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Best Practice & Research Clinical Rheumatology 26 (2012) 505533

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Best Practice & Research Clinical


Rheumatology
journal homepage: www.elsevierhealth.com/berh

Autoinammatory syndromes and cellular responses to


stress: pathophysiology, diagnosis and new treatment
perspectives
Sinisa Savic a, b,1, Laura J. Dickie b, Miriam Wittmann b, c, d,
Michael F. McDermott b, *
a

Department of Clinical Immunology, St. Jamess University Hospital, Leeds, UK


NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute of Molecular Medicine, University of Leeds,
Leeds, UK
c
Centre for Skin Sciences, School of Life Sciences, University of Bradford, UK
d
Bradford Teaching Hospitals NHS Foundation Trust, Department of Dermatology, Bradford, UK
b

Keywords:
Autoinammation
FMF (familial Mediterranean fever)
TRAPS (TNF receptor-associated periodic
fever syndrome)
NLRP3 (Nod-like receptor family,
pyrin domain-containing
protein 3) inammasome
Biological therapy
IL-1b TNF
ROS (reactive oxygen species)
Metabolism

The term autoinammatory disease was rst proposed in 1999 to


encompass some of the distinct clinicopathologic features of
a group of monogenic conditions, characterised by recurrent
episodes of inammation, without high-titre autoantibodies or
antigen-specic T cells. It was subsequently observed that several
of these conditions were caused by mutations in proteins involved
in the innate immune response, including, among others,
components of the NLRP3 inammasome, cytokine receptors
(tumour necrosis factor receptor 1 (TNFR1)) and receptor antagonists (interleukin 1 receptor antagonist (IL-1RA)). More recently,
additional mechanisms linking innate immune-mediated inammation with a variety of cellular processes, including protein
misfolding, oxidative stress and mitochondrial dysfunction, have
been recognised to play a role in the pathogenesis of some
monogenic autoinammatory conditions, and also in more
common diseases such as type 2 diabetes (T2D), previously
perceived as a metabolic disorder, but reclassied as a chronic
inammatory condition. NLRP3 inammasome activation is
induced by islet amyloid polypeptides (IAPPs) in T2D and this
condition may, in future, be more commonly treated with targeted

* Corresponding author. NIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute of
Molecular Medicine, Wellcome Trust Brenner Building, St. Jamess University Hospital, Leeds LS9 7TF, UK. Tel.: 44 113 343
8641; fax: 44 113 343 8502.
E-mail addresses: s.savic@leeds.ac.uk (S. Savic), m.mcdermott@leeds.ac.uk (M.F. McDermott).
1
Tel.: 44 113 206 5567; fax: 44 113 206 7250.
1521-6942/$ see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.berh.2012.07.009

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anti-cytokine therapies. Caspase 1 activation and release of IL-1b/


IL-1 family members is central to the pathogenesis of many
autoinammatory syndromes, as evidenced by the effectiveness of
anti-IL-1 biologics in treating these disorders. However, many
patients continue to experience symptoms of chronic inammation, and it will be necessary to translate discoveries on the
immunopathology of these conditions into more effective therapies. For example, in tumour necrosis factor receptor-associated
periodic fever syndrome (TRAPS), the pathogenesis may vary
with each mutation and therefore future approaches to treatment
of individual patients will require a more tailored approach based
on genetic and functional studies.
2012 Elsevier Ltd. All rights reserved.

Introduction
Discovery of periodic fever syndromes early history of autoinammation
The term periodic disease was rst employed by Hobart Reimann in 1948 to describe a clinical
syndrome which manifested as benign paroxysmal peritonitis, periodic fevers, cyclical neutropenia and
intermittent arthralgia [1]. In 1958, Heller et al. introduced the designation familial Mediterranean
fever (FMF) for the syndrome described by Reimann, based on its increased prevalence in people of
Mediterranean descent and characteristic clinical features [2]. However, FMF, which usually has an
autosomal recessive inheritance, is not restricted to these ethnic groups. Over subsequent years came
recognition of the clinical aspects of other genetically determined recurrent fevers, both autosomal
dominant and recessive, which were all collectively termed hereditary periodic fevers (HPFs) (Table 1).
The autosomal dominant conditions include tumour necrosis factor (TNF) receptor-associated
periodic fever syndrome (TRAPS) (this condition was previously termed familial Hibernian fever in
1982 [3]), familial cold autoinammatory syndrome (FCAS), also known as familial cold urticaria (FCU),
rst described in 1940 [4], MuckleWells syndrome (MWS), characterised by urticaria, deafness and
amyloidosis, described in 1962 [5] and chronic infantile neurological cutaneous articular syndrome
(CINCA; also known as neonatal-onset multisystemic inammatory disease, abbreviated to NOMID)
rst described in 1981 [6]. The three syndromes, MWS, FCAS and CINCA/NOMID, are all closely related
as they share a number of clinical features and a common genetic basis. In 2001, a heterozygous
mutation in the CIAS1/NLRP3 gene was found to be responsible for FCAS and MWS [7]. A year later,

Table 1
Comparison of autoinammation and autoimmunity.
Autoinammation

Autoimmunity

Immunological disruption
Main cellular involvement
Antibody involvement
Clinical features
Conceptual understanding
Main genetic susceptibility

Innate immunity
Neutrophils, macrophages
Few or no autoantibodies
Recurrent, often seemingly unprovoked attacks
Tissue-specic factors/danger signals
Cytokine and bacterial sensing pathways

Therapy
Examples

Anti-cytokine (IL-1, TNF, IL-6)


Monogenic hereditary periodic fevers,
polygenic Crohns disease,
spondylarthropathies

Adaptive immunity
B and T cells
Autoantibodies present
Continuous progression
Breaking of self-tolerance
MHC class II associations and
adaptive response genes
Anti-B and T cell
Monogenic ALPS and IPEX,
polygenic RA and SLE

MHC major histocompatibility complex; IL interleukin; TNF tumour necrosis factor; ALPS autoimmune lymphoproliferative
syndrome; IPEX immune dysregulation polyendocrinopathy, enteropathy X-linked syndrome; RA Rheumatoid arthritis; SLE
Systemic lupus erythematosus. Adapted from McGonagle D, McDermott MF. A proposed classication of the immunological
diseases. PLoS Med 2006;3(8):e297 [15].

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a mutation in the same CIAS1/NLRP3 gene was reported to also cause CINCA/NOMID [8]. Subsequently,
the umbrella term cryopyrin-associated periodic fever syndromes (CAPS) was introduced to highlight
the common genetic basis of these conditions.
Hyperimmunoglobulinaemia D with periodic fever syndrome (HIDS) is an autosomal recessive HPF
characterised by recurrent episodes of fever associated with lymphadenopathy, abdominal pain and
skin rash, rst reported in 1984 [9]. The association of HIDS with homozygous mutations in the
mevalonate kinase (MVK) gene was rst described in 1999 [10,11].
With the identication of some of the genes underlying the HPFs, the term autoinammatory
disease was rst proposed in 1999 to encompass some of the distinct clinicopathologic features of
these conditions, characterised by recurrent episodes of inammation, without high-titre autoantibodies or antigen-specic T cells [1214].
Autoinammation one end of immunological disease continuum
McGonagle and McDermott proposed in 2006 that the majority of inammatory disorders are
situated along an immunologic disease continuum (IDC), with genetic disorders of innate and adaptive
immunity located at either end of the spectrum [15]. HPFs are the prototypical genetically determined
innate immune-mediated diseases, which may be associated with signicant tissue destruction
without evidence of adaptive immune responses and are designated as autoinammatory due to their
distinct immunopathological features (Table 1).
There is increasing evidence that a combination of environmental, immunogenic and genetic
aetiologies is instrumental in causing polygenic autoinammatory and autoimmune diseases.
Recognition of the central contribution of innate immune-related factors at target sites of disease
has led to the idea of classifying some conditions (such as Behets syndrome, psoriasis, psoriatic
arthritis (PsA) and gout) as having major autoinammatory components [16,17]. Dysregulated
innate immunity has been demonstrated in Crohns disease (CD), a polygenic disorder in which
a breach in stability of the intestinal mucosal barrier defences causes abnormal handling of
commensal luminal bacteria. CD has been classied as a polygenic autoinammatory condition [18].
Mutations in the NOD2 (NLRC2) gene encoding nucleotide-binding oligomerisation domaincontaining protein 2 (NOD2)(NLRC2 protein), also known as caspase recruitment domaincontaining protein 15 (CARD15 or IBD1), are present in about 20% of Caucasian patients with CD
[19,20]. The autophagy pathway has also been linked with CD through association with a coding
single-nucleotide polymorphism (SNP) (T300A) in the ATG16L1 gene (chromosome 2q) [21,22].
ATG16L1 encodes a protein involved in the autophagic mechanism, whereby intracellular bacteria
are processed by lysosomal degradation; thus, a defect in this pathway may produce an inappropriate response to gut bacteria.
A number of studies have established the contribution of the interleukin (IL)-23 receptor gene
(IL23R) to CD risk [23,24]. The IL23R gene has also been associated with major histocompatibility
complex (MHC) human leukocyte antigen (HLA) class I-related conditions, such as spondyloarthritis
[25], psoriasis [26] and Behets disease [27]. Although CD does not usually have HLA class I associations, a genetic overlap exists between CD and some MHC class I-associated diseases, including
psoriasis [28].
These aforementioned inammatory diseases exhibit dysregulated innate immunity and are
genetically distinct from autoimmunity, but may demonstrate some evidence of adaptive immune
responses [29]. Classical autoimmune diseases, with autoantibody and MHC class II associations,
including celiac disease and systemic lupus erythematosus (SLE), have adaptive immune genetic
associations, including cytotoxic T-lymphocyte antigen-4 (CTLA4) and protein tyrosine phosphatase,
non-receptor type 22 (PTPN22) that regulates some signalling pathways in T and B cells.
The proposed IDC classication is relevant to the clinical situation, because innate immunemediated disorders respond better to cytokine antagonism whereas autoimmune-mediated diseases
may respond to anti-T and B cell therapies. Furthermore, some conditions such as systemic juvenile
idiopathic arthritis (sJIA) and ankylosing spondylitis (AS) have been reclassied as autoinammatory
diseases primarily based on response to IL-1 antagonism in the case of sJIA [30] and innate immune
system abnormalities in the case of AS [31].

