Autoinflammatory diseases

Autoinﬂammatory
Diseases
Pannipa Kittipongpattana, MD.
10 April 2020
Division of Pediatric Allergy and Immunology
King Chulalongkorn Memorial Hospital

Outline
- Basis of autoinflammatory diseases
- Pathophysiologic mechanism
- Common autoinflammatory diseases and
treatment

Autoinflammatory diseases
- Dysregulation of innate immune system (myeloid cells)
- Without high titer of autoantibodies or Antigen-specific T cells
- Recurrent episodes of unprovoked inflammation
- Manifestations may include:
- Fever, rash, serositis, arthritis, meningitis, and uveitis
- Lymphadenopathy and splenomegaly
- Secondary amyloidosis
- Onset is usually in childhood
- Elevated inflammatory markers (CRP, ESR) during disease flares
Nigrovic, PA. Periodic fever syndromes and other autoinflammatory diseases: An overview. In:
UpToDate, Post, ET (Ed), UpToDate, Waltham, MA, 2018.

Abbas, et al. Cellular and Molecular Immunology, 9th ed

Autoinflammatory diseases: Mechanisms
- Interferonopathies: SAVI, CANDLE
- Inflammasomopathies: FMF, CAPS, NLRC4
- Non inflammasome related conditions: TRAPS, MKD, Blau disease,
PAPA, DIRA, DITRA, DADA2
Middleton’s allergy: Principles and practice 9th edition

Recognition of PAMPs and DAMPs
● PAMPs: pathogen-associated
molecular patterns (PAMPs)
● DAMPs: damage-associated
molecular patterns (DAMPs)
● Receptors are called pattern
recognition receptors (PRRs)
○ expressed by phagocytes,
dendritic cells, epithelial cells,
mast cells, and many others
○ expressed
■ Plasma membrane
■ Phagocytic vesicles
■ Cytosol
AIM2, Absent in melanoma; CDSs, cytosolic DNA sensors; CLRs, C-type lectin–like receptors; DAMP, damage-associated molecular pattern; DC, dendritic cells; MDA, melanoma
differentiation-associated gene; NLRs, NOD-like receptors; NOD, nucleotide oligomerization domain; PAMP, pathogen-associated molecular pattern; RLRs, RIG-like receptors; SP-D, surfactant
protein D; STING, stimulator of IFN genes; TLRs, toll-like receptors. Abbas, et al. Cellular and Molecular Immunology, 9th ed

● TLRs structure
○ Extracellular regions
■ Leucine-rich repeats for ligand binding
■ Cysteine-rich motifs
○ Cytoplasmic tails
■ Toll/IL-1 receptor domain for signaling
● 9 different functional TLRs in human
○ Plasma membrane
■ TLR 1, 2, 6,(10) bacterial lipopeptides
■ TLR 4 lipopolysaccharide
■ TLR 5 flagellin
○ Endosomal membrane
■ TLR 3 ds RNA
■ TLR 7, 8 ss RNA
■ TLR 9 CpG motifs
Toll-like receptors (TLRs)
FIGURE 4.2 Structure, location, and specificities of mammalian TLRs.
Note that some TLRs are expressed on the cell surface and others in
endosomes. TLRs may form homodimers or heterodimers. TIR , Toll IL-1
receptor; LPS , lipopolysaccharide; dsRNA , double stranded RNA; ssRNA ,
single stranded RNA.
Middleton’s allergy: Principles and practice 9th ed

Signaling pathways
PRRs bind to PAMPs and DAMPs
Activate signal transduction pathways
Promote antimicrobial and proinflammatory
functions

IFN , interferon; IRFs , interferon regulatory factors;
NF-κB , nuclear factor kappa B.
MYD88, myeloid differentiation primary response gene 88;
TRIF, TIR domain–containing adaptor protein inducing interferon β
Signaling pathways and functions of TLRs
NF-ϰB
IRF
Pro IL-1β
TNF-α
others
IFN type 1
MyD88
TRIF
TLR
1,2, 5,
6, 10
TLR 3
TLR 7, 9
TLR 4
MyD88-dependent,
TRIF-independent pathway

