dan kastner primer april 27 - northwest …...4 the inflammasomopathies manthiram et al. nat immunol...

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Autoinflammatory Diseases:A Primer

Dan Kastner, MD, PhD

Intramural Research Program

NHGRI/NIH/DHHS

April 27, 2018

Disclosures

Nothing to disclose

Learning Objectives

• Discuss the distinction between autoinflammatoryand autoimmune diseases

• Enumerate various autoinflammatory diseases and list their most common clinical manifestations

• Discuss the diagnosis and pathophysiology of selected autoinflammatory diseases

• Delineate treatment options for selected autoinflammatory diseases

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The Systemic Autoinflammatory Diseases: What Are They and Why Should You Care?• Recurring episodes of seemingly unprovoked localized

and systemic inflammation, without high titer autoantibodies, antigen-specific T cells, or evidence of overt infection

• Dramatic evidence of inflammation

• Disorders of innate immunity, providing new insights into human biology

p13.3 p13.2p13.13

Chromosome 16p

Telomere Centromere

PKD1, TSC2

D16S3373

NK4

OR1F2

v57c10

v9

ZNF213ZNF205(ZNF210)

OR1F1v57c7 v57c7x4

MEFVZNF200

D16S3082D16S468/

S3070 D16S3405 D16S2617 AFMef101 D16S3275

FPM315

CREBBP

Pyrin / Marenostrin

NH2 COOH

bZIP B-Box

Coiled-coil B30.2PYD

Cell 90:797, 1997

Positional Cloning of MEFV, the Gene Mutated in Familial Mediterranean Fever (FMF)

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Curr Opin Immunol12:479, 2000

NEJM 343:338, 2000

Manthiram et al. Nat Immunol 18:832, 2017

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The Inflammasomopathies


FMF: Clinical Features

Peritonitis (air-fluid levels)

Pleurisy (left pleural effusion)

Posterior pericardial effusion

Chronic arthritis of the hip

Erysipeloid erythema

PMNs, synovial fluid Renal amyloidosis

IL-1 Inhibition in FMF Amyloidosis

Chae et al PNAS 103:9982, 2006

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Pyrin S242R in a Family with a Severe Dominantly Inherited Autoinflammatory

Disease: PAAND

Masters et al. Science Transl Med 8:332ra45, 2016



Hyperimmunoglobulinemia D with Periodic Fever Syndrome (HIDS)

•3 – 7 day febrile episodes

•Abdominal pain

•Arthritis/arthralgia

•Diffuse maculopapular rash

•Prominent cervical adenopathy

•Aphthous ulcers

•Onset within first year of life

•Episodes sometimes induced by childhood immunizations

•Amyloidosis very rare

Rheumatology 5th edn, 1648, 2011

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781Pyrin

domain B-BOX CC1 B30.2

413SH3

261

FCH CC1

30A230T E250Q

**

PSTPIP1

pyrin Shoham et al., PNAS 100:13501, 2003

PAPA Syndrome (Pyogenic Arthritis with PyodermaGangrenosum and Acne)



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Familial Cold Autoinflammatory Syndrome (FCAS)

• Fever, hives-like skin rash upon generalized exposure to cold

• Rash occurs about 2 hr after cold exposure

• Not true urticaria: neutrophils, not mast cells

• Dominant inheritance

125 250 500 1000 2000 4000 8000–10

0102030405060708090

100110

He

ari

ng

Le

ve

l in

dH

BL

–100

102030405060708090

100110

125 250 500 1000 2000 4000 8000

Muckle-Wells Syndrome

•Inflammatory episodes

–Fever

–Limb pain

–Urticarial rash

•Sensorineural hearing loss

•Systemic amyloidosisRheumatology 5th edn, 1653, 2011

Neonatal-Onset Multisystem InflammatoryDisease (NOMID)/Chronic Infantile NeurologicCutaneous and Articular Syndrome (CINCA)

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Treatment of 18 NOMID Patients with the IL-1 Receptor Antagonist Anakinra

Goldbach-Mansky R et al. N Engl J Med 2006;355:581-592



NLRC4-Macrophage Activation Syndrome/Syndrome of Enterocolitis and Autoinflammation Associated with

Mutation in NLRC4 (SCAN4)

Canna et al. Nature Genet 46:1140, 2014 and Romberg et al. Nature Genet 46:1135, 2014

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Aksentijevich I et al. N Engl J Med 2009;360:2426‐2437

