Autoinflammatory_syndromes_with_a_dermat.pdf

doi: 10.1111/j.1346-8138.2007.00342.x Journal of Dermatology 2007; 34: 601–618
© 2007 Japanese Dermatological Association 601
Blackwell Publishing Asia
REVIEW ARTICLE
Autoinflammatory syndromes with a dermatological
perspective
Nobuo KANAZAWA, Fukumi FURUKAWA
Department of Dermatology,Wakayama Medical University,Wakayama, Japan
ABSTRACT
The term autoinflammatory syndromes describes a distinct group of systemic inflammatory diseases apparently
different from infectious, autoimmune, allergic and immunodeficient ones. Originally, it was almost synonymous
with clinically defined hereditary periodic fever syndromes, including familial Mediterranean fever, hyper
immunoglobulin D syndrome with periodic fever and tumor necrosis factor receptor-associated periodic
syndrome. Similar but distinct periodic fever syndromes accompanied by urticarial rash, familial cold autoinflam-
matory syndrome, Muckle–Wells syndrome and chronic infantile neurological cutaneous articular syndrome, have
all been reportedly associated with CIAS1 mutations and are collectively called cryopyrin-associated periodic
syndromes. Consequently, the concept of autoinflammatory syndromes has been spread to contain other
systemic inflammatory diseases: rare hereditary diseases with or without periodic fevers, such as pyogenic sterile
arthritis, pyoderma gangrenosum and acne syndrome, Blau syndrome and chronic recurrent multifocal osteomyelitis,
and the more common collagen disease-like diseases, such as Behcet’s disease, Crohn’s disease, sarcoidosis
and psoriatic arthritis. These diseases are all caused by or associated with mutations of genes regulating innate
immunity and have common clinical features accompanied with activation of neutrophils and/or monocytes/
macrophages. In this review, major autoinflammatory syndromes are summarized and the pathophysiology of
related skin disorders is discussed in association with dysregulated innate immune signaling.
Key words: autoinflammatory syndromes, gene mutations, hereditary periodic fever syndromes, innate immunity,
NOD-LRR proteins.
INTRODUCTION
The term autoinflammatory syndromes was desig-
nated by Kastner and O’Shea in 1999 to describe a
group of systemic inflammatory diseases apparently
different from infectious, autoimmune, allergic and
immunodeficient ones.1,2
Originally, it was almost
synonymous with clinically defined hereditary
periodic fever syndromes, including familial
Mediterranean fever (FMF), hyper immunoglobulin D
syndrome with periodic fever (HIDS) and tumor
necrosis factor receptor-associated periodic syn-
drome (TRAPS).3
While the clinical features of these
diseases look similar to infections or rheumatological
diseases, neither a distinct pathogen or autoantibody
can be identified. Discovery of the responsible genes,
especially the one encoding the tumor necrosis
factor (TNF) receptor, has made it clear that these
diseases are caused by mutations of genes critical
for inflammatory signaling. Other related periodic
fever syndromes accompanied with urticarial rash,
familial cold autoinflammatory syndrome (FCAS),
Muckle–Wells syndrome (MWS) and chronic infantile
neurological cutaneous articular syndrome (CINCA),
have all been reportedly associated with CIAS1 muta-
tions and are collectively called cryopyrin-associated
periodic syndromes (CAPS).4
Because cryopyrin
forms the caspase-activating inflammasome and is
Correspondence: Nobuo Kanazawa, M.D., Ph.D., Department of Dermatology,Wakayama Medical University, 811-1 Kimiidera,Wakayama 641-0012,
Japan. Email: nkanazaw@wakayama-med.ac.jp
Received 4 April 2007; accepted 12 April 2007.

N. Kanazawa and F. Furukawa
602 © 2007 Japanese Dermatological Association
regulated by pyrin, the molecule responsible for FMF,
CAPS is now considered as another pole of the
major autoinflammatory syndromes.5
Consequently,
the concept of autoinflammatory syndromes has
been spread to include other rare hereditary diseases
with or without periodic fevers, such as pyogenic
sterile arthritis, pyoderma gangrenosum and acne
syndrome (PAPAS), Blau syndrome (BS), and chronic
recurrent multifocal osteomyelitis (CRMO). In another
limb, discovery of related gene mutations in more
common diseases, such as Behcet’s disease (BD),
Crohn’s disease (CD), sarcoidosis and psoriatic
arthritis (PsA), further spread the spectrum of
autoinflammatory syndromes to so-called collagen
disease-like diseases.6,7
As the common patho-
physiology, these diseases share hyperactivation of
neutrophils and/or monocytes/macrophages, accom-
panied with genetically predisposed dysregulation
of innate immune signaling. In this context, though
no related genetic abnormality has yet been found,
similar abnormal signaling might be associated
with pathogenesis of other idiopathic chronic
inflammatory diseases, such as idiopathic urticaria,
vasculitis, inflammatory keratosis, pustulosis, non-
infectious granulomatosis, as well as febrile adult-
onset Still’s disease.