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Immunopathogenesis
Many paths lead to autoinammation
Masters et al. have proposed a classication scheme for autoinammatory disorders based on
molecular mechanisms rather than clinical classication [13]. They have dened six categories of
autoinammatory disease: IL-1b activation disorders (inammasomopathies), nuclear factor (NF)kappaB (NF-kB) activation syndromes, protein misfolding disorders, complement regulatory diseases,
disturbances of cytokine signalling and macrophage activation syndromes. Therefore, in the 15 years
that have elapsed since discovery of the genetic basis of FMF (the most prevalent HPF), the study of
HPFs has evolved from the initial concept of autoinammatory disease into novel classications of
these diseases with delineation of the central role of the innate immune system and the functional
basis of some of these conditions. We explore several of these concepts and some newly proposed
mechanisms in more detail.
Cytokine excess NLRP3 inammasome activation in the pathogenesis of CAPS
IL-1b is a potent pro-inammatory cytokine, which is synthesised early in response to infection and
tissue injury by cells of the innate immune system. It has multiple effects, including induction of fever
and hepatic acute phase response, recruitment of neutrophils and induction of other pro-inammatory
cytokines, such as TNF and IL-6 [32]. In excess, IL-1b can have detrimental physiological effects leading
to tissue damage, bone reabsorption, collagen deposition and, in very large amounts, it can cause
haemodynamic shock [33]. Tight regulation of IL-1b synthesis and release is therefore essential to
ensuring that the inammatory response is of appropriate magnitude to deal with the threat posed by
infection but, coincidentally, causing the least harm to the host. In part, this is achieved by having
a number of different steps governing the synthesis, release and action of IL-1b.
IL-1b is rst synthesised as an inactive 269-residue precursor (pro-IL-1b). Caspase-1 is a cysteineprotease that processes both pro-IL-1b and pro-IL-18 to generate the bioactive cytokines, IL-1b and IL18, and to initiate pathogen-specic immune responses [34]. The inactive pro-IL-1b form is found in
monocytes, macrophages and dendritic cells, but only at very low levels in the absence of proinammatory stimuli. Pro-IL-1b synthesis, or the priming step in IL-1b production, is induced by
a number of pro-inammatory pathways that recognise pathogen- or danger-associated molecular
patterns (PAMPS and DAMPS, respectively)(Fig. 1). For example, lipopolysaccharide (LPS) activation of
Toll-like receptor (TLR)4 and muramyl dipeptide (MDP) stimulation of NOD2 are two pathways that
recognise a large number of the common Gram-negative and Gram-positive bacterial pathogens.
Together with the pro-inammatory cytokine, TNF, but also IL-1a and IL-1b itself, all of these pathways
stimulate pro-IL-1b production by activating the transcription factor NF-kB [35].
The maturation of pro-IL-1b into the biologically active cytokine is dependent on the presence of
secondary stimuli, which ultimately activate caspase-1 to cleave the immature cytokine into mature
form, IL-1b. This process is dependent on various macromolecular platforms termed inammasomes.
The NLRP3 inammasome is the most studied caspase-1-activating complex and the one which is
mutated and functionally abnormal in CAPS. NLRP3 activation is itself a complex multi-stage process. It
requires a priming step in monocytes, which is thought to increase the expression of NLRP3 in the
target cells, in addition to usually requiring a second signal in macrophages, which may involve
intracellular potassium (K) ux, adenosine triphosphate (ATP) and/or reactive oxygen species (ROS)
[36] (Fig. 1). The importance of the second signal is discussed in some detail later.
So in the resting state, NLRP3 expression in cells is very low and the activation requires transcription
of NLRP3, which can be induced by signals such as LPS, TNF and IL-1b that also promote the transcription of pro-IL-1b. The second signal is thought to be required for assembly of the NLRP3 inammasome and also its activation in macrophages [37]. NLRP3 protein contains a central NACHT or
nucleotide-binding and oligomerisation domain, which has a role in assembly of the inammasome.
The majority of CAPS-causing mutations are found in the NACHT domain of NLRP3.
Early studies suggested that NLRP3 mutations in CAPS probably lead to gain of function as
macrophages from MWS patients were found to produce signicantly more IL-1b compared to healthy

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509

Fig. 1. Integration of NLRP3, ER stress and mitochondria-mediated inammatory responses in autoinammatory disease. ER stress
caused by various metabolic disturbances or accumulation of misfolded proteins (for example misfolded TNFR1 in TRAPS) is sensed
by the ER-luminal domain of ATF6, PERK and IRE1 (1). ATF6 translocates to the Golgi where its cytoplasmic domain is cleaved to
become transcription factor fATF6 (2). PERK and IRE1 are autophosphorylated at the cytoplasmic domains; PERK then phosphorylates eIF2a, leading to inhibition of general protein synthesis (3). At the same time this permits the translation of transcription
factor ATF4. Activated IRE1 splices XBP1 mRNA to produce transcription factor sXBP1 (4). fATF6, ATF4 and sXBP1 translocate to the
nucleus where they induce expression of genes important for UPR (5). IRE1, via interaction with TRAF and IKK, also controls NF-kB
and JNK activation leading to enhanced proinammatory cytokine secretion (TNF, IL-6, pro-IL-1b) (6). ER stress can also (in certain
tissues-hetaocytes) directly induces proteins of the acute phase response, such as CRP through cyclic AMP-responsive element
binding protein hepatocyte (CREBH) (7). Upregulation of E3 ubiquitin ligases through the action of pro-inammatory cytokines and
sXBP1 leads activation of the ER associated degradation (ERAD) pathway which targets proteins with ubiquitin to promote proteosomal degradation (8). Impaired degradation of the ubiquitinated proteins in cells under metabolic stress is one of the proposed
mechanisms in proteasome-associated autoinammatory syndromes (9). The mitochondria and the ER are interlinked through
calcium signalling. Mitochondria are able to take up Ca2 and are in close proximity to the Ca2 release sites of the ER, which can
cause alterations in ROS production. Disturbances in mitochondrial homeostasis can also cause disturbances in the ER function (10).
ROS generated from the mitochondria and from oxidative protein folding in the ER are thought to be involved in NLRP3 activation,
which is mutated in CAPS. As a result of increases in cellular ROS, TXNIP dissociates from thioredoxin and instead binds to NLRP3,
facilitating IL-1b secretion (11, 12).

controls [38]. However, the precise mechanisms responsible for this have not been fully worked out.
One suggestion is that these mutations lead to spontaneous oligomerisation of the NLRP3 inammasome subunits around mutated NACHT domain [39], possibly by removing an inhibitory loop, making
the mutated inammasome constitutively turned on and independent of the need for secondary
signals for its activation. This leads to subsequent caspase-1 activation with excessive and inappropriate IL-1b release. This hypothesis is supported by observations that LPS alone is sufcient to cause
caspase-1 activation in macrophages harbouring CAPS-causing mutations. Furthermore, cytosolic K
that normally prevents activation of the NLRP3-inammasome fails to do so if cells contain NLRP3associated mutations [40,41].

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Recently, a mouse model of CAPS was developed by two different groups, which recapitulated
many concepts relevant to the pathogenesis of CAPS [40,41]. They were able to demonstrate that
inammation in different tissues was mainly due to neutrophil inltration and not dependent on B
and T cells. In addition, the inammatory response was also conditional on expression of the mutated
NLRP3 in the cells of myeloid origin and excessive production of IL-1b. An interesting observation,
which was also seen in CAPS patients, was IL-1b-dependent skewing of T-helper response towards
Th17 phenotype. While IL-1b seems to be involved in polarisation towards the Th17 lineage, it also has
a well described and strong impact on the production of the Th1 lymphokine interferon gamma (IFNg)
in activated cells [42]. Indeed, the proliferation of all CD4 T cell subsets may be enhanced by IL-1b
[43]. The exact relevance of these observations in the pathogenesis of CAPS is still unclear as the
patients readily respond to IL-1 blockade. This latter observation offers further supporting evidence of
the principal role that aberrant IL-1b release plays in the pathogenesis of CAPS. It is still unclear,
however, which triggers precipitate attacks in all CAPS patients, how these triggers operate and why
only certain tissues and organs are affected, and why some mutations are associated with a more
severe clinical phenotype.
The importance of tight regulation of IL-1 activity is further illustrated by another autoinammatory
condition that shares some clinical features with the more severe spectrum of CAPS diseases (NOMID/
CINCA) but has a somewhat different immunopathological basis. Deciency of the IL-1 receptor
antagonist (DIRA) is an autosomal recessive disease resulting from mutations in IL-1RN, the gene
encoding the IL-1 receptor antagonist (IL-1Ra) [44]. IL-1Ra is produced at the same time as IL-1a and
IL-1b and limits the effects of these two cytokines on their common receptor. Interestingly, stromal
cells (broblasts), which mainly express IL-1a (but not b), are also an important source of IL-1Ra and
may make an important contribution to local tissue IL-1 activity control. We have recently shown that
dermal broblasts are also signicant producers of IL-18 binding protein (IL-18BP), another endogenous antagonist, but not IL-18 [45]. This nding supports the emerging role of tissue-resident stomal
cells as regulators of inammatory responses. Unopposed action of IL-1 cytokines in DIRA results in
a perinatal onset of skin pustulosis, joint swelling and various bone malformations, including painful
osteolytic lesions, periostitis affecting the distal ribs and long bones and heterotopic bone formation
[44]. The somewhat different clinical phenotype seen in DIRA, in comparison with CINCA/NOMID,
suggests the possibility of a greater role for IL-1a in disease pathogenesis. DIRA patients respond
rapidly to anakinra, which is a synthetic IL-1 receptor antagonist (IL-Ra) [46].
The role of NLRP3 in the pathogenesis of CAPS is reasonably well established, with general agreement that gain-of-function mutations lead to the excessive IL-1b release. Inappropriate activation of
the NLRP3 inammasome and excessive IL-1b release has also been implicated in the pathogenesis of
a number of other conditions, including T2D, where the role of chronic inammation in disease
pathogenesis has recently gained greater recognition. Here the accumulation of IAPP is thought to lead
to inappropriate NLRP3 inammasome activation and release of IL-1b with detrimental consequences
for pancreatic b islet cells [47].
However, more recently, NLRP3 activation has been shown to have a protective role in two unrelated conditions, possibly through the induction of IL-18. In CD, reduced NLRP3 expression resulting
from sequence changes in the promoter region has been associated with increased risk of developing
the disease [48]. The explanation for this association is not entirely resolved and likely to be quite
complex. NLRP3 expression and activation has a protective role in the majority of animal models of
induced colitis [49,50], which is contrary to the expectation that reduced NLRP3 expression, as
demonstrated in monocytes of CD patients [51,52], might be expected to reduce inammation in the
bowel. However, this may not be entirely surprising since it is possible that appropriate NLRP3 activity
is essential to maintain the immunological barrier to commensal gut micro-organisms. In addition,
IL-18, whose maturation is also dependent on NLRP3 inammasome, has been shown to have a specic
role in promoting the repair of gut epithelium [53]. Another line of evidence is based on the observation that active caspase-1 is involved in the non-conventional secretion of leaderless proteins at
least in epithelial cells which line all barrier organs [54]. All members of the IL-1 family are leaderless
proteins, and this is also true for important anti-inammatory molecules, such as IL-37 [55]. However,
so far, experimental evidence for impaired secretion of anti-inammatory mediators in patients with
impaired caspase-1 activation is still lacking.