Deficiency of the IL-1 Receptor Antagonist (DIRA)

The TNF Receptor-Associated Periodic Syndrome (TRAPS)

Hull et al. Medicine (Baltimore) 81:349 (2002)

Rheumatology 5th edn. 1637-57, 2011

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The Interferonopathies


STING‐Associated Vasculopathy with Onset in Infancy (SAVI)

Liu et al. NEJM 371:507, 2014

The Interferonopathies


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Liu et al Arthritis Rheum 64:895-907, 2012

Huber et al Cell 148:727-738, 2012

NF-B-Mediated Autoinflammation


Zhou et al., Nat Genet 48:67, 2016

Zhou et al., PNAS 113:10127, 2016

Disorders of Deubiquitination

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NF-B-Mediated Autoinflammation


Variants of CARD15/NOD2 Underly Both Crohn’s Disease and Granulomatous Arthritis (Blau Syndrome) /

Early-Onset Sarcoidosis (EOS)

Crohn’s Disease,

Nature 411, 599 (2001)

Blau Syndrome

Miceli-Richard et al., Nature Genet 29:19, 2001

Summary

• The systemic autoinflammatory diseases are disorders of innate immunity

• Several autoinflammatory diseases are disorders of IL-1 signaling, with significant therapeutic response to IL-1 inhibitors

• The interferonopathies are disorders of type I interferon signaling, and may respond to JAK inhibitors

• Disorders of NF-B signaling include otulipeniaand Blau syndrome, which may respond to TNF inhibitors

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NIH Colleagues in the Laboratory

Raman SoodNHGRI

Manfred BoehmNHLBI

JaeJin ChaeNHGRI

Yong Hwan ParkNHGRI

Monique StoffelsNHGRI

Geryl WoodNHGRI

Geun-Shik LeeNHGRI

Yohei KirinoNHGRI

Masaki TakeuchiNHGRI

Elaine RemmersNHGRI

Mike OmbrelloNIAMS

Pravitt GourhNIAMS

Julie LeNHGRI Kalpana Manthiram

NHGRI

Hongying WangNHGRI

Ivona AksentijevichNHGRI

Qing ZhouNHGRI

Angeliki GiannelouNIAMS

Natalie DeuitchNHGRI

Hiro OdaNHGRI

Steve BoydenNHGRI

NIH Colleagues in the Clinic

Camilo ToroNHGRI

Hirsh KomarowNIAID

Dean MetcalfeNIAID

Bob LemboOD

Don GoldsmithDrexel

Amanda OmbrelloNHGRI

RaphaelaGoldbach-Mansky

NIAID

Debbie StoneNHGRI

Karyl BarronNIAID

Paola PintoNHGRI

Patrycja HoffmannNHGRI Bev Barham

NHGRIAnne Jones

NHGRITina Romeo

NHGRIDaniella Schwartz

NIAMS

Additional ContributorsNIH

Manfred Boehm

Hyejeong Bolan

Settara

Chandrasekharappa

Celeste Chen

David Chin

Ed Cowen

Glenn Cruse

Avanti Desai

Robin Eisch

Massimo Gadina

Eric Hanson

Sarfaraz Hasni

Chyia-Chia Lee

Daniel Long

Jonathan Lyons

Josh Milner

International

Ankara – Seza Ozen, Ezgi Batu,

Erkan Demirkaya

Beirut – André Mégarbané

Fanar – Myrna Medlej-Hashim

Genentech – Ingrid Wertz

Istanbul – Ahmet Gül, Burak Erer

Melbourne – Seth Masters

New Haven – Ken Kidd

Andrew Pakstis

Paris – Elaine Chouery

Portland – Cailin Sibley

UCSF – Tony Shum, Andy Gross

Toronto – Ron Laxer

Utrecht – Helen Leavis

Annet van Royen-Kerkof

Yokohama – Yoshi Ishigatsubo

Nobuhisa Mizuki

Yohei Kirino

Jim Mullikin

Ana Olivera

Claudia Ouyang

Sergio Rosenzweig

Colleen Satorius

Linda Scott

Richard Siegel

Masaki Takeuchi

Wanxia Tsai

Dan Yang

Michael Young

Xiaomin Yu

Zhen Yu

Kristien Zaal

Yuan Zhang

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NIH Clinical Center

[email protected]@mail.nih.gov, [email protected], referrals

dan kastner primer april 27 - northwest …...4 the inflammasomopathies manthiram et al. nat immunol...

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