![Page 1: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/1.jpg)
Autoinflammatory
Diseases
Hal Hoffman, M.D.Hal Hoffman, M.D.Professor of
Pediatrics and Medicine
UCSD Division of Allergy,
Immunology, and Rheumatology
Rady Children’s Hospital San Diego
![Page 2: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/2.jpg)
Faculty Disclosure
Hal Hoffman, MD
For the 12 months preceding this CME activity, I disclose the
following types of financial relationships:
Honoraria received from:
• Novartis, Biovitrum
Consulted for:Consulted for:
• Novartis, Biovitrum, Regenesis
Held Common Stock in:
• None
Research, clinical trial, or drug study funds received from:
• Ardea, GlaxoSmithKline, Idera
I will be discussing products that are investigational or not
labeled for use under discussion.
![Page 3: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/3.jpg)
Outline
•The autoinflammatory concept
•Hereditary fever disorders
•Clinical features•Clinical features
•Pathophysiology
• Therapy
•Expanding family of monogenic autoinflammatory diseases
![Page 4: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/4.jpg)
Immunologic Diseases
Classical Categories
•Immunodeficiency
•Allergic Diseases•Allergic Diseases
•Autoimmune Diseases
Several immunologic diseases do not fit nicely
into this standard classification system
![Page 5: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/5.jpg)
Unclassified
Inflammatory Diseases
• Gout
• Crohn’s Disease
• Sarcoidosis
• Behcet’s Disease• Behcet’s Disease
• Still’s Disease– Juvenile (Systemic onset juvenile idiopathic arthritis)
– Adult onset
• Hereditary Angioedema
• Recurrent Fever Disorders
![Page 6: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/6.jpg)
Autoinflammatory DiseasesDefinition
Disorders with recurrent
episodes of inflammation
• No evidence of pathogenic infection or IgE mediated dz
• No high titer auto-antibodies or antigen specific T cells
• Disturbances of homeostasis of cytokine responses
• Aberrant bacterial sensing
• Predominance of monocytes/neutrophils rather than lymphocytes as effector cells
![Page 7: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/7.jpg)
INNATEAUTOINFLAMMATORY
FMF, TRAPS, HIDS
Inflammatory Bowel Dz
Gout
Sarcoidosis
Ankylosing Spondylitis
Behcet’s Syndrome
McGonagle and McDermott, PLOS Medicine 2006
ADAPTIVE
AUTOIMMUNE
Behcet’s Syndrome
Rheumatoid arthritis
Celiac disease
Lupus
Type 1 Diabetes
ALPS, IPEX
![Page 8: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/8.jpg)
Hereditary Fever Disorders
• Familial Mediterranean fever (FMF)
• Hyper IgD syndrome (HIDS)
• TNF Receptor Assoc. Periodic Syndrome (TRAPS)• TNF Receptor Assoc. Periodic Syndrome (TRAPS)
![Page 9: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/9.jpg)
Hereditary Fever DisordersClinical Characteristics-Shared
• Intermittent episodes of inflammation with intervals that are relatively symptom-free– Fever
– Musculoskeletal symptoms– Musculoskeletal symptoms
– Rash
• Laboratory evidence of inflammation– ESR
– CRP
– SAA - amyloidosis
![Page 10: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/10.jpg)
Familial Mediterranean Fever
(FMF)
• More common in Jews, Arabs,Turks,
Armenians, but also in other Mediterraneans
• Usually autosomal recessive inheritance• Usually autosomal recessive inheritance
• Episodes last 1-3 days
• Symptoms - severe abdominal or chest pain,
monoarthritis, erysipelas rash on legs
• Responsive to colchicine
![Page 11: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/11.jpg)
FMF
Erysipelas-like
rash on legs
Simon et al 2005
![Page 12: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/12.jpg)
Hyper IgD syndrome (HIDS) with periodic fever
• Founder effect in Northern Europe
• Autosomal recessive inheritance
• Episodes last 3-7 days
• Episode intervals are periodic (3-6 weeks)• Episode intervals are periodic (3-6 weeks)
• Symptoms - abdominal pain, vomiting, arthralgia,
rash, lymphadenopathy, splenomegaly, aphthous
ulcers
• Labs - Increased IgD level ( >100 IU/ml or 14 mg/dl)
- Increased urinary mevalonate
![Page 13: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/13.jpg)
Maculopapular
Rash
HIDS
Photo courtesy of D. Kastner
Aphthous
ulcers
Simon et al 2005
Photo courtesy of D. Kastner
