Newer Antoinflammatory syndromesDr. Sathish Kumar, MD, DCH

Consultant Pediatric RheumatologistProfessor of Pediatrics

Christian Medical College, Vellore

Objectives• Update of the spectrum of

autoinflammatory diseases in 2016

• Different components of the innate immune response leading to autoinflammatory syndromes

• Newer Autoinflammatory syndromes described in last 2 years

Audience Question

Following are true about Autoinflammatory syndromes except

1. Genetic mutations lead to dysregulation of the innate immune system

2. Do not have autoreactive T lymphocytes

3. Lack pathogenic autoantibodies

4. Produce memory response

Here’s what started it all…..

“… are clinical disorders marked by abnormally increased inflammation, mediated predominantly by the cells and molecules of the innate immune system with a significant host predisposition…”

Kastner et al. Cell 2010;140:784-90

Autoinflammatory diseases

Autoimmunity

• Adaptive immune system:− Lymphoid cells (T cells, B cells)

and auto-antibodies• Loss of tolerance → reactivity

to self antigens

Autoinflammation

• Innate immune system:

− Neutrophils, macrophages and germline molecules

• No apparent involvement of T cells or autoantibodies

• Relapsing and remitting bouts of systemic inflammation

vs.

Innate Immune SystemPrimitive, limited specificity and

diversity of expression No memory

Adaptive Immune SystemAntigen-specific

Immunologic memory

Autoinflammation Vs. Autoimmunity

• Hereditary PFS– FMF*– TRAPS#– MVK deficiency*– CAPS#

• Others– PAPA#– DIRA*– Blau#– More and more…. # *

Monogenic Polygenic• PFAPA• S-JIA / AOSD• Behcet• Schnitzler• CRMO / SAPHO• Recurrent pericarditis• Gout• Atherosclerosis

# - autosomal dominant; * = autosomal recessive

Genetics of Autoinflammatory diseases

• Pattern recognition receptor (PRR)• Toll-like receptors (TLR)• NOD-like receptors (NLRs)• Pathogen associated molecular pattern (PAMP)• Damage associated molecular pattern (DAMP)• Inflammasome• Cellular stress response

The innate immune response is critical to the development of autoinflammatory diseases

Different activation pathways for cells of the innate immune system

Gattorno & Martini. Arthritis Rheum.2013;65:1137–1147

Intracellular Stress and Reactive Oxygen Species

Gattorno & Martini. Arthritis Rheum.2013;65:1137–1147

• Defective enzymes that cause accumulation of unprocessed substrates

• Accumulation of misfolded proteins

• Cytoskeletal migration defects

• Generation of oxidative damage

• Accumulation of endogenous nucleotides

Interleukin 1 has multiple effects

Lachmann L. Arthritis Rheum. 2011; 63:314-24

Skin

Disorder Gene Protein Year Inheritance CytokineFMF MEFV Pyrin 1997 AR IL-1

TRAPS TNFRSF1A TNFR1 1999 AD TNF, IL-1

HIDS MVK Mevalonate kinase

2000 AR IL-1

CAPS NLRP3 Cyropyrin 2001 AD IL-1

FCAS-2 NLRP12 NLRP12 2008 AD IL-1

BLAU NOD2 NOD2 2001 AD TNF?

PAPA CD2BP1 PSTPIP1 2001 AD IL-1

Majeed LPIN2 LPIN2 2005 AR IL-1

Cherubism SH2BP2 SH2BP2 2001 AD TNF

DIRA* IL-1RN IL-1Ra 2009 AR IL-1

Infantile IBD IL-10RA IL-10R 2009 AR IL-10

Monogenic Autoinflammatory Disorders(1997-2009)

Disorder Gene Protein Year Inheritance CytokineDITRA IL-36RN IL-36Ra 2011 AR IL-36

CAMPS CARD14 CARD14 2011 AD IL-17, IL-23

PRAAS/CANDLE PSMB8 Proteasome 2011 AR IFN

APLAID PLCG2 PLCϒ2 2012 AD ?

HOIL 1 DEF. RBCK1 HOIL1 2012 AR IL-1?

PHID/H SYNDR. SLC29A3 SLC29A3 2012 AR ?