HEREDITARY PERIODIC FEVER
SYNDROMES
Familial Mediterranean fever
FMF (Mendelian Inheritance in Man [MIM]: 249100),
the most common periodic fever syndrome, is an
autosomal recessive disease characterized by short
(a few hours to several days), recurrent painful
febrile attacks accompanied by high fever, peritoni-
tis, pleuritis, arthritis and skin rash.7,8
Secondary AA
amyloidosis with renal failure can develop as the
potentially lethal complication. Colchicine is effec-
tive for the attacks. This disease is concentrated in
a particular area around the Mediterranean Sea and
mostly seen among non-Ashkenazi Jews, Armenians,
Turks and Arabs (1:500–1:2000 prevalence). In
Japan, so far at least nine families have been
reported.9
Skin rash, occurring specifically but less
frequently compared with other major symptoms,
resembles erysipelas and is histologically com-
posed of massive neutrophil infiltration in dermis.10
Leukocytoclastic vasculitis such as polyarteritis
nodosa (PN) and Henoch–Schonlein purpura (HSP)
has also been reported to be associated with
FMF.11–13
In 1997, the responsible Mediterranean
fever (MEFV) gene on chromosome 16p13.3 was
shown to encode pyrin (referring to the Greek word
for fever, “pyrus”) or marenostrin (referring to the
Latin word for the Mediterranean Sea, “marenos-
trum”).14,15
More than 70 mutations have been iden-
tified in MEFV and most of them are localized in the
last exon 10 encoding B30.2 domain (Fig. 1). The
most common M694V mutation gives a major risk of
amyloidosis.16
Pyrin, composed of four domains –
pyrin domain (PYD), B-Box (BB), coiled-coil domain
(CC) and B30.2 domain – is mainly expressed in
cytoplasm of neutrophils and monocytes and inter-
acts with another PYD-bearing adaptor molecule,
apoptosis-associated speckle-like protein with a
caspase recruitment domain (ASC). Pyrin can act as
a negative regulator of ASC-mediated inflammatory
responses and therefore loss-of-function mutations
of this molecule causes hyperimmune responses
and recessive inheritance (Fig. 1).17,18
Actually, pyrin
gene-targeted mice showed caspase-1-mediated
hyperimmune phenotype.19
However, there have
been conflicting reports demonstrating pyrin-
mediated inflammatory responses and the precise
mechanisms are still undefined.20,21
In a Japanese
case of FMF accompanied with chronic myeloge-
nous leukemia, interferon-α therapy was reportedly
effective on both diseases.22
Notably, allogeneic
bone marrow transplantation was applied to a
case of FMF who also had congenital dyserythro-
poietic anemia (CDA) and cure has been obtained
even after termination of all immunosuppressive
therapy.23
Hyper immunoglobulin D syndrome with
periodic fever
HIDS (MIM: 260920) is also an autosomal recessive
disease characterized by very early onset (usually
under 1 year of age) recurrent attacks of fever,
severe abdominal pain, diarrhea, arthritis, cervical
lymphadenopathy and skin rash.24
Typically, each
attack lasts 3–7 days with a 4–8-week interval. Small
erythematous macules, papules and nodules are
frequently observed and even petechiae and purpura
are also seen during attacks.25
Histologically, mild

Autoinflammatory syndromes
vasculitis is mostly detected and Sweet syndrome-
like or cellulitis-like findings and deep vasculitis
have also been reported. Similar to FMF, HSP and
erythema elevatum diutinum (EED) have been
reported in association with HIDS (Fig. 2).26,27
A con-
stantly high serum immunoglobulin (Ig)D level is
characteristic but is neither specific nor causative
for attacks. Amyloidosis has not been reported in
association with HIDS. This disease is mostly seen
in Northern Europe (~60% are either Dutch or
French). For treatment, although benefits of colchi-
cine, corticosteroid, cyclosporine and i.v. Ig have
been reported in some cases, no uniformly success-
ful treatment has been determined.3
Notably, in a
case accompanied with EED, dapson had a better
effect than corticosteroid.27
In 1999, the mevalonate
kinase (MVK) gene on chromosome 12q24 was
identified to be responsible for this disease.28,29
MVK
phosphorylates mevalonic acid to form mevalonate
5-phosphate as the essential step of the isoprenoid/
cholesterol biosynthesis cascades following 3-
hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA)
reductase (Fig. 2).30
Undetectable MVK activity due
to mutations of the same gene causes mevalonic
aciduria (MIM: 251170), which shows growth and
mental retardation, facial deformities, cerebellar
ataxia, cataract, anemia as well as recurrent epi-
sodes similar to HIDS, and even causes death in
early childhood.31
In HIDS patients, on the other
hand, as MVK activity is reduced but still remaining,
increased levels of plasma mevalonic acid are not
so high and urinary mevalonate can be apparent
only during attacks.32
Because of the unaffected
RNA expression, HIDS-type mutations are consid-
ered to affect stability and/or maturation of MVK
protein. Notably, enzymatic activity of the mutant
MVK is reportedly sensitive to higher temperature,
providing an explanation of the periodic episodes
of HIDS.33
Accumulation of mevalonate and lack of
isoprenoids due to MVK deficiency are supposed
to cause interleukin (IL)-1-mediated inflammation
and the beneficial effect of simvastatin, a drug inhib-
iting HMG-CoA reductase, on HIDS supports this
observation.34,35
However, the precise mechanism of
how MVK deficiency leads to inflammation is not
well understood.
