflammasome components and of IL-1b
• Increased in vitro release of IL-1b (D)
• Increased expression of IL-1b in bone resorbing osteoclasts (OC)
4
2
*
15
10
5
0
0
*
60
IL-1β mRNA (AU)
*
*
20
CASP-1 mRNA (AU)
ASC mRNA (AU)
6
45
30
*
15
0
LPS stimulation
Healthy donors
CRMO: remission
CRMO:active disease
IL-1β (ng/ml)
Log scale
10
*
1
0.1
0.01
Scianaro R et al, submitted 2014
Expression of inflammasome components
in bone biopsies from CRMO patients
HEMATOSSILIN-EOSIN
Control
CRMO
ASC
Control
CONTROL ANTIBODY
Control
CRMO
CRMO
Expression of inflammasome components
in bone biopsies from CRMO patients
HEMATOSSILIN-EOSIN
Control
CRMO
NLRP3
Control
CONTROL ANTIBODY
Control
CRMO
CRMO
Expression of inflammasome components
in bone biopsies from CRMO patients
HEMATOSSILIN-EOSIN
Control
CRMO
CASP-1
Control
CONTROL ANTIBODY
Control
CRMO
CRMO
Expression of inflammasome components
in bone biopsies from CRMO patients
HEMATOSSILIN-EOSIN
Control
CRMO
IL-1β
Control
CONTROL ANTIBODY
Control
CRMO
CRMO
• Evidence from murine models in CRMO
• Role of IL-1 in genetic CRMO (Majeed syndrome)
• Inflammasome and IL-1b in CRMO
Sir George Frederick Still
(from the painting by Gerald Kelly)
Systemic Juvenile Idiopatic Arthritis
Arthritis in one or more joints with or preceded by fever of at least 2 weeks’
duration that is documented to be daily (“quotidian”) for at least 3 days, and
accompanied by one or more of the following:
1. Evanescent (nonfixed) erythematous rash
2. Generalized lymph node enlargement
3. Hepatomegaly and/or splenomegaly
4. Serositis
Petty RE, et al. ILAR classification of JIA: 2nd
Revision, Edmonton, 2001. J Rheumatol 2004
s-JIA: natural disease course
• monocyclic course (40%)
– remission within 2–4 years
• relapsing course (10%)
– flares of systemic features and mild arthritis
• persistent course (50%)
– systemic flares with persistence of arthritis
– persistence of both systemic features and
arthritis
Lomater C et al, J Rheumatol 2000
Singh-Grewal et al, A&R 2006
IL-6 in systemic JIA
An example of forward translational research
400
Synovial Fluid
IL-6 Levels (HGF Unit/ml)
IL-6 Levels (HGF Unit/ml)
Serum
*
300
200
100
0
sJIA
pJIA
oJIA
pJIA = polyarticular JIA, oJIA = oligoarticluar JIA
* p<0.001 vs other arthritides
RA
40,000
*
30,000
20,000
10,000
0
sJIA
pJIA
oJIA
RA
De Benedetti F, et al. Arthritis Rheum 1991; 34:1158–1163.
De Benedetti F, et al. Clin Exp Rheumatol 1992; 10:493–498.
De Benedetti F, et al. J Rheumatol 1997; 24:1403–1409.
Anemia
Lancet 1995
Blood 1996
Thrombocytosis
Fever
A&R 1991
Prominent
Interleukin-6
production in
systemic JIA
A&R 1991
IL6/soluble IL6R and CRP
Osteoporosis
Joint Inflammation
J Exp Med 1998
Growth Impairment
J Clin Invest 1997
Endocrinol 2001
MAS
A&R 2006
J Clin Invest 1994
A&R 2012
Tocilizumab (TCZ)
A humanized MoAb against the IL-6R
TCZ
IL-6
sIL-6R
IL-6R
gp130
MoAb = monoclonal antibody
gp130
Based on: De Benedetti F & Martini A. Arthritis Rheum 2005; 52:685–693.
TENDER: Tocilizumab (anti-IL6R) in sJIA
JIA ACR Responses Over Time
100
Patients, %
80
60
JIA ACR30
JIA ACR50
JIA ACR70
JIA ACR90
40
20
0
0
12
26
38
52
64
78
90
104
Weeks
Percentage is based on number of patients who reached time point + patients who withdrew because of insufficient
therapeutic response and are assumed to have been nonresponders.
De Benedetti et al, NEJM 2012
TENDER: Tocilizumab (anti-IL6R) in sJIA
Mean Oral Corticosteroid Dose Over Time
60% discontinued CS by week 104
0,35
0,3
Mean dose decreased to 0.04 mg/kg/day
Mean (SE) Dose
0,25
0,2
0,15
0,1
0,05
0
0
26
52
Weeks
78
Patients who withdrew have been excluded at postwithdrawal visits.
