29
7 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 b 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 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 diseasewas 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 antago- nists (interleukin 1 receptor antagonist (IL-1RA)). More recently, additional mechanisms linking innate immune-mediated inam- mation 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.: þ44 113 343 8641; fax: þ44 113 343 8502. E-mail addresses: [email protected] (S. Savic), [email protected] (M.F. McDermott). 1 Tel.: þ44 113 206 5567; fax: þ44 113 206 7250. Contents lists available at SciVerse ScienceDirect Best Practice & Research Clinical Rheumatology journal homepage: www.elsevierhealth.com/berh 1521-6942/$ see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.berh.2012.07.009 Best Practice & Research Clinical Rheumatology 26 (2012) 505533

Autoinflammatory Syndromes and Cellular Responses to Stress - Pathophysiology, Diagnosis and New Treatment Perspectives

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Best Practice & Research Clinical Rheumatology 26 (2012) 505–533

Contents lists available at SciVerse ScienceDirect

Best Practice & Research ClinicalRheumatology

journal homepage: www.elsevierheal th.com/berh

7

Autoinflammatory syndromes and cellular responses tostress: pathophysiology, diagnosis and new treatmentperspectives

Sinisa Savic a,b,1, Laura J. Dickie b, Miriam Wittmann b,c,d,Michael F. McDermott b,*aDepartment of Clinical Immunology, St. James’s University Hospital, Leeds, UKbNIHR-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute of Molecular Medicine, University of Leeds,Leeds, UKcCentre for Skin Sciences, School of Life Sciences, University of Bradford, UKdBradford Teaching Hospitals NHS Foundation Trust, Department of Dermatology, Bradford, UK

Keywords:AutoinflammationFMF (familial Mediterranean fever)TRAPS (TNF receptor-associated periodicfever syndrome)NLRP3 (Nod-like receptor family,pyrin domain-containingprotein 3) inflammasomeBiological therapyIL-1b TNFROS (reactive oxygen species)Metabolism

* Corresponding author. NIHR-Leeds MusculoMolecular Medicine, Wellcome Trust Brenner Bui8641; fax: þ44 113 343 8502.

E-mail addresses: [email protected] (S. Savic),1 Tel.: þ44 113 206 5567; fax: þ44 113 206 725

1521-6942/$ – see front matter � 2012 Elsevier Lthttp://dx.doi.org/10.1016/j.berh.2012.07.009

The term ‘autoinflammatory disease’ was first proposed in 1999 toencompass some of the distinct clinicopathologic features ofa group of monogenic conditions, characterised by recurrentepisodes of inflammation, without high-titre autoantibodies orantigen-specific T cells. It was subsequently observed that severalof these conditions were caused by mutations in proteins involvedin the innate immune response, including, among others,components of the NLRP3 inflammasome, cytokine receptors(tumour necrosis factor receptor 1 (TNFR1)) and receptor antago-nists (interleukin 1 receptor antagonist (IL-1RA)). More recently,additional mechanisms linking innate immune-mediated inflam-mation with a variety of cellular processes, including proteinmisfolding, oxidative stress and mitochondrial dysfunction, havebeen recognised to play a role in the pathogenesis of somemonogenic autoinflammatory conditions, and also in morecommon diseases such as type 2 diabetes (T2D), previouslyperceived as a metabolic disorder, but reclassified as a chronicinflammatory condition. NLRP3 inflammasome activation isinduced by islet amyloid polypeptides (IAPPs) in T2D and thiscondition may, in future, be more commonly treated with targeted

skeletal Biomedical Research Unit (NIHR-LMBRU), Leeds Institute oflding, St. James’s University Hospital, Leeds LS9 7TF, UK. Tel.: þ44 113 343

[email protected] (M.F. McDermott).0.

d. All rights reserved.

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533506

Table 1Comparison of autoinflammation and autoimmuni

Autoinflamm

Immunological disruption Innate immuMain cellular involvement Neutrophils,Antibody involvement Few or no auClinical features Recurrent, ofConceptual understanding Tissue-specifiMain genetic susceptibility Cytokine and

Therapy Anti-cytokinExamples Monogenic h

polygenic Crspondylarthr

MHC major histocompatibility complex; IL interlesyndrome; IPEX immune dysregulation polyendocSystemic lupus erythematosus. Adapted from McGdiseases. PLoS Med 2006;3(8):e297 [15].

anti-cytokine therapies. Caspase 1 activation and release of IL-1b/IL-1 family members is central to the pathogenesis of manyautoinflammatory syndromes, as evidenced by the effectiveness ofanti-IL-1 biologics in treating these disorders. However, manypatients continue to experience symptoms of chronic inflamma-tion, and it will be necessary to translate discoveries on theimmunopathology of these conditions into more effective thera-pies. For example, in tumour necrosis factor receptor-associatedperiodic fever syndrome (TRAPS), the pathogenesis may varywith each mutation and therefore future approaches to treatmentof individual patients will require a more tailored approach basedon genetic and functional studies.

� 2012 Elsevier Ltd. All rights reserved.

Introduction

Discovery of periodic fever syndromes – early history of autoinflammation

The term ‘periodic disease’ was first employed by Hobart Reimann in 1948 to describe a clinicalsyndromewhichmanifested as benign paroxysmal peritonitis, periodic fevers, cyclical neutropenia andintermittent arthralgia [1]. In 1958, Heller et al. introduced the designation ‘familial Mediterraneanfever’ (FMF) for the syndrome described by Reimann, based on its increased prevalence in people ofMediterranean descent and characteristic clinical features [2]. However, FMF, which usually has anautosomal recessive inheritance, is not restricted to these ethnic groups. Over subsequent years camerecognition of the clinical aspects of other genetically determined recurrent fevers, both autosomaldominant and recessive, whichwere all collectively termed ‘hereditary periodic fevers (HPFs)’ (Table 1).

The autosomal dominant conditions include tumour necrosis factor (TNF) receptor-associatedperiodic fever syndrome (TRAPS) (this condition was previously termed ‘familial Hibernian fever’ in1982 [3]), familial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria (FCU),first described in 1940 [4], Muckle–Wells syndrome (MWS), characterised by urticaria, deafness andamyloidosis, described in 1962 [5] and chronic infantile neurological cutaneous articular syndrome(CINCA; also known as neonatal-onset multisystemic inflammatory disease, abbreviated to NOMID)first described in 1981 [6]. The three syndromes, MWS, FCAS and CINCA/NOMID, are all closely relatedas they share a number of clinical features and a common genetic basis. In 2001, a heterozygousmutation in the CIAS1/NLRP3 gene was found to be responsible for FCAS and MWS [7]. A year later,

ty.

ation Autoimmunity

nity Adaptive immunitymacrophages B and T cellstoantibodies Autoantibodies presentten seemingly unprovoked attacks Continuous progressionc factors/danger signals Breaking of self-tolerancebacterial sensing pathways MHC class II associations and

adaptive response genese (IL-1, TNF, IL-6) Anti-B and T cellereditary periodic fevers,ohn’s disease,opathies

Monogenic ALPS and IPEX,polygenic RA and SLE

ukin; TNF tumour necrosis factor; ALPS autoimmune lymphoproliferativerinopathy, enteropathy X-linked syndrome; RA Rheumatoid arthritis; SLEonagle D, McDermott MF. A proposed classification of the immunological

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533 507

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 highlightthe common genetic basis of these conditions.

Hyperimmunoglobulinaemia D with periodic fever syndrome (HIDS) is an autosomal recessive HPFcharacterised by recurrent episodes of fever associated with lymphadenopathy, abdominal pain andskin rash, first reported in 1984 [9]. The association of HIDS with homozygous mutations in themevalonate kinase (MVK) gene was first described in 1999 [10,11].

With the identification of some of the genes underlying the HPFs, the term ‘autoinflammatorydisease’ was first proposed in 1999 to encompass some of the distinct clinicopathologic features ofthese conditions, characterised by recurrent episodes of inflammation, without high-titre autoanti-bodies or antigen-specific T cells [12–14].

Autoinflammation – one end of immunological disease continuum

McGonagle and McDermott proposed in 2006 that the majority of inflammatory disorders aresituated along an immunologic disease continuum (IDC), with genetic disorders of innate and adaptiveimmunity located at either end of the spectrum [15]. HPFs are the prototypical genetically determinedinnate immune-mediated diseases, which may be associated with significant tissue destructionwithout evidence of adaptive immune responses and are designated as autoinflammatory due to theirdistinct immunopathological features (Table 1).

There is increasing evidence that a combination of environmental, immunogenic and geneticaetiologies is instrumental in causing polygenic autoinflammatory and autoimmune diseases.Recognition of the central contribution of innate immune-related factors at target sites of diseasehas led to the idea of classifying some conditions (such as Behçet’s syndrome, psoriasis, psoriaticarthritis (PsA) and gout) as having major autoinflammatory components [16,17]. Dysregulatedinnate immunity has been demonstrated in Crohn’s disease (CD), a polygenic disorder in whicha breach in stability of the intestinal mucosal barrier defences causes abnormal handling ofcommensal luminal bacteria. CD has been classified as a polygenic autoinflammatory condition [18].Mutations in the NOD2 (NLRC2) gene encoding nucleotide-binding oligomerisation domain-containing protein 2 (NOD2)(NLRC2 protein), also known as caspase recruitment domain-containing 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 codingsingle-nucleotide polymorphism (SNP) (T300A) in the ATG16L1 gene (chromosome 2q) [21,22].ATG16L1 encodes a protein involved in the autophagic mechanism, whereby intracellular bacteriaare processed by lysosomal degradation; thus, a defect in this pathway may produce an inappro-priate 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 histocompatibilitycomplex (MHC) human leukocyte antigen (HLA) class I-related conditions, such as spondyloarthritis[25], psoriasis [26] and Behçet’s disease [27]. Although CD does not usually have HLA class I associa-tions, a genetic overlap exists between CD and some MHC class I-associated diseases, includingpsoriasis [28].

These aforementioned inflammatory diseases exhibit dysregulated innate immunity and aregenetically distinct from autoimmunity, but may demonstrate some evidence of adaptive immuneresponses [29]. Classical autoimmune diseases, with autoantibody and MHC class II associations,including celiac disease and systemic lupus erythematosus (SLE), have adaptive immune geneticassociations, 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 classification is relevant to the clinical situation, because innate immune-mediated disorders respond better to cytokine antagonism whereas autoimmune-mediated diseasesmay respond to anti-T and B cell therapies. Furthermore, some conditions such as systemic juvenileidiopathic arthritis (sJIA) and ankylosing spondylitis (AS) have been reclassified as autoinflammatorydiseases primarily based on response to IL-1 antagonism in the case of sJIA [30] and innate immunesystem abnormalities in the case of AS [31].

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533508

Immunopathogenesis

Many paths lead to autoinflammation

Masters et al. have proposed a classification scheme for autoinflammatory disorders based onmolecular mechanisms rather than clinical classification [13]. They have defined six categories ofautoinflammatory disease: IL-1b activation disorders (inflammasomopathies), 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 yearsthat have elapsed since discovery of the genetic basis of FMF (the most prevalent HPF), the study ofHPFs has evolved from the initial concept of autoinflammatory disease into novel classifications ofthese diseases with delineation of the central role of the innate immune system and the functionalbasis of some of these conditions. We explore several of these concepts and some newly proposedmechanisms in more detail.

Cytokine excess – NLRP3 inflammasome activation in the pathogenesis of CAPS

IL-1b is a potent pro-inflammatory cytokine, which is synthesised early in response to infection andtissue injury by cells of the innate immune system. It has multiple effects, including induction of feverand hepatic acute phase response, recruitment of neutrophils and induction of other pro-inflammatorycytokines, such as TNF and IL-6 [32]. In excess, IL-1b can have detrimental physiological effects leadingto tissue damage, bone reabsorption, collagen deposition and, in very large amounts, it can causehaemodynamic shock [33]. Tight regulation of IL-1b synthesis and release is therefore essential toensuring that the inflammatory response is of appropriate magnitude to deal with the threat posed byinfection but, coincidentally, causing the least harm to the host. In part, this is achieved by havinga number of different steps governing the synthesis, release and action of IL-1b.

IL-1b is first synthesised as an inactive 269-residue precursor (pro-IL-1b). Caspase-1 is a cysteine-protease that processes both pro-IL-1b and pro-IL-18 to generate the bioactive cytokines, IL-1b and IL-18, and to initiate pathogen-specific immune responses [34]. The inactive pro-IL-1b form is found inmonocytes, macrophages and dendritic cells, but only at very low levels in the absence of pro-inflammatory stimuli. Pro-IL-1b synthesis, or the priming step in IL-1b production, is induced bya number of pro-inflammatory pathways that recognise pathogen- or danger-associated molecularpatterns (PAMPS and DAMPS, respectively)(Fig. 1). For example, lipopolysaccharide (LPS) activation ofToll-like receptor (TLR)4 and muramyl dipeptide (MDP) stimulation of NOD2 are two pathways thatrecognise a large number of the common Gram-negative and Gram-positive bacterial pathogens.Together with the pro-inflammatory cytokine, TNF, but also IL-1a and IL-1b itself, all of these pathwaysstimulate 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 ofsecondary stimuli, which ultimately activate caspase-1 to cleave the immature cytokine into matureform, IL-1b. This process is dependent on various macromolecular platforms termed ‘inflammasomes’.The NLRP3 inflammasome is the most studied caspase-1-activating complex and the one which ismutated and functionally abnormal in CAPS. NLRP3 activation is itself a complex multi-stage process. Itrequires a priming step in monocytes, which is thought to increase the expression of NLRP3 in thetarget cells, in addition to usually requiring a second signal in macrophages, which may involveintracellular potassium (Kþ) flux, 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 lowand the activation requires transcriptionof NLRP3, which can be induced by signals such as LPS, TNF and IL-1b that also promote the tran-scription of pro-IL-1b. The second signal is thought to be required for assembly of the NLRP3 inflam-masome and also its activation in macrophages [37]. NLRP3 protein contains a central NACHT ornucleotide-binding and oligomerisation domain, which has a role in assembly of the inflammasome.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 asmacrophages fromMWS patients were found to produce significantly more IL-1b compared to healthy

Fig. 1. Integration of NLRP3, ER stress and mitochondria-mediated inflammatory responses in autoinflammatory disease. ER stresscaused by various metabolic disturbances or accumulation of misfolded proteins (for example misfolded TNFR1 in TRAPS) is sensedby the ER-luminal domain of ATF6, PERK and IRE1 (1). ATF6 translocates to the Golgi where its cytoplasmic domain is cleaved tobecome transcription factor fATF6 (2). PERK and IRE1 are autophosphorylated at the cytoplasmic domains; PERK then phosphor-ylates eIF2a, leading to inhibition of general protein synthesis (3). At the same time this permits the translation of transcriptionfactor ATF4. Activated IRE1 splices XBP1 mRNA to produce transcription factor sXBP1 (4). fATF6, ATF4 and sXBP1 translocate to thenucleus where they induce expression of genes important for UPR (5). IRE1, via interaction with TRAF and IKK, also controls NF-kBand JNK activation leading to enhanced proinflammatory cytokine secretion (TNF, IL-6, pro-IL-1b) (6). ER stress can also (in certaintissues-hetaocytes) directly induces proteins of the acute phase response, such as CRP through cyclic AMP-responsive elementbinding protein hepatocyte (CREBH) (7). Upregulation of E3 ubiquitin ligases through the action of pro-inflammatory cytokines andsXBP1 leads activation of the ER associated degradation (ERAD) pathway which targets proteins with ubiquitin to promote pro-teosomal degradation (8). Impaired degradation of the ubiquitinated proteins in cells under metabolic stress is one of the proposedmechanisms in proteasome-associated autoinflammatory syndromes (9). The mitochondria and the ER are interlinked throughcalcium signalling. Mitochondria are able to take up Ca2þ and are in close proximity to the Ca2þ release sites of the ER, which cancause 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).