![Page 14: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/14.jpg)
TRAPS
• No specific populations
• Autosomal dominant inheritance
• Episodes last 1 - 4 weeks
• Symptoms - arthralgia and localized myalgia,
conjunctivitis and periorbital edema, abdominal
pain, migrating painful rash
• Some response to corticosteroids
![Page 15: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/15.jpg)
TRAPS Centrifugal migratory painful
erythematous rash
Photo courtesy of D. Kastner
![Page 16: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/16.jpg)
TRAPS - Ocular Findings
Photo courtesy of D. Kastner
![Page 17: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/17.jpg)
Hereditary Fever DisordersClinical Characteristics
• Familial Mediterranean fever (FMF)
• Hyper IgD syndrome (HIDS)
• TNF Receptor Assoc. Periodic Syndrome (TRAPS)
•Other disorders• Familial cold autoinflammatory syndrome
• Muckle Wells Syndrome
• Neonatal Onset Multisystem Inflammatory Disease
![Page 18: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/18.jpg)
68 year old with
lifelong history of
urticaria-like rash,
fever, and joint
symptoms
following cold
Photo courtesy of R. Shpall
following cold
exposure
![Page 19: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/19.jpg)
Familial Cold
Autoinflammatory Syndrome
• Autosomal dominant inheritance
• Episodes last < 1 day - daily symptoms
• Symptoms -• Symptoms - urticaria-like rash, arthralgia,
myalgia, conjunctivitis after cold exposure
![Page 20: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/20.jpg)
Skin biopsy of Affected Area
Skin
H & E
Shpall et al, Br J Derm 2004
![Page 21: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/21.jpg)
MWS
Urticaria like rash
Progressive Hearing Loss
![Page 22: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/22.jpg)
Muckle Wells Syndrome
• Autosomal dominant inheritance
• Daily symptoms - episodes last 1 - 2 days
• Symptoms - urticaria-like rash, arthralgia, • Symptoms - urticaria-like rash, arthralgia,
myalgia, progressive hearing loss
![Page 23: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/23.jpg)
NOMID
Urticaria-like rash
Enlarged knees
Courtesy of R Goldbach-Mansky
CNS involvement
![Page 24: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/24.jpg)
NOMID
• Primarily sporadic, but also autosomal dominant inheritance
• Chronic inflammation with flares
• Symptoms - urticaria-like rash, deforming • Symptoms - urticaria-like rash, deforming arthropathy, dysmorphic features, growth and developmental delay, seizures
![Page 25: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/25.jpg)
Hereditary Fever DisordersClinical Characteristics-Unique
� Ethnicity
� Inheritance Pattern
Pattern and length of episodes� Pattern and length of episodes
� Specific symptoms
� Type of Rash
� Treatment responsiveness
![Page 26: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/26.jpg)
PATTERN OF EPISODES
Simon et
![Page 27: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/27.jpg)
LENGTH OF
EPISODES
Simon et
![Page 28: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/28.jpg)
• Familial Mediterranean Fever
– MEFV - Pyrin
• Hyper IgD syndrome
– MVK - Mevalonate Kinase
Autoinflammatory DiseasesGenetics
– MVK - Mevalonate Kinase
• TNF receptor associated periodic syndrome
– TNFSRIA - TNF Receptor p55
![Page 29: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/29.jpg)
No
Cleaved TNFR1
Inflammation
No
Inflammation
![Page 30: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/30.jpg)
Cleaved TNFR1
Free TNFαααα
�
�
�
Inflammation�
![Page 31: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/31.jpg)
![Page 32: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/32.jpg)
Therapy in TRAPS
• Some response to high dose corticosteroids during attacks
• Successful prospective trials of Etanercept(soluble TNF receptor) in TRAPS patients
– Hull et al 2003
– Drewe et al 2003
• Some patients do not respond adequately
– Symptom breakthrough
– Development of amyloidosis
• Other TNF directed therapies (antibodies) were ineffective or made it worse
![Page 33: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/33.jpg)
![Page 34: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/34.jpg)
HIDS
Potential Mechanisms?