AIM2, Absent in melanoma; CDSs, cytosolic DNA sensors; CLRs, C-type lectin–like receptors; DAMP,
damage-associated molecular pattern; DC, dendritic cells; MDA, melanoma differentiation-associated gene; NLRs,
NOD-like receptors; NOD, nucleotide oligomerization domain; PAMP, pathogen-associated molecular pattern;
RLRs, RIG-like receptors; SP-D, surfactant protein D; STING, stimulator of IFN genes; TLRs, toll-like receptors.
Cytosolic Receptors
● 3 major classes
○ NOD-like receptors
(NLRs)
○ RIG-like receptors
(RLRs)
○ Cytosolic DNA sensors
(CDSs)

NOD–like receptors (NLRs)
● NOD: Nucleotide oligomerization domain
● A family of more than 20 different cytosolic proteins
● Structure of NLRs
○ N-terminal effector - varies among NLRs
○ Central NOD (or NACHT)
○ C-terminal leucine-rich repeat (LRR) domain: senses ligand

DAP , Diaminopimelic acid; LRR , leucine rich repeat; MDP , muramyl dipeptide; NOD , nucleotide oligomerization domain.
TA, Transactivating domain; BIR; Baculovirus inhibition of apoptosis protein repeat; CARD, caspase recruitment and activation domain;
PYD, Pyrin domain
Abbas, et al.
Cellular and Molecular Immunology, 9th ed
Part of inflammasome
Cytosolic PRRs
NLRs family

NOD–like receptors (NLRs): NOD1 and NOD2
- Members of the NLRC (CARD-domain-containing NOD) subfamily
- Respond to bacterial cell wall peptidoglycans
- NOD1
- recognizes DAP (diaminopimelic acid), a glycosylated tripeptide derived from
gram-negative bacterial peptidoglycan
- NOD2
- recognizes MDP (muramyl dipeptide), derived from both
gram-negative and gram-positive peptidoglycans
- Highly expressed in intestinal Paneth cells in the small bowel
where it stimulates expression of antimicrobial substances
called defensins
Nature Reviews Immunology volume 6, Page 9–20(2006)

NOD–like receptors (NLRs): NOD1 and NOD2
Step
- Ligand recognition
- Conformational change
- CARD effector domains recruit multiple copies of
the RIP2 kinases (receptor-interacting protein 2)
- Form signaling complex (NOD signalosome)
- RIP2 kinases activate NF-κB
- stimulates production of inflammatory cytokines and
molecules
(MyD88-independent)
Bioorganic & Medicinal Chemistry Letters 29 (2019) 1153–11611154
DAP from
GNB
MDP from
GNB & GPB
DAP (diaminopimelic acid), MDP (muramyl dipeptide),
GNB (Gram negative bacteria), GPB (Gram positive bacteria)
AP-1 (Activator protein 1)

Blau syndrome
- NOD1 and NOD2 are important in immune responses to GI pathogen, such as
Helicobacter pylori and Listeria monocytogenes
- NOD2 gene polymorphisms increase the risk for Crohn’s disease
- Gain-of-function mutations of NOD2
→ Blau syndrome (Pediatric Granulomatous Arthritis)
Nature Reviews Immunology volume 6, Page 9–20(2006)
Acta Biochim Pol. 2013;60(3):351-60
Dermatol Clin 35 (2017) 21–38
● inappropriate NFκB signaling
● Autosomal dominant
● Early-onset autoinflammatory disorder
● Triads:
○ Granulomatous arthritis
○ Uveitis
○ Dermatitis
● Early-onset sarcoidosis (EOS) Blau syndrome

RIG-Like Receptors (RLRs)
● RIG: retinoic acid-inducible gene
● Cytosolic sensors of RNA transcripts of RNA and DNA viruses
○ dsRNA
○ RNA-DNA heteroduplexes
● Induces antiviral type I interferons (IFN-α, β)
● RLRs contain
○ 2 N-terminal CARD-domains :
interact with other signaling proteins
○ RNA-helicase domain
○ C-terminal domain
Curr Opin Immunol. 2015 Dec;37:40-5.
RNA recognition