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533 509

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 inflamma-some subunits around mutated NACHT domain [39], possibly by removing an inhibitory loop, makingthe mutated inflammasome constitutively turned on and independent of the need for secondarysignals for its activation. This leads to subsequent caspase-1 activation with excessive and inappro-priate IL-1b release. This hypothesis is supported by observations that LPS alone is sufficient to causecaspase-1 activation in macrophages harbouring CAPS-causing mutations. Furthermore, cytosolic Kþthat normally prevents activation of the NLRP3-inflammasome fails to do so if cells contain NLRP3-associated mutations [40,41].

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533510

Recently, a mouse model of CAPS was developed by two different groups, which recapitulatedmany concepts relevant to the pathogenesis of CAPS [40,41]. They were able to demonstrate thatinflammation in different tissues was mainly due to neutrophil infiltration and not dependent on Band T cells. In addition, the inflammatory response was also conditional on expression of the mutatedNLRP3 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 towardsTh17 phenotype. While IL-1b seems to be involved in polarisation towards the Th17 lineage, it also hasa well described and strong impact on the production of the Th1 lymphokine interferon gamma (IFNg)in activated cells [42]. Indeed, the proliferation of all CD4þ 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 thepatients readily respond to IL-1 blockade. This latter observation offers further supporting evidence ofthe 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 whyonly certain tissues and organs are affected, and why some mutations are associated with a moresevere clinical phenotype.

The importance of tight regulation of IL-1 activity is further illustrated by another autoinflammatorycondition that shares some clinical features with the more severe spectrum of CAPS diseases (NOMID/CINCA) but has a somewhat different immunopathological basis. Deficiency of the IL-1 receptorantagonist (DIRA) is an autosomal recessive disease resulting from mutations in IL-1RN, the geneencoding the IL-1 receptor antagonist (IL-1Ra) [44]. IL-1Ra is produced at the same time as IL-1a andIL-1b and limits the effects of these two cytokines on their common receptor. Interestingly, stromalcells (fibroblasts), which mainly express IL-1a (but not b), are also an important source of IL-1Ra andmay make an important contribution to local tissue IL-1 activity control. We have recently shown thatdermal fibroblasts are also significant producers of IL-18 binding protein (IL-18BP), another endoge-nous antagonist, but not IL-18 [45]. This finding supports the emerging role of tissue-resident stomalcells as regulators of inflammatory responses. Unopposed action of IL-1 cytokines in DIRA results ina perinatal onset of skin pustulosis, joint swelling and various bone malformations, including painfulosteolytic 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 respondrapidly 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 agree-ment that gain-of-function mutations lead to the excessive IL-1b release. Inappropriate activation ofthe NLRP3 inflammasome and excessive IL-1b release has also been implicated in the pathogenesis ofa number of other conditions, including T2D, where the role of chronic inflammation in diseasepathogenesis has recently gained greater recognition. Here the accumulation of IAPP is thought to leadto inappropriate NLRP3 inflammasome activation and release of IL-1b with detrimental consequencesfor pancreatic b islet cells [47].

However, more recently, NLRP3 activation has been shown to have a protective role in two unre-lated conditions, possibly through the induction of IL-18. In CD, reduced NLRP3 expression resultingfrom sequence changes in the promoter region has been associated with increased risk of developingthe disease [48]. The explanation for this association is not entirely resolved and likely to be quitecomplex. NLRP3 expression and activation has a protective role in the majority of animal models ofinduced colitis [49,50], which is contrary to the expectation that reduced NLRP3 expression, asdemonstrated in monocytes of CD patients [51,52], might be expected to reduce inflammation in thebowel. However, this may not be entirely surprising since it is possible that appropriate NLRP3 activityis essential to maintain the immunological barrier to commensal gut micro-organisms. In addition,IL-18, whose maturation is also dependent on NLRP3 inflammasome, has been shown to have a specificrole in promoting the repair of gut epithelium [53]. Another line of evidence is based on the obser-vation that active caspase-1 is involved in the non-conventional secretion of leaderless proteins – atleast in epithelial cells which line all barrier organs [54]. All members of the IL-1 family are leaderlessproteins, and this is also true for important anti-inflammatory molecules, such as IL-37 [55]. However,so far, experimental evidence for impaired secretion of anti-inflammatory mediators in patients withimpaired caspase-1 activation is still lacking.

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533 511

In the case of age-related macular degeneration (AMD), the roles of NLRP3 and IL-18 are somewhatcontroversial. NLRP3(�/�) but not IL-1b(�/�) mice were found to be more susceptible to two differentexperimental models of AMD and drusen (focal extracellular deposits on the Bruch’s membrane belowthe retinal pigment epithelium (RPE) in themacula) isolated from donor AMD eyes caused activation ofthe NLRP3 inflammasome [56]. Taken together, these findings suggest that drusen-induced NLRP3activation is protective in AMD due to its role in IL-18 maturation. However, two subsequent publi-cations suggest that NLRP3 activation due to oxidative stress in RPE cells [57], or resulting from Dicer1loss 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 onNLRP3 and caspase-1 activation, it is increasingly recognised that IL-1 processing and maturation canalso occur independently of these mechanisms [59]. This, in turn, might have specific implicationswhen facedwith disease states where an IL-1 signature is evident but the cause for such an observationis not obviously linked with inflammasomes or caspase-1 activation. A highly inflammatory disease tomention in this context is Netherton syndrome, which is characterised, among other symptoms, bysevere eczema and universal pruritus (itch). Netherton syndrome is the result of a loss-of-functionmutation in serine peptidase inhibitor, Kazal type 5 (SPINK5), which encodes for a serine proteaseinhibitor expressed in normal skin (lympho-epithelial Kazal-type-related inhibitor (LEKTI)) [60]. HighIL-18 expression has been demonstrated in the skin of these patients [61]. Gout also has an IL-1-mediated autoinflammatory component, and activation of neutrophils in gout is associated withproinflammatory neutrophil extracellular trap formation (NET) [62] and extracellular IL-1b production,which may be elastase mediated [59].

Gene dosage and the modifier effect – mediterranean fever (MEFV) mutations in FMF

Although the genetic cause of FMF has been known for over a decade, the exact explanation of howthe mutated pyrin gene, also known as MEFV (mediterranean fever), causes inflammation remainsincomplete. The fact that pyrin is predominantly expressed in cells of myeloid origin such as neutro-phils, monocytes and dendritic cells and that FMF has an apparent autosomal recessive pattern ofinheritance, have led to the assumption that the inflammation in FMF is caused by inappropriateactivation 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 fourdomains, an N-terminal pyrin domain (PYD), followed by two B-box zinc-finger and coiled-coildomains 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 overexpressionexperiments have demonstrated that pyrin can interact with apoptosis-associated speck-like proteincontaining a caspase recruitment domain (CARD) (ASC) to limit NLRP3 activation [63], but it can alsobind capsase-1, via the B30.2 domain [64], to negatively regulate the enzyme activity. This latter effectof pyrin is particularly interesting as it provides a plausible explanation for how these mutations mayaffect pyrin function since most pathogenic mutations are in this B30.2 domain [65]. However, over-expression 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 ofpro-inflammatory cytokines, the effects of which were particularly enhanced in cells harbouring themutated protein [67]. In addition, mice expressing truncated forms of pyrin were found not to havea phenotype resembling FMF [68], whilst the majority of pathogenic MEFV mutations are missensechanges and, to date, no null mutations have been identified [69]. All these observations suggest thatpyrin mutations in FMF result in gain rather than loss of protein function. Further support for thisnotion comes from recent work that was done in pyrin-deficient and ‘knock-in (KI)’ mice harbouringmutant 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-deficient animals and heterozygous KImice have no clinical features of FMF, suggesting that loss of pyrin function alone is insufficient torecreate the pro-inflammatory phenotype [71]. On the other hand, mice with two mutated copies ofthe gene showed a number of inflammatory features consistent with the human disease, includinggeneralised neutrophilia, dermatitis and arthritis, but the hemizygous animals showed no evidence ofthe disease [71]. Taken together, these findings suggest that disease-associated mutations lead to gain

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533512

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 ofa milder phenotype [72,73]. Furthermore, this might also explain why MEFV sequence changes havebeen identified in chronic inflammatory diseases, such as Behçet’s disease [74–77], systemic AAamyloidosis [78] and CD, [79], where they are thought to have pro-inflammatory disease-modifyingeffects.

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 ofTNFRSF1A lead to the clinical manifestations of TRAPS (Fig. 2). Nevertheless, the link between thesemutations and associated phenotypes remains poorly understood with much apparent clinicalheterogeneity 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 regulatedon 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)

Low

dose

LPS

IL-6

TNF

NF-κB activation

p50p65

JNK

P p38

P

ROS

Ca2+ XBP1

ER

Aggregated

misfolded

TNFR1 leading

to mild ER

stress

+++ MAPK activation

Antioxidants

sXBP1

TLR4

sXBP1

Fig. 2. A summary of the proposed mechanisms of TRAPS and the proinflammatory pathways they can activate Intracellularretention of mutant TNFR1 within the ER causes disruption of mitochondrial ROS production as well as activation of the XBP1 arm ofthe UPR. TRAPS cells have also been reported to be hyper-responsive to theTLR4 ligand LPS, which can also cause XBP1 splicing. It istherefore possible in TRAPS that these 2 pathways converge on the same signalling mediators, enhancing inflammatory responseseven at low dose stimulations. Antioxidant treatment is able to prevent LPS-induced XBP1 activation demonstrating a crucial role ofthe mitochondria-ER interaction in inflammatory signalling. XBP1 and mitochondrial ROS are able to cause NF-kB activation, MAPKactivation and consequently pro-inflammatory 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 inMAPK phosphatases, enhancing MAPK phosphorylation and activation. Recently, p38 has been demonstrated to directly phos-phorylate sXBP1 and enhance sXBP1 nuclear translocation, promoting transcription factor activity. This is an example of one of themany potential feedback loops that could be exacerbating inflammatory episodes in TRAPS.

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cascade [80], which will result in either cell survival, or induction of an inflammatory response.Alternatively, activation of caspase-3 will eventually lead to cell death due to apoptosis [81]. Themyriad of often conflicting effects mediated by TNFR1 is possible because the intracellular domain ofthe receptor can engage with several different intracellular pathways via the TNFR-associated deathdomain protein (TRADD)-containing macromolecular platform [82]. TNF is mainly produced byepithelial and innate immune cells, including macrophages, monocytes, neutrophils and NK cells, butalso by some T-cell subsets. TNFR1 is expressed as a homotrimer [83] on the cell surface and activatesTNFR1 and TNFR2, with both receptors also forming homotrimers following engagement of themembrane-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 metal-loprotease domain 17 ADAM17) [84]. This same enzyme also cleaves TNFR1 and TNFR2 from the cellsurface, and these soluble forms of receptors are thought to have a predominantly neutralising effecton TNF [85].

Early studies into the pathogenesis of TRAPS suggested that mutated TNFR1 might be resistant tothis enzymatic cleavage, resulting in impaired clearance of TNFR1 from the cell membrane [12]. Thiswas an attractive hypothesis as it offered an explanationwhy certain patients had low levels of solubleTNFR1 (sTNFR1) in patients’ serum between attacks. It could also possibly explain why the pathogenicmutations were either missense, small deletions or insertions found in the extracellular domains, asthese may affect the secondary structure and therefore limit access to the proteolytic cleavage site.However, the TNFR1 shedding defect is not a universally reproducible finding in all patients withTRAPS [86], whilst treatment with etanercept, which is a fusion molecule of TNFR2/FcIg, designed tomop up soluble TNF, is only partially effective [87–90].

Increased NF-kB activation [91–93] has also been associated with some mutations, and, morerecently, additional mechanisms have been suggested to explain the pro-inflammatory effects ofmutated TNFR1. Simon et al. reported that TRAPS patients demonstrated higher MAPK activation inresponse to bacterial LPS, a TLR4 ligand, than healthy controls and also showed a hyper-responsivenessto LPS whereby TNFRSF1A mutant peripheral blood mononuclear cell (PBMC) could respond to lowdose LPS (0.01 ng ml�1) [94]. Subsequently, it was shown that this might in part be due to the effects ofROS onMAPK activation [95]. Monocytes and neutrophils from TRAPS patients showed higher baselinelevels of ROS than cells from healthy donors. Increased ROS was shown to mediate increased pro-inflammatory cytokine secretion and also increased MAPK activation, which is therefore thought tobemediating the cytokine release. ROS are known to inactivateMAPK phosphatases by oxidation of thecatalytic cysteine residue, thereby enhancing MAPK activation. Somewhat surprisingly, further studiesdemonstrated the source of ROS production to be the mitochondria, mainly because of enhanced ROSproduction rather than blockedmitophagy, which was recently implicated in the pathogenesis of otherautoinflammatory conditions such as CD [96,97].

