http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(3): 381–389 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.843755

REVIEW ARTICLE

Working the endless puzzle of hereditary autoinflammatory disorders

Mod Rheumatol Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/12/14 For personal use only.

Francesco Caso1*, Luca Cantarini2*, Orso Maria Lucherini2, Paolo Sfriso1, Maria Fioretti3, Luisa Costa1, Antonio Vitale2, Mariangela Atteno4, Mauro Galeazzi2, Isabella Muscari2, Flora Magnotti2, Bruno Frediani2, Leonardo Punzi1, and Donato Rigante3 1Rheumatology Unit, Department of Medicine, University of Padua, Padua, Italy, 2Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Rheumatology Unit, Policlinico Le Scotte, University of Siena, Siena, Italy, 3Institute of Pediatrics, Università Cattolica Sacro Cuore, Rome, Italy, and 4Rheumatology Unit, University of Naples “Federico II”, Naples, Italy

Abstract

Keywords

Hereditary autoinflammatory disorders encompass manifold dysfunctions of innate immunity caused by mutations in genes coding for the main characters of the inflammatory scene: most of these conditions have an early onset, ranging from the first days of life to the first decades, and include hereditary periodic fevers, NLRP-related diseases, granulomatous and pyogenic syndromes, which are basically characterized by upturned inflammasome activity and overproduction of bioactive interleukin (IL)-1β and other proinflammatory cytokines. The discovery of a causative link between autoinflammation and IL-1β release has improved our understanding of the intimate mechanisms of innate immunity, and has likewise led to the identification of extraordinary treatments for many of these disorders.

Amyloidosis, Hereditary autoinflammatory disorders, Inflammation, Recurrent fever, Interleukin-1 β History Received 7 March 2013 Accepted 26 April 2013 Published online 18 October 2013

Abbreviations TNF-α, tumor necrosis factor alpha; IL-6, interleukin-6; TLR4, toll-like receptor 4; IL1RN, interleukin 1 receptor antagonist; RIP2, receptor-interacting serine/threonine-protein kinase 2.

Introduction The group of hereditary autoinflammatory disorders (AID) is marked by inherited dysregulation of innate immunity and aberrant release of proinflammatory cytokines, with neither evidence of antigen-specific T lymphocytes, nor specific autoantibodies [1]. The innate immune system is critical in recognizing bacterial or viral infections and in evoking the assembly of inflammasomes, the intracellular multi-protein complexes which activate caspase-1 and lead to maturation, processing and secretion of a host of inflammatory molecules [2]. The heterogeneous clinical spectrum of hereditary AID is caused by different mutations in the genes involved in the regulation of inflammatory and apoptotic signals, mostly involving components of the inflammasome, cytokine receptors, or receptor antagonists, and culminating with the aberrant release of IL-1β, the outstanding pacesetter of cytokine overproduction in febrile attacks [3]. Figure 1 shows a synthetic representation of the genes responsible for hereditary autoinflammatory disorders, and Figure 2 summarizes their pathophysiology. At a clinical level, hereditary AID are mainly characterized by recurrent and apparently spontaneous inflammatory attacks with *F. Caso and L. Cantarini equally contributed to the preparation of this manuscript. Correspondence to: Luca Cantarini, MD, PhD, Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Rheumatology Unit, Policlinico Le Scotte, University of Siena, Viale Bracci 1, 53100 Siena, Italy. Tel: ⫹ 39 (0) 577 586776. Fax: ⫹ 39 (0) 577 40450. E-mail: [email protected]

fever and variable involvement of skin, serosal membranes, joints, lymph nodes, gut, eye, nervous system and seldom other body sites. In any of these disorders, clinical features can be more or less severe, and highly variable in frequency and duration [4], with laboratory findings showing increased serum inflammatory markers during each febrile attack [5]. With regard to pathogenesis, the term “autoinflammatory” derives from the prevalent spontaneous occurrence of febrile flares in most AID, but more recently several stimuli have been identified as potential mechanisms fueling the development of inflammation [6]. On the basis of clinical features, hereditary AID are represented by at least eleven diseases, which can be subdivided into four groups. (a) Hereditary periodic fevers, including familial mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and mevalonate kinase deficiency syndrome, also known as “hyper-immunoglobulinemia syndrome” (HIDS), which represent the three AID in which fever is the main clinical feature. (b) NLRP-related diseases, where NLR stands for “nucleotidebinding domain and leucine rich repeat containing family”, which is committed to detect microbial components in the cytosol and triggers the assembly of inflammasomes: this group encompasses the cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and chronic infantile neurological cutaneous and articular syndrome (CINCAs), and the NLRP12-associated autoinflammatory disorder (NLRP12AD, also known as familial cold autoinflammatory syndrome 2, FCAS2). All these conditions represent the four AID in which skin urticaria-like rash is the predominant clinical feature.

Mod Rheumatol Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/12/14 For personal use only.

382

F. Caso et al.

Mod Rheumatol, 2014; 24(3): 381–389

Figure 1. Synthetic representation of genes (A), sequence variants and exons (B) involved in the autoinflammatory disorders. Mutations in the MEFV, TNFRSF1A, MVK, NLRP3, NLRP12, NOD2, PSTPIP1 and IL1RN genes are responsible for familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), hyper-gammaglobulinemia D syndrome (HIDS), cryopyrin-associated periodic syndromes (CAPS), NLRP12-associated autoinflammatory disorder (NLRP12AD), Blau syndrome (BS), PAPA syndrome (PAPAs) and deficiency of IL-1 receptor antagonist (DIRA), respectively.

(c) Autoinflammatory granulomatous diseases, including Blau syndrome (BS), mainly characterized by noncaseating granulomatous inflammation. (d) Lastly, autoinflammatory pyogenic diseases, including PAPA syndrome (PAPAs), with the acronym standing for pyogenic arthritis, pyoderma gangrenosum and cystic acne, deficiency of IL-1 receptor antagonist (DIRA) and the rarest Majeed syndrome (MS). Hereditary AID are usually characterized by early onset, from the first weeks of life and childhood to the first decades, but adult onset has been described prevalently in FMF and TRAPS [7]. With the aim of improving genetic diagnosis in adulthood-onset AID, a diagnostic score has been identified and validated on a large number of patients at high risk of displaying FMF or TRAPS [8,9]. As there are no evidence-based studies and no guidance on which potential genotype analysis is the appropriate one to test, this review will discuss genetic, clinical and laboratory tests useful for an ideal diagnostic approach to AID.