● RIG-I (retinoid-inducible gene I)
○ recognize RNA with a 5′ triphosphate moiety
● MDA-5 (melanoma differentiation-associated gene 5)
○ now called interferon induced with helicase domain 1 (IFIH1)
○ recognizes long dsRNA (1 to 6 kb)
longer than dsRNA that may be formed transiently in normal cells
● LGP2 (laboratory of genetics and physiology 2)
○ Regulation in the signaling pathway of RIG-I and MDA-5
1. Middleton’s allergy: Principles and practice 9th edition
2. Abbas, et al. Cellular and Molecular Immunology, 9th edition

- RLRs are recruited to the outer
mitochondrial membrane by the MAVS
(mitochondrial antiviral-signaling) protein
- leading to the formation of filaments by a
prion-like mechanism
- Activation of IRF3 and IRF7
- Induce production of type I interferons
IKKε/TBK1 (I-kappa-B
kinase-epsilon/TANK-binding kinase
1), IRF; interferon regulatory factor

Cytosolic DNA Sensors (CDSs) and the STING pathway
● Cytosolic DNA Sensors (CDSs)
○ molecules that detect microbial ds DNA in the cytosol
○ activate responses: type 1 interferon production and autophagy
● The STING (stimulator of IFN genes) pathway is an important mechanism
of dsDNA-induced activation of type 1 interferon responses
AIM2, Absent in melanoma; STING, stimulator of IFN genes

The STING pathway
- Cytosolic dsDNA activates cGAS (cyclic
GMP-AMP synthase)
- generates cGAMP
- cGAMP binds to STING (an endoplasmic
reticulum–localized transmembrane adaptor
protein)
- activates the TBK1 kinase
- activates the IRF3 transcription factor
- expression of type 1 IFN gene
FIGURE 4.5 The STING cytosolic DNA sensing pathway.
cGAS , cyclic GMP-AMP synthase; IFN , interferon;
IRF3 , interferon response factor 3.

Cytosolic DNA Sensors (CDSs) and the STING Pathway
● In addition to inducing IFN production,
○ STING stimulates autophagy, a mechanism by which cells degrade their own
organelles, such as mitochondria, by sequestering them within membrane-bound
vesicles and fusing the vesicles with lysosomes
● In innate immunity, autophagy delivers cytosolic microbes to the lysosome
● In adaptive immunity, autophagy generates peptides for presentation to
T cells

Other Cytosolic DNA Sensors (CDSs)
Some cytosolic DNA sensors may work through STING independent pathways
● RNA polymerase 3
○ binds and transcribes AT-rich microbial dsDNA into an
RNA-containing-triphosphate moiety
○ then activates the RIG-I pathway leading to type I interferon expression
● AIM2 (absent in melanoma-2)
○ recognizes cytosolic dsDNA and forms inflammasome

STING-Associated Vasculopathy with onset in Infancy (SAVI)
- Autosomal dominant
- Gain-of-function mutations in TMEM173, gene that encodes a key adaptor molecule in the
interferon pathway, STING
- STING is expressed in endothelial cells
- activation of the STING pathways results in endothelial activation and apoptosis
N Engl J Med 2014; 371:507-518
Figure 3. The STING–Interferon-β Pathway.

Clinical features and treatment of SAVI
Clinical features:
- Early onset
- Systemic inflammation: recurrent low grade fever
- Peripheral vasculitis and vasculopathy
- Pulmonary manifestation: Interstitial lung
disease/Lung fibrosis, pulmonary hypertension in
severe patient
- Low-titer autoantibodies: ANA, c-ANCA
Treatment:
- Options for treating are currently limited
- Blocking interferon signalling with inhibitors of Janus
kinase, such as tofacitinib, ruxolitinib and baricitinib,
could have some benefit
Telangiectasis
violaceous, scaling,
atrophic plaques
Interstitial lung diseaseVasculitis
N Engl J Med 2014; 371:507-518

Inflammasome
AIM2, Absent in melanoma; CDSs, cytosolic DNA sensors; CLRs, C-type lectin–like receptors; DAMP, damage-associated
molecular pattern; DC, dendritic cells; MDA, melanoma differentiation-associated gene; NLRs, NOD-like receptors; NOD,
nucleotide oligomerization domain; PAMP, pathogen-associated molecular pattern; RLRs, RIG-like receptors; SP-D, surfactant
protein D; STING, stimulator of IFN genes; TLRs, toll-like receptors.