Another important observation about the pathogenesis of TRAPS is that trafficking of the mutatedreceptor to the cell surface appears to be impaired [98]. Low surface expression of TNFR1 has beenreported in patients with TRAPS [99], and furthermore, retained aggregates of TRAPS-associatedmutant 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 productionin TRAPS patients [101]. We hypothesised that retention of the mutated receptor within the ER wouldcause a degree of ER stress and that this would facilitate activation of inflammatory pathways,including enhanced cytokine release and ROS generation, and could confer the reported hyper-responsiveness to LPS. We found that resting monocytes from TRAPS patients showed increasedexpression of protein kinase-like ER kinase (PERK) and spliced X-box binding protein 1 (sXBP1), whichare two markers of ER stress and activated as part of the unfolded protein response (UPR) [102].However, these findings were not associated with other markers of ER stress, as we found normalexpression levels of downstream target genes, such as synoviolin and DNA-damage-inducible tran-script 3. Furthermore, we confirmed that TRAPS cells showed increased baseline total andmitochondrial-specific ROS production [95], which was increased further in response to IL-6 stimu-lation. We also found that LPS promoted sXBP1 activation, which was abolished by the addition ofantioxidants [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, asother UPR pathways were not activated [103]. The sXBP1 was essential for sustained pro-inflammatorycytokine production, and mild ER stress could also greatly facilitate production of inflammatorycytokines, such as TNF and IL-6, as sXBP1 was found to bind directly to the promoter region of thesecytokines [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 nucleartranslocation and transcriptional activity [104]. Therefore, sXBP1 can explain some of the hyper-responsiveness to LPS in TRAPS, and this might be enhanced further by the effect that p38 MAPKpathway 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 genetargets of XBP1 are known to have roles in redox homeostasis and cell survival during hypoxicconditions. Interestingly, it is the unspliced form of XBP1 (uXBP1), which was found to induceexpression of antioxidant genes [105], including catalase, superoxide dismutase and thioredoxin. Thisrole was independent of sXBP1, as the spliced isoform was unable to regulate the expression levels ofthese antioxidants. We found that the uXBP1 transcript levels were not significantly elevated in TRAPSpatients when compared to HC, despite the increased ROS levels present in the patients’ cells [101].These findings 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 mutantreceptor is necessary to replicate the inflammatory phenotype of TRAPS. Mice homozygous for TRAPS-associated TNFR1 mutants, rather than suffering from spontaneous inflammatory problems, showresistance to LPS-induced septic shock [94], which is a phenotype previously described in TNFR1-deficient animals. This is in keeping with the disease model whereby retention of the mutatedreceptor within the ER provides a low-grade stimulus, onwhich other signals, including TNF itself (dueto the presence of wild-type receptor), act to induce the hyper-inflammatory state typical of TRAPS.

Novel mechanisms of autoinflammation – mutated immunoproteasome

Proteasome-associated autoinflammatory syndromes is a term that has been recently introduced tohighlight the common genetic basis of a number of rare autoinflammatory conditions with overlappingclinical features [106,107]. Hypomorphic mutations affecting the inducible b5i subunit of the PSMB8proteasome (proteasome subunit b type 8) have been reported in patients with chronic atypicalneutrophilic dermatosis with lipodystrophy and elevated temperature [108] (CANDLE), jointcontractures, muscle atrophy, microcytic anaemia and panniculitis-induced childhood-onset lipodys-trophy [109]. (JMP), Nakajo-Nishimura syndrome [106] (NNS) and Japanese autoinflammatorysyndrome with lipodystrophy [110] (JASL).

The proteasome is an evolutionarily conserved cylindrical organelle which has an essential role inprotein degradation. It is composed of two a and two b rings which combine to give it its cylindricalshape (Fig. 1). The a rings have a role in substrate capture whilst the proteolytic function is confined tothe b rings. Each ring is composed of seven individual proteins; the inner two rings are made of sevenb subunits that contain three to seven protease active sites. The proteins destined for degradation areusually tagged with polyubiqutin chains, a process that is used in regulating many cellular functionsincluding activation of NF-kB. Of particular interest is the role of the proteasome in antigen processingduring infection. Pathogen-derived proteins are degraded by the proteasome for presentation by MHCclass I molecules at the cell surface. However, this process is much more efficient and the degradationproducts fit the groove of the MHC class I molecules better when several subunits of the b ring arereplaced 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 ofthe (i) subunits is directed by type I interferons. Recent data from animal psmb8/lmp7 KO studiessuggest that the immunoproteasome also plays a part in maintaining cell homeostasis by removingdamaged 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 thatformation of the immunoproteasome is impaired in these conditions [108]. Agrawal et al. showed thatthe 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 specificallyimpaired activity of the immunoproteasome [109]. The same patients were found to have significantlyelevated IFNg and IL-6 with elevated erythrocyte sedimentation rate (ESR) and serum g globulins, butnot elevated TNF or IL-1b. This particular cytokine signature seems to be typical of impaired immu-noproteasome function, since patients with CANDLE syndrome were also found to have elevated IFNgand IL-6, but not TNF. These patients also had significantly 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-cellexpressed, and secreted (RANTES or CCL5). Further evidence that excessive IFNg signalling might playa role in the pathogenesis of this condition came from gene expression studies of the whole blood andfrom analysis of signal transducer and activator of transcription-1 (STAT-1) signalling pathway inmonocytes. The IFNg pathway was demonstrated to be the most differentially regulated, whilst, at thesame time, monocytes from CANDLE syndrome patients showed higher STAT-1 phosphorylation inresponse to IFNg compared to healthy controls and patients with CINCA/NOMID [108].

Based on these findings, it has been proposed that the ongoing IFNg stimulation in patients withCANDLE syndrome and related conditions results from inability of the immunoproteasome to dealappropriately with accumulation of damaged proteins leading to chronic cellular stress. As a result, thecellular stress remains unresolved and IFNg stimulation continues unabated. In keeping with thishypothesis is the observation that disease flares are associated with infections and other stressfulevents. Furthermore, affected tissues such as muscle and fat showed inclusion bodies which mightsuggest accumulation of oxidant-damaged/aggregated proteins leading to apoptosis.

Interestingly, lipodystrophy, which is a recognised complication of protease inhibitors (PIs), a class ofanti-human immunodeficiency virus (HIV) medication, might be caused by modulatory effects of theseagents on the proteasome. Ritonavir, for example, was shown to specifically inhibit the chymotrypsin-like activity, whilst enhancing trypsin-like activity of the proteasome [111]. Although this effect wasoriginally thought tomodulate antigen processing only, in the light of our current understanding of howchymotrypsin-like activity is affected in themutated immunoproteasome, it is possible to speculate thatthis might be one of the mechanisms which is responsible for PI-induced lipodystrophy.

Autoinflammation of the skin; IL-36 and deficiency of IL-36 receptor antagonist (DITRA) and CARD14 inpsoriasis susceptibility locus 2 (PSORS2)

A common feature of all IL-1 family members is the tight control of their released active forms andthe presence of soluble antagonists; for example, IL-1a/b are controlled by the endogenous antagonistIL-1RA, IL-18 by IL-18 binding protein (IL-18BP) and IL-36 molecules are controlled by IL-36 receptorantagonist (IL-36RA, former name IL-1F5), which shows a mode of action comparable to IL-1RA. IL-36has three different subtypes, IL-36a (IL-1F6), IL-36b (IL-1F8) and IL-36g (IL-1F9). These homologouscytokines 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 receptorbinding 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 pustularpsoriasis, as described by two independent groups [112,113]. The name DITRA has been proposed forthis autosomal recessive autoinflammatory condition. All IL-36 molecules, including the IL-36RA, showhigh biological activity only after cleavage [114]; the responsible endogenous protease, however, hasnot been identified so far.

Recent data suggest that IL-1 family members are intimately involved in the cellular response oftissue cells characterising psoriatic inflammation. IL-36 has been identified as one of the most highlyexpressed genes in lesional as compared to non-lesional psoriasis [115–117].

We have previously shown that cultured skin cells derived from psoriasis patients show increasedexpression of IL-36 upon cytokine stimulation [118], which is not paralleled by IL-36RA induction. Theintrinsic difference in the expression level of IL-36a/g between cultured and passaged cells derivedfrom psoriasis or healthy individuals is dramatic. IL-36 has not been identified as a genetic suscepti-bility locus in psoriasis genome wide association studies (GWAS). Therefore, the observed differencecould 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 forPsA are not yet available as IL-36 has only recently come into the picture for psoriatic inflammationresearch [121,122]. The best-described inducer of IL-36 messenger RNA (mRNA) expression is thesynergistic action of TNF and IL-17 [122], which are both up-regulated in psoriasis and PsA andblockade of which improve clinical symptoms.

Interestingly, PsA and skin psoriasis share common genetic variants that are important for theNF-kB-related pathways (e.g., A20 [TNFAIP3], TNIP1 and TRAF3IP2) [123,124]. Therefore, psoriaticdisease may fit into the proposed novel classification as NF-kB-related autoinflammatory condition.

In the early 1990s, GWAS undertaken to find psoriasis-susceptibility genes provided evidence forthe presence of a disease locus within theMHC on chromosome 6p21.3, referred to as PSORS1 (psoriasissusceptibility 1) (for review: [125]). It was later suggested that HLA-C was the most likely PSORS1candidate gene [126]. With regard to a second psoriasis susceptibility site called PSORS2, a recent studyrevealed CARD14 gain-of-function mutations as ‘responsible’ for the PSORS2 findings [120]. CARD14activates NF-kB and compared with wild-type, the mutated form leads to increased activity of NF-kBand up-regulation of a subset of psoriasis-associated mediators in skin-resident cells. This is the pointat which the circle closes as we have come back to the above described IL-36, which is indeed amongthe mediators found to be up-regulated in cells with mutated CARD14, along with IL-8, which attractsneutrophils, and CCL20which attracts immature dendritic and Th17 cells into the psoriatic lesions. Thisstudy thus further supports the notion that psoriasis may fit very well into the ‘NF-kB’ pathwaysubcategory.

Integration of NLRP3, ER stress and mitochondria-mediated inflammatory responses

Although the close link between metabolic stress and inflammation has long been suspected, it isonly recently that our understanding of the molecular mechanisms that underpin this relationship hassignificantly 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, therelationship between ER stress and generation of inflammatory cytokines and the role of the mito-chondria in innate immune responses, specifically mitochondrial-derived ROS (mROS).

NLRP3 inflammasome activation is a complex process and has been extensively investigated overthe last several years. Although many potential activators of the inflammasome have been identified,questions have been asked how such diverse stimuli can all cause activation of the same macromo-lecular complex. The multistage activation of the NLRP3 inflammasome was proposed to explain someof the findings, with agreement that the first stage involves up-regulation of NLRP3 expression asa result of, for example, TLR stimulation. There has been much more controversy about what processesgovern the assembly of NLRP3 inflammasome and ultimately caspase-1 activation. This field ofresearch 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 finally the ROSmodel [127]. The channel model explains the need for the ATP and Kþ flux, whereby activation of P2X7,an ATP-gated ion channel, triggers rapid Kþ efflux from the cell, which is an absolute requirement inmost proposed models of NLRP3 activation. In addition, this leads to pore formation in the cellmembrane as a result of recruitment of the pannexin 1 hemi-channel [128], which allows PAMPs suchas MDP to enter the cell and engage NLRP3. Although pore-forming microorganisms such as a-toxin-producing Staphylococcus aureus are potent activators of the inflammasome [129], this could resultfrom allowing Kþ flux 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 lyso-somal rupture, triggers NLRP3 activation. This would explain how large particulate activators, such asalum and silica can activate the NLRP3 inflammasome [130]. Cathepsin B inhibition does impair NLRP3activation in human cells [131], but similar findings have not been consistently replicated in cathepsinB 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 andthe 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 inflammasome activation in response to a varietyof 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 ROS-dependent process, since in unstimulated cells TXNIP is constitutively bound to and inhibited by theoxidoreductase, thioredoxin. As a result of increases in cellular ROS concentration, TXNIP dissociatesfrom thioredoxin and binds to NLRP3. This model is supported by observations that KO or knockdownby small interfering RNA (siRNA) of TXNIP leads to reduced IL-1b secretion, whilst the knockdown ofthioredoxin enhances NLRP3 activation [134,135]. Furthermore, pharmacological blockade of ROS hasalso been shown to reduce inflammasome activation [136].

Although ROS appear to be important activators of the NLRP3 inflammasome, the source of suchROS has been debated. NLRP3 inflammasome activation is not impaired in patients with chronicgranulomatous disease (CGD), who are deficient in one of the NOX components [137]. Traditionally,mROS was not regarded to have an important role in innate immune responses. However, morerecently, mROS has been seen as a much more likely candidate after the discovery that it can begenerated in response to bacteria in a TLR-dependent fashion. Coupling of TLR1/2/4 signalling tomitochondrial complex I was demonstrated via TNF receptor-associated factor 6 (TRAF6), an evolu-tionarily 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 inNLRP3 activation has been shown more specifically by Zhou et al. who not only demonstrated inhi-bition of NLRP3 activation by disrupting mROS generation but also the physical proximity between theactivated NLRP3 inflammasome andmitochondria. In resting cells, NLRP3 localises to the ER structures,but in the activated state, NLRP3 and ASC, an adaptor protein of the NLRP3 inflammasome, have a peri-nuclear location and co-localise with ER and mitochondria organelle clusters [139]. It is perhaps notsurprising that mROS is possibly one of the main activators of the NLRP3 inflammasome, since it isproduced in response to many cellular stresses, including increased metabolic rate, hypoxia ormembrane damage, which, in turn, places NLRP3 inflammasome activation at the centre of manyimportant cellular responses.