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In the case of age-related macular degeneration (AMD), the roles of NLRP3 and IL-18 are somewhat
controversial. NLRP3(/) but not IL-1b(/) mice were found to be more susceptible to two different
experimental models of AMD and drusen (focal extracellular deposits on the Bruchs membrane below
the retinal pigment epithelium (RPE) in the macula) isolated from donor AMD eyes caused activation of
the NLRP3 inammasome [56]. Taken together, these ndings suggest that drusen-induced NLRP3
activation is protective in AMD due to its role in IL-18 maturation. However, two subsequent publications suggest that NLRP3 activation due to oxidative stress in RPE cells [57], or resulting from Dicer1
loss or Alu RNA exposure, may have detrimental effects resulting in AMD [58].
Although the discussion so far has been mostly focussed on IL-1b release that is dependent on
NLRP3 and caspase-1 activation, it is increasingly recognised that IL-1 processing and maturation can
also occur independently of these mechanisms [59]. This, in turn, might have specic implications
when faced with disease states where an IL-1 signature is evident but the cause for such an observation
is not obviously linked with inammasomes or caspase-1 activation. A highly inammatory disease to
mention in this context is Netherton syndrome, which is characterised, among other symptoms, by
severe eczema and universal pruritus (itch). Netherton syndrome is the result of a loss-of-function
mutation in serine peptidase inhibitor, Kazal type 5 (SPINK5), which encodes for a serine protease
inhibitor expressed in normal skin (lympho-epithelial Kazal-type-related inhibitor (LEKTI)) [60]. High
IL-18 expression has been demonstrated in the skin of these patients [61]. Gout also has an IL-1mediated autoinammatory component, and activation of neutrophils in gout is associated with
proinammatory neutrophil extracellular trap formation (NET) [62] and extracellular IL-1b production,
which may be elastase mediated [59].
Gene dosage and the modier effect mediterranean fever (MEFV) mutations in FMF
Although the genetic cause of FMF has been known for over a decade, the exact explanation of how
the mutated pyrin gene, also known as MEFV (mediterranean fever), causes inammation remains
incomplete. The fact that pyrin is predominantly expressed in cells of myeloid origin such as neutrophils, monocytes and dendritic cells and that FMF has an apparent autosomal recessive pattern of
inheritance, have led to the assumption that the inammation in FMF is caused by inappropriate
activation of the innate immune system and the result of reduced or complete loss of pyrin function.
Pyrin has a complex structure and expression pattern. The full-length human pyrin, which has four
domains, an N-terminal pyrin domain (PYD), followed by two B-box zinc-nger and coiled-coil
domains and a C-terminal B30.2 domain, is expressed in the cytoplasm, whilst the short forms,
which are created by caspase-1-mediated cleavage, migrate to the nucleus. Various overexpression
experiments have demonstrated that pyrin can interact with apoptosis-associated speck-like protein
containing a caspase recruitment domain (CARD) (ASC) to limit NLRP3 activation [63], but it can also
bind capsase-1, via the B30.2 domain [64], to negatively regulate the enzyme activity. This latter effect
of pyrin is particularly interesting as it provides a plausible explanation for how these mutations may
affect pyrin function since most pathogenic mutations are in this B30.2 domain [65]. However, overexpression of pyrin has also been shown to induce caspase-1 activation in cells that stably express ASC
[66]. Furthermore, short-forms of pyrin were shown to promote NF-kB activation and transcription of
pro-inammatory cytokines, the effects of which were particularly enhanced in cells harbouring the
mutated protein [67]. In addition, mice expressing truncated forms of pyrin were found not to have
a phenotype resembling FMF [68], whilst the majority of pathogenic MEFV mutations are missense
changes and, to date, no null mutations have been identied [69]. All these observations suggest that
pyrin mutations in FMF result in gain rather than loss of protein function. Further support for this
notion comes from recent work that was done in pyrin-decient and knock-in (KI) mice harbouring
mutant human B30.2 domains, since the murine pyrin homologue does not contain B30.2 domain [70].
Similarly, to mice expressing the truncated protein [68], pyrin-decient animals and heterozygous KI
mice have no clinical features of FMF, suggesting that loss of pyrin function alone is insufcient to
recreate the pro-inammatory phenotype [71]. On the other hand, mice with two mutated copies of
the gene showed a number of inammatory features consistent with the human disease, including
generalised neutrophilia, dermatitis and arthritis, but the hemizygous animals showed no evidence of
the disease [71]. Taken together, these ndings suggest that disease-associated mutations lead to gain

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of pyrin function but that disease expression depends on the amount of mutated protein produced.
This might explain why certain heterozygous pyrin mutations result in disease manifestation, albeit of
a milder phenotype [72,73]. Furthermore, this might also explain why MEFV sequence changes have
been identied in chronic inammatory diseases, such as Behets disease [7477], systemic AA
amyloidosis [78] and CD, [79], where they are thought to have pro-inammatory disease-modifying
effects.
The role of dysregulated unfolded protein response in the complex pathophysiology of TRAPS
A variety of mechanisms have been suggested to explain how autosomal dominant mutations of
TNFRSF1A lead to the clinical manifestations of TRAPS (Fig. 2). Nevertheless, the link between these
mutations and associated phenotypes remains poorly understood with much apparent clinical
heterogeneity between different mutations as well as among patients with the same mutation.
The reason for this might be due to the complexity of TNF signalling pathways, which are regulated
on multiple levels and have a multitude of effects. Activation of tumour necrosis factor receptor 1
(TNFR1), for example, can lead to activation of NF-kB and the mitogen-activated protein kinase (MAPK)

Aggregated
misfolded
TNFR1 leading
to mild ER
stress

Low
dose
LPS

TLR4

ER
XBP1

Ca2+
ROS

Antioxidants
sXBP1

MAPK activation

+++

P
p38

P
JNK
p65

p50

sXBP1

IL-6
TNF

NF-B activation
Fig. 2. A summary of the proposed mechanisms of TRAPS and the proinammatory pathways they can activate Intracellular
retention of mutant TNFR1 within the ER causes disruption of mitochondrial ROS production as well as activation of the XBP1 arm of
the UPR. TRAPS cells have also been reported to be hyper-responsive to theTLR4 ligand LPS, which can also cause XBP1 splicing. It is
therefore possible in TRAPS that these 2 pathways converge on the same signalling mediators, enhancing inammatory responses
even at low dose stimulations. Antioxidant treatment is able to prevent LPS-induced XBP1 activation demonstrating a crucial role of
the mitochondria-ER interaction in inammatory signalling. XBP1 and mitochondrial ROS are able to cause NF-kB activation, MAPK
activation and consequently pro-inammatory cytokine release. TRAPS patients have been reported to have enhanced MAPK
(particularly p38 and JNK) activation, which is due to effects of mitochondrial ROS on oxidation of the catalytic cysteine residues in
MAPK phosphatases, enhancing MAPK phosphorylation and activation. Recently, p38 has been demonstrated to directly phosphorylate sXBP1 and enhance sXBP1 nuclear translocation, promoting transcription factor activity. This is an example of one of the
many potential feedback loops that could be exacerbating inammatory episodes in TRAPS.