Figure 1. Schematic view of signaling pathways through cryopyrin, Nod2 and Nod1. Cryopyrin and Nods are shown as
dimers. Major genetic mutations associated with autoinflammatory diseases are shown by X. Sar, sarcoidosis.

Tumor necrosis factor receptor-associated
periodic syndrome
TRAPS (MIM: 142680) represents the autosomal
dominantly transmitted group of hereditary periodic
fever syndromes, despite having clinical character-
istics similar to FMF. This syndrome has been called
various names such as familial “Hibernian” fever
(FHF, Hibernia is the ancient name of Ireland), auto-
somal dominant familial periodic fever, and FMF-like
syndrome with amyloidosis. Clinically, TRAPS is
characterized by recurrent episodes of fever, myalgia,
rash, arthralgia, abdominal pain and conjunctivitis
that usually last longer than 5 days.36,37
The most
common cutaneous manifestation is a centrifugal
migratory, erythematous patch overlying the area
with myalgia.38
Less frequently, urticaria-like plaques
and generalized serpiginous patches and plaques
occur. Histologically, perivascular and interstitial
infiltrate of mononuclear cells is apparent. Small
vessel vasculitis and recurrent panniculitis leading
to misdiagnosis of Weber–Christian’s disease has
been reported to be associated with TRAPS.39
Coincidence of TRAPS and systemic lupus ery-
thematosus (SLE) was also reported (Fig. 3).40
Unlike FMF, colchicine is ineffective, but this dis-
ease does respond to high-dose oral prednisone.
Successful treatment using tacrolimus (FK506)
was also reported.41
AA amyloidosis leading to renal
dysfunction develops in approximately a quarter of
affected families. In 1999, the gene encoding the
55-kDa TNF receptor (TNF receptor superfamily 1A,
TNFRSF1A) on chromosome 12p13.3 was recog-
nized to be responsible for this syndrome and the
disease was therefore designated as TRAPS.1
More than 50 mutations have been reported, most
of which are single nucleotide missense mutations
in exons 2, 3 and 4, constituting the first two
cysteine-rich domains of the extracellular portion,
Figure 2. (a) Cholesterol synthesis cascades and abnormal signaling in hyper immunoglobulin D syndrome with periodic
fever (HIDS). (b) Erythema elevatum diutinum observed in lower extremities of a HIDS patient. (c) Histologically,
leukocytoclastic vasculitis is apparent. Pictures are kindly provided by Prof. S. Miyagawa.

and the remaining is a splicing mutation in intron 3.
Some of them have been identified not only in
affected individuals but also in unaffected relatives.
Considering that the age of onset of this disease
ranges from 2 weeks to 53 years, it is possible that
unaffected relatives with such mutations may
develop symptoms in the future. It should also be
noted that there are reportedly non-febrile cases.42
As the reduced level of serum soluble TNFR which
potentially have an antagonistic effect, is observed
in affected patients, defective shedding of surface
TNFR by these mutations, causing long-lasting
activation signal, is considered responsible for
hyperimmune phenotype of this disease (Fig. 3).1,2
Effect of the anti-TNF drug, Etanercept, a recom-
binant TNFR fused with human IgG1, is compatible
with this hypothesis.43
However, heterogeneity of
surface TNFR shedding among TRAPS patients and
between cell types has been reported and recent
observations raise another hypothesis that intracel-
lular aggregation of misfolded TNFR1 causes hyper-
immune response independent of TNF signaling.44–47
Actually, better effects have been reported with anti-
IL-1 therapy on a TRAPS patient than with anti-TNF.48
Clinical features of classical hereditary periodic fever
syndromes are summarized in Table 1.