• Decreased stability of Mevalonate Kinase protein leading to reduced, but not absent enzyme function (Mevalonic Aciduria)
– Remaining function may be affected by elevated – Remaining function may be affected by elevated temperature (immunization and infection)
• Increased IL-1B mediated inflammation
• Decreased apoptosis of lymphocytes
![Page 35: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/35.jpg)
Therapy in HIDS?
• High dose corticosteroids at attack onset
– Some reduction in severity of attacks
• Statins (HMG coA reductase inhibitors)
– Reduce mevalonate
– Some potential improvement in attack frequency
• Etanercept (soluble TNF receptor)
– Reduced acute phase reactants
– Reduced attack severity and frequency
![Page 36: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/36.jpg)
![Page 37: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/37.jpg)
Chromosome 1p Chromosome 1q
1q44
Markers Genetic
Positional Cloning
Markers
Genes
Genetic
Mapping
GAGCCGCC GTCGGCTCCGDNA BasesT
C
Heterozygous Mutations in FCAS and MWS patients
Sequencing
![Page 38: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/38.jpg)
Gene and Protein Structure
Mutations
CIAS1 (NLRP3)
Cold Induced Autoinflammatory Syndrome 1
Cryopyrin (NALP3)
Mutations
NAD
Hoffman et al, Nature Genetics 2001
Nucleotide Oligomerization
Domain (NOD)
Leucine Rich Repeat
(LRR)
![Page 39: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/39.jpg)
CIAS1 Mutations
FCAS MWSV198M
R260W
L353P
A439V
E525K
E627G
L305P
D303N
T348M
A352V
A439T
G569R
S710CM659K
CIAS1 Exon 3
L353PR488K
NBS Domain NAD Domain
Cryopyrin
G301D
![Page 40: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/40.jpg)
NLRP3 Mutations - 82
FCAS MWSV198M
R260W
L353PA439V
E525K
E627G
L305P
D303N
T348M
A352VA439T
G569RNOMID
F309S H358R
T436N
F523LY570C
F573S
M662T
R260L
L632F
E354D
R260P
D303G
T436I
L264H
L264R
Q306L
S710C
A439PI172T
G326E
M659K
NLRP3 Exon 3
NBS Domain
A374NT436N
R488KT405P
NAD Domain
Cryopyrin
S331RG301DG326E
Infevers – Touitou et al
![Page 41: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/41.jpg)
Severity
Cryopyrin Associated Periodic
Syndromes:
A Spectrum of One Disease
Severity
FCAS MWS NOMID
![Page 42: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/42.jpg)
Modeling mutations
![Page 43: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/43.jpg)
Nucleotide binding Leucine rich Repeat (NLR) family
NLRP1
NLRP2-14
NOD1
NOD2
PYD CARDNACHT NAD LRR FIIND
Ipaf
Naip
CIITA
Apaf-1
RIP2
ASC
CARDINAL
kinase
WD40
adaptors
![Page 44: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/44.jpg)
PYD
NBSCryopyrin PYD
CARDASC
Activated
Monocyte
Macrophage
CARDCardinal
CARDCARD
Inflammasome
LRR
Inflammasome
HSP90 SGT1
K efflux
ATP
P2X7
K
channel
Caspase
1
Urate/CPPD
crystals
Silica and
Asbestos
Cholesterol
Cytokine
expression
IL-1ββββ
caspase
1
Cleaves
NucleusSecretory
Lysosome
Pro-IL-1ββββ
NF-κκκκB
IL-1
Receptor
Agostini et al, Immunity 2004
IL-6
Islet
amyloid
Cholesterol
![Page 45: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/45.jpg)
FMF & CAPS - Pathogenesis
• Structurally related proteins (pyrin and cryopyrin) both have Pyrin domains involved in protein-protein interactions
![Page 46: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/46.jpg)
PYD
NBSCryopyrin PYD
CARDASC
Activated
Monocyte
Macrophage
CARDCardinal
CARDCARD
Inflammasome
LRR
CAPS and FMF Pathogenesis
HSP90 SGT1
K efflux
ATP
P2X7
K channel
Caspase 1
�
�
COLD
PYDBB
Pyrin
�
Cytokine
expression
IL-1β
caspase 1
Cleaves
NucleusSecretory
Lysosome
Pro-IL-1β
NF-κB
IL-1
Receptor
Agostini et al, Immunity 2004
�
�
IL-6
![Page 47: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/47.jpg)
PYD
NBSCryopyrin PYD
CARDASC
Activated
Monocyte
Macrophage
CARDCardinal
CARDCARD
Inflammasome
LRR
Targeted Therapy for CAPS
HSP90 SGT1
K efflux
ATP
P2X7
K channel
Caspase 1
Cytokine
expression
IL-1β
caspase 1
Cleaves
NucleusSecretory
Lysosome
Pro-IL-1β
NF-κB
IL-1
Receptor
Anakinra
IL-6
![Page 48: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/48.jpg)
Anakinra
Approved for
Rheumatoid
Arthritis in
2001
Hoffman JACI 2009
![Page 49: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/49.jpg)
Experimental Cold Challenges
• 4°C room for greater than 30 minutes
• Serial monitoring of vital signs and
symptoms for 24 hourssymptoms for 24 hours
• Collection of blood and skin tissue before
and during development of symptoms and
after resolution.