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513

cascade [80], which will result in either cell survival, or induction of an inammatory response.
Alternatively, activation of caspase-3 will eventually lead to cell death due to apoptosis [81]. The
myriad of often conicting effects mediated by TNFR1 is possible because the intracellular domain of
the receptor can engage with several different intracellular pathways via the TNFR-associated death
domain protein (TRADD)-containing macromolecular platform [82]. TNF is mainly produced by
epithelial and innate immune cells, including macrophages, monocytes, neutrophils and NK cells, but
also by some T-cell subsets. TNFR1 is expressed as a homotrimer [83] on the cell surface and activates
TNFR1 and TNFR2, with both receptors also forming homotrimers following engagement of the
membrane-bound form of TNF (mTNF). In addition, TNFR1 can recognise a soluble form of TNF (sTNF),
released from the cell membrane by the TNF-a converting enzyme (TACE/a disintegrin and metalloprotease domain 17 ADAM17) [84]. This same enzyme also cleaves TNFR1 and TNFR2 from the cell
surface, and these soluble forms of receptors are thought to have a predominantly neutralising effect
on TNF [85].
Early studies into the pathogenesis of TRAPS suggested that mutated TNFR1 might be resistant to
this enzymatic cleavage, resulting in impaired clearance of TNFR1 from the cell membrane [12]. This
was an attractive hypothesis as it offered an explanation why certain patients had low levels of soluble
TNFR1 (sTNFR1) in patients serum between attacks. It could also possibly explain why the pathogenic
mutations were either missense, small deletions or insertions found in the extracellular domains, as
these may affect the secondary structure and therefore limit access to the proteolytic cleavage site.
However, the TNFR1 shedding defect is not a universally reproducible nding in all patients with
TRAPS [86], whilst treatment with etanercept, which is a fusion molecule of TNFR2/FcIg, designed to
mop up soluble TNF, is only partially effective [8790].
Increased NF-kB activation [9193] has also been associated with some mutations, and, more
recently, additional mechanisms have been suggested to explain the pro-inammatory effects of
mutated TNFR1. Simon et al. reported that TRAPS patients demonstrated higher MAPK activation in
response to bacterial LPS, a TLR4 ligand, than healthy controls and also showed a hyper-responsiveness
to LPS whereby TNFRSF1A mutant peripheral blood mononuclear cell (PBMC) could respond to low
dose LPS (0.01 ng ml1) [94]. Subsequently, it was shown that this might in part be due to the effects of
ROS on MAPK activation [95]. Monocytes and neutrophils from TRAPS patients showed higher baseline
levels of ROS than cells from healthy donors. Increased ROS was shown to mediate increased proinammatory cytokine secretion and also increased MAPK activation, which is therefore thought to
be mediating the cytokine release. ROS are known to inactivate MAPK phosphatases by oxidation of the
catalytic cysteine residue, thereby enhancing MAPK activation. Somewhat surprisingly, further studies
demonstrated the source of ROS production to be the mitochondria, mainly because of enhanced ROS
production rather than blocked mitophagy, which was recently implicated in the pathogenesis of other
autoinammatory conditions such as CD [96,97].
Another important observation about the pathogenesis of TRAPS is that trafcking of the mutated
receptor to the cell surface appears to be impaired [98]. Low surface expression of TNFR1 has been
reported in patients with TRAPS [99], and furthermore, retained aggregates of TRAPS-associated
mutant protein have been reported in the endoplasmic reticulum (ER) of transfected cells [100].
Although earlier studies reported no clear evidence of ER stress associated with this phenomenon [94],
we recently investigated the possible convergence of ER stress pathways and enhanced ROS production
in TRAPS patients [101]. We hypothesised that retention of the mutated receptor within the ER would
cause a degree of ER stress and that this would facilitate activation of inammatory pathways,
including enhanced cytokine release and ROS generation, and could confer the reported hyperresponsiveness to LPS. We found that resting monocytes from TRAPS patients showed increased
expression of protein kinase-like ER kinase (PERK) and spliced X-box binding protein 1 (sXBP1), which
are two markers of ER stress and activated as part of the unfolded protein response (UPR) [102].
However, these ndings were not associated with other markers of ER stress, as we found normal
expression levels of downstream target genes, such as synoviolin and DNA-damage-inducible transcript 3. Furthermore, we conrmed that TRAPS cells showed increased baseline total and
mitochondrial-specic ROS production [95], which was increased further in response to IL-6 stimulation. We also found that LPS promoted sXBP1 activation, which was abolished by the addition of
antioxidants [101]. The importance of sXBP1 in TLR4 signalling was previously demonstrated by

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Martinon et al. who showed that sXBP1 is generated in response to LPS independently of ER stress, as
other UPR pathways were not activated [103]. The sXBP1 was essential for sustained pro-inammatory
cytokine production, and mild ER stress could also greatly facilitate production of inammatory
cytokines, such as TNF and IL-6, as sXBP1 was found to bind directly to the promoter region of these
cytokines [103]. Interestingly, sXBP1 was also recently linked with the p38 MAPK signalling pathway;
Lee et al. reported that p38 was able to directly phosphorylate sXBP1 leading to enhanced nuclear
translocation and transcriptional activity [104]. Therefore, sXBP1 can explain some of the hyperresponsiveness to LPS in TRAPS, and this might be enhanced further by the effect that p38 MAPK
pathway activation has on sXBP1 stability.
The link between ER and oxidative stress, although previously established, in this situation is,
however, less clear. XBP1 does also have a role in oxidative stress responses since a number of gene
targets of XBP1 are known to have roles in redox homeostasis and cell survival during hypoxic
conditions. Interestingly, it is the unspliced form of XBP1 (uXBP1), which was found to induce
expression of antioxidant genes [105], including catalase, superoxide dismutase and thioredoxin. This
role was independent of sXBP1, as the spliced isoform was unable to regulate the expression levels of
these antioxidants. We found that the uXBP1 transcript levels were not signicantly elevated in TRAPS
patients when compared to HC, despite the increased ROS levels present in the patients cells [101].
These ndings suggest a possible defect in the antioxidative responses in TRAPS patients.
Lastly, the murine models of TRAPS suggest that expression of both the wild type and mutant
receptor is necessary to replicate the inammatory phenotype of TRAPS. Mice homozygous for TRAPSassociated TNFR1 mutants, rather than suffering from spontaneous inammatory problems, show
resistance to LPS-induced septic shock [94], which is a phenotype previously described in TNFR1decient animals. This is in keeping with the disease model whereby retention of the mutated
receptor within the ER provides a low-grade stimulus, on which other signals, including TNF itself (due
to the presence of wild-type receptor), act to induce the hyper-inammatory state typical of TRAPS.
Novel mechanisms of autoinammation mutated immunoproteasome
Proteasome-associated autoinammatory syndromes is a term that has been recently introduced to
highlight the common genetic basis of a number of rare autoinammatory conditions with overlapping
clinical features [106,107]. Hypomorphic mutations affecting the inducible b5i subunit of the PSMB8
proteasome (proteasome subunit b type 8) have been reported in patients with chronic atypical
neutrophilic dermatosis with lipodystrophy and elevated temperature [108] (CANDLE), joint
contractures, muscle atrophy, microcytic anaemia and panniculitis-induced childhood-onset lipodystrophy [109]. (JMP), Nakajo-Nishimura syndrome [106] (NNS) and Japanese autoinammatory
syndrome with lipodystrophy [110] (JASL).
The proteasome is an evolutionarily conserved cylindrical organelle which has an essential role in
protein degradation. It is composed of two a and two b rings which combine to give it its cylindrical
shape (Fig. 1). The a rings have a role in substrate capture whilst the proteolytic function is conned to
the b rings. Each ring is composed of seven individual proteins; the inner two rings are made of seven
b subunits that contain three to seven protease active sites. The proteins destined for degradation are
usually tagged with polyubiqutin chains, a process that is used in regulating many cellular functions
including activation of NF-kB. Of particular interest is the role of the proteasome in antigen processing
during infection. Pathogen-derived proteins are degraded by the proteasome for presentation by MHC
class I molecules at the cell surface. However, this process is much more efcient and the degradation
products t the groove of the MHC class I molecules better when several subunits of the b ring are
replaced by the inducible (i) subunits b1i, b2i and b5i. The resulting so-called immunoproteasome,
assembled with these alternative subunits, is highly expressed in haemopoietic cells and expression of
the (i) subunits is directed by type I interferons. Recent data from animal psmb8/lmp7 KO studies
suggest that the immunoproteasome also plays a part in maintaining cell homeostasis by removing
damaged proteins accumulated as a result of various cellular processes including oxidative stress.
In silico analysis of the mutated b5i subunits found in CANDLE and JMP syndromes suggest that
formation of the immunoproteasome is impaired in these conditions [108]. Agrawal et al. showed that
the proteasome from JMP patients had markedly reduced chymotrypsin-like activity but preservation

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of trypsin and peptidyl glutamyl peptide-hydrolysing function, which is in keeping with specically
impaired activity of the immunoproteasome [109]. The same patients were found to have signicantly
elevated IFNg and IL-6 with elevated erythrocyte sedimentation rate (ESR) and serum g globulins, but
not elevated TNF or IL-1b. This particular cytokine signature seems to be typical of impaired immunoproteasome function, since patients with CANDLE syndrome were also found to have elevated IFNg
and IL-6, but not TNF. These patients also had signicantly elevated levels of IFNg-inducible protein 10
(IP-10 or C-X-C motif chemokine 1 CXCL10), and elevated levels of monocyte chemotactic protein 1
(MCP-1 or Chemokine (C-C motif) ligand 2 CCL2) and regulated upon activation, normal T-cell
expressed, and secreted (RANTES or CCL5). Further evidence that excessive IFNg signalling might play
a role in the pathogenesis of this condition came from gene expression studies of the whole blood and
from analysis of signal transducer and activator of transcription-1 (STAT-1) signalling pathway in
monocytes. The IFNg pathway was demonstrated to be the most differentially regulated, whilst, at the
same time, monocytes from CANDLE syndrome patients showed higher STAT-1 phosphorylation in
response to IFNg compared to healthy controls and patients with CINCA/NOMID [108].
Based on these ndings, it has been proposed that the ongoing IFNg stimulation in patients with
CANDLE syndrome and related conditions results from inability of the immunoproteasome to deal
appropriately with accumulation of damaged proteins leading to chronic cellular stress. As a result, the
cellular stress remains unresolved and IFNg stimulation continues unabated. In keeping with this
hypothesis is the observation that disease ares are associated with infections and other stressful
events. Furthermore, affected tissues such as muscle and fat showed inclusion bodies which might
suggest accumulation of oxidant-damaged/aggregated proteins leading to apoptosis.
Interestingly, lipodystrophy, which is a recognised complication of protease inhibitors (PIs), a class of
anti-human immunodeciency virus (HIV) medication, might be caused by modulatory effects of these
agents on the proteasome. Ritonavir, for example, was shown to specically inhibit the chymotrypsinlike activity, whilst enhancing trypsin-like activity of the proteasome [111]. Although this effect was
originally thought to modulate antigen processing only, in the light of our current understanding of how
chymotrypsin-like activity is affected in the mutated immunoproteasome, it is possible to speculate that
this might be one of the mechanisms which is responsible for PI-induced lipodystrophy.
Autoinammation of the skin; IL-36 and deciency of IL-36 receptor antagonist (DITRA) and CARD14 in
psoriasis susceptibility locus 2 (PSORS2)
A common feature of all IL-1 family members is the tight control of their released active forms and
the presence of soluble antagonists; for example, IL-1a/b are controlled by the endogenous antagonist
IL-1RA, IL-18 by IL-18 binding protein (IL-18BP) and IL-36 molecules are controlled by IL-36 receptor
antagonist (IL-36RA, former name IL-1F5), which shows a mode of action comparable to IL-1RA. IL-36
has three different subtypes, IL-36a (IL-1F6), IL-36b (IL-1F8) and IL-36g (IL-1F9). These homologous
cytokines all bind to the same receptor which consists of IL-1RAcP (also shared by IL-1a,b and IL-33)
and IL-1Rrp2. Therefore, IL-36RA, which competes with these cytokines for IL-1Rrp2 receptor
binding and prevents recruitment of IL-1RAcP, balances the functional activity of all IL-36 members.
Recently, loss-of-function mutations of the IL-36RA have been associated with severe pustular
psoriasis, as described by two independent groups [112,113]. The name DITRA has been proposed for
this autosomal recessive autoinammatory condition. All IL-36 molecules, including the IL-36RA, show
high biological activity only after cleavage [114]; the responsible endogenous protease, however, has
not been identied so far.
Recent data suggest that IL-1 family members are intimately involved in the cellular response of
tissue cells characterising psoriatic inammation. IL-36 has been identied as one of the most highly
expressed genes in lesional as compared to non-lesional psoriasis [115117].
We have previously shown that cultured skin cells derived from psoriasis patients show increased
expression of IL-36 upon cytokine stimulation [118], which is not paralleled by IL-36RA induction. The
intrinsic difference in the expression level of IL-36a/g between cultured and passaged cells derived
from psoriasis or healthy individuals is dramatic. IL-36 has not been identied as a genetic susceptibility locus in psoriasis genome wide association studies (GWAS). Therefore, the observed difference
could be due to genetic variants in signalling pathways, as suggested by a recent study of gain-of-