Familial Mediterranean fever FMF (OMIM 249100) is the most common among AID, an autosomal recessive disease caused by mutations in the MEFV gene, located on the short arm of chromosome 16, composed of 10 exonic

sequences, and encoding the pyrin protein: the biological function of pyrin has been the subject of intensive research, revealing that it is mainly expressed in neutrophils and activated monocytes, but also in skin, peritoneum and synovial fibroblasts [10]. Pyrin binds apoptosis-associated speck-like protein with a caspase recruitment domain, which is an adaptor protein involved in the activation of caspase-1: loss-of-function MEFV mutations could potentially lead to autoinflammation by reducing the pyrin inhibitory role and enhancing IL-1β production at the inflammasome level [11]. However, other gain-of-function MEFV mutations can cause an autoinflammatory phenotype and give rise to a dominant-like pattern of inheritance for the disease [12]. To date, more than 200 MEFV mutations have been identified, mainly in people from the Mediterranean basin (Jews, Turks, Armenians, Arabs, Italians and North Africans), but the disease has nowadays been reported worldwide [13]. The classic FMF phenotype is characterized by recurrent and self-limited attacks of fever, variably associated with transient sterile serositis, synovitis or erysipelas-like rash, which usually start in the first decade. Each attack lasts typically 12–72 h, involving one or more body sites, but attack frequency is very irregular and varies from one episode every 2–4 weeks to one episode every 3 months. In some cases, a recurrent fever reaching peaks until 40°C might be the only clinical sign, mostly in children [14]. Abdominal

Mod Rheumatol Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/12/14 For personal use only.

DOI 10.3109/14397595.2013.843755

Hereditary autoinflammatory disorders and IL-1 inhibition

383

Figure 2. Schematic representation of the pathophysiology of the autoinflammatory disorders. Familial Mediterranean fever (FMF) and cryopyrinassociated periodic syndromes (CAPS) are due to mutations on pyrin and cryopirin genes, respectively, that lead to inflammasome activation, resulting in abnormal IL-1β production. In tumor necrosis factor receptor-associated periodic syndrome (TRAPS), the intracellular accumulation of mutated TNF receptors (named TNFRSF1A) leads to enhanced inflammatory response by endoplasmic reticulum (ER) stress response and increased mitochondrial (MT) levels of reactive oxygen species (ROS). Hyper-gammaglobulinemia D syndrome (HIDS) is associated with enhanced IL-1β production and inflammation by isoprenoid deficiency, due to mutations related to the gene encoding for the mevalonate kinase enzyme (MK). NLRP12-associated autoinflammatory disorder (NLRP12AD) and Blau syndrome (BS) are due to dysregulated function of the nuclear factor-kB (NFkB), through mutations on NLRP12 and NOD2 genes, respectively. PAPA syndrome (PAPAs) is related to PSTPIP1 mutations, leading to abnormal interaction between PSTPIP1, pyrin and caspase-1-activating inflammasome. Deficiency of the IL-1 receptor antagonist (DIRA) is due to mutations on the gene coding for IL-1 receptor antagonist (IL1RA), which lead to imbalance in the IL-1β-dependent inflammatory cascade. TNF-α, tumor necrosis factor alpha; IL-6, interleukin-6; TLR4, toll-like receptor 4; IL1RN, interleukin 1 receptor antagonist; RIP2, receptor-interacting serine/threonine-protein kinase 2.

pain occurs in more than 90% of patients and can represent the first sign of the disease. Other FMF frequent manifestations are pleurisy, usually unilateral in above 45% of cases, and pericarditis in 1% of cases. Monoarticular arthritis and arthralgias can be localized mainly at large joints in more than 50% of patients: the analysis of joint aspirates is sterile and shows a predominant amount of neutrophils [15]. In some cases, juvenile idiopathic arthritis, spondyloarthritides and rheumatoid arthritis have been described in overlap with FMF [16]. Erysipelas-like erythematosus rash is another clinical mark of FMF: this skin lesion has a short duration (of 12–48 h), and is characterized by a soft, warm, red area with

diameter of above 10–15 cm and localized on the extensor surface of legs or feet [17]. Other transient cutaneous signs which have been observed in FMF patients are different vasculitic syndromes involving all-sized vessels (as Henoch–Schöenlein purpura, polyarteritis nodosa and Takayasu’s arteritis) [18]. In rare cases, aseptic meningitis and severe protracted myalgia can be observed during the acute flare of the disease [19,20]. Inflammatory periods are characterized by elevation of acute phase proteins and various pleiotropic cytokines: we usually find increased erythrosedimentation rate (ESR), C-reactive protein (CRP), serum amyloid-A (SAA), fibrinogen or immunoglobulins A and D, combined with

Mod Rheumatol Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/12/14 For personal use only.

384

F. Caso et al.

neutrophilic leukocytosis, thrombocythemia and sometimes with anemia [21]. A subclinical inflammation detected on laboratory investigations can be at times demonstrated between inflammatory attacks, even if patients appear symptom free [22]. The risk of amyloidosis, due to the progressive production of the protein SAA and its deposition in different organs, represents the most dangerous long-term FMF complication: a secondary amyloidosis can occur also in patients without any inflammatory attacks, defining an FMF phenotype 2, in contrast to the classic overt phenotype 1 [23]. FMF diagnosis is centered on the Tel Hashomer criteria, which are divided into major and minor ones: major criteria are represented by (a) recurrent febrile episodes with peritonitis, pleurisy, pericarditis or synovitis, (b) AA amyloidosis in the absence of another predisposing disease and (c) good clinical response to daily administration of colchicine; minor criteria are represented by (a) recurrent febrile episodes, (b) erysipelas-like erythematous rash and (c) positive FMF family history in a first-degree relative [24]. The presence of two major criteria or the presence of one major criterion and two minor ones confirms the diagnosis of FMF, while the presence of one major and one minor criterion can only address toward a probable diagnosis. In this last case, especially for atypical cases or in low-prevalence ethnic groups, diagnosis can be supported by the presence of two MEFV mutations (in homozygosity or compound heterozygosity) by molecular analysis [25]. On the other hand, a clinical picture consistent with FMF in a patient carrying only one or no MEFV mutations does not exclude the disease. Among MEFV gene mutations, the most common of these, M694V (in the exon 10) in the homozygous state, correlates with an early clinical onset, severe joint involvement and higher risk of amyloidosis [26]. With regard to therapy, FMF rarely responds to nonsteroidal anti-inflammatory drugs and corticosteroids, even at high doses. Treatment of choice requires colchicine, with a single daily dose (ranging from 0.25 mg/day in children aged 1–2 years to 0.5 mg/day for those aged 3–6 years and 1–2 mg/day in the other ages) [27]. Colchicine is effective in reducing frequency, duration and intensity of FMF attacks and in reducing the risk of amyloidosis through multiple actions on the cytoskeleton, leukocyte chemotaxis and inflammasome [28]. However, there are nonresponder or intolerant patients, for whom anti-TNF blockers or IL-1 antagonists, as the IL-1 receptor antagonist anakinra (at the dose of 1–3 mg/kg/day by daily subcutaneous injection) or the human anti-IL-1β monoclonal antibody canakimumab (by subcutaneous administration once every 4–8 weeks), might be working therapeutic options, leading to the reversion of disease and normalization of acute phase reactants [29].