Inflammasome
- multiprotein complexes
oligomers of sensor,
adaptor, and caspase-1
- form in the cytosol
- response to cytosolic
PAMPs and DAMPs
- generate active forms of
IL-1β and IL-18
ASC , Apoptosis-associated speck-like protein containing a CARD

Inflammasomes
● NLRs found in inflammasomes are
○ NLRB
○ NLRC4
○ NLRP
● non-NLR sensors are
○ AIM2 family: AIM2 and IFI16
contain a DNA sensing and a
pyrin domain
○ Pyrin contains an N-terminal
pyrin domain
DAP , Diaminopimelic acid; LRR , leucine rich repeat; MDP , muramyl dipeptide; NOD , nucleotide
oligomerization domain.

FIGURE 4.6 The inflammasome.
The activation of the NLRP3 inflammasome, which processes pro–IL-1 to active IL-1, is shown. Inflammasomes
with other NLRP proteins function in a similar way. Various PAMPs or DAMPs induce pro–IL-1β expression
through pattern recognition receptor signaling. ASC , Apoptosis-associated speck-like protein containing a CARD; IL-1 ,
interleukin-1.
NLRP3 inflammasome
- binding of a ligand
- multiple NLRP3 form an oligomer
- Each NLRP3 binds to ASC, adapter
(apoptosis-associated speck-like protein containing
a CARD)
- Triggers conformational changes of other ASC in
the cytosol by a prion-like self-propagating
mechanism
- formation of ASC filaments cluster
- recruit pro-caspase-1
- clustering of pro-caspase-1 → active caspase-1

Inflammasomes
● Inflammasome stimuli are associated with infections and cell stress
○ microbial products
○ environmentally or endogenously derived crystals
○ reduction in cytosolic potassium ion (K +
)
Sensors Stimuli
● NLRC4 flagellin, components of the type III secretion system of bacteria
● NLRP1 anthrax lethal toxin
● NLRP3 uric acid crystals, aluminum hydroxide crystals used in vaccine adjuvants,
ATP released from mitochondria, silica, bacterial products,
bacterial toxins produced by streptococci and staphylococci,
bacterial DNA-RNA hybrids, and the influenza virus
● NLRP12 Yersinia species’s PAMPs
● Pyrin Rho family GTPases

Inflammasome
● Inflammasome activation also causes pyroptosis
● Pyroptosis
○ caspase-mediated cleavage of gasdermin D
○ leads to formation of membrane pores
○ release of inflammatory mediators: IL-1β, IL-18, TNF, IL-6, and IL-8
● Pyroptosis may be induced by activation of
○ caspase-1
○ different caspase (caspase-11 in rodents | caspase-4, 5 in humans)
LPS in the cytosol can directly bind to caspase-11, leading to pyroptosis
and inflammasome activation
● The amplification of inflammation
○ enhances bacterial clearance, but also
○ severe systemic reaction to inflammatory cytokines

Cell Res. 2015 Nov;25(11):1183-4.

Inflammasomes: Disease
● Crystal induced arthritis
○ Gout (monosodium urate crystals)
○ Pseudogout (calcium pyrophosphate crystals)
● Occupational lung disease
○ Silicosis
○ Asbestosis
● Autoinflammatory syndromes
○ FMF
○ CAPS
○ NLRC4 inflammasomopathy
○ PAPA
○ MKD

Familial mediterranean fever (FMF)
● Most common monogenic autoinflammatory disease
● Gene MEFV 16p13 (AR >> AD)
● Protein Pyrin
● Childhood/adolescence onset (90% before 20-year-old)
● How mutation of the gene lead to increase inflammation is controversial
● Clinical manifestation
○ Recurrent episodes of
■ Fever
■ serositis (peritonitis, pleuritis, synovitis)
○ The frequency can be varies, usually 2-4 weeks interval
○ Arthritis is often monoarthritis of a large joint
○ 30% involves skin: erysipelas-like lesions
○ Complications:
■ Amyloidosis
■ ESRD (deposition of amyloid A)
The Rheumatologist, August 1, 2008.
Westwell-Roper et al. Pediatric Rheumatology (2019) 17:22