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function variants in CARD14 [119,120], post-translational regulators or epigenetic in nature. Data for
PsA are not yet available as IL-36 has only recently come into the picture for psoriatic inammation
research [121,122]. The best-described inducer of IL-36 messenger RNA (mRNA) expression is the
synergistic action of TNF and IL-17 [122], which are both up-regulated in psoriasis and PsA and
blockade of which improve clinical symptoms.
Interestingly, PsA and skin psoriasis share common genetic variants that are important for the
NF-kB-related pathways (e.g., A20 [TNFAIP3], TNIP1 and TRAF3IP2) [123,124]. Therefore, psoriatic
disease may t into the proposed novel classication as NF-kB-related autoinammatory condition.
In the early 1990s, GWAS undertaken to nd psoriasis-susceptibility genes provided evidence for
the presence of a disease locus within the MHC on chromosome 6p21.3, referred to as PSORS1 (psoriasis
susceptibility 1) (for review: [125]). It was later suggested that HLA-C was the most likely PSORS1
candidate gene [126]. With regard to a second psoriasis susceptibility site called PSORS2, a recent study
revealed CARD14 gain-of-function mutations as responsible for the PSORS2 ndings [120]. CARD14
activates NF-kB and compared with wild-type, the mutated form leads to increased activity of NF-kB
and up-regulation of a subset of psoriasis-associated mediators in skin-resident cells. This is the point
at which the circle closes as we have come back to the above described IL-36, which is indeed among
the mediators found to be up-regulated in cells with mutated CARD14, along with IL-8, which attracts
neutrophils, and CCL20 which attracts immature dendritic and Th17 cells into the psoriatic lesions. This
study thus further supports the notion that psoriasis may t very well into the NF-kB pathway
subcategory.
Integration of NLRP3, ER stress and mitochondria-mediated inammatory responses
Although the close link between metabolic stress and inammation has long been suspected, it is
only recently that our understanding of the molecular mechanisms that underpin this relationship has
signicantly advanced (Fig. 1). The three key areas of research that have mostly contributed to this are:
NLRP3 activation and the role of this process in the pathogenesis of conditions such as T2D, the
relationship between ER stress and generation of inammatory cytokines and the role of the mitochondria in innate immune responses, specically mitochondrial-derived ROS (mROS).
NLRP3 inammasome activation is a complex process and has been extensively investigated over
the last several years. Although many potential activators of the inammasome have been identied,
questions have been asked how such diverse stimuli can all cause activation of the same macromolecular complex. The multistage activation of the NLRP3 inammasome was proposed to explain some
of the ndings, with agreement that the rst stage involves up-regulation of NLRP3 expression as
a result of, for example, TLR stimulation. There has been much more controversy about what processes
govern the assembly of NLRP3 inammasome and ultimately caspase-1 activation. This eld of
research was led by the late Jurg Tschopp who proposed three different, mutually non-exclusive,
models of NLRP3 activation: the channel model, the lysosome rupture model and nally the ROS
model [127]. The channel model explains the need for the ATP and K ux, whereby activation of P2X7,
an ATP-gated ion channel, triggers rapid K efux from the cell, which is an absolute requirement in
most proposed models of NLRP3 activation. In addition, this leads to pore formation in the cell
membrane as a result of recruitment of the pannexin 1 hemi-channel [128], which allows PAMPs such
as MDP to enter the cell and engage NLRP3. Although pore-forming microorganisms such as a-toxinproducing Staphylococcus aureus are potent activators of the inammasome [129], this could result
from allowing K ux through the pore alone, rather than direct binding of the NLRP3, which, so far,
has not been demonstrated for most of the known activators.
The lysosome rupture model suggests that the lysosomal protein cathepsin B, released after lysosomal rupture, triggers NLRP3 activation. This would explain how large particulate activators, such as
alum and silica can activate the NLRP3 inammasome [130]. Cathepsin B inhibition does impair NLRP3
activation in human cells [131], but similar ndings have not been consistently replicated in cathepsin
B KO mouse models [132,133].
The usual sources of endogenous ROS are nicotinamide adenine dinucleotide phosphate (NADPH)
oxidases (NOX), which are active in phagosomes, the Erol-1DPI oxidative folding system in the ER and
the mitochondrial electron transport chain (ETC). It would therefore make sense if NLRP3 activation

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was governed by changes in ROS, as this would allow inammasome activation in response to a variety
of important cellular stresses. NLRP3 was found to associate with thioredoxin-interacting protein
(TXNIP; also known as VDuP1) after cells were treated with NLRP3 activators [134]. This is an ROSdependent process, since in unstimulated cells TXNIP is constitutively bound to and inhibited by the
oxidoreductase, thioredoxin. As a result of increases in cellular ROS concentration, TXNIP dissociates
from thioredoxin and binds to NLRP3. This model is supported by observations that KO or knockdown
by small interfering RNA (siRNA) of TXNIP leads to reduced IL-1b secretion, whilst the knockdown of
thioredoxin enhances NLRP3 activation [134,135]. Furthermore, pharmacological blockade of ROS has
also been shown to reduce inammasome activation [136].
Although ROS appear to be important activators of the NLRP3 inammasome, the source of such
ROS has been debated. NLRP3 inammasome activation is not impaired in patients with chronic
granulomatous disease (CGD), who are decient in one of the NOX components [137]. Traditionally,
mROS was not regarded to have an important role in innate immune responses. However, more
recently, mROS has been seen as a much more likely candidate after the discovery that it can be
generated in response to bacteria in a TLR-dependent fashion. Coupling of TLR1/2/4 signalling to
mitochondrial complex I was demonstrated via TNF receptor-associated factor 6 (TRAF6), an evolutionarily conserved signalling intermediate in Toll pathways (ECSIT) [138]. As already mentioned,
mROS have also been particularly implicated in the pathogenesis of TRAPS [95]. The role of mROS in
NLRP3 activation has been shown more specically by Zhou et al. who not only demonstrated inhibition of NLRP3 activation by disrupting mROS generation but also the physical proximity between the
activated NLRP3 inammasome and mitochondria. In resting cells, NLRP3 localises to the ER structures,
but in the activated state, NLRP3 and ASC, an adaptor protein of the NLRP3 inammasome, have a perinuclear location and co-localise with ER and mitochondria organelle clusters [139]. It is perhaps not
surprising that mROS is possibly one of the main activators of the NLRP3 inammasome, since it is
produced in response to many cellular stresses, including increased metabolic rate, hypoxia or
membrane damage, which, in turn, places NLRP3 inammasome activation at the centre of many
important cellular responses.
The connection between NLRP3 and cellular stress does not stop there since activation of NLRP3 was
recently shown to occur in response to ER stress independently of UPR pathways [140]. The ER stresstriggered UPR has traditionally been associated with accumulation of misfolded proteins within the
ER and attempts by the cell to rectify this problem. However, ER stress and components of the UPR
pathway also induce inammatory responses, through several distinct mechanisms. inositol-requiring
enzyme 1 (IRE1) and PERK can activate the NF-kB, which is essential for initiating inammation
through the induction of a number of pro-inammatory genes. These pathways converge to reduce
availability of the inhibitor of NF-kB, IkB. In the case of the PERK pathway, this is due to its effect on global
protein synthesis through the activation of eukaryotic initiation factor 2a (eIF2a), which appears to affect
IkB more than NF-kB, as the former has a shorter half-life [141]. IRE1 achieves NF-kB activation through its
association with the adaptor protein TRAF2. The IRE1-TRAF2 complex can recruit IkB, which is then
phosphorylated and degraded, resulting in nuclear translocation of NF-kB [142]. Furthermore, this
complex also activates c-Jun N-terminal kinases (JNKs), which in turn phosphorylates transcription factor
activator protein 1 (AP1) [143]. The latter, similarly to NF-kB, induces transcription of pro-inammatory
genes. NF-kB activation has also been linked to ROS and oxidative stress, generated as a result of an
increased protein load on the ER and the demand for additional disulde bond formation. Although the
mechanism(s) involved is poorly understood, the observation that NF-kB activation can be reduced by
antioxidants and calcium chelators supports this claim [144]. This last observation might be particularly
relevant to NLRP3 activation associated with ER stress, which is also dependent on the presence of ROS.
This interplay between NLRP3 activation, mROS and ER stress provides an explanation of how
multiple mechanisms involving metabolic stress, innate immune activation and production of
inammatory cytokines, come together in the pathogenesis of some common chronic inammatory
conditions, considered to be autoinammatory in nature. Examples include spondyloarthropathies,
such as AS, inammatory bowel disease, such as CD, T2D and arteriosclerosis, to name just a few
amongst an ever increasing list.
AS was one of the rst inammatory conditions where this link to UPR was investigated. HLA-B27,
which is an AS susceptibility locus, is prone to misfolding within the ER [145]. B27/Hub2m-transgenic