![Page 50: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/50.jpg)
![Page 51: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/51.jpg)
RashSkin following cold challenge
Hoffman et al, Lancet 2004
![Page 52: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/52.jpg)
99.3
98.6
97.9
99.3
98.6
97.9
97.2
96.5
(F)
97.2
96.5
(F)
![Page 53: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/53.jpg)
![Page 54: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/54.jpg)
![Page 55: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/55.jpg)
Anakinra in MWS
• Reduced symptoms
in MWS patients
Hawkins et al, 2003
in MWS patients
• Decreased systemic
inflammation
SAA levels
![Page 56: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/56.jpg)
Significant
Efficacy in
NOMID
Goldbach-Mansky et al 2007
• Reduced symptoms• Reduced symptoms
• Improved growth/development
• Decreased systemic
inflammation
• Improved CNS signs
![Page 57: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/57.jpg)
Anakinra in CAPS
• Clinical trials demonstrating remarkable efficacy in – FCAS (Ross et al 2008)
– MWS (Leslie et al 2006)
– NOMID (Goldbach-Mansky et al 2007)– NOMID (Goldbach-Mansky et al 2007)
• Unfavorable features– Short half life ( < 12 hours )
– Painful injection reactions
– No interest by pharmaceutical company
![Page 58: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/58.jpg)
Rilonacept
IL-1 TRAP
• Rilonacept: a dimeric fusion
protein (251 kDa) that is a
specific blocker of IL-1 -
incorporating components
IL-1RAcP
“Trapped”
IL-1
required for IL-1 signalling
– IL-1 receptor subtype
– IL-1 receptor accessory
protein
• Prolonged circulation half-life
in-vivo (8.6 days)
IL-R1
Fc region
IL-1
2
![Page 59: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/59.jpg)
• Fully human IgG1 anti-
IL-1β mAb
Action• Direct binding to IL-1β
Canakinumab
Canakinumab
• Direct binding to IL-1β
• Half life > 21 days
• No cross-reactivity with human
IL-1α or IL-1RaIL-1β
![Page 60: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/60.jpg)
FDA
approved
Hoffman JACI 2009
![Page 61: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/61.jpg)
Translational research model in the
monogenic autoinflammatory diseases
Patients/Families
Novel
Therapy
Disease
Characterization
Protein
function
Gene
identificationInflammatory
Pathways
![Page 62: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/62.jpg)
Anakinra in other
recurrent fever disorders
• Successful trials of Anakinra in TRAPS patients
– Simon et al 2004
– Gatttorno et al 2008
– Sacre et al 2008
• Successful trials of Anakinra in HIDS patients
– Bodar et al 2005
– Calliez et al 2006
• Successful trials of Anakinra in FMF patients
– Gattringer et al 2007
– Calligaris et al 2008
![Page 63: Dr. Hal Hoffman.ppt - AAIFNCaaifnc.org/Documents/symposium_2012/Dr._Hal_Hoffman.pdf · Faculty Disclosure Hal Hoffman, MD For the 12 months preceding this CME activity, I disclose](https://reader031.vdocuments.mx/reader031/viewer/2022030406/5a7ffd8f7f8b9a24668bce1e/html5/thumbnails/63.jpg)
Summary
• Autoinflammatory diseases are a new category of inflammatory diseases
• The hereditary fever disorders are excellent examples of translational research success research success
• IL-1 targeted therapy has demonstrated proven efficacy in CAPS, but also other autoinflammatory diseases