Clinical criteria for the diagnosis of FMF
Diagnosis: ≥ 1 major or 2 minor or 1 minor + 5
supportive criteria
Westwell-Roper et al. Pediatric Rheumatology (2019) 17:22

Treatment of FMF
● Colchicine
○ First line treatment
○ Dual effect
■ RhoA activation
■ microtubule destabilization
● Anti IL-1 treatment
○ Use in colchicine- resistant or
intolerant of colchicine
○ Anakinra, Canakinumab,
Rilonacept
● NSAIDs: during acute attacks
● Glucocorticoids
○ Beneficial during attack but not
in preventing attack

Cryopyrin-associated periodic syndromes (CAPS)
- Gene NLRP3 (CIAS1), 1q44 , Gain-of-function mutation
- Protein NLRP3 (Cryopyrin)
- 3 phenotypes:
- Familial cold autoinflammatory syndrome (FCAS)
- Muckle–Wells syndrome (MWS)
- Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile
neurological cutaneous and articular syndrome (CINCA)
Nat Immunol. 2017 Jul 19;18(8):832-842

Clinical features of Cryopyrin-associated periodic syndromes (CAPS)
Open Access Rheumatology: Research and Reviews 2014:6 15–25
Features FCAS MWS NOMID/CINCA
Severity Mild Moderate severe
Age of onset (yr) <1 <20 <1
Duration of attack (days) <2 1-2 ? (chronic persistent)
Fever Yes Yes Yes
Trigger Cold induced None None
Cutaneous Cold induced urticarial-like lesions Urticarial-like lesions Urticarial-like lesions
Musculoskeletal Arthralgia common, occasional mild myalgia Arthralgia common, arthritis can occur Epiphyseal bone formation
Eye involvement Conjunctivitis Conjunctivitis, episcleritis Optic disc edema, uveitis
Distinguishing clinical
symptoms
Cold induced urticarial-like lesions Sensorineural hearing loss Chronic aseptic meningitis, mental retardation,
sensorineural hearing loss, arthropathy
Amyloidosis No Frequent (25%) Frequent (25%)

Diagnosis of CAPS
- No validated criteria
- Rely on clinical features
- Mutation analysis of the NLRP3 gene
- Genetic testing cannot distinguish
between FCAS, MWS and NOMID
Kuemmerle-Deschner JB, et al. Ann Rheum Dis 2017;76:942–947.

Treatment of CAPS
- Anti IL-1 treatment
- The first line treatment
- Early treatment may prevent disease-associated damages
- 70% response to anti IL-1 treatment
- Other agents:
- Case reports suggest that other drugs may be effective in patients with
NOMID/CINCA, including
- Thalidomide
- Anti-IL-6 receptor antibody (Tocilizumab)
Haar T, et al. Ann Rheum Dis. 2013 May;72(5):678-85.
Kallinich T, et al. Scand J Rheumatol. 2005;34(3):246.
Matsubara T, et al. Arthritis Rheum. 2006;54(7):2314.

NLRC4 inflammasomopathy
● Autosomal dominant
● Gene NLRC4, 2p22 , Gain of function mutations
● 3 phenotypes
○ Autoinflammation with infantile enterocolitis (AIFEC)
○ Neonatal-onset multisystem inflammatory disease (NOMID)
○ Familial cold autoinflammatory syndrome (FCAS4)
● Rapid case identification using:
○ Disease biomarkers like elevated serum IL-18 concentrations
○ Characteristic skin
○ Biopsy findings and
○ Ultimately diagnostic gene sequencing
Romberg et al. Curr Opin Allergy Clin Immunol. 2017 Dec;17(6):398-404.