The connection between NLRP3 and cellular stress does not stop there since activation of NLRP3 wasrecently shown to occur in response to ER stress independently of UPR pathways [140]. The ER stress-triggered UPR has traditionally been associated with accumulation of misfolded proteins within theER and attempts by the cell to rectify this problem. However, ER stress and components of the UPRpathway also induce inflammatory responses, through several distinct mechanisms. inositol-requiringenzyme 1 (IRE1) and PERK can activate the NF-kB, which is essential for initiating inflammationthrough the induction of a number of pro-inflammatory genes. These pathways converge to reduceavailability of the inhibitor of NF-kB, IkB. In the case of the PERK pathway, this is due to its effect on globalprotein synthesis through the activation of eukaryotic initiation factor 2a (eIF2a), which appears to affectIkBmore thanNF-kB, as the formerhas a shorterhalf-life [141]. IRE1 achievesNF-kB activation through itsassociation with the adaptor protein TRAF2. The IRE1-TRAF2 complex can recruit IkB, which is thenphosphorylated and degraded, resulting in nuclear translocation of NF-kB [142]. Furthermore, thiscomplex also activates c-JunN-terminal kinases (JNKs),which in turnphosphorylates transcription factoractivator protein 1 (AP1) [143]. The latter, similarly to NF-kB, induces transcription of pro-inflammatorygenes. NF-kB activation has also been linked to ROS and oxidative stress, generated as a result of anincreased protein load on the ER and the demand for additional disulfide bond formation. Although themechanism(s) involved is poorly understood, the observation that NF-kB activation can be reduced byantioxidants and calcium chelators supports this claim [144]. This last observationmight be particularlyrelevant 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 howmultiple mechanisms involving metabolic stress, innate immune activation and production ofinflammatory cytokines, come together in the pathogenesis of some common chronic inflammatoryconditions, considered to be autoinflammatory in nature. Examples include spondyloarthropathies,such as AS, inflammatory bowel disease, such as CD, T2D and arteriosclerosis, to name just a fewamongst an ever increasing list.

AS was one of the first inflammatory 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 andgastrointestinal inflammation [146]. There is circumstantial evidence that macrophages from theseanimals, when stimulatedwith IFNa, IFNb or TNF, demonstrate amore active UPR compared to controls[147]. This observationwas made on the basis of elevated BiP and sXBP1 mRNA levels in bone marrow-derivedmacrophages from these animals. More recently, UPR induced either by HLA-B27misfolding orby pharmacological agents, was shown to act synergistically with LPS to induce macrophages fromthese animals to produce IL-23 [148]. Furthermore, elevated IL-23 and IL-17 transcript levels werefound in CD11þ antigen presenting cells (APC) and in CD4þ T cells, respectively, from the coloniclamina propria of the transgenic animals [149]. The form of colitis usually seen in these animals wasassociated with a sixfold expansion of Th17 cells. However, here is evidence that IL-17 in spondy-loarthritis is secreted by innate immune cells rather than T cells in the facet joints of patients withspondyloarthritis [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 Ca2þ release, activation of UPRand CCAAT/-enhancer-binding protein homologous protein (CHOP)-induced apoptosis [152]. Severalinflammatory pathways, including NF-kB, JNK, p38 and ERK1 and 2 (extracellular-signal-regulatedkinase) are activated by loading macrophages with free cholesterol, with IRE1 and PERK potentiallyplaying a role in NF-kB and JNK activation [153]. Furthermore, oxidised lipids also induce UPR in humanaortic endothelial cells [154]. Finally, in vitro studies have linked ER stress-induction of activatingtranscription factor 4(ATF4) and sXBP1 with the production of inflammatory cytokine IL-6 and the IL-8and CXCL3 chemokines. This was demonstrated in human aortic endothelial cells at baseline and asa result of the accumulation of oxidised lipids [154]. More recently, cholesterol crystals have been shownto activate the NLRP3 inflammasome 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 mentionedhere but many excellent reviews have recently beenwritten on this subject and readers are encouragedto consult these for further information.

Clinical considerations

How to recognise autoinflammatory diseases

Inherited or monogenic autoinflammatory syndromes are very rare, apart from FMF, which hasa high prevalence in some specific ethnic groups (see below). Even in the case of TRAPS, which isthought to be the most common autosomal-dominant HPF, the estimated prevalence in Europe is only1 per million [156]. The majority of patients will present in childhood, although in rare instances thefirst recognised clinical manifestation may occur in adolescence or early adulthood. Therefore, thelikelihood of encountering a patient with a recognised HPF or making a new diagnosis in a routineadult clinical practice is quite small. However, there are many more patients who will present withchronic inflammatory illnesses of unknown aetiology who do not necessarily have a recognisedmonogenic syndrome. Various attempts at developing clinical criteria or guidelines to identify which ofthese patients should be considered for genetic testing have been made [157,158]. So far, there are nouniversally agreed recommendations, which is not surprising considering there is a significant clinicaloverlap between certain autoinflammatory conditions and also their relative rarity. The diagnosis istherefore dependent on a high degree of clinical suspicion, experience and, when available, confor-mation by a genetic test.

To assist with these efforts databases such as INFEVERS (http://fmf.igh.cnrs.fr/ISSAID/infevers/) andthe Eurofever Project (http://www.printo.it/eurofever/autoinflammatory_diseases.asp), have beendeveloped to systemically collect clinical and genetic information on patients with all monogenicautoinflammatory syndromes, including HPFs. This has led to improved recognition of the spectrum ofclinical problems associated with these conditions as well as development of targeted treatmentstrategies.

The question whether a patient has an autoinflammtory syndrome usually arises after the morecommon clinical problems associatedwith fevers and inflammation, such as chronic infections, systemicautoimmune diseases and paraneoplastic inflammatory 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 ofunexplained and seemingly unprovoked attacks of ‘fever’ or systemic inflammation that might involveserosal surfaces and joints, unexplained skin rashes and a family history of similar problems. There arealso some more specific signs/symptoms typical of each condition, outlined in Table 2.

Routine clinical investigations are usually unhelpful in differentiating between various forms ofautoinflammatory syndromes. Elevated inflammatory markers (ESR, C-reactive protein (CRP) and neu-trophilia) are commonly found during the attacks but are non-specific. Elevated inflammatory markersmay also be seen between episodes and in otherwise asymptomatic patients, suggesting the persistenceof subclinical inflammation, which is an important risk factor for developing reactive systemic AAamyloidosis, recognised as the most important complication associated with mortality in many cases.

An expanding number of conditions are being recognised as autoinflammatory in nature and therehave been various attempts to classify these. The IDC classification has attempted to find a place forautoinflammatory conditions in the wider context of immune-mediated diseases [15], whilst Masterset al. have used criteria principally based on the immunopathological features [13]. A separate clas-sification, which combines clinical and immunopathogical features, is offered by the INFEVERSwebsite,which divides monogenic autoinflammatory syndromes into the following categories: hereditaryrecurrent fevers (CAPS, TRAPS, FMF, NLRP12-associated periodic syndrome (NAPS12) and mevalonatekinase deficiency (MKD)), pyogenic disorders (DIRA, DITRA, Majeed syndrome and pyogenic sterilearthritis, 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 treatmentrecommendations.

FMF

This is the most common HPF which has relatively high prevalence in populations from easternMediterranean area, including Turks, Jews (primarily non-Ashkenazi), Armenians and Arabs. Almost allpatients will become symptomatic within the first two decades of life (>90%), whist two-thirds willpresent before the age of 5. Typically, attacks are sudden, and apparently unprovoked, but varioustriggers such as physical or emotional exertion, the menstrual cycle and diet have been recognised toprecipitate the attack [159]. Characteristic features of the attack include high fever lasting from hours to3–4 days and serositis involving peritoneum (90%), pleura (45%), scrotum (5%) and pericardium (1%).Interestingly, skin erythema, which is usually associatedwith arthritis, tends tomainly involve the distalendof the lower limbs, usually betweenknee andankle andon thedorsumof the foot in the ankle region.

The long-term complications of FMF may involve encapsulating peritonitis and chronic destructivearthritis, particularly affecting hips and knees. However, these are rare and AA amyloidosis is much lessfrequent since the introduction of colchicine.

A diagnosis of FMF can be made based on clinical criteria alone, especially in areas of high diseasesprevalence. Genetic testing will support clinical diagnosis, although care must be taken when inter-preting genetic results since not all individuals with homozygous mutations will necessarily developthe 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 isalso essential to preventing complications such as AA amyloidosis by taking it on a regular basis. In rarepatients, 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] aswell as anti-TNF infliximab [163] have shown therapeutic potential.

CAPS

CAPS spectrum of monogenic diseases associated with gain-of-function mutations in NLRP3 (alsoknown as CIAS) gene include FCAS, which is the mildest form, MWS moderate and NOMID/CINCAwhich is the most severe manifestation of this disease continuum. These conditions share a number ofclinical features but are also distinct disease entities. All three forms typically present in childhood and,

Table 2Monogenic autoinflammatory syndromes.

Monogenic disease Gene Clinical manifestations Treatment Proposed mechanism

Hereditary periodic feversFMF MEFV Fever, sterile peritonitis,

monoarthritis, pleuritis,serositis, skin erythema

Colchicine in themain but somereports of IL-1 andTNF inhibitors

ASC-dependent IL-1bexcessive release;gene dosage effect

TRAPS TNFRSF1A Prolonged fever,peritonitis,myalgias, arthralgias,erysipelas-like rash,periorbital oedema,amyoidosis

IL-1, IL-6 and TNFinhibitors,corticosteroids

Defective receptorshedding; intracellularreceptor retention;hyper-responsive toLPS; proinflammatorycytokine releasetriggered by mROS;XBP1 activation

CAPS; FCAS,MWS andCINCA/NOMID

CIAS1/NLRP3 Urticaria, deafness andamyloidosis, arthalgias

IL-1 inhibitors ExcessiveNLRP3-dependentIL-1b release;IL-1b-dependentskewing of T-helperresponse towardsTh17 phenotype

HIDS MVK Fever associated withlymphadenopathy,abdominal pain andskin rash

IL-1 and TNFinhibitors

NLRP3-dependentIL-1b release

NAPS12 NLRP12 High fever, arthralgia,myalgia, urticaria,sensorineuralhearing loss.

IL-1 inhibitors Decreased inhibitionof NF-kB;ROS-mediatedimpairment ofIL-1b secretion kinetics

Pyogenic disordersDIRA IL1RN Perinatal onset of skin

pustulosis, joint swelling,bone malformations(osteolytic lesions,periostitisand heterotopicbone formation)

IL-1 inhibitors Unapposed IL-1aand IL-1b signalling

DITRA IL-36RA Severe pustular psoriasis IL-1 inhibitors Loss-of-functionmutations;unapposedIL-36 signalling

PAPA CD2BP1 Arthritis, and pyodermagangrenosum

Oral antibiotics,IL-1 and TNF inhibitors

Enhancedpyrin-mediated ASCrecruitmentfollowed by IL-1bsecretion

Majeed’sSyndrome

LPIN2 Chronic recurrent multifocalosteomyelitis, bonecontractures, congenitaldyserythropoietic anaemia

NSAIDs Uncontrolledinflammationfollowing oxidativestress

Proteasomedisabilities

JMP, NNS,CANDLE, JASL

PSMB8 Neutrophilic dermatosis,lipodystrophy, elevatedtemperature, jointcontractures, muscleatrophy, microcyticanaemia

Prednisone,IL-6 inhibitor

Impaired formationof the immunoproteosome,IFNg signature,cellular stress

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Table 2 (continued )

Monogenic disease Gene Clinical manifestations Treatment Proposed mechanism

Granulomatous disordersCRMO Unknown Multifocal osteomyelitis NSAIDs and steroids. UnknownBlau NOD2 Familial granulomatous

arthritis, skin granulomasand sardoidosis

NSAIDs, methotrexate,TNF inhibitors

ConstitutiveNF-kB activation

ASC Apoptosis-associated Speck-like protein containing a carboxy-terminal CARD; CANDLE chronic atypical neutrophilicdermatosis with lipodystrophy and elevated temperature; JASL Japanese autoinflammatory syndromewith lipodystrophy; CAPSCryopyrin-Associated Periodic Syndromes; CD2BP1 CD2-binding protein 1; CIAS1 cold induced autoinflammatory syndrome 1;CINCA/NOMID Chronic Infantile Neurological Cutaneous and Articular syndrome/Neonatal-Onset Multisystem InflammatoryDisease; CRMO Chronic Recurrent Mutifocal Osteomyelitis; DIRA Deficiency of the IL-1 Receptor Antagonist; DITRA deficiency inthirty-six receptor antagonist; NSAIDs Non-steroidal anti-inflammatory drugs; FCAS Familial Cold Auto-inflammatorySyndrome; FMF Familial Mediterranean Fever; HIDS Hyperimmunoglobulinemia D with periodic fever Syndrome; IFN inter-feron; IL Interleukin; IL1RN Interleukin Receptor Antagonist; JMP joint contractures, muscle atrophy, microcytic anemia, andpanniculitis-induced childhood-onset lipodystrophy; LPIN2 lipin 2; LPS Lypopolysaccaride; MEFV Mediterranean fever; mROSmitochondrial reactive oxygen species; MVK mevalonate kinase; MWS Muckle-Wells Syndrome; NAPS12 NLRP12-associatedPeriodic Syndrome; NF-kB Nuclear Factor kB; NLRP NACHT domain-, Leucine-rich Repeat-, and PYD-containing protein; NNSNakajo-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; TNFTumor Necrosis Factor; TNFRSF1a TNF receptor superfamily member 1A; TRAPS TNF-Receptor-associated periodic Syndrome;XBP1 X-box binding protein 1.

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in the case of CINCA/NOMID, symptoms might be present at birth. In keeping with different degrees ofseverity of the diseasemanifestations, fever attacks in FCAS, which are usually precipitated by exposureto cold, last up to 24 h, in MWS can be several days and in CINCA/NOMID inflammatory processes hasa 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 ofMWS. More severe disease manifestations such as meningitis, mental retardation and bony over-growth tend to be present principally in CINCA/NOMID patients.

CAPS is one of those rare conditions where understanding of the disease pathogenesis has helped toformulate a targeted and effective treatment strategy, and at the same time the excellent treatmentresponse that followed administration of anti-IL-1 therapy elegantly confirmed that the hypothesis ofdisease pathogenesis was correct [164].

