3 717 lessons learned from caps: genes, pathways and ... · –msk: arthralgia . laboratory tests...
TRANSCRIPT
Susa Benseler
Section of Rheumatology
Alberta Children’s Hospital
Lessons learned from CAPS:
Genes, pathways and clinical care
PYR LRRs NACHT
133 Exon 3 717
11 12 13 14 G755R G755A
H458H C461C H463H I480F R488K A495V F523C F523L(C>A) F523L(C>G) E525K L534L R554X T557A Y563N G569R Y570C Y570F F573S T587I E627G L632F M659K M662T Q703K S710C 398 - 56C>T
Y141Y R168Q I172T S196N V198M T219T A242A C259W R260W R260L R260P R260R V262A L264F L264H L264R L264V G301D D303H D303N D303G L305P Q306L G307V F309S
D310D
P315L G326E S331R P340P L344L T348M V351M V351L A352V L353P E354D H358R A374D T405P L411L S343S T436P T436N T436I A439T A439P A439V F443L
E311K
Exon 3
NACHT - domain
Objectives
• To review the pathophysiology of cryopyrin associated periodic syndromes CAPS.
• To discuss the clinical spectrum and distinct organ diseases
• To discuss CAPS treatment options, monitoring approaches and patient outcomes
• a tired child……
Patient 1, 07 year old boy
• HPI:
– 3 month history of joint pains, no swelling or
warmth of any joints, quit soccer team
– Multiple episodes of low grade fevers, no
pattern, associated with red eyes and rashes,
possible viral illnesses in late fall and winter
– ``not as active as peers``
• pmHx:
– healthy, chickenpox at age 4
Examination
• O/E
– Thriving well
– Vital signs: Temp 37.9
C, normal HR, BP
– General physical
examination:
• Fatigued, hearing loss,
otherwise normal
– MSK: arthralgia
Laboratory tests
• Inflammatory
markers:
– ESR 22mm/hr
– CRP 56mg/l
– WBC 14.5, normal
diff
– Remainder normal
including TSH
– Urine normal
Sensorineural hearing loss
Increase in
hearing
thresholds in high
frequencies
Hearing thresholds
Symptoms
• Fever, fatigue
• Arthralgia
• Conjunctivitis
• Rash
– Non itchy
– Urticaria-like
– Cold-induced
• Sensorineural
hearing loss
Kuemmerle-Deschner, ART 2011
Family history
Suspected diagnosis:
monogenic periodic fever syndrome
Cryopyrin associated periodic
syndrome CAPS
DD autoinflammatory diseases
DD autoinflammatory diseases
DD autoinflammatory diseases
DD autoinflammatory diseases
Cryopyrin Associated Periodic
Syndrome (CAPS)
Familial Cold-induced Autoinflammatory
Syndrom (FCAS)
Muckle Wells Syndrome (MWS)
Neonatal-Onset Multisystem Inflammatory
Disease (NOMID/CINCA)
Sp
ectru
m o
f dis
ease
mild
severe
Courtesy Dr. Kuemmerle-Deschner
Gene: NLRP3
• Location: 1q44
• Name: NLR (nucleotide-binding domain
and leucine rich repeat containing family).
pyrin domain containing 3 (previously
CIAS1)
• Encodes and therefore provides
instructions for making a protein called
cryopyrin
• Gatekeeper protein of the immune system
NLRP3 mutations
Infevers database, 2013
Gatekeeper
Jurg Tschopp & Kate Schroder
Nature Reviews Immunology 2010
Loss of gatekeeper
Jurg Tschopp & Kate Schroder
Nature Reviews Immunology 2010
IL1β
Cryopyrin Associated Periodic
Syndrome (CAPS)
Familial Cold-induced Autoinflammatory
Syndrom (FCAS)
Muckle Wells Syndrome (MWS)
Neonatal-Onset Multisystem Inflammatory
Disease (NOMID/CINCA)
Sp
ectru
m o
f dis
ease
mild
severe
Courtesy Dr. Kuemmerle-Deschner
A B
0
5
10
15
20
25
30
35
40
45
<70' 70's 80's 90's >2000
Decade of birth
MKD
CAPS
TRAPS
FMF
Dia
gn
osis
d
ela
y (y
ears
)
31
58
21
8
12
6
25
15
25
15
28
51
50
40
225
Toplak, ARD, 2012
Time to diagnosis of CAPS
Familial Cold-induced
Autoinflammatory Syndrome (FCAS)
• Cutaneous Manifestations of two affected siblings from Family B
(A,B) and one affected child from Family A (C).
• A. 16 month old boy after a 5 minute exposure to 5°C atmosphere
outdoor exposure followed by 5 minutes at room temperature. B. 34
month old boy at room temperature for 2 hours, crying. C. 4 year old
girl bathing indoors at room temperature.