Immunological Reviews 2015, 265(1):6-21
Randilea Dawn Nichols. Systemic Effects downstream of NAIP/NLRC4 Inflammasome Activation in vivo © 2017.
NLRC4
NLRC4 is activated
via contact with the
NLR family of
apoptosis inhibitory
protein (NAIP)
NLRC4 does not
directly interact with
its flagellin / T3SS)
NLRC4 contains CARD allowing direct
contact with pro-caspase-1 without ASC
absent of ASC, the pathway will favor
pyroptosis over cytokine production

Autoinflammation with infantile enterocolitis (AIFEC)
● episodes of extreme acute inflammation ~ MAS-like
● AIFEC flare VS MAS
○ Similarity
■ IL-1β: fever, tachycardia
■ IFNγ: hemophagocytosis
■ myeloid cell activation and cytotoxic T-cell
dysfunction
■ hypertriglyceridemia, coagulopathy, cytopenias
■ elevated soluble IL-2 receptor and poor in-vitro cytotoxicity
○ Distinguishing features
■ Markedly high IL-18 > 104 pg/ml in AIFEC
■ severe, secretory, neonatal diarrhea is a feature of AIFEC
Intestinal biopsy
mixed inflammatory
infiltrate, villous flattening
with tissue edema,
epithelial erosions and
tissue autolysis.

Autoinflammation with infantile enterocolitis (AIFEC)
- Survivors are of short stature and exhibit anemia of chronic disease
- Between flares, untreated AIFEC patients display moderately
elevated acute phase reactants and highly elevated serum IL-18
concentrations
- Amyloidosis has not yet been described in AIFEC patients

FCAS4
- Heterozygous NLRC4 H443P variant
- Symptoms were mild and not require treatment
- Cells exposed to cold in vitro spontaneously produced IL-1β
- Phenotypic similarities to NLRP3-associated familial cold
autoinflammatory syndrome (FCAS1)

NLRC4-associated NOMID
● Heterozygous S445P NLRC4 variant
○ developed inflammatory symptoms early in life
○ not affect long-term survival
○ prominent skin manifestations: nodular and urticarial rash
○ conjunctivitis or uveitis
○ lacked MAS or infantile enterocolitis
○ highly elevated serum IL-18 concentration
○ skin biopsies: lymphohistiocytic (~AIFEC)

4 published AIFEC-associated NLRC4 mutations: V341A, T337S, T337N and S171F

Treatment of NLRC4 inflammasomopathies
- FCAS4 well controlled with NSAIDs or nothing
- skin and NOMID were effectively treated with Anakinra, other
disease features were not
- MAS-like episodes were successfully treated with corticosteroids,
cyclosporine and IVIg
- Enterocolitis usually resolves if the patient survive their infancy
- Experimenting therapies
- Recombinant IL-18 binding protein
- Blockade of IFN-γ

Pyogenic Arthritis Pyoderma gangrenosum, and Acne syndrome (PAPA)
- PSTPIP1, 15q24
- proline-serine-threonine-phosphatase
-interaction protein 1
- Pathogenesis is not fully understood
- PSTPIP1 directly interacts with pyrin.
Mutation might directly activate the
pyrin inflammasome
Demidowich A, et al. Arthritis Rheum. 2012 Jun;64(6):2022-7.
Yu J, et al. Mol Cell. 2007 Oct 26; 28(2): 214–227.
Mechanism of activation of pyrin by PSTPIP1

Clinical features of PAPA
- Age of onset: first decade
- In childhood
- recurrent sterile, erosive arthritis occurring spontaneously or after minor trauma
- By puberty
- joint symptoms subsides
- cutaneous symptoms increase
- severe cystic acne
- Pathergy with abscesses at the sites of injections
- recurrent non-healing sterile ulcers, “pyoderma gangrenosum”
Demidowich A, et al. Arthritis Rheum. 2012 Jun;64(6):2022-7.
Braun-Falco M, et al. J Am Acad Dermatol. 2012 Mar;66(3):409-15.
Yamamoto et al., J Genet Syndr Gene Ther 2013, 4:9
Cystic acne Pyoderma gangrenosum

Treatment of PAPA
- The treatment is depending on the dominant manifestation
- No controlled studies are available
- Anti-TNF and anti-IL1 therapies: partial response
- Corticosteroid: oral or intra-articular corticosteroids.
- Benefit in arthritis
- Partial response, necessitating long-term corticosteroids
https://www.printo.it/pediatric-rheumatology/AU/info/23/PAPA-Syndrome
Stone D,et al. Pediatr Rheumatol Online J. 2015;13(Suppl 1):P138.