Tumor necrosis factor receptor-associated periodic syndrome TRAPS (OMIM 142680) is an autosomal dominantly inherited disease caused by missense mutations in the tumor necrosis factor (TNF) super family receptor 1A or p55-TNF receptor gene (named TNFRSF1A), located on the short arm of chromosome 12, encoding the 55-kD receptor of TNF [30]. To date, more than 90 TNFRSF1A mutations have been associated with TRAPS, the majority of which are localized in the first two N-terminal cysteine-rich domains CRD1 and CRD2: CRD1 is the pre-ligand binding assembly domain and is thought to mediate TNF receptor self-assembly, while CRD2 interacts with TNF-α in its trimeric form [31]. TRAPS-associated mutations are mostly single-nucleotide missense within exon 2, 3, 4 or 6, and encode for the extracellular region of the TNF receptor. About 50% of these mutations (known as “structural mutations”) involve cysteine residues, which have a crucial role for the intramolecular disulfide bonds and the three-dimensional structure of the receptor, and lead to an impaired conformation and stability of the receptor itself [32]. Other genetic TNFRSF1A variants are

Mod Rheumatol, 2014; 24(3): 381–389

caused by introduction or deletion of proline residues (P46L, L67P, S86P and R92P) or by hydrogen-bond stabilization of the receptor (T50M, I170N) [33]. In addition, several variants involving other residues, also called nonstructural mutations, are associated with milder clinical manifestations: among these, low-penetrance variants P46L and R92Q show distinctive clinical features and occur also in 1–5% of the general population [34]. Pathogenetic mechanisms leading to autoinflammation are still not clarified in TRAPS. Misfolding or impaired shedding of the mutant TNF receptor can cause a constitutive inflammatory state, through the secretion of proinflammatory cytokines as IL-1, IL-8 and IL-12, but other mutated TNF receptors aggregate in the cytoplasm, leading to increased mitochondrial production of reactive oxygen species and inflammasome activation [35]. At a clinical level, the disease is characterized by recurrent inflammatory attacks typically lasting from 1 to 3 weeks, recurring at least 2–6 times each year, often associated with abdominal complaint, muscle cramps or myalgia that migrate in a centrifugal pattern, arthralgias mainly affecting large joints, migratory erythematous plaques with underlying myalgia, periorbital edema, painful conjunctivitis and transient serosal inflammation [36]. The average age at disease onset is around 3 years, but cases diagnosed from infancy to late adulthood exist [37]. Myalgia displays centrifugal migration and is due to monocytic fasciitis [38]. In particular, TRAPS can be a cause of recurrent idiopathic pericarditis [39]. Patients with a positive family history of pericardial involvement or pericarditis refractory to standard therapy should be screened for TNFRSF1A mutations [40]. In TRAPS, laboratory tests commonly show increased ESR, CRP, fibrinogen, haptoglobin, white blood cell and platelet counts in the course of acute inflammatory episodes, which usually return to normal during nonacute phases. Also frequent is polyclonal hyper-gammaglobulinemia due to stimulation of immunoglobulin synthesis by numerous proinflammatory cytokines. Acute phase reactants might be elevated in patients with TRAPS even between febrile episodes, although at a lower level, but the most determinant laboratory element of the nonfebrile phase is the low serum level of the soluble receptor (less than 1 ng/ml) at least in a subset of patients with a defective release of TNF receptors from cell membranes [41]. Prognosis is mainly determined by the risk of renal amyloidosis: deposition of amino-terminal fragment of SAA in kidney in the form of amyloid fibrils might lead to the development of renal failure in about 25% of TRAPS patients, especially those who carry mutations involving cysteine residues. The measurement of SAA is a valid warning sign, as elevated concentrations are associated with a higher risk of progressive amyloid deposition in various parenchymas [42]. Molecular TNFRSF1A analysis (at least evaluating exons 2 and 5) is required for a specific diagnosis. Low-penetrance TNFRSF1A variants may cause oligosymptomatic TRAPS, and atypical inflammatory responses may contribute to adulthood-onset disease expression [43]. Adultonset TRAPS patients may present a phenotype that mimics other AID, such as FMF, even in terms of shortness of inflammatory attacks, leading to misdiagnosis and improper management [44]. There are patients who gain some symptomatic relief from highdose nonsteroidal anti-inflammatory drugs, while colchicine or immunomodulators such as methotrexate, cyclosporine and thalidomide produce little benefit. The identification of TNFRSF1A mutations as the genetic cause of TRAPS coincided with the wider use of biological agents in medicine and raised the possibility that blocking TNF could potentially represent a primary therapeutic goal in these patients. Anti-TNF therapy in TRAPS has been based on etanercept, a recombinant human p75-TNF receptor-Fc fusion protein, comprising two receptors linked by an IgG1-Fc fragment [45]. In contrast, the administration of other anti-TNF agents, such as infliximab, a mouse-human chimeric monoclonal IgG1 antibody to TNF, and adalimumab, a fully humanized anti-TNF

Mod Rheumatol Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/12/14 For personal use only.

DOI 10.3109/14397595.2013.843755

Hereditary autoinflammatory disorders and IL-1 inhibition

monoclonal antibody, have led to enhanced anti-apoptotic activity and oversecretion of proinflammatory cytokines, with paradoxical exacerbation of TRAPS clinical picture [46]. The efficacy of etanercept has been shown in a single patient and case-series of patients of different age with fully penetrant TRAPS phenotypes, as evidenced by decreased frequency of attacks or decreased severity of disease [47]. However, a decrease in responsiveness to etanercept over time has also been described, underscoring its nonspecific anti-inflammatory properties [48]. A significant number of TRAPS patients have needed to switch their therapy to anti-IL-1β therapy: anakinra has been shown to prevent disease relapses and induce a prompt disease remission [49]. Long-lasting drugs targeting IL-1, such as canakinumab, might overcome the need for daily injections [50]. Since IL-6 levels may be elevated in TRAPS, it has been hypothesized that tocilizumab, a humanized monoclonal antibody that binds specifically to both soluble and membrane-bound IL-6 receptors and inhibits IL-6 receptormediated signaling, might be effective [51].

are compound heterozygous for missense MVK mutations, and in above 90% of cases, the most reported one is the V377I, along with the same or a different mutation in the second allele, resulting in a reduced activity of the MK enzyme. The final diagnosis requires either MVK genotype analysis or the reduced MK activity demonstration [64]. Until today, there is no established effective therapy for HIDS. Nonsteroidal anti-inflammatory drugs and corticosteroids represent the most frequently therapeutic options used to mitigate HIDS inflammatory attacks. Therapy with colchicine, cyclosporine, methotrexate and thalidomide has shown total inefficacy in the control of the recurrence and intensity of attacks. Statins, and in particular simvastatin (20 mg/day), have been used with the aim of reducing the mevalonate production with a partial temporary success (since mevalonate is the product of the enzyme 3-hydroxy-3-methylglutarylcoenzyme A reductase) [65]. The use of biologic treatments in HIDS is still under evaluation: anti-TNF treatment (etanercept at the dose of 0.8 mg/kg once a week) has been proposed in few patients with partial efficacy [66]; IL-1 antagonists (as anakinra daily injections or canakinumab injections every 4–8 weeks) have been used, showing a remarkable efficacy in mitigating the severity of inflammatory attacks [67].