After anakinra was shown to be effective in treatment of all forms of CAPS [164–166], several otheranti-IL-1 biologics have been developed. Rilanocept, which is a fusion protein consisting of the humanIL-1 receptor extracellular domains and the Fc portion of human IgG1, was shown to be efficacious inthe 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 andsafe treatment in a randomised withdrawal study of 35 patients with FCAS and MWS [168]. Unlikecanakinumab, which binds to IL-1b only, anakinra and rilanocept can also neutralise IL-1a. Consideringthat all three agents are equally efficacious in treatment of CAPS, this would suggest that IL-1b is thepivotal cytokine responsible for clinical disease manifestations in CAPS.

TRAPS

The clinical course, severity, disease manifestation and treatment responses can vary greatlybetween different patients with TRAPS. This probably reflects the complexity of the disease patho-genesis, which, as discussed, might be mutation specific. The attacks of fever and inflammation are lessdistinct when compared to FMF and can last for weeks. In a significant proportion of patients, thedisease has a chronic course, and some patients despite appearing clinically well will have persistentlyelevated inflammatory markers. This is particularly important to consider when considering treatmentoptions, 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 periorbitaloedema and centrifugal erythematous rash that is usually associated with painful myalgia. The rash canaffect any part of thebody but it haspredilection for the upper limbs andproximal endof the lower limbs.

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Treatment options for TRAPS will depend on the course of the disease and complications. Somepatients have very infrequent attacks, which might respond well to on-demand treatment withsystemic steroids. In patients with more chronic disease, a course of steroids might be ineffective andtreatment choices include several classes of anti-cytokine therapies. Etanercept, which is a recombi-nant human TNFR (p75)-Fc fusion protein composed of the extracellular region of the TNFR2 fused toan Fc portion of IgG1, was the first biological therapy used in TRAPS.

Etanercept, initially demonstrated good efficacy [169,170] and has been reported to induceregression of amyloidosis [87,171] and reduction of CRP [88]. However, there are reports of poor orvariable response [90,172,173]. The role for other anti-TNF agents, such as infliximab (a chimaericmonoclonal antibody), is less clear. Although it is thought to be a more potent inhibitor of TNF thanetanercept, most reports on use in TRAPS suggest that it is not successful and in fact has been reportedto exacerbate symptoms [171,174]. Functional studies have demonstrated that infliximab can increasec-Rel activity; a member of the NF-kB transcription factor family with anti-apoptotic properties whichcauses an increase in IL-1b and IL-6 [175] and reduced secretion of the anti-inflammatory cytokine IL-4and anti-apoptotic IL-7 [176]. There has been a case study reporting the successful use of infliximab inone 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 beingdescribed, but there has been at least one report, so far, of non-response to anakinra [90].

Lastly tocilizumab, a humanisedmonoclonal antibody that targets IL-6 receptor a-chain, is the latestbiologic to be tried in TRAPS. The results are so far mixed as the earlier report of its successful use ina patient (C33Y mutation) who previously had failed both etanercept and anakinra therapy [179], havenow been shown to be short-lived (personal communication). However, there are at least two othercases, one of whom is being treated in our practice, who so far have favourably responded to thistreatment. A larger study, incorporating TRAPS patients with different TNFR1 mutations, is required tofully examine the potential efficacy of tocilizumab in this condition.

HIDS

Despite the name, elevated levels of IgD are not universally found amongst all patients [180], andtherefore an alternative term for this condition, MKD, is preferred by many as it more accuratelyreflects the underlying pathology. Unlike mevalonate kinase aciduria (MVA), where the affectedpatients have complete absence of MVK activity, in patients with MKD, some enzyme function ispreserved (usually around 10% of normal), which is enough to avoid complications of MVA such ascongenital 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 deficiency leads to the inflammatory phenotype char-acteristic of MKD remains largely incomplete. The pathogenesis of this condition has been discussed inmore 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 typicallyprecipitated by vaccination, infection or physical and emotional stress. Fever and chills usually precedecervical lymphadenopathy, abdominal pain with vomiting and diarrhoea, which might develop as theattack 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 fromcentres in France and Belgium found that three patients died fromHIDS-related causes and the diseaseremained highly active in >50% of surviving symptomatic patients, which suggests that HIDS mighthave a more severe phenotype than previously thought [183]. Interestingly, 13 of these patients alsohad a history of recurrent or severe infections and three patients were found to have hypo-gammaglobulinaemia. This raised the possibility that HIDS might be paradoxically associated with animmunodeficiency state in some patients.

The diagnosis of MKD is supported by finding of elevated polyclonal IgD levels, however, this is notdiagnostic for reasons outlined above as well as for the fact that high IgD can be found in otherinflammatory conditions such as FMF. Probably diagnostically more useful is demonstrating thepresence of mevalonate in urine, which in MKD is more likely to be present during a typical attack.

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Alternatively, it is possible to measure MVK activity, but ultimately the diagnosis should be confirmedby genetic testing.

A number of different treatment options have been suggested. Etanercept has shown some benefit[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 associateddisorder (NLRP12AD), but also as FCAS2 since it clinically resembles this condition. However, NAPS12 isa very rare disorder, inherited in autosomal-dominant fashion and, to date, only a few affected familieshave been described [185,186]. The attacks of urticarial rash, arthralgia and myalgia are typicallyprecipitated by exposure to cold and associated with a systemic inflammatory response.

It has been suggested that NLRP12 is a negative regulator of NF-kB [187] and that the mutatedprotein 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 anakinrahas 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 toassociation with another pathology, but clinically mimic HPFs are Periodic fever Aphthous stomatitisand Pharyngitis (PFAPA) and Schnitzler’s 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 3–8weeks) of fever lasting 3–6 days, which is associated with aphthous stomatitis, sterile pharyngitis andcervical adenitis and, according to the original set of diagnostic criteria, the first episode should occurbefore the age of 5 years. Although patients with PFAPA can have a positive family history [190], a cleargenetic basis for this condition has not been identified. However, some patients with classic HPFs fitinto diagnostic criteria for PFAPA [191], therefore, there should be a high index of suspicion and a lowthreshold for considering genetic testing for known monogenic HPFs in patients with PFAPA.

The pathogenesis of PFAPA remains unclear but peripheral cell and gene expression profilingstudies suggest involvement of both innate and adaptive immune responses [192]. These suggest thatduring the flares there is environmentally triggered complement and IL-1b/18 axis activation andinduction of TH1-chemokines leading to retention of activated T cells in peripheral tissues [193].

Based on thesefindings IL-1b inhibitionwith anakinrawasusedonfivepatientswith acute attackswithgood effect [193]. Other treatment options for PFAPA include one to three doses of corticosteroids(usually w 1 mg kg�1 prednisolone per dose), which are generally effective in aborting a flare, but mayshorten the asymptomatic intervals [194]. In fact, rapid responsiveness to steroid is so typical of PFAPA thatthis characteristic has been suggested to be a part of diagnostic criteria [195]. Another medical therapywhich showed effectiveness in PFAPA is the H2 blocker cimetidine [194]. Although tonsillectomy or ade-notonsillectomy canpotentially be curative in treatment of PFAPA, their precise role in themanagement ofthis condition is still under deliberation. Twomost recentmeta-analysis do not provide sufficient evidenceto support the routine use of tonsillectomy or adenotonsillectomy over medical treatment [196,197].

Schnitzler’s syndrome is a rare disease presenting in adults with fevers, chronic urticarial rash, bonepain hyperostosis and lymphadenopathy associated with monoclonal paraprotein, usually of IgMisotype [198]. A proportion of patients (20%) will develop overt plasma cell malignancy. Inflammatorysymptoms seem to respond readily to anakinra [199–201] without affecting paraprotein levels.

Conclusions

Since it was first introduced over a decade ago, autoinflammation has gone from being a somewhathypothetical concept to a recognised term that embodies an expanding area of clinical practice and

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533524

medical research. Although the principles of autoinflammation are most clearly evident in the path-ogenesis of rare monogenic diseases of the innate immunity, it is the study and understanding of theseconditions that has brought us closer to a better understanding of the inflammatory processes thatunderpin some more common conditions that have a wider impact on the human health. This isparticularly timely in the current climate of rapid medical development in the field of targeted bio-logics therapies, which might help us transform how we approach and treat these conditions.

Practice points

� Monogenic autoinflammatory diseases are rare and the majority present in childhood.� Autoinflammatory diseases are predominantly characterised by involvement of the innateimmune system in their pathogenesis.

� Among other classification criteria used to define these conditions include the principalimmunopathogenic mechanisms involved and clinical manifestations.

� Targeted anti-IL-1 biologics are extremely efficacious in treatment of CAPS and are alsoproving to be effective in a number of other monogenic autoinflammatory diseases, includingTRAPS and HIDS to a lesser extent.

� IL-1 receptor antagonist, which inhibits both IL-1a and IL-1b, is the specific therapy for DIRA.� Anti-TNF therapy is the treatment of choice for a number of polygenic autoinflammatorydiseases, including AS, CD and psoriasis.

Research agenda

� Anti-IL-6 directed therapy may be beneficial in treatment of TRAPS, based on the immuno-pathology of this condition and one preliminary study, but further studies are necessary inlarger numbers of patients.

� The relevance of IL-1b-dependent skewing of T-helper response towards Th17 phenotype inCAPS patients.

� Although a plethora of activators have been described for the NLRP3 inflammasome, theactual ligand(s) remain unknown.

� Further development of novel therapies is necessary for autoinflammatory diseases; potentialareas of development include small molecules that can either activate or inhibit specificsignalling pathways and anti-oxidants as adjunct therapies.

� The interplay of the micro-organisms inhabiting the human body (the microbiome) andinnate and adaptive immune systems in the clinical phenotype of autoinflammatory condi-tions is likely to be an area of intense investigation in the future.

Conflict of interest statement

None of the authors has any conflicts of interest to declare.

Acknowledgements

S. Savic and M.F. McDermott are supported by Arthritis Research UK, M. Wittmann by the LeedsFoundation for Dermatological Research, andM.Wittmann andM.F. McDermott by the Biomedical andHealth Research Centre, University of Leeds. Partial funding by the NIHR-LMBRU.

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List of abbreviations

AMD age-related macular degenerationAP1 activator protein 1APC antigen presenting cellsAS ankylosing spondylitisASC apoptosis-associated speck-like protein containing a CARDATF4 activating transcription factor 4ATP adenosine triphosphateCANDLE chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatureCAPS cryopyrin-associated periodic fevers syndromesCARD15 caspase recruitment domain-containing protein 15CCL Chemokine (C-C motif) ligandCD Crohn’s diseaseCGD chronic granulomatous diseaseCHOP CCAAT/-enhancer-binding protein homologous proteinCINCA chronic infantile neurological cutaneous articular syndromeCTLA4 cytotoxic T-lymphocyte antigen-4CXCL10 C-X-C motif chemokine 1DAMPS danger-associated molecular patternsDIRA Deficiency of the IL-1 receptor antagonistDITRA deficiency in thirty-six receptor antagonisteIF2a eukaryotic Initiation Factor 2aER endoplasmic reticulumERK extracellular-signal-regulated kinaseESR erythrocyte sedimentation rateETC electron transport chainFCAS familial cold autoinflammatory syndromeFCU familial cold urticariaFMF familial Mediterranean feverGWAS genome wide association studiesHIDS Hyperimmunoglobulinaemia D with periodic fever syndromeHLA human leukocyte antigenHPF hereditary periodic feversIAPP islet amyloid polypeptideIDC immunologic disease continuumIFNg interferon gammaIL interleukinIL-1Ra IL-1 receptor antagonistIL-18BP IL-18 binding proteinIL-36RA IL-36 receptor antagonistIkB inhibitor of kBIP-10 IFNg-inducible protein 10JMP joint contractures, muscle atrophy, microcytic anaemia, and panniculitis-induced

childhood-onset lipodystrophyJNK c-Jun N-terminal kinasesLPS lipopolysaccharideMAPK mitogen-activated protein kinase; MCP-1, monocyte chemotactic protein 1MDP muramyl dipeptide

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MEFV Mediterranean feverMHC major histocompatibility complexmROS mitochondrial-derived ROSmTNF membrane bound TNFMVK mevalonate kinaseMWS Muckle–Wells syndromeNADPH nicotinamide adenine dinucleotide phosphateNAPS12 NLRP12-associated periodic syndromeNF-kB NF-kappaBNLRP3 Nod-like receptor family, pyrin domain-containing protein 3NNS Nakajo-Nishimura syndromeNOD2 nucleotide-binding oligomerization domain-containing protein 2NOMID neonatal-onset multisystemic inflammatory diseaseNOX NADPH oxidasePAMPS pathogen-associated molecular patternsPERK protein kinase-like ER kinasePI protease inhibitorsPsA psoriatic arthritisPSORS1 psoriasis susceptibility locus 1PSORS2 psoriasis susceptibility locus 2PTPN22 protein tyrosine phosphatase, non-receptor type 22PYD pyrin domainRANTES regulated upon activation, normal T-cell expressed, and secretedROS reactive oxygen speciesRPE retinal pigment epitheliumsJIA systemic juvenile idiopathic arthritisSLE systemic lupus erythematosusSTAT-1 signal transducer and activator of transcription-1sTNF soluble form of TNF; sTNFR1, soluble TNFR1sXBP1 spliced X-box binding protein 1TACE TNF-a converting enzyme (a disintegrin and metalloprotease domain 17 (ADAM17))T2D type 2 diabetesTLR4 Toll-like receptor-4TNF tumour necrosis factorTRADD TNFR-associated death domain proteinTRAF6 TNF receptor-associated factor 6TRAPS TNF receptor-associated periodic fever syndromeTXNIP thioredoxin-interacting proteinUPR unfolded protein responseuXBP1 unspliced XBP1

References

[1] Reimann HA. Periodic disease; a probable syndrome including periodic fever, benign paroxysmal peritonitis, cyclicneutropenia and intermittent arthralgia. Journal of American Medical Association 1948;136(4):239–44.

[2] Heller H, Sohar E, Sherf L. Familial Mediterranean fever. American Medical Association Archives of Internal Medicine1958;102(1):50–71.

[3] Williamson LM, Hull D, Mehta R, Reeves WG, Robinson BH, Toghill PJ. Familial Hibernian fever. Quarterly Journal ofMedicine 1982;51(204):469–80.

[4] Kile RL. RH: a case of cold urticaria with an unusual family history. Journal of American Medical Association 1940;114:1067–8.