Mevalonate kinase deficiency (MKD)
Hyperimmunoglobulinemia D with periodic fever syndromes (HIDS)
- AR
- MVK gene, 12q24
- Protein mevalonate kinase
- Mutation resulting in activation of pyrin
- Onset in infancy
- Clinical spectrum depending on level of residual MVK activity
Clinical Reviews in Allergy & Immunology 54, pages 454–479 (2018)

Pathogenesis of MKD

Clinical features of MKD
- Episodes last 3-7 days
- Intervals: periodic every 3-6 weeks
- Triggers: stress, infection, vaccination
- Symptoms
- Fever
- Skin rash: Maculopapular, urticarial, morbilliform, aphthous
ulcers
- GI: abdominal pain, diarrhea, splenomegaly
- Arthralgia/arthritis
- Prominent cervical lymphadenopathy

Investigations of MKD
- Genetic testing: mutation in MVK gene
- Urinary excretion of mevalonic acid
- For diagnosis and follow up
- Increased during attacks
- Decreased MVK enzyme activity in leukocytes or fibroblasts
- Increased serum levels og IgD (>100 IU/ml)
- 20% of MKD patients have normal IgD levels
- Do not correlate to severity

Treatment in MKD
- Corticosteroids
- Fever attacks dramatic response
- Anti-IL1
- Anakinra response rate 30-70%
- Canakinumab response rate >50%
- Anti-TNF
- Etanercept response rate 50%

TNF receptor- associated periodic syndrome (TRAPS)
- Loss-of-function mutation in TNFRSF1A, gene encoding TNF receptor 1 (TNFR1)
- lead to enhanced NFκB activation and reactive oxygen species (ROS) production
- Pathogenesis of TRAPS remains unclear
- Age onset: infancy to adulthood
Clinical features:
- Episodes last 1-4 weeks
- Recurrent ≥ 2-6 times/year
- Symptoms:
- Prolonged fever
- Skin: urticarial rash, migratory painful erythematous rash
- Eye: conjunctivitis, periorbital edema
- GI: abdominal pain, serositis
- MSK: myalgia, arthritis/arthralgia, fasciitis
- Complications: amyloidosis (10-20% in untreated patient)
Nat Immunol. 2017 Jul 19;18(8):832-842.

Gattorno M, et al. Ann Rheum Dis 2019;78:1025–1032. doi:10.1136/annrheumdis-2019-215048
Diagnosis of TRAPS
- Rely on clinical
- Mutation analysis of
TNFRSF1A gene
- Distinguish TRAPS
from FMF
- Longer duration of
Attack
- Skin & eye
manifestation

Treatment of TRAPS
Rheumatol Int (2018) 38:3–11

Deficiency of the IL-1 receptor antagonist (DIRA)
- Autosomal recessive
- Gene IL1RN
- IL-1 receptor antagonist (IL-1Ra)
- Mutation lead to Increase responses to
IL-1α, IL-1β
Arch Dermatol. 2012 Mar;148(3):381-4.

Clinical features and treatment of DIRA
Clinical features:
- Neonatal onset
- Low grade fever
- Skin pustulosis
- Pyogenic bone lesions: osteomyelitis, periostitis
Treatment:
- Anti IL-1: anakinra
(dramatic response, lifelong treatment)
Advances in Clinical Chemistry, 2015

Deficiency of the IL-36 receptor antagonist (DITRA)
- Gene IL36RN
- IL-36 receptor antagonist
(IL-36Ra)
- IL-36 is a Member of IL-1
family, has role in innate
immune response
N Engl J Med 2011; 365:620-628

Clinical features and treatment of DITRA
Clinical features:
- Varied onset
- High grade fever
- Sterile pustulosis psoriasis
- Oligoarthritis
- Glossitis
Treatment:
- Not clear optimal treatment
- Anti IL-1
- Anti-TNF agents
N Engl J Med 2011; 365:620-628
generalized pustular psoriasis glossitis mixed with the
pustular lesions of
generalized pustular
psoriasis