Hyper-immunoglobulinemia syndrome HIDS (OMIM 260920) is an autosomal recessive disease, caused by mutations in the MVK gene, located on the long arm of chromosome 12, encoding the enzyme mevalonate kinase (MK), which is qualitatively or quantitatively deficient, explaining why the disease has been renamed as “mevalonate kinase deficiency syndrome” [52]. MK is a peroxysomal enzyme involved in the ATP-dependent phosphorylation of mevalonic acid to 5-phosphomevalonate, a key molecule in the pathway of isoprenoids and cholesterol, and MVK mutations are responsible for a reduced enzymatic activity of MK, with subsequent dysrupted biosynthesis of isoprenoid and cholesterol and accumulation of mevalonic acid in plasma and urine [53]. Although the link between the metabolic abnormality and inflammasome involvement is poorly understood, it has been shown a concomitant role of IL-1 in the pathogenesis of the disease [54], making HIDS as a “double” syndrome in which metabolic and autoinflammatory aspects are intertwined. The rare total deficiency of MK is known as “mevalonic aciduria” (OMIM 610377) and is characterized by slightly reduced or normal ranges of serum cholesterol concentrations and a steady increase in urinary mevalonic acid, while it clinically gives recurrent febrile episodes, stunted growth, dysmorphic features, microcephaly, cerebellar atrophy, psychomotor retardation, ataxia, retinal dystrophy and cataract [55]. HIDS is indeed related to a partial deficiency of MK, and most patients have been initially recognized in Northern-Western Europe [56]: the disease usually begins at an early age (infancy or early childhood) with irregular recurrent inflammatory attacks consisting with high-grade fever, headache, mucosal aphthosis, gastrointestinal involvement (with pain, vomiting, and/or diarrhea), painful cervical or generalized lymphadenopathy, splenomegaly and skin rashes of polymorphic nature. Moreover, transient joint involvement can be present in above 60% of patients [57]. Febrile attacks generally have an average duration of 3–7 days, and occur every 4–6 weeks, being frequently triggered or precipitated by vaccinations, infections, menses, emotional and psychic stress. The frequency of attacks is higher during childhood and adolescence, with persistence into adulthood in a milder form [58]. Unlike other AID, amyloidosis is very rare in HIDS, although it has been described in few cases [59]. Other rare clinical features described in HIDS are B-cell cytopenia, chronic hepatitis with neonatal onset and recurrent pericarditis [60–62]. Laboratory findings in febrile flares show leucocytosis, increased ESR and CRP, while polyclonal IgD level might be increased (over 100 mg/L) in both the febrile and nonfebrile periods. IgA levels can be increased in over 80% of HIDS patients, and urinary mevalonic acid is usually increased during febrile attacks [63]. Most HIDS patients

385

Cryopyrin-associated periodic syndromes CAPS, also known as “cryopyrinopathies”, encompass a spectrum of three autosomal-dominantly inherited AID, mostly reported in the Caucasian population and starting in infancy [68]. Different clinical signs may vary from relatively mild to substantially severe ones, distinguishing a mildest form, FCAS, an intermediate form, MWS, and a severe form, CINCAs. All these three conditions are caused by different dominant inherited or de novo mutations in the NLRP3 gene, located on the long arm of chromosome 1: NLRP3 gene contains nine exons and encodes the inflammasome key-component cryopyrin (also named NLRP3) [69]. Unlike FCAS and MWS, which are familiar diseases, most cases of CINCAs are sporadic and no NLRP3 mutations can be demonstrated in approximately 40% of these patients [70]. Cryopyrin belongs to the family of the nucleotide-binding domain and leucine-rich proteins, acting as intracellular “sensors” of danger signals arising from cellular insults, such as infection, tissue damage and metabolic deregulation, and showing an essential role in the caspase-1 activation with final cleavage of proIL-1β into its mature form [71]. NLRP3 mutations lead to cryopyrins with gain-of-function, which generate an upregulated activation of the inflammasome with IL-1 overproduction [72]. Clinically, in all three conditions, we find a nonitching urticaria-like rash with neutrophilic infiltration, which usually represents the first clinical feature appraised. FCAS (OMIM 120100) generally has its onset in the first months of life and appears after exposure to cold environment or rapid changes in temperatures: inflammatory attacks of short duration (from 1–2 to 24 h) are characterized by fever, migratory rash, conjunctivitis, headache, fatigue, myalgia, arthralgia and joint stiffness. These attacks are self-limited with spontaneous resolution. Laboratory findings usually display increased inflammatory markers during febrile attacks. Sensorineural deafness is generally absent, while the occurrence of amyloidosis is infrequent [73]. MWS (OMIM 191900) starts in early childhood with periodically recurring or subcontinuous features, such as urticaria-like skin eruption, arthralgia or nonerosive polyarthritis, conjunctivitis and mild fever. Optic nerve atrophy and sensorineural deafness might be observed in adulthood. Trigger mechanisms, such as cold exposure, infections, physical, and/or emotional stress, might precipitate the clinical picture. In MWS patients, there is a relevant risk of developing amyloidosis, if the disease is disregarded [74]. CINCAs (OMIM 607115, also known as “neonatal onset multisystem inflammatory disease”, NOMID) can be considered as

Mod Rheumatol Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/12/14 For personal use only.

386

F. Caso et al.

the most severe phenotype of CAPS. A diffuse and changeable urticaria-like rash represents the most striking sign of CINCAs, which appears within a few days after birth [75]. Chronic aseptic meningitis with the presence of neutrophils in the cerebrospinal fluid can develop progressively during childhood. Other sporadic features are conjunctivitis, uveitis, papillitis, and optic nerve atrophy, progressive sensorineural hearing loss, combined with facial dysmorphisms, bony hypertrophy of growth plates, and deforming arthritis of knees [76]. AA amyloidosis leading to renal impairment can be a complication of the disease, occurring in about 20% of patients [77]. To date, more than 90 different NLRP3 mutations have been identified, the majority of which are localized in the exon 3, encoding the NBS domain of the cryopyrin protein, highly conserved throughout evolution, but even somatic mosaicism in pluripotent stem cells committed to hematopoietic progenitor stem cells or ectoderm-derived nonhematopoietic cells has been observed in several mutation-negative patients [78]. CAPS patients’ mononuclear cells secrete large amounts of IL-1β: the pivotal role of IL-1β has been demonstrated in several clinical studies using IL-1 blocking agents that led to rapid resolution of the inflammatory disease manifestations. Canakinumab has been recently registered for patients with CAPS (2–4 mg/kg by subcutaneous administration once in every 4–8 weeks according to the severity of the single patient), showing to be effective both in the control of symptoms and in the acute phase reactant levels [79].