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533 527

[5] Muckle TJ. Wellsm: urticaria, deafness, and amyloidosis: a new heredo-familial syndrome. Quarterly Journal ofMedicine 1962;31:235–48.

[6] Prieur AM, Griscelli C. Arthropathy with rash, chronic meningitis, eye lesions, and mental retardation. Journal ofPediatrics 1981;99(1):79–83.

[7] Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nature Genetics 2001;29(3):301–5.

[8] Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, et al. Chronic infantile neurological cutaneous andarticular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells andchondrocytes. American Journal of Human Genetics 2002;71(1):198–203.

[9] van der Meer JW, Vossen JM, Radl J, van Nieuwkoop JA, Meyer CJ, Lobatto S, et al. Hyperimmunoglobulinaemia D andperiodic fever: a new syndrome. Lancet 1984;1(8386):1087–90.

[10] Drenth JP, Cuisset L, Grateau G, Vasseur C, van de Velde-Visser SD, de Jong JG, et al. Mutations in the gene encodingmevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. NatureGenetics 1999;22(2):178–81.

[11] Houten SM, Kuis W, Duran M, de Koning TJ, van Royen-Kerkhof A, Romeijn GJ, et al. Mutations in MVK, encodingmevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nature Genetics 1999;22(2):175–7.

*[12] McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, et al. Germline mutations in theextracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatorysyndromes. Cell 1999;97(1):133–44.

[13] Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology ofautoinflammatory disease. Annual Review of Immunology 2009;27:621–68.

[14] Savic S, Dickie LJ, Battellino M, McDermott MF. Familial Mediterranean fever and related periodic fever syndromes/autoinflammatory diseases. Current Opinion in Rheumatology 2012;24(1):103–12.

*[15] McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLoS Medicine 2006;3(8):e297.[16] Gul A. Behcet’s disease as an autoinflammatory disorder. Current Drug Targets Inflammation and Allergy 2005;4(1):

81–3.*[17] Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflam-

masome. Nature 2006;440(7081):237–41.[18] Kastner DL, Aksentijevich I, Goldbach-Mansky R. Autoinflammatory disease reloaded: a clinical perspective. Cell 2010;

140(6):784–90.[19] Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with

susceptibility to Crohn’s disease. Nature 2001;411(6837):603–6.[20] Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, et al. Association of NOD2 leucine-rich repeat

variants with susceptibility to Crohn’s disease. Nature 2001;411(6837):599–603.[21] Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, et al. A genome-wide association scan of nonsynonymous

SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genetics 2007;39(2):207–11.[22] Brest P, Lapaquette P, Souidi M, Lebrigand K, Cesaro A, Vouret-Craviari V, et al. A synonymous variant in IRGM alters

a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn’s disease. Nature Genetics2011;43(3):242–5.

[23] Cho JH, Brant SR. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology 2011;140(6):1704–12.

[24] Taylor KD, Targan SR, Mei L, Ippoliti AF, McGovern D, Mengesha E, et al. IL23R haplotypes provide a large populationattributable risk for Crohn’s disease. Inflammatory Bowel Diseases 2008;14(9):1185–91.

[25] Reveille JD, Sims AM, Danoy P, Evans DM, Leo P, Pointon JJ, et al. Genome-wide association study of ankylosingspondylitis identifies non-MHC susceptibility loci. Nature Genetics 2010;42(2):123–7.

[26] Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, et al. Genome-wide scan reveals association of psoriasis withIL-23 and NF-kappaB pathways. Nature Genetics 2009;41(2):199–204.

[27] Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C, et al. Genome-wide association study identifiesvariants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet’s disease. Nature Genetics 2010;42(8):698–702.

[28] Lees CW, Barrett JC, Parkes M, Satsangi J. New IBD genetics: common pathways with other diseases. Gut 2011;60(12):1739–53.

[29] McGonagle D, Aziz A, Dickie LJ, McDermott MF. An integrated classification of pediatric inflammatory diseases, basedon the concepts of autoinflammation and the immunological disease continuum. Pediatric Research 2009;65(5 Pt 2):38R–45R.

[30] Rossi-Semerano L, Kone-Paut I. Is Still’s disease an autoinflammatory syndrome? International Journal of Inflamma-tion 2012;2012:480373.

[31] Ambarus C, Yeremenko N, Tak PP, Baeten D. Pathogenesis of spondyloarthritis: autoimmune or autoinflammatory?Current Opinion in Rheumatology 2012;24(4):351–8.

[32] Dinarello CA. A clinical perspective of IL-1beta as the gatekeeper of inflammation. European Journal of Immunology2011;41(5):1203–17.

[33] Okusawa S, Gelfand JA, Ikejima T, Connolly RJ, Dinarello CA. Interleukin 1 induces a shock-like state in rabbits.Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. Journal of Clinical Investigation1988;81(4):1162–72.

[34] Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annual Review of Immunology2009;27:519–50.

[35] Ozkurede VU, Franchi L. Immunology in clinic review series; focus on autoinflammatory diseases: role of inflam-masomes in autoinflammatory syndromes. Clinical and Experimental Immunology 2012;167(3):382–90.

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533528

[36] Netea MG, Nold-Petry CA, Nold MF, Joosten LA, Opitz B, van der Meer JH, et al. Differential requirement for theactivation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages. Blood 2009;113(10):2324–35.

[37] Martinon F, Tschopp J. Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death andDifferentiation 2007;14(1):10–22.

[38] Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processinginflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 2004;20(3):319–25.

[39] Dowds TA, Masumoto J, Zhu L, Inohara N, Nunez G. Cryopyrin-induced interleukin 1beta secretion in monocytic cells:enhanced activity of disease-associated mutants and requirement for ASC. Journal of Biological Chemistry 2004;279(21):21924–8.

[40] Brydges SD, Mueller JL, McGeough MD, Pena CA, Misaghi A, Gandhi C, et al. Inflammasome-mediated disease animalmodels reveal roles for innate but not adaptive immunity. Immunity 2009;30(6):875–87.

[41] Meng G, Zhang F, Fuss I, Kitani A, Strober W. A mutation in the Nlrp3 gene causing inflammasome hyperactivationpotentiates Th17 cell-dominant immune responses. Immunity 2009;30(6):860–74.

[42] Renne J, Schafer V, Werfel T, Wittmann M. Interleukin-1 from epithelial cells fosters T cell-dependent skin inflam-mation. The British Journal of Dermatology 2010;162(6):1198–205.

[43] Ben-Sasson SZ, Hu-Li J, Quiel J, Cauchetaux S, Ratner M, Shapira I, et al. IL-1 acts directly on CD4 T cells to enhancetheir antigen-driven expansion and differentiation. Proceedings of the National Academy of Sciences U S A 2009;106(17):7119–24.

[44] Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, et al. An autoinflammatory diseasewith deficiency of the interleukin-1-receptor antagonist. The New England Journal of Medicine 2009;360(23):2426–37.

[45] Wittmann M, Bachmann M, Doble R, Pfeilschifter J, Werfel T, Müehl H. IL-27 regulates IL-18 binding protein in skinresident cells. Plos One 2012;7(6):e38751.

[46] Reddy S, Jia S, Geoffrey R, Lorier R, Suchi M, Broeckel U, et al. An autoinflammatory disease due to homozygousdeletion of the IL1RN locus. The New England Journal of Medicine 2009;360(23):2438–44.

*[47] Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, et al. Activation of the NLRP3 inflammasomeby islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nature Immunology2010;11(10):897–904.

[48] Villani AC, Lemire M, Fortin G, Louis E, Silverberg MS, Collette C, et al. Common variants in the NLRP3 regioncontribute to Crohn’s disease susceptibility. Nature Genetics 2009;41(1):71–6.

[49] Allen IC, TeKippe EM, Woodford RM, Uronis JM, Holl EK, Rogers AB, et al. The NLRP3 inflammasome functions asa negative regulator of tumorigenesis during colitis-associated cancer. Journal of Experimental Medicine 2010;207(5):1045–56.

[50] Zaki MH, Boyd KL, Vogel P, Kastan MB, Lamkanfi M, Kanneganti TD. The NLRP3 inflammasome protects against loss ofepithelial integrity and mortality during experimental colitis. Immunity 2010;32(3):379–91.

[51] van Heel DA, Ghosh S, Butler M, Hunt KA, Lundberg AM, Ahmad T, et al. Muramyl dipeptide and toll-like receptorsensitivity in NOD2-associated Crohn’s disease. Lancet 2005;365(9473):1794–6.

[52] Li J, Moran T, Swanson E, Julian C, Harris J, Bonen DK, et al. Regulation of IL-8 and IL-1beta expression in Crohn’sdisease associated NOD2/CARD15 mutations. Human Molecular Genetics 2004;13(16):1715–25.

[53] Zaki MH, Vogel P, Body-Malapel M, Lamkanfi M, Kanneganti TD. IL-18 production downstream of the Nlrp3 inflam-masome confers protection against colorectal tumor formation. Journal of Immunology 2010;185(8):4912–20.

[54] Keller M, Ruegg A, Werner S, Beer HD. Active caspase-1 is a regulator of unconventional protein secretion. Cell 2008;132(5):818–31.

[55] Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, Dinarello CA. IL-37 is a fundamental inhibitor of innateimmunity. Nature Immunology 2010;11(11):1014–22.

[56] Doyle SL, Campbell M, Ozaki E, Salomon RG, Mori A, Kenna PF, et al. NLRP3 has a protective role in age-related maculardegeneration through the induction of IL-18 by drusen components. Nature Medicine 2012.

[57] Kauppinen A, Niskanen H, Suuronen T, Kinnunen K, Salminen A, Kaarniranta K. Oxidative stress activates NLRP3inflammasomes in ARPE-19 cells - implications for age-related macular degeneration (AMD). Immunology Letters2012.

[58] Tarallo V, Hirano Y, Gelfand BD, Dridi S, Kerur N, Kim Y, et al. DICER1 loss and Alu RNA induce age-related maculardegeneration via the NLRP3 inflammasome and MyD88. Cell 2012;149(4):847–59.

[59] Wittmann M, Kingsbury SR, McDermott MF. Is caspase 1 central to activation of interleukin-1? Joint Bone Spine 2011;78(4):327–30.

[60] Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD, et al. Mutations in SPINK5, encoding a serineprotease inhibitor, cause Netherton syndrome. Nature Genetics 2000;25(2):141–2.

[61] Hosomi N, Fukai K, Nakanishi T, Funaki S, Ishii M. Caspase-1 activity of stratum corneum and serum interleukin-18level are increased in patients with Netherton syndrome. The British Journal of Dermatology 2008;159(3):744–6.

[62] Mitroulis I, Kambas K, Chrysanthopoulou A, Skendros P, Apostolidou E, Kourtzelis I. Neutrophil extracellular trapformation is associated with IL-1beta and autophagy-related signaling in gout. PLoS One 2011;6(12):e29318.

[63] Papin S, Cuenin S, Agostini L, Martinon F, Werner S, Beer HD, et al. The SPRY domain of Pyrin, mutated infamilial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1beta pro-cessing. Cell Death and Differentiation 2007;14(8):1457–66.

[64] Chae JJ, Wood G, Masters SL, Richard K, Park G, Smith BJ, et al. The B30.2 domain of pyrin, the familial Mediterraneanfever protein, interacts directly with caspase-1 to modulate IL-1beta production. Proceedings of the National Academyof Sciences U S A 2006;103(26):9982–7.

[65] Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterraneanfever. The International FMF Consortium. Cell 1997;90(4):797–807.

[66] Yu JW, Fernandes-Alnemri T, Datta P, Wu J, Juliana C, Solorzano L, et al. Pyrin activates the ASC pyroptosome inresponse to engagement by autoinflammatory PSTPIP1 mutants. Molecular Cell 2007;28(2):214–27.

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533 529

[67] Chae JJ, Wood G, Richard K, Jaffe H, Colburn NT, Masters SL, et al. The familial Mediterranean fever protein, pyrin, iscleaved by caspase-1 and activates NF-kappaB through its N-terminal fragment. Blood 2008;112(5):1794–803.

[68] Chae JJ, Komarow HD, Cheng J, Wood G, Raben N, Liu PP, et al. Targeted disruption of pyrin, the FMF protein, causesheightened sensitivity to endotoxin and a defect in macrophage apoptosis. Molecular Cell 2003;11(3):591–604.

[69] Aksentijevich I, Kastner DL. Genetics of monogenic autoinflammatory diseases: past successes, future challenges.Nature Reviews Rheumatology 2011;7(8):469–78.

[70] Chae JJ, Centola M, Aksentijevich I, Dutra A, Tran M, Wood G, et al. Isolation, genomic organization, and expressionanalysis of the mouse and rat homologs of MEFV, the gene for familial mediterranean fever. Mammalian Genome2000;11(6):428–35.

*[71] Chae JJ, Cho YH, Lee GS, Cheng J, Liu PP, Feigenbaum L, et al. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1beta activation and severe autoinflammation in mice. Immunity 2011;34(5):755–68.

[72] Marek-Yagel D, Berkun Y, Padeh S, Abu A, Reznik-Wolf H, Livneh A, et al. Clinical disease among patients heterozygousfor familial Mediterranean fever. Arthritis and Rheumatism 2009;60(6):1862–6.

[73] Kone-Paut I, Hentgen V, Guillaume-Czitrom S, Compeyrot-Lacassagne S, Tran TA, Touitou I. The clinical spectrum of 94patients carrying a single mutated MEFV allele. Rheumatology (Oxford) 2009;48(7):840–2.

[74] Imirzalioglu N, Dursun A, Tastan B, Soysal Y, Yakicier MC. MEFV gene is a probable susceptibility gene for Behcet’sdisease. Scandinavian Journal of Rheumatology 2005;34(1):56–8.

[75] Dursun A, Durakbasi-Dursun HG, Zamani AG, Gulbahar ZG, Dursun R, Yakicier C. Genetic analysis of MEFV gene pyrindomain in patients with Behcet’s disease. Mediators of Inflammation 2006;2006(3):41783.

[76] Ayesh S, Abu-Rmaileh H, Nassar S, Al-Shareef W, Abu-Libdeh B, Muhanna A, et al. Molecular analysis of MEFVgene mutations among Palestinian patients with Behcet’s disease. Scandinavian Journal of Rheumatology 2008;37(5):370–4.