RARE HEREDITARY AUTOINFLAMMATORY
SYNDROMES
Cryopyrin-associated periodic syndromes
FCAS (MIM: 120100), previously called familial cold
urticaria (FCU), is an autosomal dominant disease
characterized by early-onset cold-induced urticarial
itchy rash accompanied with chills, fever, arthralgia,
mialgia, headache and conjunctivitis, which can
Figure 3. (a) Shedding of tumor necrosis factor receptor (TNFR) and abnormal signaling in tumor necrosis factor
receptor-associated periodic syndrome (TRAPS). (b) Edematous erythema observed in cheeks and periorbital area of a
TRAPS patient. (c) Multiple serpiginous patches and plaques in lower extremities. Pictures are kindly provided by Dr H. Ida.

appear with change of temperature and disappear
within 24 h.49
Amyloidosis develops in some cases.
MWS (MIM: 191900), also called urticaria–deafness–
amyloidosis syndrome, shows progressive sen-
sorineural deafness as well as amyloidosis and
urticarial rash, which is not always induced by cold,
and is inherited in an autosomal dominant trait.50
CINCA (MIM: 607115), named neonatal-onset mul-
tisystemic inflammatory disease (NOMID) in North
America, is another autosomal dominant disease
including many de novo cases, and shows the most
severe phenotype characterized by a distinct triad
of skin rash, arthritis and disorders of the central
nervous system which appears immediately after
birth.51,52
In 2001, the gene CIAS1 (cold-induced
autoinflammatory syndrome 1) on chromosome
1q44, which encodes cryopyrin (NALP3, PYPAF1),
was identified to be responsible for FCAS and MWS.53
Consequently, presence of CIAS1 mutations in
CINCA has been demonstrated and now these three
diseases are considered to form a spectrum of
CAPS.4,54
Cryopyrin is mainly expressed in cytoplasm
of monocytes and composed of three domains:
PYD, nucleotide oligomerization domain (NOD) and
leucine-rich repeats (LRR). More than 50 mutations
have been identified in CIAS1 and all of them are
localized in exon 3 encoding the central NOD
domain. Among FCAS, MWS and CINCA, mutations
are present in one or more disorders and, notably,
the overlapping pattern correlates with severity of
the diseases (FCAS/MWS or MWS/CINCA).55
Cryopyrin, in association with ASC and procaspase-
1, forms inflammasome, the cytoplasmic platform
activating caspase-1-mediated inflammatory sig-
nals.56–58
Actually, in CAPS patients, high serum IL-1
levels are apparent and the anti-IL-1 drug, Anakinra,
has a dramatic effect.59–61
Recently, it has been
reported that cryopyrin recognizes bacterial RNA as
well as imiquimod, which is used as an adjuvant in
antiviral and antitumor therapy, to activate IL-1β
and IL-18 secretion through an independent path-
way of toll-like receptor (TLR)-mediated signals.62
Table 1. Comparison of clinical features of familial Mediterranean fever (FMF), hyper immunoglobulin D syndrome with
periodic fever (HIDS) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
FMF HIDS TRAPS
Ethnic
Armenians, Arabs,
Jewish and Turkish Dutch and French Not restricted
Attack
Duration (days) 1–3 2–7 7–21
Fever + + +
Abdominal pain + + +
Chest pain + – +
Arthralgia + + +
Myalgia – – +
Lymphadenopathy – + –
Conjunctivitis and/or
periorbital edema
– – +
Eruption
Distribution Lower legs Extremities Generalized
Gross finding Erysipelas-like erythema Small erythematous macules, Large erythematous migratory
papules and nodules patches and plaques
Histology Dermal neutrophilic infiltrate Mild vasculitis Perivascular infiltrate of
lymphocytes and monocytes
AA amyloidosis + – +
Inheritance Autosomal recessive Autosomal recessive Autosomal dominant
Blood marker – High immunoglobulin D Low soluble tumor necrosis
factor receptor (not consistent)
Gene and protein MEFV, pyrin (marenostrin) MVK, mevalonate kinase TNFRSF1A, p55 TNFR
Treatment Colchicine Corticosteroids, dapson
(not consistent)
Corticosteroids,
Etanercept, Anakinra

Gain-of-function mutations in NOD of cryopyrin are
considered to cause uncontrolled IL-1β and IL-18
secretion leading to characteristic periodic fever of
CAPS (Fig. 1). Interestingly, a case of CINCA with
somatic mosaic CIAS1 mutation showing milder
phenotype has been reported (Fig. 4).63
Pyogenic sterile arthritis, pyoderma
gangrenosum and acne syndrome
PAPAS (MIM: 604416), a very rare autosomal dominant
disorder characterized by pyogenic arthritis, pyo-
derma gangrenosum and cystic acne, was originally
designated by Lindor et al. in 1997.64
Early-onset
episodic inflammation leading to joint destruction is