NLRP12-associated autoinflammatory disorder NLRP12AD is a rare autosomal dominantly inherited disease caused by NLRP12 gene mutations, which cause an abnormal synthesis of NLRP12 protein (recently renamed “monarch 1”), which is another regulator of immunity against pathogens. Clinically, the disease is depicted by recurrent episodes of fever lasting from 5 to 10 days, skin rash triggered by cold exposure, headache, joint symptoms, lymphadenopathy and abdominal pain: very few patients have been reported, and successful treatment with corticosteroids, nonsteroidal anti-inflammatory drugs, and anakinra has been documented [80].

Granulomatous diseases BS (OMIM 186580) and early-onset sarcoidosis (OMIM 609464) are rare granulomatous AID, characterized by hyperactivation of chronic inflammatory response and a distinct triad of noncaseating joint, uveal tract and skin inflammatory lesions [81]. The first is an autosomal dominantly inherited disorder, due to mutations in the nucleotide-binding oligomerization domain 2 (NOD2 or CARD15) gene, mapped on the long arm of the chromosome 16, and the most commonly observed are missense substitutions affecting arginine residue at position 334 [82]. NOD2 encodes a multi-domain protein of 1040 amino acids, named NOD2, which is a member of the NOD-like receptor family, playing the role of general detector against invasive bacterial infections via nuclear factor-κB pathway, mainly expressed in the major components of granulomatous inflammation, as dendritic cells [83]. Clinically, BS is characterized by early-onset recurrent noncaseating granulomatous arthritis, uveitis and rash, though atypical manifestations involving kidney, heart, liver and pulmonary interstitium have been reported; onset occurs mostly with articular and cutaneous involvement, while eye symptoms typically appear between 7 and 12 years of age [84]. Joint manifestations are usually symmetric polyarthritides with painless tenosynovial cysts, involving wrists, metacarpo/metatarso-phalangeal, and proximal interphalangeal joints of hands and feet, ankles and occasionally elbows: the evolution toward “boutonnière finger deformities”, camptodactyly and decreased motion of large joints is largely reported [85]. Skin

Mod Rheumatol, 2014; 24(3): 381–389

manifestations are characterized by noncaseating granulomatous lesions with multinucleated giant cells and epithelioid cells with “comma-shaped bodies”, but the most relevant morbidity of BS is eye involvement, mostly in the form of recurrent granulomatous panuveitis, which can evolve into cataract, band keratopathy and chorioretinitis [86]. Treatment of BS is unscheduled and based on anecdotal experiences with nonsteroidal anti-inflammatory drugs, corticosteroids, immunosuppressant drugs, thalidomide or biologics. Corticosteroids in different dosages are generally effective in controlling most BS clinical features. In order to avoid the appearance of side-effects or in the case of insufficient response, additional treatment with immunosuppressive agents should be encouraged, and TNF-antagonists (infliximab) or IL-1 antagonists should be tried [87]. BS familial form needs to be differentiated from early-onset sarcoidosis, a sporadic multiorganic disease, histologically defined by noncaseating epithelioid granulomata of lung, lymph node and eye: histopathologic studies can reveal proliferating giant cells and epithelioid cells in the lesions, which are commonly observed in adult-onset sarcoidosis [88].

Pyogenic diseases Among pyogenic disorders belonging to hereditary AID, PAPAs (OMIM 604416) is a rare autosomal dominant inherited disease, starting in childhood, characterized by recurrent self-limited arthritis with accumulation of sterile and neutrophil-rich material in the joints, combined with severe skin involvement in terms of poorly healing pyoderma gangrenosum and nodulocystic acne, occasionally induced by traumas or insertion of central venous lines, and worsening with puberty [89]. The disease is caused by mutations in the CD2BP1 gene, encoding the CD2-binding protein 1 (also named PSTPIP1), a protein interacting with pyrin and caspase-1-activating inflammasome complexes [90]. Treatment of PAPAs is dependent on the dominant clinical sign: arthritides usually respond promptly to corticosteroids; pyoderma gangrenosum is usually treated with local immunosuppressant drugs, though a potential response to oral cortisteroids has been observed too; biological treatment with anti-TNF (infliximab and etanercept) or anti-IL1 blockers have shown efficacy on both joint and skin manifestations in some reports [91]. Transmitted with autosomal recessive inheritance, DIRA (OMIM 612852) is due to missense mutations in the IL1RN gene, leading to the deficiency of functional IL-1 receptor antagonist protein, and subsequent unbalanced IL-1 activity in the patient. Clinically, the disease is remarkably characterized by multifocal osteomyelitis and severe pustulosis with ichthyosis-like changes emerging in the neonatal period, mimicking a neonatal sepsis involving bones and skin, without fever and with persistently increased ESR and CRP. Treatment of DIRA requires the administration of IL-1 receptor antagonist, anakinra, at the dosage of 1 mg/ kg/day by daily subcutaneous administration, which gives a rapid clinical improvement within days or weeks [92]. Another very rare disease reported for the first time in 1989 in two brothers and one female cousin from Jordan is MS (OMIM 609628), mainly characterized by febrile attacks with recurrent early-onset multifocal osteomyelitis, congenital dyserythropoietic anemia and diffuse neutrophilic dermatosis. This is an autosomal recessive disease due to homozygous LPIN2 gene mutations, but the role of lipin 2 in the inflammatory circuits has not been clarified. Due to its rarity, treatment is empiric and based on nonsteroidal anti-inflammatory drugs and corticosteroids [93].

Conclusions Unfortunately there are no directives, ethical guidelines, evidencebased studies or clinical pathways to hold in patients with hereditary AID, mostly for decisions in the therapeutic management.

Mod Rheumatol Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/12/14 For personal use only.