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rats, that overexpress the human HLA-B27 gene, develop arthropathy, psoriasis-like skin lesions and
gastrointestinal inammation [146]. There is circumstantial evidence that macrophages from these
animals, when stimulated with IFNa, IFNb or TNF, demonstrate a more active UPR compared to controls
[147]. This observation was made on the basis of elevated BiP and sXBP1 mRNA levels in bone marrowderived macrophages from these animals. More recently, UPR induced either by HLA-B27 misfolding or
by pharmacological agents, was shown to act synergistically with LPS to induce macrophages from
these animals to produce IL-23 [148]. Furthermore, elevated IL-23 and IL-17 transcript levels were
found in CD11 antigen presenting cells (APC) and in CD4 T cells, respectively, from the colonic
lamina propria of the transgenic animals [149]. The form of colitis usually seen in these animals was
associated with a sixfold expansion of Th17 cells. However, here is evidence that IL-17 in spondyloarthritis is secreted by innate immune cells rather than T cells in the facet joints of patients with
spondyloarthritis [150,151].
NLRP3 activation and ER stress have both been implicated in the pathogenesis of arteriosclerosis.
Here, the accumulation of free cholesterol in the ER membrane leads to Ca2 release, activation of UPR
and CCAAT/-enhancer-binding protein homologous protein (CHOP)-induced apoptosis [152]. Several
inammatory pathways, including NF-kB, JNK, p38 and ERK1 and 2 (extracellular-signal-regulated
kinase) are activated by loading macrophages with free cholesterol, with IRE1 and PERK potentially
playing a role in NF-kB and JNK activation [153]. Furthermore, oxidised lipids also induce UPR in human
aortic endothelial cells [154]. Finally, in vitro studies have linked ER stress-induction of activating
transcription factor 4(ATF4) and sXBP1 with the production of inammatory cytokine IL-6 and the IL-8
and CXCL3 chemokines. This was demonstrated in human aortic endothelial cells at baseline and as
a result of the accumulation of oxidised lipids [154]. More recently, cholesterol crystals have been shown
to activate the NLRP3 inammasome and release IL-1b in mouse and human macrophages [155].
It is beyond the scope of this chapter to discuss the pathogenesis of all the conditions mentioned
here but many excellent reviews have recently been written on this subject and readers are encouraged
to consult these for further information.
Clinical considerations
How to recognise autoinammatory diseases
Inherited or monogenic autoinammatory syndromes are very rare, apart from FMF, which has
a high prevalence in some specic ethnic groups (see below). Even in the case of TRAPS, which is
thought to be the most common autosomal-dominant HPF, the estimated prevalence in Europe is only
1 per million [156]. The majority of patients will present in childhood, although in rare instances the
rst recognised clinical manifestation may occur in adolescence or early adulthood. Therefore, the
likelihood of encountering a patient with a recognised HPF or making a new diagnosis in a routine
adult clinical practice is quite small. However, there are many more patients who will present with
chronic inammatory illnesses of unknown aetiology who do not necessarily have a recognised
monogenic syndrome. Various attempts at developing clinical criteria or guidelines to identify which of
these patients should be considered for genetic testing have been made [157,158]. So far, there are no
universally agreed recommendations, which is not surprising considering there is a signicant clinical
overlap between certain autoinammatory conditions and also their relative rarity. The diagnosis is
therefore dependent on a high degree of clinical suspicion, experience and, when available, conformation by a genetic test.
To assist with these efforts databases such as INFEVERS (http://fmf.igh.cnrs.fr/ISSAID/infevers/) and
the Eurofever Project (http://www.printo.it/eurofever/autoinammatory_diseases.asp), have been
developed to systemically collect clinical and genetic information on patients with all monogenic
autoinammatory syndromes, including HPFs. This has led to improved recognition of the spectrum of
clinical problems associated with these conditions as well as development of targeted treatment
strategies.
The question whether a patient has an autoinammtory syndrome usually arises after the more
common clinical problems associated with fevers and inammation, such as chronic infections, systemic
autoimmune diseases and paraneoplastic inammatory conditions, have been considered and excluded.

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Clues which might point towards the diagnosis of an HPF usually involve a long-standing history of
unexplained and seemingly unprovoked attacks of fever or systemic inammation that might involve
serosal surfaces and joints, unexplained skin rashes and a family history of similar problems. There are
also some more specic signs/symptoms typical of each condition, outlined in Table 2.
Routine clinical investigations are usually unhelpful in differentiating between various forms of
autoinammatory syndromes. Elevated inammatory markers (ESR, C-reactive protein (CRP) and neutrophilia) are commonly found during the attacks but are non-specic. Elevated inammatory markers
may also be seen between episodes and in otherwise asymptomatic patients, suggesting the persistence
of subclinical inammation, which is an important risk factor for developing reactive systemic AA
amyloidosis, recognised as the most important complication associated with mortality in many cases.
An expanding number of conditions are being recognised as autoinammatory in nature and there
have been various attempts to classify these. The IDC classication has attempted to nd a place for
autoinammatory conditions in the wider context of immune-mediated diseases [15], whilst Masters
et al. have used criteria principally based on the immunopathological features [13]. A separate classication, which combines clinical and immunopathogical features, is offered by the INFEVERS website,
which divides monogenic autoinammatory syndromes into the following categories: hereditary
recurrent fevers (CAPS, TRAPS, FMF, NLRP12-associated periodic syndrome (NAPS12) and mevalonate
kinase deciency (MKD)), pyogenic disorders (DIRA, DITRA, Majeed syndrome and pyogenic sterile
arthritis, pyoderma gangrenosum, and acne (PAPA)), granulomatous diseases (CD/Blau syndrome (BS)/
early-onset sarcoidosis (EOS) and Cherubism), proteasome instability disorders (JMP, NNS, CANDLE)
and reproductive wastage (recurrent hydatidiform moles (RHMs)) (Table 2).
Below is a description of some of the more common HPFs with the current treatment
recommendations.
FMF
This is the most common HPF which has relatively high prevalence in populations from eastern
Mediterranean area, including Turks, Jews (primarily non-Ashkenazi), Armenians and Arabs. Almost all
patients will become symptomatic within the rst two decades of life (>90%), whist two-thirds will
present before the age of 5. Typically, attacks are sudden, and apparently unprovoked, but various
triggers such as physical or emotional exertion, the menstrual cycle and diet have been recognised to
precipitate the attack [159]. Characteristic features of the attack include high fever lasting from hours to
34 days and serositis involving peritoneum (90%), pleura (45%), scrotum (5%) and pericardium (1%).
Interestingly, skin erythema, which is usually associated with arthritis, tends to mainly involve the distal
end of the lower limbs, usually between knee and ankle and on the dorsum of the foot in the ankle region.
The long-term complications of FMF may involve encapsulating peritonitis and chronic destructive
arthritis, particularly affecting hips and knees. However, these are rare and AA amyloidosis is much less
frequent since the introduction of colchicine.
A diagnosis of FMF can be made based on clinical criteria alone, especially in areas of high diseases
prevalence. Genetic testing will support clinical diagnosis, although care must be taken when interpreting genetic results since not all individuals with homozygous mutations will necessarily develop
the disease and, as discussed, some with heterozygous status will have the condition.
The mainstay of treatment for FMF remains colchicine, which in addition to treating acute attacks is
also essential to preventing complications such as AA amyloidosis by taking it on a regular basis. In rare
patients, whose disease is refractory to colchicine, or who are unable to take it due to the side effects,
alternatives such as anti-IL-1 biologics anakinra [160,161] and, more recently, canakinumab [162] as
well as anti-TNF iniximab [163] have shown therapeutic potential.
CAPS
CAPS spectrum of monogenic diseases associated with gain-of-function mutations in NLRP3 (also
known as CIAS) gene include FCAS, which is the mildest form, MWS moderate and NOMID/CINCA
which is the most severe manifestation of this disease continuum. These conditions share a number of
clinical features but are also distinct disease entities. All three forms typically present in childhood and,

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Table 2
Monogenic autoinammatory syndromes.
Monogenic disease

Gene

Hereditary periodic fevers


FMF
MEFV

Clinical manifestations

Treatment

Proposed mechanism

Fever, sterile peritonitis,


monoarthritis, pleuritis,
serositis, skin erythema

Colchicine in the
main but some
reports of IL-1 and
TNF inhibitors
IL-1, IL-6 and TNF
inhibitors,
corticosteroids

ASC-dependent IL-1b
excessive release;
gene dosage effect

TRAPS

TNFRSF1A

Prolonged fever,
peritonitis,
myalgias, arthralgias,
erysipelas-like rash,
periorbital oedema,
amyoidosis

CAPS; FCAS,
MWS and
CINCA/NOMID

CIAS1/NLRP3

Urticaria, deafness and


amyloidosis, arthalgias

IL-1 inhibitors

HIDS

MVK

IL-1 and TNF


inhibitors

NAPS12

NLRP12

Fever associated with


lymphadenopathy,
abdominal pain and
skin rash
High fever, arthralgia,
myalgia, urticaria,
sensorineural
hearing loss.