SAVI TMEM173 STING 2014 AD IFN

DADA2 CECR1 ADA2 2014 AR ?

NLRC4-MAS* NLRC4 NLRC4 2014 AD IL-1, IL-18

SIFD* TRNT1 TRNT1 2014 AR IL-6

TRAPS 11 TNFRSFIIA TNFR11 2014 AD TNF IL-1, IL-18

HA-20* TNFAIP3 A20 2015 AD Multiple

Monogenic Autoinflammatory Disorders(2011-2016)

• Familial Mediterranean Fever (FMF)• Mevalonate Kinase Deficiency (aka HIDS)• Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS)

Hoffman. Nat Rev Rheum 2009; 5: 249-256

Classic Periodic Fever Syndromes

• Familial Mediterranean Fever (FMF)• Mevalonate Kinase Deficiency (aka HIDS)• Tumor Necrosis Factor Receptor Associated Periodic Syndrome

(TRAPS)

Classic Periodic Fever Syndromes

Hashkes P. Pediatr Clin N Am.2012;59:447–470

Familial cold autoinflammatory Muckle–Wells syndromeNOMID/CINCA syndrome (FCAS)(MWS) • Progressive chronic

• Autosomal dominant • Autosomal dominant meningitis• Cold-induced • Urticarial rash • Urticarial rash

– Urticarial rash • Sensorineural deafness • Deafness– Arthralgia • AA amyloidosis (in 25% of • Visual and intellectual– Conjunctivitis patients) leading to renal damage

failure

• Destructive arthritis

MILDSEVERE

NOMID: Neonatal-onset multisystem inflammatory disease; CINCA: chronic infantile neurological cutaneous and articular syndromeImage copyright: FCAS and MWS: HJ Lachmann; NOMID/CINCA: Club Rhumatismes et Inflammations.

Neutrophilic urticarial syndromes:CAPS

Familial cold autoinflammatory syndrome (FCAS)

• Autosomal dominant• Cold-induced

– Urticarial rash– Arthralgia– Conjunctivitis

Muckle–Wells syndrome (MWS)

• Autosomal dominant• Urticarial rash• Sensorineural deafness• AA amyloidosis (in 25% of

patients) leading to renal failure

NOMID/CINCA• Progressive chronic

meningitis• Urticarial rash• Deafness• Visual and intellectual

damage• Destructive arthritis

MILD SEVERE

NOMID: Neonatal-onset multisystem inflammatory disease; CINCA: chronic infantile neurological cutaneous and articular syndromeImage copyright: FCAS and MWS: HJ Lachmann; NOMID/CINCA: Club Rhumatismes et Inflammations.

Neutrophilic urticarial syndromes:CAPS

Autosomal dominant

Mutation of NOD2/CARD 15

Triad of: granulomatous polyarthritis/ Post or panuveitis/ Skin Rash

Granulomatous Skin Lesions with Minimal orLow-grade Fever Attacks – Blau syndrome

Wouters et al. Pediatric Rheumatology. 2014;12:33

Blau

Activation Pathways of the Innate ImmuneSystem

Gattorno & Martini. Arthritis Rheum.2013;65:1137–1147

• With inflammatory bone disease– Deficiency of the interleukin-1 receptor antagonist (DIRA)– Majeed Syndrome

• With pyogenic arthritis– Pyogenic sterile arthritis, pyoderma gangrenosum and acne

(PAPA) syndrome• With inflammatory bowel disease

– Early onset inflammatory bowel disease• Without other organ manifestations

– Deficiency of the interleukin-36 receptor antagonist (DITRA)• CARD 14 mediated psoriasis (CAMPS)

Pustular Skin Rashes and Episodic or Continuous Fevers

Aksentijevich et al. N Engl J Med. 2009;360:2426-37

Autosomal recessivemutation IL1RN

Pustular rash Osteitis, osteomyelitis

Deficiency of the interleukin-1 receptor antagonist (DIRA)

DIRA

Gattorno & Martini. Arthritis Rheum.2013;65:1137–1147

Activation Pathways of the Innate Immune System

Autosomal Recessive, mutation of LPIN2

Congenital dyserythropoeitic anemia, Chronic recurrent multifocal osteomyelitis (CRMO), Sweet’s-like skin rash