[77] Esmaeili M, Bonyadi M, Khabbazi A, Ebrahimi AA, Sharif SK, Hajialilo M, et al. Common MEFV mutations in IranianAzeri Turkish patients with Behcet’s disease. Scandinavian Journal of Rheumatology 2011;40(5):383–6.

[78] Aganna E, Hawkins PN, Ozen S, Pettersson T, Bybee A, McKee SA, et al. Allelic variants in genes associated withhereditary periodic fever syndromes as susceptibility factors for reactive systemic AA amyloidosis. Genes andImmunity 2004;5(4):289–93.

[79] Fidder H, Chowers Y, Ackerman Z, Pollak RD, Crusius JB, Livneh A, et al. The familial Mediterranean fever (MEVF) geneas a modifier of Crohn’s disease. American Journal of Gastroenterology 2005;100(2):338–43.

[80] Wajant H, Scheurich P. TNFR1-induced activation of the classical NF-kappaB pathway. FEBS Journal 2011;278(6):862–76.

[81] Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell2003;114(2):181–90.

[82] Ermolaeva MA, Michallet MC, Papadopoulou N, Utermohlen O, Kranidioti K, Kollias G, et al. Function of TRADD intumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses. Nature Immunology 2008;9(9):1037–46.

[83] Chan FK. Three is better than one: pre-ligand receptor assembly in the regulation of TNF receptor signaling. Cytokine2007;37(2):101–7.

[84] Black RA. Tumor necrosis factor-alpha converting enzyme. International Journal of Biochemistry and Cell Biology2002;34(1):1–5.

[85] Aderka D, Engelmann H, Maor Y, Brakebusch C, Wallach D. Stabilization of the bioactivity of tumor necrosis factor byits soluble receptors. Journal of Experimental Medicine 1992;175(2):323–9.

[86] Aganna E, Hammond L, Hawkins PN, Aldea A, McKee SA, van Amstel HK, et al. Heterogeneity among patients withtumor necrosis factor receptor-associated periodic syndrome phenotypes. Arthritis and Rheumatism 2003;48(9):2632–44.

[87] Drewe E, Huggins ML, Morgan AG, Cassidy MJ, Powell RJ. Treatment of renal amyloidosis with etanercept in tumournecrosis factor receptor-associated periodic syndrome. Rheumatology (Oxford) 2004;43(11):1405–8.

[88] Nowlan ML, Drewe E, Bulsara H, Esposito N, Robins RA, Tighe PJ, et al. Systemic cytokine levels and the effects ofetanercept in TNF receptor-associated periodic syndrome (TRAPS) involving a C33Y mutation in TNFRSF1A. Rheu-matology (Oxford) 2006;45(1):31–7.

[89] Cantarini L, Lucherini OM, Galeazzi M, Fanti F, Simonini G, Baldari CT, et al. Tumour necrosis factor receptor-associatedperiodic syndrome caused by a rare mutation in the TNFRSF1A gene, and with excellent response to etanercepttreatment. Clinical and Experimental Rheumatology 2009;27(5):890–1.

[90] Quillinan N, Mannion G, Mohammad A, Coughlan R, Dickie LJ, McDermott MF, et al. Failure of sustained response toetanercept and refractoriness to anakinra in patients with T50M TNF-receptor-associated periodic syndrome. Annalsof the Rheumatic Diseases 2011;70(9):1692–3.

[91] Yousaf N, Gould DJ, Aganna E, Hammond L, Mirakian RM, Turner MD, et al. Tumor necrosis factor receptor I frompatients with tumor necrosis factor receptor-associated periodic syndrome interacts with wild-type tumor necrosisfactor receptor I and induces ligand-independent NF-kappaB activation. Arthritis and Rheumatism 2005;52(9):2906–16.

[92] Churchman SM, Church LD, Savic S, Coulthard LR, Hayward B, Nedjai B, et al. A novel TNFRSF1A splice mutationassociated with increased nuclear factor kappaB (NF-kappaB) transcription factor activation in patients withtumour necrosis factor receptor associated periodic syndrome (TRAPS). Annals of the Rheumatic Diseases 2008;67(11):1589–95.

[93] Nedjai B, Hitman GA, Yousaf N, Chernajovsky Y, Stjernberg-Salmela S, Pettersson T, et al. Abnormal tumor necrosisfactor receptor I cell surface expression and NF-kappaB activation in tumor necrosis factor receptor-associatedperiodic syndrome. Arthritis and Rheumatism 2008;58(1):273–83.

[94] Simon A, Park H, Maddipati R, Lobito AA, Bulua AC, Jackson AJ, et al. Concerted action of wild-type and mutant TNFreceptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. Proceedings of the NationalAcademy of Sciences U S A 2010;107(21):9801–6.

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533530

*[95] Bulua AC, Simon A, Maddipati R, Pelletier M, Park H, Kim KY, et al. Mitochondrial reactive oxygen species promoteproduction of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). Journal ofExperimental Medicine 2011;208(3):519–33.

[96] Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, et al. Sequence variants in the autophagy geneIRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nature Genetics 2007;39(7):830–2.

[97] Cloonan SM, Choi AM. Mitochondria: commanders of innate immunity and disease? Current Opinion in Immunology2012;24(1):32–40.

[98] Lobito AA, Kimberley FC, Muppidi JR, KomarowH, Jackson AJ, Hull KM, et al. Abnormal disulfide-linked oligomerizationresults in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS).Blood 2006;108(4):1320–7.

[99] Todd I, Radford PM, Draper-Morgan KA, McIntosh R, Bainbridge S, Dickinson P, et al. Mutant forms of tumour necrosisfactor receptor I that occur in TNF-receptor-associated periodic syndrome retain signalling functions but showabnormal behaviour. Immunology 2004;113(1):65–79.

[100] Rebelo SL, Bainbridge SE, Amel-Kashipaz MR, Radford PM, Powell RJ, Todd I, et al. Modeling of tumor necrosis factorreceptor superfamily 1A mutants associated with tumor necrosis factor receptor-associated periodic syndromeindicates misfolding consistent with abnormal function. Arthritis and Rheumatism 2006;54(8):2674–87.

*[101] Dickie LJ, Aziz AM, Savic S, Lucherini OM, Cantarini L, Geiler J, et al. Involvement of X-box binding protein 1 andreactive oxygen species pathways in the pathogenesis of tumour necrosis factor receptor-associated periodicsyndrome. Annals of the Rheumatic Diseases 2012.

[102] Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annual Review of Biochemistry 2005;74:739–89.*[103] Martinon F, Chen X, Lee AH, Glimcher LH. TLR activation of the transcription factor XBP1 regulates innate immune

responses in macrophages. Nature Immunology 2010;11(5):411–8.[104] Lee J, Sun C, Zhou Y, Gokalp D, Herrema H, Park SW, et al. p38 MAPK-mediated regulation of Xbp1s is crucial for

glucose homeostasis. Nature Medicine 2011;17(10):1251–60.[105] Liu Y, Adachi M, Zhao S, Hareyama M, Koong AC, Luo D, et al. Preventing oxidative stress: a new role for XBP1. Cell

Death and Differentiation 2009;16(6):847–57.[106] Arima K, Kinoshita A, Mishima H, Kanazawa N, Kaneko T, Mizushima T, et al. Proteasome assembly defect due to

a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimurasyndrome. Proceedings of the National Academy of Sciences U S A 2011;108(36):14914–9.

[107] Goldbach-Mansky R. Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenicautoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1. ClinicalExperimental Immunology 2012;167(3):391–404.

[108] Liu Y, Ramot Y, Torrelo A, Paller AS, Si N, Babay S, et al. Mutations in proteasome subunit beta type 8 cause chronicatypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic andphenotypic heterogeneity. Arthritis and Rheumatism 2012;64(3):895–907.

[109] Agarwal AK, Xing C, DeMartino GN, Mizrachi D, Hernandez MD, Sousa AB, et al. PSMB8 encoding the beta5i pro-teasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lip-odystrophy syndrome. American Journal of Human Genetics 2010;87(6):866–72.

[110] Kitamura A, Maekawa Y, Uehara H, Izumi K, Kawachi I, Nishizawa M, et al. A mutation in the immunoproteasomesubunit PSMB8 causes autoinflammation and lipodystrophy in humans. Journal of Clinical Investigation 2011;121(10):4150–60.

[111] Schmidtke G, Holzhutter HG, Bogyo M, Kairies N, Groll M, de Giuli R, et al. How an inhibitor of the HIV-I proteasemodulates proteasome activity. Journal of Biological Chemistry 1999;274(50):35734–40.

[112] Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, et al. Interleukin-36-receptor antagonist deficiency andgeneralized pustular psoriasis. The New England Journal of Medicine 2011;365(7):620–8.

[113] Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla V, et al. Mutations in IL36RN/IL1F5 areassociated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. AmericanJournal of Human Genetics 2011;89(3):432–7.

[114] Towne JE, Renshaw BR, Douangpanya J, Lipsky BP, Shen M, Gabel CA, et al. Interleukin-36 (IL-36) ligands requireprocessing for full agonist (IL-36alpha, IL-36beta, and IL-36gamma) or antagonist (IL-36Ra) activity. Journal of Bio-logical Chemistry 2011;286(49):42594–602.

[115] Mitsui H, Suarez-Farinas M, Belkin DA, Levenkova N, Fuentes-Duculan J, Coats I, et al. Combined use of laser capturemicrodissection and cDNA microarray analysis identifies locally expressed disease-related genes in focal regions ofpsoriasis vulgaris skin lesions. The Journal of Investigative Dermatology 2012;132(6):1615–26.

[116] Johnston A, Xing X, Guzman AM, Riblett M, Loyd CM, Ward NL, et al. IL-1F5, -F6, -F8, and -F9: a novel IL-1 familysignaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression. Journal ofImmunology 2011;186(4):2613–22.

[117] Blumberg H, Dinh H, Trueblood ES, Pretorius J, Kugler D, Weng N, et al. Opposing activities of two novel members ofthe IL-1 ligand family regulate skin inflammation. Journal of Experimental Medicine 2007;204(11):2603–14.

[118] Muhr P, Zeitvogel J, Heitland I, Werfel T, Wittmann M. Expression of interleukin (IL)-1 family members upon stimu-lation with IL-17 differs in keratinocytes derived from patients with psoriasis and healthy donors. The British Journalof Dermatology 2011;165(1):189–93.

[119] Jordan CT, Cao L, Roberson ED, Duan S, Helms CA, Nair RP, et al. Rare and common variants in CARD14, encoding anepidermal regulator of NF-kappaB, in psoriasis. American Journal of Human Genetics 2012;90(5):796–808.

[120] Jordan CT, Cao L, Roberson ED, Pierson KC, Yang CF, Joyce CE, et al. PSORS2 is due to mutations in CARD14. AmericanJournal of Human Genetics 2012;90(5):784–95.

[121] Towne J, Sims J. IL-36 in psoriasis. Current Opinion in Pharmacology 2012.[122] Carrier Y, Ma HL, Ramon HE, Napierata L, Small C, O'Toole M, et al. Inter-regulation of Th17 cytokines and the IL-36

cytokines in vitro and in vivo: implications in psoriasis pathogenesis. Journal of Investigative Dermatology 2011;131(12):2428–37.

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533 531

[123] Nograles KE, Brasington RD, Bowcock AM. New insights into the pathogenesis and genetics of psoriatic arthritis.Nature Clinical Practice Rheumatology 2009;5(2):83–91.

[124] Hebert HL, Ali FR, Bowes J, Griffiths CE, Barton A, Warren RB. Genetic susceptibility to psoriasis and psoriatic arthritis:implications for therapy. The British Journal of Dermatology 2012;166(3):474–82.

[125] Capon F, Barker JN. The quest for psoriasis susceptibility genes in the postgenome-wide association studies era:charting the road ahead. The British Journal of Dermatology 2012;166(6):1173–5.

[126] Nair RP, Stuart PE, Nistor I, Hiremagalore R, Chia NV, Jenisch S, et al. Sequence and haplotype analysis supports HLA-Cas the psoriasis susceptibility 1 gene. American Journal of Human Genetics 2006;78(5):827–51.

[127] Schroder K, Zhou R, Tschopp J. The NLRP3 inflammasome: a sensor for metabolic danger? Science 2010;327(5963):296–300.

[128] Pelegrin P, Surprenant A. Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gatedP2X7 receptor. The EMBO Journal 2006;25(21):5071–82.

[129] Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K, Roose-Girma M, et al. Cryopyrin activates the inflam-masome in response to toxins and ATP. Nature 2006;440(7081):228–32.

[130] Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate theNALP3 inflammasome through phagosomal destabilization. Nature Immunology 2008;9(8):847–56.

[131] Newman ZL, Leppla SH, Moayeri M. CA-074Me protection against anthrax lethal toxin. Infection and Immunology2009;77(10):4327–36.

[132] Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in theinnate immune response to amyloid-beta. Nature Immunology 2008;9(8):857–65.

[133] Dostert C, Guarda G, Romero JF, Menu P, Gross O, Tardivel A, et al. Malarial hemozoin is a Nalp3 inflammasomeactivating danger signal. PLoS One 2009;4(8):e6510.

*[134] Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflamma-some activation. Nature Immunology 2010;11(2):136–40.

[135] Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3inflammasome sensing of asbestos and silica. Science 2008;320(5876):674–7.

[136] Bauernfeind F, Bartok E, Rieger A, Franchi L, Nunez G, Hornung V. Cutting edge: reactive oxygen species inhibitorsblock priming, but not activation, of the NLRP3 inflammasome. Journal of Immunology 2011;187(2):613–7.

[137] van Bruggen R, Koker MY, Jansen M, van Houdt M, Roos D, Kuijpers TW, et al. Human NLRP3 inflammasome activationis Nox1-4 independent. Blood 2010;115(26):5398–400.

[138] West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, et al. TLR signalling augments macrophagebactericidal activity through mitochondrial ROS. Nature 2011;472(7344):476–80.

[139] Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature 2011;469(7329):221–5.

[140] Menu P, Mayor A, Zhou R, Tardivel A, Ichijo H, Mori K, et al. ER stress activates the NLRP3 inflammasome via an UPR-independent pathway. Cell Death and Disease 2012;3:e261.