characteristic and the disease was also called
familial recurrent arthritis to distinguish it from juve-
nile idiopathic arthritis (JIA). By the clinical features
of inflammatory attacks which usually last several
days, this disease is also called periodic fever with
aphtous stomatitis, pharyngitis and cervical aden-
opathy (PFAPA).65
In 2002, the gene proline/serine/
threonine phosphatase-interacting protein 1 (PSTPIP1;
also called CD2 antigen-binding protein 1 [CD2BP1])
on chromosome 15q24–25.1 has been identified
to be responsible for this disease.66
PSTPIP1 has
originally been identified as a cytoskeletal protein co-
localizing with actin filaments and can be dephos-
phorylated by proline, glutamate, serine, threonine
(PEST)-type tyrosine phosphatase (PTP-PEST) to
further guide the PTP towards dephosphorylation of
Wiscott–Aldrich syndrome protein (WASP).67
More-
over, PSTPIP1 interacts with pyrin, which co-localizes
with microtubules and actin filaments, and the
identified disease-associated mutations in its CC
domain increase the PSTPIP1-pyrin binding, result-
ing in inhibition of pyrin-mediated regulation of
inflammatory signals (Fig. 1).68–70
Though only two
families have reportedly been affected with this dis-
ease, an old family reported in 1975 is considered to
have the same disease.71
Blau syndrome and early-onset sarcoidosis
Sarcoidosis is a multiorganic inflammatory disease
withunknownetiology,characterizedbythehistological
features of noncaseating epithelioid granulomas
and typically by the clinical triad of lung, lymph node
and eye involvement. A rare but distinct type of
sarcoidosis, characterized by onset in infancy and a
triad of arthritis, uveitis and skin rash, was called
early-onset sarcoidosis (EOS; MIM: 609464) or
preschool sarcoidosis.72
In 1985, a large family having
EOS-like systemic granulomatosis was reported by
Edward B. Blau and a new entity, designated as BS
(MIM: 186580) was defined as a distinct disease from
EOS by its autosomal dominant inheritance.73
Histo-
logically, it is hard to distinguish these diseases from
sarcoidosis, however, the clinical features are clearly
different; onset is usually before 4 years of age and
Figure 4. Urticarial rash in trunk (a,b) and elbow joint swelling (c) observed in a chronic infantile neurological cutaneous
articular syndrome (CINCA) patient. (d) On roentgenogram, enlargement of hard bone is apparent. Pictures are kindly
provided by Dr N. Kambe.

there is sequential skin, joint and eye involvement
without affecting the lung and hilar lymph nodes.
Rather, this disease can be easily misdiagnosed as
JIA unless histological examination is done.74
Skin
lesions most commonly show scaly maculopapules
with tapioca-like appearance and are described as
the lichenoid-type, which are rarely seen among
sarcoidosis in adults (Fig. 5).75
Erythema nodosum
also appears in EOS.76
In 2001, heterogenous muta-
tions of caspase recruitment domain 15 (CARD15)
gene on chromosome 16q12 were identified in BS
families.77
Nod2, which is encoded by CARD15, is
mainly expressed in cytoplasm of monocytes and
composed of three domains, CARD, NOD and
LRR. In contrast with cryopyrin, Nod2 recognizes
muramyl dipeptide (MDP), which is the minimum
and common immunocompetent module of both
Gram-negative and -positive bacterial cell wall
peptidoglycan (PGN) and interacts through CARD
with RICK (RIP2-like kinase), instead of ASC, result-
ing in NF-κB activation (Fig. 1).78
Later, the same and
other novel gain-of-function mutations of CARD15
were identified in EOS patients and therefore Blau
syndrome and EOS share the same etiology.76
Recently, by the result of international registry, the
term pediatric granulomatous arthritis was proposed
to unify CARD15 mutation-related BS and EOS79
Interestingly, the disease-associated mutations in
NOD of CARD15, R334W/Q and D382E, correspond
to CAPS-associated CIAS1 mutations, R260Q and
D303N, respectively.80
Chronic recurrent multifocal osteomyelitis and
Majeed syndrome
CRMO (MIM: 259680) was originally described in 1972
as a subacute or chronic multifocal osteomyelitis
affecting the metaphyses of the long bones.81
Although most CRMO cases are sporadic, a con-
sanguineous Arab family having CRMO with CDA
and neutrophilic dermatosis or Sweet syndrome was
reported in 1989 by Majeed et al. and the disease
was termed Majeed syndrome (MIM: 609628).82
Furthermore, mouse chronic multifocal osteomyelitis
(cmo), showing a quite similar phenotype to CRMO,
were transmitted in an autosomal recessive manner.