.
104
De Benedetti et al, NEJM 2012
Reverse translation identifying the role of
IL-1 in sJIA using IL-1 inhibitors
• Clinical response to anakinra in patients with sJIA
FEVER
ARTHRITIS
41
14
Active joint count
Temperature (°C)
p=0.001
40
39
38
37
36
p=0.006
12
10
8
6
4
2
0
-2
0
2
4
6
8
Coloured lines represent individual sJIA patients
Black arrow indicates time of treatment initiation
12
-2
0
2
4
6
8
12
Pascual V, et al. J Exp Med 2005; 209:1479–1486
Reverse translation identifying the role of
IL-1β in sJIA using IL-1 inhibitors
• Sera from patients induce IL-1b production from normal
PBMC
• Increased expression of IL-1b related genes
Pascual V, et al. J Exp Med 2005; 209:1479–1486
β-SPECIFIC 2: canakinumab (anti-IL1b) in s-JIA
ACR Responses at the End of the Study (Part II)
n
43
Canakinumab
42 41 38 32
31
Modified from Brunner H et al. ACR2012
Ruperto et al, NEJM 2012
Clinically Relevant Outcomes
Evidence from randomized clinical trials
“.. never compare clinical trial”
Tocilizumab 1
1
Canakinumab 2
(1 year)
OUTCOME
(Variable)
(median 113 days)
59%
ACR90 + absence of fever
51%
28%
Clinically inactive disease
31%
48%
Absence of active arthritis
Not reported
52%
Stopped glucocorticoids
33%
De Benedetti, NEJM 2012
2
Ruperto, NEJM 2012
IL-1 and IL-6 inhibitors in sJIA
The agenda for the near future
• Predictors of disease severity
– clinical and laboratory predictors of persistent disease
• Early treatment
• Clinically relevant outcomes
– ACR90, clinically inactive disease, no active arthritis, off
glucocorticoids……. JADAS, growth, radiological progression
• Use in clinical practice
– Tapering glucocorticoids, background MTX
• Treatment failures
– Switching from anti-IL1 to anti-IL6 and viceversa
• Future issues
– Predictors of response, withdrawing therapies, MAS
• Long term safety
TENDER
Argentina
Cuttica
Espada
Garay
Australia
Allen
Chaitow
Murray
Belgium
Joos
Wouters
Brazil
Silva
Xavier
Canada
Roth
Schneider
Czech Republic
Dolezalova
Germany
Horneff
Huppertz
Minden
Greece
Mantzourani
Siammopoulou
Vougiouka
Italy
Cortis
Gerloni
Martini
Mexico
Burgos
Maldonado
Netherlands
Wulffraat
Norway
Flato
Poland
Zuber
Slovakia
Rovensky
Spain
Calvo
Garcia
UK
Baildam
Woo
Brown
Chalom
Jerath
Kimura
Lovell
Myones
O'Neill
Onel
Spalding
Zemel
USA
Zulian
Consuegra
β-SPECIFIC 2
PRCSG Site Investigators
Canada
R. Schneider, E. Haddad, K. Houghton
United States
G. Higgins, D. l. Kingsbury, J. Lopez-Benitez, K. Marzan, P. Morris, K. Schikler, A. Grom, D. Lovell,
H. Brunner
PRINTO Site Investigators
Argentina
R. Cuttica
Austria
W. Emminger
Belgium
C. Wouters, L. Goffin, R. Joos, B. Lauwerys
Brazil
F. Sztajnbok,, S. Knupp, M. Hilario, S. Radominski
France
M. Desjonqueres, M. Fischbach, I. Koné-Paut, P. Quartier
Germany
T. Kallinich, R. Berner, M. Frosch, A. Thon, R. Trauzeddel, E. Weibarth-Riedel, G. Horneff
Greece
T. Constantin, M. Trachana
Israel
Y. Uziel, J. Barash, L. Harel, Y. Berkun, R. Brik
Italy
R. Cimaz, S. Viola, M. Alessio, F. Corona, V. Gerloni, N. Ruperto, A. Martini
Netherlands
N. M. Wulffraat
Norway
B. Flato
Peru
M. A. Ferrandiz
Poland
L. Rutkowska-Sak
Sweden
B. Magnusson
Spain
M. Luz Gamir, I. Calvo, J. Anton, J. Carlos Robledillos
Switzerland
M. Hofer
Turkey
S. Ozen, O. Kasapcopur, E. Unsa, M. Erguven, H. Ozdogan
United Kingdom
K. Nistala, A. Chieng, H. Foster, A. Ramanan, N. Wilkinson, L. McCann
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