3 717 Lessons learned from CAPS: Genes, pathways and ... · –MSK: arthralgia . Laboratory tests ... Clinical phenotypes across the age spectrum in Muckle-Wells Syndrome: A proposed

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




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



IL1β


Syndrome (CAPS)


Syndrom (FCAS)




Sp

ectru

m o

f dis

ease

mild

severe


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


Syndrome (CAPS)


Syndrom (FCAS)




Sp

ectru

m o

f dis

ease

mild

severe



• 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


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


Audiogramm einer 5 Jahre alten

Patientin Patient (6 years)

Father (37 years)

Hearing loss in three generations


Patientin

Patient (6 years)

Father (37 years)

Grandmother (67 years)


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


Organ disease in MWS


Syndrome (CAPS)


Syndrom (FCAS)




Sp

ectru

m o

f dis

ease

mild

severe


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


Inflammatory Disease NOMID


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

http://www.cri-net.com/prive/base_images/periodique/grande/pri_I_06.jpg



Treatment of CAPS: IL1 blockade

Loss of gatekeeper

IL1β



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



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

Documents

3 717 Lessons learned from CAPS: Genes, pathways and ... · –MSK: arthralgia . Laboratory tests ... Clinical phenotypes across the age spectrum in Muckle-Wells Syndrome: A proposed