Hoffman, J All Clin Immun 2009
Neutrophilic dermatitis
Hoffman, J All Clin Immun 2009
Neutrophilic dermatitis
Hashkes, The Rheumatologist 2014
Associated symptoms
• Fatigue
• Fevers
• Arthralgia/myalgia
• Conjunctivitis
Cryopyrin Associated Periodic
Syndrome (CAPS)
Familial Cold-induced Autoinflammatory
Syndrom (FCAS)
Muckle Wells Syndrome (MWS)
Neonatal-Onset Multisystem Inflammatory
Disease (NOMID/CINCA)
Sp
ectru
m o
f dis
ease
mild
severe
Courtesy Dr. Kuemmerle-Deschner
Muckle Wells Syndrome (MWS)
• Triad of triad of urticaria, deafness, and
amyloidosis (Muckle, Wells, 1962)
• Clinical presentation
Kuemmerle-Deschner, AR 2013
Figure 3 Clinical phenotypes across the age spectrum in Muckle-Wells Syndrome: A proposed model for inherited autoinflammatory diseases
Childhood Adulthood
Systemic inflammatory phenotype
Organ-disease phenotype phenotype
Clinical symptoms and age
Kuemmerle-Deschner, AR 2013
Correspondence analysis
Dimension 1 (67%)
Dim
en
sio
n 2
(33%
)
-1.0 -0.5 0.0 0.5 1.0
-0.5
0.0
0.5
10 years
11-20 years
>20 years
irritability
fatigue
relapsing fever
headacheeye symptoms
hearing lossskin rash
musculoskeletal
abdominal pain
Clinical symptoms and age
Kuemmerle-Deschner, AR 2013
Audiogramm einer 5 Jahre alten
Patientin Patient (6 years)
Father (37 years)
Hearing loss in three generations
Audiogramm einer 5 Jahre alten
Patientin
Patient (6 years)
Father (37 years)
Grandmother (67 years)
Audiogramm einer 5 Jahre alten
Patientin
Patient (6 years)
Father (37 years)
Grandmother (67 years)
Hearing thresholds
Hearing loss in three generations
Cochlear inflammation
Inflammation End-organ damage
Inner ear inflammation on MRI
Figures courtesy of Raphaela Goldbach-Mansky
Hearing loss
NLRP3 mutation and hearing loss
0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Age in years
Pu
re T
on
e A
vera
ge (
PTA
) ri
ght
ear
[dB
]
Controls E311K
V198M T348M
A 439 V
Kuemmerle-Deschner, AR 2012
Organ disease in MWS
Cryopyrin Associated Periodic
Syndrome (CAPS)
Familial Cold-induced Autoinflammatory
Syndrom (FCAS)
Muckle Wells Syndrome (MWS)
Neonatal-Onset Multisystem Inflammatory
Disease (NOMID/CINCA)
Sp
ectru
m o
f dis
ease
mild
severe
Courtesy Dr. Kuemmerle-Deschner
Neonatal-Onset Multisystem
Inflammatory Disease NOMID • chronic infantile neurologic cutaneous
and articular syndrome CINCA first
described in 1981 by Prieur and Griscelli
• Early onset of severe organ disease and
inflammation
– Skin
– MSK: bones
– CNS
Neonatal-Onset Multisystem
Inflammatory Disease NOMID
Neonatal-Onset Multisystem
Inflammatory Disease NOMID
Pre-term birth (30%), SGA
Fevers
Skin: early onset urticaria like rash
MSK: non directional growth due to
Inflammation, destructive arthritis
CNS: meningitis, hydrocephalus, seizures, developmental delay, hearing loss
Eyes: conjunctivitis, uveitis, scleritis, papilledema
Treatment of CAPS: IL1 blockade
Loss of gatekeeper
IL1β
Jurg Tschopp & Kate Schroder
Nature Reviews Immunology 2010
Treatment of CAPS: IL1 blockade
Anakinra Rilonacept Canakinumab
Half life 4 hours 67 hours 21-28 days
costs/year
[USD]
17.000 250.000 100.000
Clinical instruments:
• MWS disease activity score MWS-DAS
(physician derived)
• AIDAI questionnaire (patient diary)
Laboratory markers:
• C-reactive protein CRP
• Serum amyloid A SAA
• Neutrophil markers: MRP S100A8 and A9
Disease activity in CAPS
Kuemmerle-Deschner, AR 2010, Lotze/Tracey Nat Rev Immunol 2005
Foell et al. J Leukoc Biol 2007, Piram, ARD 2014
Myeloid-Related Protein (MRP) 8/14
• MRP 8/14 calcium binding
proteins (S100A8/S100A9)
• form heterocomplexes in
cytosol of neutrophils and
macrophages
• identified as ligands and
activators of TLR-4 assigned
to the Damage Associated
Molecular Pattern (DAMPS)
Ca2+
Ca2+
Ca2+
Ca2+
hMRP8/hMRP14
RAGE
PAMP
„Pathogen
Associated
Molecular
Pattern“
TLR TLR NOD
Pattern recognition
of the innate immune system
Exogenous ligands
Endogenous ligands
alarmins
Danger Signals
DAMP
„Damage
Associated
Molecular
Pattern“
Lotze/Tracey Nat Rev Immunol 2005
Foell et al. J Leukoc Biol 2007
RAGE
PAMP
„Pathogen
Associated
Molecular