Recently, PSTPIP2 on murine chromosome 18,
highly homologous to PSTPIP1, has been identified
as the responsible gene for this mutant mouse.83
A
PSTPIP2 mutation was also discovered in the lupo
mouse, a chemically-induced mutant mice charac-
terized by necrotic osteolysis of paws and necrotic
ears.84
PSTPIP2 directly regulates F-actin bundling
and activate macrophage motility through filopodia
formation.85
Actually, the lupo phenotype is accom-
panied by macrophage infiltration and transferred
by bone marrow transplantation in the absence
of lymphocytes.84
On the other hand, homozygous
mutations of the LPIN2 gene on chromosome 18p11
encoding Lipin2 have been identified in Majeed
syndrome families.86,87
Lipin2 is related to Lipin1,
which is responsible for human lipodystrophy as well
as murine fatty liver dystrophy (fld), and thus consid-
ered to have a role on adipose tissue development
and triglyceride metabolism.88
This result provides
another piece of evidence to support a conceptual
relationship between lipid metabolism and inflam-
mation. It remains undefined whether human
PSTPIP2 gene on chromosome 18q12 is associated
with sporadic CRMO cases, in which the responsi-
ble gene locus has been mapped on chromosome
18q21–22.89
COLLAGEN DISEASE-LIKE CHRONIC
INFLAMMATORY DISEASES
Behcet’s disease
BD, which was given the name of a Turkish physi-
cian, is characterized by recurrent episodes of oral
aphthae, genital ulcers, skin lesions such as papular
pustulosis and nodular erythemas, and eye lesions
such as uveitis and retinal vasculitis, with or without
high fever.90
Histologically, systemic perivasculitis is
characteristic in which early neutrophilic infiltration,
endothelial cell swelling and fibrinoid necrosis are
observed. Especially, neuro-, vasculo- and digestive
tract-BD are defined by the affected organs. Colch-
icine is effective for the attacks. Distribution of this
disease is concentrated along the “Silk Road”, from
Turkey to Japan. Genetically, human leukocyte anti-
gen (HLA)-B51, whose distribution is closely related
with that of BD patients, is known as the greatest
risk factor for the disease.91
Furthermore, several
genes both within and outside the HLA locus, such
as TNF, major histocompatibility complex class I
chain-related gene (MIC), factor V, and intracellular
adhesion molecule (ICAM), have been reported to

Figure 5. Lichenoid papules in trunk (a) and arm (b), and joint swelling of hand (c) and foot (d) observed in an early-onset
sarcoidosis (EOS) patient. (e) Histologically, presence of non-caseating epithelioid cell granuloma containing giant cells
is apparent.

be associated with BD.90,92
However, no single
causative gene has been identified and genetic
abnormalities are considered to have a role in mod-
ulating immune responses, including leukocyte
activation and coagulation pathway, against trigger-
ing microbial antigens (e.g. Streptococcus species).
In this context, MEFV mutations were intensely
investigated in BD, because of its high similarity to
FMF. Four mutations have been shown to be more
prevalent in the patients than in controls, indicating
that MEFV is another susceptibility gene for BD.93
Interestingly, there was a report of a case with a
diagnosis of both FMF and BD. As this case had
only a single allele with the mutated MEFV gene, it
has been postulated that the hyperactive immune
status in BD visualized the subclinical genetic
abnormality in the FMF carrier.94
R92Q mutation of
TNFR1 was also reportedly associated with BD.95
Actually, there are two patients with paired MVK
mutations, showing both features of BD and HIDS,
however, no significant association of MVK, CIAS1,
PSTPIP1 and CARD15 mutations has been observed
in BD patients.96,97
Thus, precise role of these muta-
tions in BD should be carefully investigated.98
Crohn’s disease and sarcoidosis
CD is a major inflammatory bowel disease (IBD),
which sometimes accompanies skin diseases, such
as pyoderma gangrenosum and sarcoidosis. Histo-
logically, CD is characterized by early neutrophilic
infiltration, granuloma formation and later ulcera-
tion. Dietary arrangement and oral antibiotics, rather
than immunosuppressants, are effective for CD.
CARD15, the gene responsible for BS, was first
identified to be associated with CD.99,100
CARD15 is
not only a susceptibility gene, but the homozygous
1007 frame-shift mutations cause the disease.