DOI 10.3109/14397595.2013.843755

Hereditary autoinflammatory disorders and IL-1 inhibition

The most ominous complication of undiagnosed or neglected AID remains reactive AA amyloidosis, due to the progressive deposition of the amino-terminal fragment of amyloid fibrils in various organs [94]. It is highly encouraged to exclude a subclinical inflammation and monitorize the risk of a subtle latent amyloidosis through the evaluation of SAA, a 104-amino-acid protein synthesized and secreted by liver as a result of different proinflammatory stimuli during both inflammatory attacks and interfebrile intervals. Kidney is the main target organ in the deposition of amyloid fibrils, followed by the insidious onset of nephrotic syndrome and even chronic renal failure. If not effectively treated, amyloidosis invariably leads to end-stage kidney disease and renal replacement therapy, which are still associated with a poor outcome [95]. Other body sites involved in this process are liver, spleen, gastrointestinal tube, adrenal glands, and heart. Traditionally amyloidosis occurs in patients with an earlier and more severe clinical onset, but also in a minority of those without inflammatory attacks or no evidence of subclinical inflammation. Factors that contribute to the risk of amyloidosis include the duration and degree of SAA elevation, polymorphisms in the SAA gene and the type of AID [96]. Although corticosteroids and colchicine have been used for a long period, the most recent use of anti-cytokine therapies, in particular anti-IL-1β agents, has revolutionized the overall prognosis of hereditary AID and opened new horizons in the prevention of amyloidosis.

14. McDermott MF, Aksentijevich I. The autoinflammatory syndromes. Curr Opin Allergy Clin Immunol. 2002;2:511–6. 15. Savic S, Dickie LJ, Battellino M, McDermott MF. Familial Mediterranean fever and related periodic fever syndromes/autoinflammatory diseases. Curr Opin Rheumatol. 2012;24:103–12. 16. Akkoc N, Gul A. Familial Mediterranean fever and seronegative arthritis. Curr Rheumatol Rep. 2011;13:388–94. 17. Radakovic S, Holzer G, Tanew A. Erysipelas-like erythema as a cutaneous sign of familial Mediterranean fever: a case report and review of the histopathologic findings. J Am Acad Dermatol. 2013;68:e61–3. 18. Aksu K, Keser G. Coexistence of vasculitides with familial Mediterranean fever. Rheumatol Int. 2011;31:1263–74. 19. Karachaliou I, Karachalios G, Charalabopoulos A, Charalabopoulos K. Meningitis associated with familial Mediterranean fever. Int J Clin Pract Suppl. 2005;147:60–1. 20. Senel K, Melikoglu MA, Baykal T, Melikoglu M, Erdal A, Ugur M. Protracted febrile myalgia syndrome in familial Mediterranean fever. Mod Rheumatol. 2010;20:410–2. 21. Medlej-Hashim M, Loiselet J, Lefranc G, Mégarbané A. Familial Mediterranean Fever (FMF): from diagnosis to treatment. Sante. 2004;14:261–6. 22. Rigante D, Capoluongo E. The plodding diagnosis of monogenic autoinflammatory diseases in childhood: from the clinical scenery to laboratory investigation. Clin Chem Lab Med. 2011;49:783–91. 23. Altunoğlu A, Erten S, Canoz MB, Yuksel A, Ceylan GG, Balci S, et al. Phenotype 2 familial Mediterranean fever: evaluation of 22 case series and review of the literature on phenotype 2 FMF. Ren Fail. 2013;35:226–30. 24. Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40:1879–85. 25. Koné-Paut I, Hentgen V, Guillaume-Czitrom S, Compeyrot-Lacassagne S, Tran TA, Touitou I. The clinical spectrum of 94 patients carrying a single mutated MEFV allele. Rheumatology (Oxford). 2009;48:840–2. 26. Rigante D, La Torraca I, Ansuini V, Compagnone A, Sallì A, Stabile A. The multi-face expression of familial Mediterranean fever in the child. Eur Rev Med Pharmacol Sci. 2006;10:163–71. 27. Rigante D, La Torraca I, Avallone L, Pugliese AL, Gaspari S, Stabile A. The pharmacological basis of treatment with colchicine in children with familial Mediterranean fever. Eur Rev Med Pharmacol Sci. 2006;10:173–8. 28. Taskiran EZ, Cetinkaya A, Balci-Peynircioglu B, Akkaya YZ, Yilmaz E. The effect of colchicine on pyrin and pyrin interacting proteins. J Cell Biochem. 2012;113:3536–46. 29. Ozturk MA, Kanbay M, Kasapoglu B, Onat AM, Guz G, Furst DE, et al. Therapeutic approach to familial Mediterranean fever: a review update. Clin Exp Rheumatol. 2011;29(4 Suppl 67):S77–86. 30. Cantarini L, Lucherini OM, Muscari I, Frediani B, Galeazzi M, Brizi MG, et al. Tumour necrosis factor receptor-associated periodic syndrome (TRAPS): state of the art and future perspectives. Autoimmun Rev. 2012;12:38–43. 31. Chan FK, Chun HJ, Zheng L, Siegel RM, Bui KL, Lenardo MJ. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science. 2000;288:2351–4. 32. McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97:133–44. 33. Aksentijevich I, Galon J, Soares M, Mansfield E, Hull K, Oh HH, et al. The tumor-necrosis factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers. Am J Hum Genet. 2001;69:301–14. 34. Ravet N, Rouaghe S, Dodé C, Bienvenu J, Stirnemann J, Lévy P, et al. Clinical significance of P46L and R92Q substitutions in the tumor necrosis factor superfamily 1A gene. Ann Rheum Dis. 2006;65: 1158–62. 35. Turner MD, Chaudhry A, Nedjai B. Tumour necrosis factor receptor trafficking dysfunction opens the TRAPS door to pro-inflammatory cytokine secretion. Biosci Rep. 2012;32:105–12. 36. Dodé C, André M, Bienvenu T, Hausfater P, Pêcheux C, Bienvenu J, et al; French Hereditary Recurrent Inflammatory Disorder Study Group. The enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 2002;46:2181–8.

Conflict of interest None.

References 1. Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev. 2012;11:348–56. 2. Lamkanfi M, Dixit VM. Inflammasomes: guardians of cytosolic sanctity. Immunol Rev. 2009;227:95–105. 3. Kanazawa N. Rare hereditary autoinflammatory disorders: towards an understanding of critical in vivo inflammatory pathways. J Dermatol Sci. 2012;66:183–9. 4. Touitou I, Koné-Paut I. Autoinflammatory diseases. Best Pract Res Clin Rheumatol. 2008;22:811–29. 5. Cantarini L, Rigante D, Brizi MG, Lucherini OM, Sebastiani GD, Vitale A, et al. Clinical and biochemical landmarks in systemic autoinflammatory diseases. Ann Med. 2012;44:664–73. 6. Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–68. 7. Muscari I, Iacoponi F, Cantarini L, Lucherini OM, Simonini G, Brizi MG, et al. The diagnostic evaluation of patients with potential adult-onset autoinflammatory disorders: our experience and review of the literature. Autoimmun Rev. 2012;12:10–3. 8. Cantarini L, Lucherini OM, Iacoponi F, Cimaz R, Simonini G, Rigante D, et al. Development and preliminary validation of a diagnostic score for identifying patients affected with adult-onset autoinflammatory disorders. Int J Immunopathol Pharmacol. 2010;23:1133–41. 9. Cantarini L, Iacoponi F, Lucherini OM, Obici L, Brizi MG, Cimaz R, et al. Validation of a diagnostic score for the diagnosis of autoinflammatory diseases in adults. Int J Immunopathol Pharmacol. 2011;24:695–702. 10. Soriano A, Manna R. Familial Mediterranean fever: new phenotypes. Autoimmun Rev. 2012;12:31–7. 11. Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C, et al. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood. 2000;95:3223–31. 12. Chae JJ, Wood G, Richard K, Jaffe H, Colburn NT, Masters SL, et al. The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappaB through its N-terminal fragment. Blood. 2008;112:1794–803. 13. Ben-Chetrit E, Touitou I. The impact of MEFV gene identification on FMF: an appraisal after 15 years. Clin Exp Rheumatol. 2012;30 (3 Suppl 72):S3–6.