Majeed Syndrome

Herlin. Ann Rheum Dis 2013;72:410-3

Autoinflammatory bone disorders

Hedrich et al. Pediatric Rheumatology 2013, 11:47

Autosomal Dominant Mutation in PSTPIP1

Early onset episodes of “septic arthritis” deforming arthritis Later development of pyoderma gangrenosum, cystic acne

Pyogenic arthritis, pyoderma gangrenosum, Acne (PAPA) syndrome

Nguyen et al JAAD 2013; 68: 834–853

PAPA

Gattorno & Martini. Arthritis Rheum.2013;65:1137–1147

Activation Pathways of the Innate Immune System

Perianal fistula Polyarthritis FolliculitisAutosomal recessive Mutations in IL10 receptor (IL10RA, IL10RB) and IL10 encoding genes loss of IL10 signaling

•Very early-onset severe IBD with bloody diarrhea, FTT, oral ulcers and fistula development •Painful arthritis with effusions, Folliculitis

Snapper. Gastroenterol Hepatol 2015; 11: 554–556

Very–early-onset inflammatory boweldisease

And now, a new group of autoinflammatory diseases described

in last 2 years……

Three New Monogenic Autoinflammatory Diseases

Crow. Nature reviews Immunology 2015; 15:429-440

Interferon signaling

STING-associated vasculopathy of infancySAVI

Liu et al. N Engl J Med 2014;371:507-18

Mutations in TMEM173, the Gene Encoding STING

STING - stimulator of interferon genes

Role of STING in IFN signaling

Stoffels & Kastner. Annu. Rev. Genom. Hum. Genet. 2016. 17:245–72

SAVI

CANDLE

Type I interferonopathy related proteins andrelevant immune signalling genes

Zhou et al. N Engl J Med 2014;370:911-20

• Autosomal recessive, mutation in CECR1

• PAN-like disease, variable severity

• Intermittent fevers• Recurrent lacunar strokes• Livedoid rash• Vasculopathy/itis• Hepatosplenomegaly• Hypogammaglobulinemia

Deficiency of adenosine deaminase 2:DADA-2

Cat eye syndrome chromosome region, candidate 1 (CECR1) gene encodes the ADA2 protein

Deficiency of Adenosine Deaminase 2 and Vasculopathy (DADA2)

Stoffels & Kastner. Annu. Rev. Genom. Hum. Genet. 2016. 17:245–72

NLRC4 Inflammasome Activation in Early-Onset Fever and Macrophage Activation Syndrome

• Autosomal recessive, mutation in NLRC4 inflammasone

• Infantile enterocolitis• Macrophage

activation syndrome• fever, malaise• splenomegaly• vomiting, loose

stools

Romberg et al. Nat Genet. 2014; 46: 1135–1139

NLR family, caspase recruitment domain (CARD) containing 4 -NLRC4

NLRC4 inflammasome and MAS

Stoffels & Kastner. Annu. Rev. Genom. Hum. Genet. 2016. 17:245–72

NLRC4 – NORD like receptor family, caspase recruitment domain (CARD) containing 4 ASC - apoptosis-associated speck-like protein with a CARD NAIP- NOD-like receptor family, apoptosis inhibitory protein

Nguyen et al JAAD 2013; 68: 834–853

Also known as: CANDLE, Joint contracture muscle atrophy microcytic anemia and panniculitis-induced lipodystrophy (JMP)

Autosomal recessive mutation in PSMB8 gene

Early onset recurrent fevers, violaceous plaques, eyelid swelling, lipodystrophy, microcytic anemia and systemic inflammation

Chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature (CANDLE)

syndrome

CANDLE

Type I interferonopathy related proteins andrelevant immune signaling genes

Crow. Nature reviews Immunology 2015; 15:429-440

To summarise

Protesome associated AIS

Haploinsufficiency of A20

• Think of autoinflammatory diseases when…..– Unexplained recurrent fever with characteristic symptoms– Skin rashes

• Unexplained urticaria• Granulomatous skin lesions• Pustular rash• Livedoid rash• Panniculitis• Chilblains

– Infantile IBD– Unexplained early onset vasculitis/vasculopathy

More to come in future ………….with New technologies

Take home messages……