Pyogenic disorders
DIRA

IL1RN

DITRA

IL-36RA

PAPA

Majeeds
Syndrome

Proteasome
disabilities
JMP, NNS,
CANDLE, JASL

Defective receptor
shedding; intracellular
receptor retention;
hyper-responsive to
LPS; proinammatory
cytokine release
triggered by mROS;
XBP1 activation
Excessive
NLRP3-dependent
IL-1b release;
IL-1b-dependent
skewing of T-helper
response towards
Th17 phenotype
NLRP3-dependent
IL-1b release

IL-1 inhibitors

Decreased inhibition
of NF-kB;
ROS-mediated
impairment of
IL-1b secretion kinetics

Perinatal onset of skin


pustulosis, joint swelling,
bone malformations
(osteolytic lesions,
periostitis
and heterotopic
bone formation)
Severe pustular psoriasis

IL-1 inhibitors

Unapposed IL-1a
and IL-1b signalling

IL-1 inhibitors

CD2BP1

Arthritis, and pyoderma


gangrenosum

Oral antibiotics,
IL-1 and TNF inhibitors

LPIN2

Chronic recurrent multifocal


osteomyelitis, bone
contractures, congenital
dyserythropoietic anaemia

NSAIDs

Loss-of-function
mutations;
unapposed
IL-36 signalling
Enhanced
pyrin-mediated ASC
recruitment
followed by IL-1b
secretion
Uncontrolled
inammation
following oxidative
stress

PSMB8

Neutrophilic dermatosis,
lipodystrophy, elevated
temperature, joint
contractures, muscle
atrophy, microcytic
anaemia

Prednisone,
IL-6 inhibitor

Impaired formation
of the immunoproteosome,
IFNg signature,
cellular stress

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505533

521

Table 2 (continued )
Monogenic disease

Gene

Granulomatous disorders
CRMO
Unknown
Blau
NOD2

Clinical manifestations

Treatment

Proposed mechanism

Multifocal osteomyelitis
Familial granulomatous
arthritis, skin granulomas
and sardoidosis

NSAIDs and steroids.


NSAIDs, methotrexate,
TNF inhibitors

Unknown
Constitutive
NF-kB activation

ASC Apoptosis-associated Speck-like protein containing a carboxy-terminal CARD; CANDLE chronic atypical neutrophilic
dermatosis with lipodystrophy and elevated temperature; JASL Japanese autoinammatory syndrome with lipodystrophy; CAPS
Cryopyrin-Associated Periodic Syndromes; CD2BP1 CD2-binding protein 1; CIAS1 cold induced autoinammatory syndrome 1;
CINCA/NOMID Chronic Infantile Neurological Cutaneous and Articular syndrome/Neonatal-Onset Multisystem Inammatory
Disease; CRMO Chronic Recurrent Mutifocal Osteomyelitis; DIRA Deciency of the IL-1 Receptor Antagonist; DITRA deciency in
thirty-six receptor antagonist; NSAIDs Non-steroidal anti-inammatory drugs; FCAS Familial Cold Auto-inammatory
Syndrome; FMF Familial Mediterranean Fever; HIDS Hyperimmunoglobulinemia D with periodic fever Syndrome; IFN interferon; IL Interleukin; IL1RN Interleukin Receptor Antagonist; JMP joint contractures, muscle atrophy, microcytic anemia, and
panniculitis-induced childhood-onset lipodystrophy; LPIN2 lipin 2; LPS Lypopolysaccaride; MEFV Mediterranean fever; mROS
mitochondrial reactive oxygen species; MVK mevalonate kinase; MWS Muckle-Wells Syndrome; NAPS12 NLRP12-associated
Periodic Syndrome; NF-kB Nuclear Factor kB; NLRP NACHT domain-, Leucine-rich Repeat-, and PYD-containing protein; NNS
Nakajo-Nishimura syndrome; NOD2 nucleotide-binding oligomerization domain containing 2; PAPA Pyogenic Arthritis,
Pyoderma gangrenosum, and Acne syndrome; PSMB8 proteasome subunit, beta type 8; ROS Reactive Oxygen Species; TNF
Tumor Necrosis Factor; TNFRSF1a TNF receptor superfamily member 1A; TRAPS TNF-Receptor-associated periodic Syndrome;
XBP1 X-box binding protein 1.

in the case of CINCA/NOMID, symptoms might be present at birth. In keeping with different degrees of
severity of the disease manifestations, fever attacks in FCAS, which are usually precipitated by exposure
to cold, last up to 24 h, in MWS can be several days and in CINCA/NOMID inammatory processes has
a chronic rather than periodic course. Other disease manifestations include urticarial-like skin rash,
which is present in all patients, arthralgia, conjunctivitis and progressive hearing loss that is typical of
MWS. More severe disease manifestations such as meningitis, mental retardation and bony overgrowth tend to be present principally in CINCA/NOMID patients.
CAPS is one of those rare conditions where understanding of the disease pathogenesis has helped to
formulate a targeted and effective treatment strategy, and at the same time the excellent treatment
response that followed administration of anti-IL-1 therapy elegantly conrmed that the hypothesis of
disease pathogenesis was correct [164].
After anakinra was shown to be effective in treatment of all forms of CAPS [164166], several other
anti-IL-1 biologics have been developed. Rilanocept, which is a fusion protein consisting of the human
IL-1 receptor extracellular domains and the Fc portion of human IgG1, was shown to be efcacious in
the treatment of FCAS and MWS in 44 patients in a placebo-controlled study [167]. Canakinumab,
which is a monoclonal antibody directed against IL-1b was also demonstrated to be an effective and
safe treatment in a randomised withdrawal study of 35 patients with FCAS and MWS [168]. Unlike
canakinumab, which binds to IL-1b only, anakinra and rilanocept can also neutralise IL-1a. Considering
that all three agents are equally efcacious in treatment of CAPS, this would suggest that IL-1b is the
pivotal cytokine responsible for clinical disease manifestations in CAPS.
TRAPS
The clinical course, severity, disease manifestation and treatment responses can vary greatly
between different patients with TRAPS. This probably reects the complexity of the disease pathogenesis, which, as discussed, might be mutation specic. The attacks of fever and inammation are less
distinct when compared to FMF and can last for weeks. In a signicant proportion of patients, the
disease has a chronic course, and some patients despite appearing clinically well will have persistently
elevated inammatory markers. This is particularly important to consider when considering treatment
options, as such patients might be at greater risk of developing AA amyloidosis.
Some disease manifestations that are typical of TRAPS, but not always present, include periorbital
oedema and centrifugal erythematous rash that is usually associated with painful myalgia. The rash can
affect any part of the body but it has predilection for the upper limbs and proximal end of the lower limbs.

522

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505533

Treatment options for TRAPS will depend on the course of the disease and complications. Some
patients have very infrequent attacks, which might respond well to on-demand treatment with
systemic steroids. In patients with more chronic disease, a course of steroids might be ineffective and
treatment choices include several classes of anti-cytokine therapies. Etanercept, which is a recombinant human TNFR (p75)-Fc fusion protein composed of the extracellular region of the TNFR2 fused to
an Fc portion of IgG1, was the rst biological therapy used in TRAPS.
Etanercept, initially demonstrated good efcacy [169,170] and has been reported to induce
regression of amyloidosis [87,171] and reduction of CRP [88]. However, there are reports of poor or
variable response [90,172,173]. The role for other anti-TNF agents, such as iniximab (a chimaeric
monoclonal antibody), is less clear. Although it is thought to be a more potent inhibitor of TNF than
etanercept, most reports on use in TRAPS suggest that it is not successful and in fact has been reported
to exacerbate symptoms [171,174]. Functional studies have demonstrated that iniximab can increase
c-Rel activity; a member of the NF-kB transcription factor family with anti-apoptotic properties which
causes an increase in IL-1b and IL-6 [175] and reduced secretion of the anti-inammatory cytokine IL-4
and anti-apoptotic IL-7 [176]. There has been a case study reporting the successful use of iniximab in
one TRAPS patient; however, this patient had the R92Q variant which is not a structural mutation [177].
Anakinra is an alternative to anti-TNF agents and has shown promising results in TRAPS [178],
particularly in patients who do not respond to etanercept, with normalised acute phase reactants being
described, but there has been at least one report, so far, of non-response to anakinra [90].
Lastly tocilizumab, a humanised monoclonal antibody that targets IL-6 receptor a-chain, is the latest
biologic to be tried in TRAPS. The results are so far mixed as the earlier report of its successful use in
a patient (C33Y mutation) who previously had failed both etanercept and anakinra therapy [179], have
now been shown to be short-lived (personal communication). However, there are at least two other
cases, one of whom is being treated in our practice, who so far have favourably responded to this
treatment. A larger study, incorporating TRAPS patients with different TNFR1 mutations, is required to
fully examine the potential efcacy of tocilizumab in this condition.
HIDS
Despite the name, elevated levels of IgD are not universally found amongst all patients [180], and
therefore an alternative term for this condition, MKD, is preferred by many as it more accurately
reects the underlying pathology. Unlike mevalonate kinase aciduria (MVA), where the affected
patients have complete absence of MVK activity, in patients with MKD, some enzyme function is
preserved (usually around 10% of normal), which is enough to avoid complications of MVA such as
congenital malformations, severe psychomotor retardation and early death.
The normal function of MVK is in the cholesterol, farnasyl and isoprenoid biosynthesis pathway.
However, the explanation of how this enzyme deciency leads to the inammatory phenotype characteristic of MKD remains largely incomplete. The pathogenesis of this condition has been discussed in
more detail in the review by Stoffels et al. [181].
Most of the patients with MKD will present in the early childhood, and the attacks are typically
precipitated by vaccination, infection or physical and emotional stress. Fever and chills usually precede
cervical lymphadenopathy, abdominal pain with vomiting and diarrhoea, which might develop as the
attack progresses [182]. Other clinical features are outlined in Table 2.
Although MKD is not usually associated with AA amyloidosis, a recent survey of 50 patients from
centres in France and Belgium found that three patients died from HIDS-related causes and the disease
remained highly active in >50% of surviving symptomatic patients, which suggests that HIDS might
have a more severe phenotype than previously thought [183]. Interestingly, 13 of these patients also
had a history of recurrent or severe infections and three patients were found to have hypogammaglobulinaemia. This raised the possibility that HIDS might be paradoxically associated with an
immunodeciency state in some patients.
The diagnosis of MKD is supported by nding of elevated polyclonal IgD levels, however, this is not
diagnostic for reasons outlined above as well as for the fact that high IgD can be found in other
inammatory conditions such as FMF. Probably diagnostically more useful is demonstrating the
presence of mevalonate in urine, which in MKD is more likely to be present during a typical attack.