CARD15 is the first identified non-HLA gene related
with CD, which corresponds to the IBD1 locus
mapped on chromosome 16q12. In contrast with
BS-associated CARD15 mutations, CD-associated
mutations are localized in the LRR domain and cause
loss-of-function of Nod2 to reduce MDP-induced
NF-κB signaling.101
Therefore, CARD15 mutation-
associated CD might be caused by immunodefi-
ciency for enterobacteria, such as Mycobacterium
avium paratuberculosis (MAP).102
Nevertheless,
because gene targeting experiments showed
conflicting results, the role of CARD15 mutations in
CD is somehow enigmatic.103,104
The most recent
study showed that Nod2 deficiency rather upregu-
lates TLR2 responses and increases susceptibility
to bacterial antigen-specific T-helper (Th)1-type
colitis, and thus provided an appropriate model of
human CD.105
Similarly, in the case of sarcoidosis,
involvement of bacteria, such as Mycobacterium
tuberculosis and Propionibacterium acnes, has
been proposed.106
In contrast with EOS, no associ-
ation of CARD15 mutations has been reported in
adult-type sarcoidosis.107–110
However, recently,
significant association of one CD-type mutation was
shown by an analysis of Greek sarcoidosis patients.111
Considering that no association of CARD15 muta-
tions has been identified in Japanese CD patients,
heterogenous genetic background of this disease
among ethnic groups is proposed.112,113
More
interestingly, association of variant CARD4 on
chromosome 7p14–15, encoding Nod1 related with
Nod2, has been revealed in Japanese sarcoidosis
patients.114
Nod1 recognizes γ-D-glutamyl-meso-
diaminopimelic acid (iE-DAP), a distinct component
of bacterial PGN contained in most Gram-negative
and several Gram-positive bacteria, and activate
NF-κB through interaction with RICK (Fig. 1).80
Association of a polymorphism in CARD4 with IBD
has also been reported, along with the following
negative results.115–118
Notably, involvement of Nod1
in intracellular recognition of P. acnes and impaired
bacterial sensing by the sarcoidosis-associated
Nod1 variant has been revealed.114
Psoriatic arthritis and atopic dermatitis
Psoriasis is a major chronic inflammatory skin disease,
characterized by epidermal hyperproliferation and
infiltrate of inflammatory cells including neutrophils
and lymphocytes. As the significant coincidence
of psoriasis and CD is established and one of the
psoriasis-associated loci is located on 16q overlapping
the IBD1 locus, association of the IBD1 gene with
psoriasis was postulated.119,120
However, investigation
by several groups revealed no association of CD-type
CARD15 mutations in psoriasis.121–124
Instead, the
susceptible locus (PSORAS1) of PsA, which appears
in more than 10% of psoriasis patients, was mapped
on chromosome 16q, and consequently association
of CD-type CARD15 mutations with PsA was

reported.125,126
However, following reports by other
groups failed to reveal the association.127–130
As
discussed above, this controversy might be due to
the different ethnicities.131
Interestingly, CARD15
polymorphisms have been reported to be rather
associated with allergy or atopic diseases.132,133
Considering that psoriasis and atopic dermatitis
(AD) are known as major chronic inflammatory skin
diseases associated with Th1 and Th2 response,
respectively, Nod2 might be involved in regulation of
Th1/Th2 balance. This idea is compatible with the
observation of gene-targeted mice.134
Notably,
association of CARD4 variants with allergy has also
been reported, also suggesting involvement of
Nod1 in regulation of Th1/Th2 balance.135,136
Genetic
aspects of autoinflammatory syndromes are sum-
marized in Table 2.
RELATED INFLAMMATORY SKIN DISEASES
Juvenile idiopathic arthritis and adult-onset
Still’s disease
JIA includes a broad spectrum of arthritis of
unknown origin, which appears before 16 years of
age.137
JIA is the most common rheumatic disease
in the pediatric field but is somehow “wastebasket”
diagnosis. The above-mentioned autoinflammatory
diseases mostly affect joints in childhood and should
be carefully distinguished from JIA. This disease is
divided into several distinct subtypes depending on
the affected joints; systemic arthritis (Still’s disease),
polyarthritis (five or more joints affected) and oli-
goarthritis (four or less joints affected). The systemic
type, representing 4–17% of all JIA, shows charac-
teristic periodic spiking fever of at least 2-week
duration and associated skin rash and polyarthritis.