Pattern“
TLR TLR NOD
Lotze/Tracey Nat Rev Immunol 2005
Foell et al. J Leukoc Biol 2007
Exogenous ligands
Endogenous ligands
alarmins
Danger Signals
e.g. S100 proteins
MRP8/14
DAMP
„Damage
Associated
Molecular
Pattern“
Pattern recognition
of the innate immune system
Rheumatoid arthritis Psoriasis arthritis Dermatomyositis Glomerulonephritis (SLE)
MRP8/MRP14 expression
in human diseases
Kane et al. Arthritis Rheum. 48, 1676-1685 (2003) Seeliger et al. Am. J. Pathol. 163, 147-156 (2003) Frosch et al. J. Leuko. Biol. 75, 198-206 (2004)
controls
active
remission
MR
P8/M
RP
14 / n
g/m
l
0
500
1000
1500
2000
2500* MRP8/MRP14 serum
concentrations reflect local
disease activity
Physician’s global assessment (5 point scale)
of disease activity and assessment of skin disease on a
5-point scale (1=absent, 2=minimal, 3=mild,
4=moderate, 5=severe). Remission: ≤2
Patient’s global assessment (5 point scale)
Inflammatory markers C-reactive protein (CRP) and
serum amyloid A (SAA) Remission: normal serum
values (below 10 mg/L) of CRP and SAA
Monitoring treatment response
Definitions of response
• Complete Response:
Disease activity and assessment of skin disease on a
5-point scale ≤2
plus
normal serum values of CRP and SAA on day 8 of therapy
• Partial response:
Absence of complete response but reduction of CRP
and/or SAA from baseline by > 30 % but not reaching
normal values (<10mg/l) and physician’s global
assessment improvement from baseline by one step
• Anakinra, Rilonacept (FCAS) and
Canakinumab have excellent efficacy
– Improvement or resolution of clinical signs
and symptoms of active inflammation
– Improvement or normalization of inflammatory
markers
Treatment efficacy
Clinical applications
for IL1 blockade
Dinarello, van der Meer
Semin Immunol 2013
MWS disease activity
at baseline and on anakinra
ESR and CRP
at baseline and on anakinra
before IL-1Ra during IL-1Ra
0
20
40
60
CR
P m
g/d
l
ES
R m
m/h
IL-1Ra during IL-1Ra
0
2
4
6
p=0,013 p=0,008
before IL-1Ra
healthy controls
during IL-1Ra
0
2000
4000
6000
8000
MRP8/14 markers at baseline
and on anakinra
• MRP 8/14 levels
decreased significantly in
successfully treated
patients (p<0,001)
• but were still elevated in
comparison to healthy
controls (<450ng/ml)
even without clinical signs
of inflammation
p<0,001
Excellent response of inflammatory
markers to IL1 blockade
CRP levels ESR values
Kuemmerle-Deschner, ART 2013
Kuemmerle-Deschner, ART 2013
S100A12: response to anakinra
and canakinumab
Canakinumab induced
a complete clinical
response in all cases
0
0,5
1
1,5
2
2,5
3
3,5
BL-PatDia D8-PatDia
0
1
2
3
4
5
6
BL-DisAct D8-DisAct
Patients assessment
Physician assessment
Immediately pre first treatment Day 8 post treatment
Immediately pre first treatment Day 8 post treatment
Canakinumab induced
a complete biochemical
response in all cases
1
2
3
4
7
8
10
11
14
15
17
19
mean
0,1
1
10
100
Baseline Day 8
1
2
3
4
7
8
10
11
14
15
17
19
mean
0,1
1
10
100
Baseline Day 8
0,1
1
10
100
1000
Baseline Day 80,1
1
10
100
1000
Baseline Day 8
SAA
CRP
Efficacy of anti IL1 therapy for
organ disease: hearing
Early detection of hearing loss
• Standard 4 pure-tone-average (4PTA) and
proposed high frequency pure-tone-
average (HF-PTA)
• 4PTA range includes 0.5, 1, 2, and 4 kHz
• The proposed HF-PTA captures high
frequency at 6 and 8 kHz
Early detection of hearing loss: Standard 4
pure-tone-average (4PTA) and proposed high
frequency pure-tone-average (HF-PTA)
PTA versus HF PTA for early
detection of hearing loss
Normal PTA
Abnormal HF-PTA
Abnormal PTA
Abnormal HF-PTA
Early hearing loss is reversible
Efficacy of anti IL1 therapy for
organ disease: hearing
MWS patient follow-up
assessments
After treatment with anakinra
Cochlear inflammation
Inflammation
Hearing loss and MRI
Resolving cochlear inflammation
Figures courtesy of Raphaela Goldbach-Mansky
Objectives
• To review the pathophysiology of cryopyrin associated periodic syndromes CAPS.
• To discuss the clinical spectrum and distinct organ diseases
• To discuss CAPS treatment options, monitoring approaches and patient outcomes