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature
(CANDLE)
- Gene PSMB8 (proteasome subunit β
type 8), loss of function mutation
- Leading to defective proteasome
assembly → accumulation of
ubiquitinated proteins
- Sustained production of type-1 IFN
Arthritis Rheum. 2012 Mar;64(3):895-907.
Front. Immunol., 09 August 2017

Clinical features and treatment of CANDLE
Clinical features:
- Infant-onset recurrent fever
- Progressive facial lipoatrophy
- Skin manifestations: 3 types
- Acral, perniotic lesions: intense, red or purplish, edematous
plaques mostly located on the nose, ears, fingers, or toes
- Annular plaques
- Perioral and periocular edema
- Neuro: intracranial calcification
Treatment
- No therapies for CANDLE have been consistently effective:
- spanning methotrexate, corticosteroids, cyclosporine,
azathioprine, and IVIG
- JAK1/2 kinase inhibitor (baricitinib) may be helpful
American Journal of Clinical Dermatology (2019) 20:539–564

Deficiency of adenosine deaminase 2 (DADA2)
- Loss of function mutations in ADA2
(formerly CECR1)
- Pathogenesis unclear
- ADA2 is a growth factor for endothelial
cells and promotes the differentiation of M2
macrophages
- Deficiency results in
- decreased vascular integrity
- predominance of proinflammatory M1
macrophages
- perivascular inflammation mediated
by tumor necrosis factor (TNF)
Pediatr Rheumatol Online J. 2016 Sep 8;14(1):51.
N Engl J Med. 2019 Apr 18;380(16):1582-1584.

Clinical features and Treatment of DADA2
Clinical features:
- Fever
- Early-onset vasculopathy: lacunar stroke,
livedo racemosa, portal hypertension,
polyarteritis nodosa
- Mild immunodeficiency: low serum IgM
- Hematologic abnormality: red-cell aplasia, and
neutropenia
N Engl J Med. 2019 Apr 18;380(16):1582-1584.
livedo racemosa MRI indicating acute
small-vessel ischemia in the
brain
Treatment:
- No defined treatment strategies
- Exogenous ADA2 replacement
- immunomodulatory drugs such as TNF inhibitors
- Hematopoietic stem-cell transplantation may be helpful in
severe phenotype

Periodic Fever with Aphthous Stomatitis, pharyngitis and Adenitis
(PFAPA)
- Most common cause of periodic fever in childhood
- No gene identified
- Onset: before age 5 year and resolves by adolescence
- Episodes of fever lasting 3–6 days, recurrence every 3–8 weeks
- Associated with 1/3 of:
- aphthous stomatitis
- cervical adenitis
- pharyngitis
- Asymptomatic between episodes
- Normal growth
- Proposed contributors to pathogenesis include infection, abnormal host immune
responses, or combined
Vanoni et al. Pediatric Rheumatology (2016) 14:38

Treatment of PFAPA
- Glucocorticoids: rapid resolution of flare
- Colchicine: second line treatment to
prevent frequently recurrent fever
episodes
- Cimetidine: helpful in 30% of patient
- Tonsillectomy: should be reserved for
selected patients refractory to medical
treatment
- Intermittent anakinra: helpful in aborting
episodes
Vanoni et al. Pediatric Rheumatology (2016) 14:38

Summary of Diseases
Cytosolic sensors
Inflammasomes
Cytokine
receptors
Others
Blau syndrome NOD2
SAVI STING
FMF Pyrin
CAPS NLRP3
AIFEC NLRC4
PAPA PSPTIP1
MKD/HID MVK
TRAP TNFRN
DIRA IL1RN
DITRA IL36RN
CANDLE PSMB8 ~ Proteasome
DADA2 ADA2 ~ Macrophage
IL1β
IFN
TNF
NFϰB

Approach to autoinflammatory diseases
Textbook of Autoinflammation pp 203-223, Feb 2019
AR AD AR/AD AD AD AD AD AR
PFAPA MKD TRAPS FMF FCAS MWS NOMID/
CINCA
PAPA DADA2

IUIS 2017. J Clin Immunol. 2018 Jan;38(1):96-128.

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