[141] Deng J, Lu PD, Zhang Y, Scheuner D, Kaufman RJ, Sonenberg N, et al. Translational repression mediates activation ofnuclear factor kappa B by phosphorylated translation initiation factor 2. Molecular Cell Biology 2004;24(23):10161–8.

[142] Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH. Autocrine tumor necrosis factor alpha links endoplasmic reticulumstress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Molecular Cell Biology 2006;26(8):3071–84.

[143] Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, et al. Coupling of stress in the ER to activation of JNKprotein kinases by transmembrane protein kinase IRE1. Science 2000;287(5453):664–6.

[144] Pahl HL, Baeuerle PA. Activation of NF-kappa B by ER stress requires both Ca2þ and reactive oxygen intermediates asmessengers. FEBS Letters 1996;392(2):129–36.

[145] Colbert RA, DeLay ML, Klenk EI, Layh-Schmitt G. From HLA-B27 to spondyloarthritis: a journey through the ER.Immunological Reviews 2010;233(1):181–202.

[146] Hammer RE, Maika SD, Richardson JA, Tang JP, Taurog JD. Spontaneous inflammatory disease in transgenic ratsexpressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell 1990;63(5):1099–112.

[147] Turner MJ, Delay ML, Bai S, Klenk E, Colbert RA. HLA-B27 up-regulation causes accumulation of misfolded heavychains and correlates with the magnitude of the unfolded protein response in transgenic rats: implications for thepathogenesis of spondylarthritis-like disease. Arthritis and Rheumatism 2007;56(1):215–23.

[148] Qian BF, Tonkonogy SL, Sartor RB. Aberrant innate immune responses in TLR-ligand activated HLA-B27 transgenic ratcells. Inflammatory Bowel Diseases 2008;14(10):1358–65.

[149] DeLay ML, Turner MJ, Klenk EI, Smith JA, Sowders DP, Colbert RA. HLA-B27 misfolding and the unfolded proteinresponse augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis andRheumatism 2009;60(9):2633–43.

[150] Yeremenko N, Baeten D. IL-17 in spondyloarthritis: is the T-party over? Arthritis Research and Therapy 2011;13(3):115.[151] Appel H, Maier R, Wu P, Scheer R, Hempfing A, Kayser R, et al. Analysis of IL-17(þ) cells in facet joints of patients with

spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediatedadaptive immune response. Arthritis Research and Therapy 2011;13(3):R95.

[152] Feng B, Yao PM, Li Y, Devlin CM, Zhang D, Harding HP, et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nature Cell Biology 2003;5(9):781–92.

[153] Li Y, Schwabe RF, DeVries-Seimon T, Yao PM, Gerbod-Giannone MC, Tall AR, et al. Free cholesterol-loaded macrophagesare an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis. Journal of Biological Chemistry 2005;280(23):21763–72.

[154] Gargalovic PS, Gharavi NM, Clark MJ, Pagnon J, Yang WP, He A, et al. The unfolded protein response is an importantregulator of inflammatory genes in endothelial cells. Arteriosclerosis, Thrombosis and Vascular Biology 2006;26(11):2490–6.

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533532

[155] Rajamaki K, Lappalainen J, Oorni K, Valimaki E, Matikainen S, Kovanen PT, et al. Cholesterol crystals activate the NLRP3inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One2010;5(7):e11765.

[156] Lachmann HJ. Clinical immunology review series: an approach to the patient with a periodic fever syndrome. Clinicaland Experimental Immunology 2011;165(3):301–9.

[157] Piram M, Frenkel J, Gattorno M, Ozen S, Lachmann HJ, Goldbach-Mansky R, et al. A preliminary score for theassessment of disease activity in hereditary recurrent fevers: results from the AIDAI (auto-inflammatory diseasesactivity index) consensus conference. Annals of the Rheumatic Diseases 2011;70(2):309–14.

[158] Toplak N, Frenkel J, Ozen S, Lachmann HJ, Woo P, Kone-Paut I, et al. An international registry on autoinflammatorydiseases: the eurofever experience. Annals of the Rheumatic Diseases 2012;71(7):1177–82.

[159] Yenokyan G, Armenian HK. Triggers for attacks in familial Mediterranean fever: application of the case-crossoverdesign. American Journal of Epidemiology 2012;175(10):1054–61.

[160] Ozen S, Bilginer Y, Aktay Ayaz N, Calguneri M. Anti-interleukin 1 treatment for patients with familial Mediterraneanfever resistant to colchicine. Journal of Rheumatology 2011;38(3):516–8.

[161] Stankovic Stojanovic K, Delmas Y, Torres PU, Peltier J, Pelle G, Jeru I, et al. Dramatic beneficial effect of interleukin-1inhibitor treatment in patients with familial Mediterranean fever complicated with amyloidosis and renal failure.Nephrology Dialysis Transplantation 2012;27(5):1898–901.

[162] Hacihamdioglu DO, Ozen S. Canakinumab induces remission in a patient with resistant familial Mediterranean fever.Rheumatology (Oxford) 2012;51(6):1041.

[163] Ozcakar ZB, Yuksel S, Ekim M, Yalcinkaya F. Infliximab therapy for familial Mediterranean fever-related amyloidosis:case series with long term follow-up. Clinical Rheumatology 2012.

*[164] Hawkins PN, Lachmann HJ, McDermott MF. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome. TheNew England Journal of Medicine 2003;348(25):2583–4.

[165] Hoffman HM, Rosengren S, Boyle DL, Cho JY, Nayar J, Mueller JL, et al. Prevention of cold-associated acute inflam-mation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 2004;364(9447):1779–85.

[166] Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, et al. Neonatal-onset multisysteminflammatory disease responsive to interleukin-1beta inhibition. The New England Journal of Medicine 2006;355(6):581–92.

[167] Hoffman HM, Throne ML, Amar NJ, Sebai M, Kivitz AJ, Kavanaugh A, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlledstudies. Arthritis and Rheumatism 2008;58(8):2443–52.

[168] Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, et al. Use of canakinumab in thecryopyrin-associated periodic syndrome. The New England Journal of Medicine 2009;360(23):2416–25.

[169] Jesus AA, Oliveira JB, Aksentijevich I, Fujihira E, Carneiro-Sampaio MM, Duarte AJ, et al. TNF receptor-associatedperiodic syndrome (TRAPS): description of a novel TNFRSF1A mutation and response to etanercept. European Jour-nal of Pediatrics 2008;167(12):1421–5.

[170] Hull KMAI, Singh H, Dean J, Yarboro C, O’Shea JJ, Kastner DL. Efficacy of etanercept for the treatment of patients withTNF receptor associated periodic syndrome (TRAPS). Arthritis and Rheumatism 2003;48(Suppl.) [S378-Abstract 977].

[171] Drewe E, McDermott EM, Powell PT, Isaacs JD, Powell RJ. Prospective study of anti-tumour necrosis factor receptorsuperfamily 1B fusion protein, and case study of anti-tumour necrosis factor receptor superfamily 1A fusion protein, intumour necrosis factor receptor associated periodic syndrome (TRAPS): clinical and laboratory findings in a series ofseven patients. Rheumatology (Oxford) 2003;42(2):235–9.

[172] Jacobelli S, Andre M, Alexandra JF, Dode C, Papo T. Failure of anti-TNF therapy in TNF receptor 1-associated periodicsyndrome (TRAPS). Rheumatology (Oxford) 2007;46(7):1211–2.

[173] Simsek I, Kaya A, Erdem H, Pay S, Yenicesu M, Dinc A. No regression of renal amyloid mass despite remission ofnephrotic syndrome in a patient with TRAPS following etanercept therapy. Journal of Nephrology 2010;23(1):119–23.

[174] Church LD, Churchman SM, Hawkins PN, McDermott MF. Hereditary auto-inflammatory disorders and biologics.Springer Seminars in Immunopathology 2006;27(4):494–508.

[175] Nedjai B, Hitman GA, Quillinan N, Coughlan RJ, Church L, McDermott MF, et al. Proinflammatory action of the anti-inflammatory drug infliximab in tumor necrosis factor receptor-associated periodic syndrome. Arthritis and Rheu-matism 2009;60(2):619–25.

[176] Nedjai B, Quillinan N, Coughlan RJ, Church L, McDermott MF, Hitman GA, et al. Lessons from anti-TNF biologics:infliximab failure in a TRAPS family with the T50M mutation in TNFRSF1A. Advances in Experimental Medicine andBiology 2011;691:409–19.

[177] Krelenbaum M, Chaiton A. Successful treatment with infliximab of a patient with tumor necrosis factor-associatedperiodic syndrome (TRAPS) who failed to respond to etanercept. Journal of Rheumatology 2010;37(8):1780–2.

[178] Gattorno M, Pelagatti MA, Meini A, Obici L, Barcellona R, Federici S, et al. Persistent efficacy of anakinra in patientswith tumor necrosis factor receptor-associated periodic syndrome. Arthritis and Rheumatism 2008;58(5):1516–20.

[179] Vaitla PM, Radford PM, Tighe PJ, Powell RJ, McDermott EM, Todd I, et al. Role of interleukin-6 in a patient with tumornecrosis factor receptor-associated periodic syndrome: assessment of outcomes following treatment with the anti-interleukin-6 receptor monoclonal antibody tocilizumab. Arthritis and Rheumatism 2011;63(4):1151–5.

[180] Ammouri W, Cuisset L, Rouaghe S, Rolland MO, Delpech M, Grateau G, et al. Diagnostic value of serum immunoglo-bulinaemia D level in patients with a clinical suspicion of hyper IgD syndrome. Rheumatology (Oxford) 2007;46(10):1597–600.

[181] Stoffels M. SA: hyper-IgD syndrome or mevalonate kinase deficiency. Current Opinion in Rheumatology 2011[Epub ahead of print].

[182] van der Hilst JC, Bodar EJ, Barron KS, Frenkel J, Drenth JP, van der Meer JW, et al. Long-term follow-up, clinical features,and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore) 2008;87(6):301–10.

S. Savic et al. / Best Practice & Research Clinical Rheumatology 26 (2012) 505–533 533

[183] Bader-Meunier B, Florkin B, Sibilia J, Acquaviva C, Hachulla E, Grateau G, et al. Mevalonate kinase deficiency: a surveyof 50 patients. Pediatrics 2011;128(1):e152–9.

[184] Bodar EJ, Kuijk LM, Drenth JP, van der Meer JW, Simon A, Frenkel J. On-demand anakinra treatment is effective inmevalonate kinase deficiency. Annals of the Rheumatic Diseases 2011;70(12):2155–8.

[185] Jeru I, Duquesnoy P, Fernandes-Alnemri T, Cochet E, Yu JW, Lackmy-Port-Lis M, et al. Mutations in NALP12 causehereditary periodic fever syndromes. Proceedings of the National Academy of Sciences U S A 2008;105(5):1614–9.

[186] Borghini S, Tassi S, Chiesa S, Caroli F, Carta S, Caorsi R, et al. Clinical presentation and pathogenesis of cold-inducedautoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis and Rheumatism 2011;63(3):830–9.

[187] Lich JD, Williams KL, Moore CB, Arthur JC, Davis BK, Taxman DJ, et al. Monarch-1 suppresses non-canonical NF-kappaBactivation and p52-dependent chemokine expression in monocytes. Journal of Immunology 2007;178(3):1256–60.

[188] Jeru I, Le Borgne G, Cochet E, Hayrapetyan H, Duquesnoy P, Grateau G, et al. Identification and functional conse-quences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis and Rheumatism 2011;63(5):1459–64.

[189] Jeru I, Hentgen V, Normand S, Duquesnoy P, Cochet E, Delwail A, et al. Role of interleukin-1beta in NLRP12-associated autoinflammatory disorders and resistance to anti-interleukin-1 therapy. Arthritis and Rheumatism2011;63(7):2142–8.

[190] Cochard M, Clet J, Le L, Pillet P, Onrubia X, Gueron T, et al. PFAPA syndrome is not a sporadic disease. Rheumatology(Oxford) 2010;49(10):1984–7.

[191] Gattorno M, Caorsi R, Meini A, Cattalini M, Federici S, Zulian F, et al. Differentiating PFAPA syndrome from monogenicperiodic fevers. Pediatrics 2009;124(4):e721–8.

[192] Brown KL, Wekell P, Osla V, Sundqvist M, Savman K, Fasth A, et al. Profile of blood cells and inflammatory mediators inperiodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. BMC Pediatrics 2010;10:65.

[193] Stojanov S, Lapidus S, Chitkara P, Feder H, Salazar JC, Fleisher TA, et al. Periodic fever, aphthous stomatitis, pharyngitis,and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. Proceedings ofthe National Academy of Sciences U S A 2011;108(17):7148–53.

[194] Feder HM, Salazar JC. A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatrica 2010;99(2):178–84.

[195] Padeh S, Brezniak N, Zemer D, Pras E, Livneh A, Langevitz P, et al. Periodic fever, aphthous stomatitis, pharyngitis, andadenopathy syndrome: clinical characteristics and outcome. Journal of Pediatrics 1999;135(1):98–101.

[196] Peridis S, Pilgrim G, Koudoumnakis E, Athanasopoulos I, Houlakis M, Parpounas K. PFAPA syndrome in children:a meta-analysis on surgical versus medical treatment. International Journal of Pediatric Otorhinolaryngology 2010;74(11):1203–8.

[197] Garavello W, Pignataro L, Gaini L, Torretta S, Somigliana E, Gaini R. Tonsillectomy in children with periodic fever withaphthous stomatitis, pharyngitis, and adenitis syndrome. Journal of Pediatrics 2011;159(1):138–42.

[198] Soubrier M. Schnitzler syndrome. Joint Bone Spine 2008;75(3):263–6.[199] Dybowski F, Sepp N, Bergerhausen HJ, Braun J. Successful use of anakinra to treat refractory Schnitzler’s syndrome.

Clinical Experimental Rheumatology 2008;26(2):354–7.[200] Besada E, Nossent H. Dramatic response to IL1-RA treatment in longstanding multidrug resistant Schnitzler’s

syndrome: a case report and literature review. Clinical Rheumatology 2010;29(5):567–71.[201] Gran JT, Midtvedt O, Haug S, Aukrust P. Treatment of Schnitzler’s syndrome with anakinra: report of three cases and

review of the literature. Scandinavian Journal of Rheumatology 2011;40(1):74–9.