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505533

523

Alternatively, it is possible to measure MVK activity, but ultimately the diagnosis should be conrmed
by genetic testing.
A number of different treatment options have been suggested. Etanercept has shown some benet
[182], but more recently, anakinra has been used successfully in a number of cases [184].
NAPS12
NAPS12, associated with mutations in NLRP12 gene, is alternatively known as NLRP12 associated
disorder (NLRP12AD), but also as FCAS2 since it clinically resembles this condition. However, NAPS12 is
a very rare disorder, inherited in autosomal-dominant fashion and, to date, only a few affected families
have been described [185,186]. The attacks of urticarial rash, arthralgia and myalgia are typically
precipitated by exposure to cold and associated with a systemic inammatory response.
It has been suggested that NLRP12 is a negative regulator of NF-kB [187] and that the mutated
protein has reduced ability to suppress NF-kB activation [185]. This original claim was later disputed,
but it was shown that cells harbouring the mutated NLRP12 have heightened response to PAMPs,
which was associated with increased ROS and a change in the antioxidant kinetics [186,188].
Despite demonstrating a possible IL-1b disease signature in these patients, the response to anakinra
has been variable [189].
Conditions that mimic HPFs
Two conditions that are not considered true HPFs because of lack of a clear genetic basis, or due to
association with another pathology, but clinically mimic HPFs are Periodic fever Aphthous stomatitis
and Pharyngitis (PFAPA) and Schnitzlers syndrome, respectively.
PFAPA is usually considered to be a benign, self-limiting paediatric condition but, more recently,
adult cases have also been described. It is characterised by recurrent episodes (usually every 38
weeks) of fever lasting 36 days, which is associated with aphthous stomatitis, sterile pharyngitis and
cervical adenitis and, according to the original set of diagnostic criteria, the rst episode should occur
before the age of 5 years. Although patients with PFAPA can have a positive family history [190], a clear
genetic basis for this condition has not been identied. However, some patients with classic HPFs t
into diagnostic criteria for PFAPA [191], therefore, there should be a high index of suspicion and a low
threshold for considering genetic testing for known monogenic HPFs in patients with PFAPA.
The pathogenesis of PFAPA remains unclear but peripheral cell and gene expression proling
studies suggest involvement of both innate and adaptive immune responses [192]. These suggest that
during the ares there is environmentally triggered complement and IL-1b/18 axis activation and
induction of TH1-chemokines leading to retention of activated T cells in peripheral tissues [193].
Based on these ndings IL-1b inhibition with anakinra was used on ve patients with acute attacks with
good effect [193]. Other treatment options for PFAPA include one to three doses of corticosteroids
(usually w 1 mg kg1 prednisolone per dose), which are generally effective in aborting a are, but may
shorten the asymptomatic intervals [194]. In fact, rapid responsiveness to steroid is so typical of PFAPA that
this characteristic has been suggested to be a part of diagnostic criteria [195]. Another medical therapy
which showed effectiveness in PFAPA is the H2 blocker cimetidine [194]. Although tonsillectomy or adenotonsillectomy can potentially be curative in treatment of PFAPA, their precise role in the management of
this condition is still under deliberation. Two most recent meta-analysis do not provide sufcient evidence
to support the routine use of tonsillectomy or adenotonsillectomy over medical treatment [196,197].
Schnitzlers syndrome is a rare disease presenting in adults with fevers, chronic urticarial rash, bone
pain hyperostosis and lymphadenopathy associated with monoclonal paraprotein, usually of IgM
isotype [198]. A proportion of patients (20%) will develop overt plasma cell malignancy. Inammatory
symptoms seem to respond readily to anakinra [199201] without affecting paraprotein levels.
Conclusions
Since it was rst introduced over a decade ago, autoinammation has gone from being a somewhat
hypothetical concept to a recognised term that embodies an expanding area of clinical practice and

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S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505533

medical research. Although the principles of autoinammation are most clearly evident in the pathogenesis of rare monogenic diseases of the innate immunity, it is the study and understanding of these
conditions that has brought us closer to a better understanding of the inammatory processes that
underpin some more common conditions that have a wider impact on the human health. This is
particularly timely in the current climate of rapid medical development in the eld of targeted biologics therapies, which might help us transform how we approach and treat these conditions.

Practice points
 Monogenic autoinammatory diseases are rare and the majority present in childhood.
 Autoinammatory diseases are predominantly characterised by involvement of the innate
immune system in their pathogenesis.
 Among other classication criteria used to dene these conditions include the principal
immunopathogenic mechanisms involved and clinical manifestations.
 Targeted anti-IL-1 biologics are extremely efcacious in treatment of CAPS and are also
proving to be effective in a number of other monogenic autoinammatory diseases, including
TRAPS and HIDS to a lesser extent.
 IL-1 receptor antagonist, which inhibits both IL-1a and IL-1b, is the specic therapy for DIRA.
 Anti-TNF therapy is the treatment of choice for a number of polygenic autoinammatory
diseases, including AS, CD and psoriasis.

Research agenda
 Anti-IL-6 directed therapy may be benecial in treatment of TRAPS, based on the immunopathology of this condition and one preliminary study, but further studies are necessary in
larger numbers of patients.
 The relevance of IL-1b-dependent skewing of T-helper response towards Th17 phenotype in
CAPS patients.
 Although a plethora of activators have been described for the NLRP3 inammasome, the
actual ligand(s) remain unknown.
 Further development of novel therapies is necessary for autoinammatory diseases; potential
areas of development include small molecules that can either activate or inhibit specic
signalling pathways and anti-oxidants as adjunct therapies.
 The interplay of the micro-organisms inhabiting the human body (the microbiome) and
innate and adaptive immune systems in the clinical phenotype of autoinammatory conditions is likely to be an area of intense investigation in the future.

Conict of interest statement


None of the authors has any conicts of interest to declare.
Acknowledgements
S. Savic and M.F. McDermott are supported by Arthritis Research UK, M. Wittmann by the Leeds
Foundation for Dermatological Research, and M. Wittmann and M.F. McDermott by the Biomedical and
Health Research Centre, University of Leeds. Partial funding by the NIHR-LMBRU.

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505533

List of abbreviations
AMD
AP1
APC
AS
ASC
ATF4
ATP
CANDLE
CAPS
CARD15
CCL
CD
CGD
CHOP
CINCA
CTLA4
CXCL10
DAMPS
DIRA
DITRA
eIF2a
ER
ERK
ESR
ETC
FCAS
FCU
FMF
GWAS
HIDS
HLA
HPF
IAPP
IDC
IFNg
IL
IL-1Ra
IL-18BP
IL-36RA
IkB
IP-10
JMP
JNK
LPS
MAPK
MDP

age-related macular degeneration


activator protein 1
antigen presenting cells
ankylosing spondylitis
apoptosis-associated speck-like protein containing a CARD
activating transcription factor 4
adenosine triphosphate
chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature
cryopyrin-associated periodic fevers syndromes
caspase recruitment domain-containing protein 15
Chemokine (C-C motif) ligand
Crohns disease
chronic granulomatous disease
CCAAT/-enhancer-binding protein homologous protein
chronic infantile neurological cutaneous articular syndrome
cytotoxic T-lymphocyte antigen-4
C-X-C motif chemokine 1
danger-associated molecular patterns
Deciency of the IL-1 receptor antagonist
deciency in thirty-six receptor antagonist
eukaryotic Initiation Factor 2a
endoplasmic reticulum
extracellular-signal-regulated kinase
erythrocyte sedimentation rate
electron transport chain
familial cold autoinammatory syndrome
familial cold urticaria
familial Mediterranean fever
genome wide association studies
Hyperimmunoglobulinaemia D with periodic fever syndrome
human leukocyte antigen
hereditary periodic fevers
islet amyloid polypeptide
immunologic disease continuum
interferon gamma
interleukin
IL-1 receptor antagonist
IL-18 binding protein
IL-36 receptor antagonist
inhibitor of kB
IFNg-inducible protein 10
joint contractures, muscle atrophy, microcytic anaemia, and panniculitis-induced
childhood-onset lipodystrophy
c-Jun N-terminal kinases
lipopolysaccharide
mitogen-activated protein kinase; MCP-1, monocyte chemotactic protein 1
muramyl dipeptide

525

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S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505533

MEFV
MHC
mROS
mTNF
MVK
MWS
NADPH
NAPS12
NF-kB
NLRP3
NNS
NOD2
NOMID
NOX
PAMPS
PERK
PI
PsA
PSORS1
PSORS2
PTPN22
PYD
RANTES
ROS
RPE
sJIA
SLE
STAT-1
sTNF
sXBP1
TACE
T2D
TLR4
TNF
TRADD
TRAF6
TRAPS
TXNIP
UPR
uXBP1

Mediterranean fever
major histocompatibility complex
mitochondrial-derived ROS
membrane bound TNF
mevalonate kinase
MuckleWells syndrome
nicotinamide adenine dinucleotide phosphate
NLRP12-associated periodic syndrome
NF-kappaB
Nod-like receptor family, pyrin domain-containing protein 3
Nakajo-Nishimura syndrome
nucleotide-binding oligomerization domain-containing protein 2
neonatal-onset multisystemic inammatory disease
NADPH oxidase
pathogen-associated molecular patterns
protein kinase-like ER kinase
protease inhibitors
psoriatic arthritis
psoriasis susceptibility locus 1
psoriasis susceptibility locus 2
protein tyrosine phosphatase, non-receptor type 22
pyrin domain
regulated upon activation, normal T-cell expressed, and secreted
reactive oxygen species
retinal pigment epithelium
systemic juvenile idiopathic arthritis
systemic lupus erythematosus
signal transducer and activator of transcription-1
soluble form of TNF; sTNFR1, soluble TNFR1
spliced X-box binding protein 1
TNF-a converting enzyme (a disintegrin and metalloprotease domain 17 (ADAM17))
type 2 diabetes
Toll-like receptor-4
tumour necrosis factor
TNFR-associated death domain protein
TNF receptor-associated factor 6
TNF receptor-associated periodic fever syndrome
thioredoxin-interacting protein
unfolded protein response
unspliced XBP1

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