The same disease onset in adults is rare and called
adult-onset Still’s disease. Such a phenotype is quite
similar to that of hereditary periodic fever syndromes
and involvement of IL-1 in the pathophysiology is also
the same as that of autoinflammatory syndromes.138
Genetically, association of polymorphisms in the IL-
6 and the macrophage migration inhibitory factor
(MIF) genes has been reported.139–141
Schnitzler syndrome
Schnitzler syndrome is a rare inflammatory disorder,
characterized by periodic fever, urticarial rash,
arthralgia or arthritis, and bone pain, along with
monoclonal IgM or IgG gammopathy.142
Clinical
similarity with CAPS and effectiveness of anti-IL-1
therapy lead us to hypothesize that Schnitzler
syndrome is an acquired autoinflammatory syndrome,
however, no mutation of CIAS1 and CARD15 has
been identified in the patients.143,144
Rather, presence
of cases forming lymphoma and effectiveness of anti-
CD20 therapy suggest a major role of dysregulated
B cells in this disease.145,146
Others
Most autoinflammatory diseases show skin mani-
festations and some distinct skin diseases are
reportedly associated with each autoinflammatory
disorder. As described above, appearance of PN
and HSP in FMF, EED in HIDS, cold-induced urticaria
in CAPS, pyoderma gangrenosum in PAPAS,
lichenoid sarcoidosis in BS, and Sweet syndrome
in Majeed syndrome, have been reported. These
diseases are mostly idiopathic and share characteristic
features of hyperactivation of neutrophils and/or
monocytes/macrophages following chronic or
recurrent course. Considering the possibility that
these skin disorders develop as the first symptom
of systemic involvement or as the sole clinically-
apparent manifestation, association of similar genetic
abnormalities might be hidden in these diseases,
especially in some specific subtypes. In addition,
involvement of bacteria in CD and sarcoidosis
reminds us of the possibility that similar and/or
opposite genetic abnormalities are associated with
focal infection or id-reaction, showing systemic hyper-
reaction to bacteria and/or bacterial products.
CONCLUDING REMARKS: INTERPLAY
BETWEEN BEDSIDE AND BENCH
Recent expansion of identified genes responsible
for various autoinflammatory diseases has dramati-
cally improved our understanding of innate immune
signaling pathway, especially the signaling mediated
by CATERPILLER or NOD-LRR proteins (NLR).147
Intracellular NLR, similar to membranous TLR,
represent mammalian homologues of plant resistance
(R) proteins and regulate three important path-
ways of inflammation, NF-κB activation, IL-1β
secretion and apoptosis.148,149
Now, NLR form a

huge family of more than 20 molecules including
Nod2 and cryopyrin, along with apoptosis-regulating
apoptotic protease activating factor-1 (Apaf-1).147,148
The newest nomenclature of NLR approved by
the Human Genome Organization Gene Nomen-
clature Committee (HGNC) is shown in; http://www.
gene.ucl.ac.uk/nomenclature/genefamily/nlr.php.
Further analyses of genetic and/or functional abnor-
malities of NLR and associating molecules, such as
PSTPIP and Lipin, in various diseases of sporadic or
familial origin, and rare or common appearance, will
further improve our understanding of inflammation
and immune regulation and will provide more candidate
abnormalities related with diseases. Actually, very
recently, association of CARD7, encoding another
NLR family molecule NALP1, has been identified in
vitiligo-related various autoimmune disorders.150
Thus, by the effective interplay between bedside and
bench, this field is dramatically expanding.
ACKNOWLEDGEMENTS
We would like to thank Prof. S. Miyagawa (Nara
Medical University), Dr H. Ida (Nagasaki University)
and Dr N. Kambe (Kyoto University) for kindly providing
precious pictures. We also thank Drs I. Okafuji and R.
Nishikomori (Kyoto University) for fruitful discussions
and Profs Y. Miyachi and T. Nakahata (Kyoto University)
and Prof. H. Nishimura (Wakayama Medical University)
for continuous encouragement. This work was
supported by the Ministry of Education, Sciences,
Sports, and Culture of Japan grant no. 17659337.
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Table
2.
Genetic
characteristics
of
autoinflammatory
syndromes
in
men
and
mice
FMF
HIDS
TRAPS
CAPS
PAPAS
BS,
EOS
CRMO
Majeed
cmo
mice
CD,
PsA
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Recessive
Recessive
Dominant
Dominant
Dominant
Dominant
Recessive
Recessive
Recessive
Recessive
Year
gene
discovered
1997
1999
1999
2001,
2002
2002
2001,
2005
–
2005
2006
2000,
2003
Chromosome
16p13.3
12q24
12p13.3
1q44
15q24-25.1
16q12.1-13
18q21.3-22
18p11
18
16q12-13
Gene
MEFV
MVK
TNFRSF1A
CIAS1
PSTPIP1
CARD15
–
LPIN2
PSTPIP2
CARD15
Protein
Pyrin
/Marenostrin
Mevalonate
kinase
55
kDa
TNF
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Cryopyrin
PSTPIP1
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Nod2
–
Lipin2
PSTPIP2
Nod2
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of
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55
74
51
69
4
12
–
3
1
81
Most
frequent
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M694V
V377I
R92Q
R260W
A230T,
R334W
–
T180fs,
L1007fs
E250Q
S734L
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