387

Mod Rheumatol Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/12/14 For personal use only.

388

F. Caso et al.

37. Rigante D, Cantarini L, Imazio M, Lucherini OM, Sacco E, Galeazzi M, et al. Autoinflammatory diseases and cardiovascular manifestations. Ann Med. 2011;43:341–6. 38. Hull KM, Wong K, Wood GM, Chu WS, Kastner DL. Monocytic fasciitis: a newly recognized clinical feature of tumor necrosis factor receptor dysfunction. Arthritis Rheum. 2002;46:2189–94. 39. Cantarini L, Lucherini OM, Baldari CT, Laghi Pasini F, Galeazzi M. Familial clustering of recurrent pericarditis may disclose tumour necrosis factor receptor-associated periodic syndrome. Clin Exp Rheumatol. 2010;28:405–7. 40. Cantarini L, Lucherini OM, Brucato A, Barone L, Cumetti D, Iacoponi F, et al. Clues to detect tumor necrosis factor receptorassociated periodic syndrome (TRAPS) among patients with idiopathic recurrent acute pericarditis: results of a multicentre study. Clin Res Cardiol. 2012;101:525–31. 41. Rigante D. The protean visage of systemic autoinflammatory syndromes: a challenge for inter-professional collaboration. Eur Rev Med Pharmacol Sci. 2010;14:1–18. 42. Stankovic K, Grateau G. Auto inflammatory syndromes: Diagnosis and treatment. Joint Bone Spine. 2007;74:544–50. 43. Federici L, Rittore-Domingo C, Koné-Paut I, Jorgensen C, Rodière M, Le Quellec A, et al. A decision tree for genetic diagnosis of hereditary periodic fever in unselected patients. Ann Rheum Dis. 2006;65: 1427–32. 44. Sinožić D, Toplak N, Milotić I. Tumor necrosis factor receptorassociated periodic fever syndrome in a 58-year-old man: caution not to discount TRAPS as a diagnosis in older patients. J Clin Rheumatol. 2011;17:325–8. 45. Bulua AC, Mogul DB, Aksentijevich I, Singh H, He DY, Muenz LR, et al. Efficacy of etanercept in the tumor necrosis factor receptorassociated periodic syndrome: a prospective, open-label, doseescalation study. Arthritis Rheum. 2012;64:908–13. 46. Scallon B, Cai A, Solowski N, Rosenberg A, Song XY, Shealy D, et al. Binding and functional comparison of two types of tumor necrosis factor antagonists. J Pharmacol Exp Ther. 2002;301:418–26. 47. Cantarini L, Rigante D, Lucherini OM, Cimaz R, Laghi Pasini F, Baldari CT, et al. Role of etanercept in the treatment of tumor necrosis factor receptor-associated periodic syndrome: personal experience and review of the literature. Int J Immunopathol Pharmacol. 2010;23:701–7. 48. Gattorno M, Pelagatti MA, Meini A, Obici L, Barcellona R, Federici S, et al. Persistent efficacy of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 2008;58:1516–20. 49. Obici L, Meini A, Cattalini M, Chicca S, Galliani M, Donadei S, et al. Favourable and sustained response to anakinra in tumour necrosis factor receptor-associated periodic syndrome (TRAPS) with or without AA amyloidosis. Ann Rheum Dis. 2011;70:1511–2. 50. Brizi MG, Galeazzi M, Lucherini OM, Cantarini L, Cimaz R. Successful treatment of tumor necrosis factor receptor-associated periodic syndrome with canakinumab. Ann Intern Med. 2012;156:907–8. 51. Vaitla PM, Radford PM, Tighe PJ, Powell RJ, McDermott EM, Todd I, et al. Role of interleukin-6 in a patient with tumor necrosis factor receptor-associated periodic syndrome: assessment of outcomes following treatment with the anti-interleukin-6 receptor monoclonal antibody tocilizumab. Arthritis Rheum. 2011;63:1151–5. 52. Houten SM, Wanders RJ, Waterham HR. Biochemical and genetic aspects of mevalonate kinase and its deficiency. Biochim Biophys Acta. 2000;1529:19–32. 53. Haas D, Hoffmann GF. Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome. Orphanet J Rare Dis. 2006;1:13. 54. Frenkel J, Rijkers GT, Mandey SH, Buurman SW, Houten SM, Wanders RJ, et al. Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome. Arthritis Rheum. 2002;46:2794–803. 55. Prasad C, Salvadori MI, Rupar CA. Severe phenotypic spectrum of mevalonate kinase deficiency with minimal mevalonic aciduria. Mol Genet Metab. 2012;107:756–9. 56. Toplak N, Dolezalovà P, Constantin T, Sedivà A, Pašić S, Cižnar P, et al; Eastern/Central European autoinflammatory collaborating group for the Paediatric Rheumatology International Trials Organization (PRINTO) and Eurofever Project. Periodic fever syndromes in Eastern and Central European countries: results of a pediatric multinational survey. Pediatr Rheumatol Online J. 2010;8:29. 57. van der Hilst JC, Bodar EJ, Barron KS, Frenkel J, Drenth JP, van der Meer JW, et al; International HIDS Study Group. Long-term

Mod Rheumatol, 2014; 24(3): 381–389

58. 59.

60. 61.

62. 63. 64. 65.

66. 67. 68.

69. 70.

71. 72. 73. 74. 75. 76. 77.

78.

