what is new - newer autoinflammatory syndromes - dr t sathish kumar
TRANSCRIPT
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……