79.

follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore). 2008;87:301–10. Simon A, Kremer HP, Wevers RA, Scheffer H, De Jong JG, Van Der Meer JW, et al. Mevalonate kinase deficiency: Evidence for a phenotypic continuum. Neurology. 2004;62:994–7. Obici L, Manno C, Muda AO, Picco P, D’Osualdo A, Palladini G, et al. First report of systemic reactive (AA) amyloidosis in a patient with the hyperimmunoglobulinemia D with periodic fever syndrome. Arthritis Rheum. 2004;50:2966–9. Sornsakrin M, Wenner K, Ganschow R. B cell cytopenia in two brothers with hyper-IgD and periodic fever syndrome. Eur J Pediatr. 2009;168:825–31. Tahara M, Sakai H, Nishikomori R, Yasumi T, Heike T, Nagata I, et al. Patient with neonatal-onset chronic hepatitis presenting with mevalonate kinase deficiency with a novel MVK gene mutation. Mod Rheumatol. 2011;21:641–5. Breda L, Nozzi M, Di Marzio D, De Sanctis S, Gattorno M, Chiarelli F. Recurrent pericarditis in hyper-IgD syndrome. Clin Exp Rheumatol. 2009;27:695. Bader-Meunier B, Florkin B, Sibilia J, Acquaviva C, Hachulla E, Grateau G, et al; SOFREMIP, CRI. Mevalonate kinase deficiency: a survey of 50 patients. Pediatrics. 2011;128:e152–9. van der Hilst JC, Frenkel J. Hyperimmunoglobulin D syndrome in childhood. Curr Rheumatol Rep. 2010;12:101–7. Simon A, Drewe E, van der Meer JW, Powell RJ, Kelley RI, Stalenhoef AF, et al. Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Clin Pharmacol Ther. 2004;75:476–83. Topaloğlu R, Ayaz NA, Waterham HR, Yüce A, Gumruk F, Sanal O. Hyperimmunoglobulinemia D and periodic fever syndrome; treatment with etanercept and follow-up. Clin Rheumatol. 2008;27:1317–20. Galeotti C, Meinzer U, Quartier P, Rossi-Semerano L, Bader-Meunier B, Pillet P, et al. Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency. Rheumatology (Oxford). 2012;51:1855–9. Cantarini L, Lucherini OM, Frediani B, Brizi MG, Bartolomei B, Cimaz R, et al. Bridging the gap between the clinician and the patient with cryopyrin-associated periodic syndromes. Int J Immunopathol Pharmacol. 2011;24:827–36. Miyamae T. Cryopyrin-associated periodic syndromes: diagnosis and management. Paediatr Drugs. 2012;14:109–17. Lepore L, Paloni G, Caorsi R, Alessio M, Rigante D, Ruperto N, et al. Follow-up and quality of life of patients with cryopyrin-associated periodic syndromes treated with Anakinra. J Pediatr. 2010;157: 310–5. Kubota T, Koike R. Cryopyrin-associated periodic syndromes: background and therapeutics. Mod Rheumatol. 2010;20:213–21. Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep. 2011;11:12–20. Stych B, Dobrovolny D. Familial cold auto-inflammatory syndrome (FCAS): characterization of symptomatology and impact on patients’ lives. Curr Med Res Opin. 2008;24:1577–82. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum. 2004;50:607–12. Goldbach-Mansky R. Current status of understanding the pathogenesis and management of patients with NOMID/CINCA. Curr Rheumatol Rep. 2011;13:123–31. Rigante D, Ansuini V, Caldarelli M, Bertoni B, La Torraca I, Stabile A. Hydrocephalus in CINCA syndrome treated with anakinra. Childs Nerv Syst. 2006;22:334–7. Neven B, Marvillet I, Terrada C, Ferster A, Boddaert N, Couloignier V, et al. Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum. 2010;62:258–67. Tanaka N, Izawa K, Saito MK, Sakuma M, Oshima K, Ohara O, et al. High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. Arthritis Rheum. 2011;63:3625–32. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, et al. Use of canakinumab in the cryopyrinassociated periodic syndrome. N Engl J Med. 2009;360:2416–25.

Mod Rheumatol Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/12/14 For personal use only.

DOI 10.3109/14397595.2013.843755

Hereditary autoinflammatory disorders and IL-1 inhibition

80. Jéru I, Le Borgne G, Cochet E, Hayrapetyan H, Duquesnoy P, Grateau G, et al. Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis Rheum. 2011;63:1459–64. 81. Sfriso P, Caso F, Tognon S, Galozzi P, Gava A, Punzi L. Blau syndrome, clinical and genetic aspects. Autoimmun Rev. 2012;12:44–51. 82. Rose CD, Martin TM, Wouters CH. Blau syndrome revisited. Curr Opin Rheumatol. 2011;23:411–8. 83. Chen G, Shaw MH, Kim YG, Nuñez G. NOD-like receptors: role in innate immunity and inflammatory disease. Annu Rev Pathol. 2009;4:365–98. 84. Villanueva-Mendoza C, Arellanes-García L, Cubas-Lorenzo V, Jimenez-Martinez MC, Flores-Suárez LF, Zenteno JC. Familial case of Blau syndrome associated with a CARD15/NOD2 mutation. Ophthalmic Genet. 2010;31:155–8. 85. Borzutzky A, Fried A, Chou J, Bonilla FA, Kim S, Dedeoglu F. NOD2associated diseases: Bridging innate immunity and autoinflammation. Clin Immunol. 2010;134:251–61. 86. Punzi L, Furlan A, Podswiadek M, Gava A, Valente M, De Marchi M, et al. Clinical and genetic aspects of Blau syndrome: a 25-year follow-up of one family and a literature review. Autoimmun Rev. 2009;8:228–32. 87. Yasui K, Yashiro M, Tsuge M, Manki A, Takemoto K, Yamamoto M, et al. Thalidomide dramatically improves the symptoms of early-onset sarcoidosis/Blau syndrome: its possible action and mechanism. Arthritis Rheum. 2010;62:250–7.

88. Heiligenhaus A, Wefelmeyer D, Wefelmeyer E, Rösel M, Schrenk M. The eye as a common site for the early clinical manifestation of sarcoidosis. Ophthalmic Res. 2011;46:9–12. 89. Tallon B, Corkill M. Peculiarities of PAPA syndrome. Rheumatology (Oxford). 2006;45:1140–3. 90. Smith EJ, Allantaz F, Bennett L, Zhang D, Gao X, Wood G, et al. Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review. Curr Genomics. 2010;11:519–27. 91. Schellevis MA, Stoffels M, Hoppenreijs EP, Bodar E, Simon A, van der Meer JW. Variable expression and treatment of PAPA syndrome. Ann Rheum Dis. 2011;70:1168–70. 92. Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360:2426–37. 93. Ferguson PJ, Chen S, Tayeh MK, Ochoa L, Leal SM, Pelet A, et al. Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet. 2005;42:551–7. 94. Obici L, Merlini G. Amyloidosis in autoinflammatory syndromes. Autoimmun Rev. 2012;12:14–7. 95. Obici L, Merlini G. AA amyloidosis: basic knowledge, unmet needs and future treatments. Swiss Med Wkly. 2012;142:w13580. 96. van der Hilst JC. Recent insights into the pathogenesis of type AA amyloidosis. Sci World J. 2011;11:641–50.

389