Search

Systemic autoinflammatory diseases (SAID) are a growing family of disorders of the innate immune system. Over the years, there have been changes in the definition, classification and nomenclature of SAID as new syndromes and pathophysiologic mechanisms continue to be described. Recognizing the clinical manifestations of SAID is important for their early diagnosis and management. The field continues to advance with potential new therapies underway., Competing Interests: Disclosure There was no financial support, grants or benefits from commercial sources utilized for the elaboration of this article. S. Nazzar Romero with Aurinia pharmaceuticals. D. McCurdy has no disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Notch pathway is a highly conserved intracellular signaling route that modulates a vast variety of cellular processes including proliferation, differentiation, migration, cell fate and death. Recently, the presence of a strict crosstalk between Notch signaling and inflammation has been described, although the precise molecular mechanisms underlying this interplay have not yet been fully unravelled. Disruptions in Notch cascade, due both to direct mutations and/or to an altered regulation in the core components of Notch signaling, might lead to hypo- or hyperactivation of Notch target genes and signaling molecules, ultimately contributing to the onset of autoinflammatory diseases. To date, alterations in Notch signaling have been reported as associated with three autoinflammatory disorders, therefore, suggesting a possible role of Notch in the pathogenesis of the following diseases: hidradenitis suppurativa (HS), Behçet disease (BD), and giant cell arteritis (GCA). In this review, we aim at better characterizing the interplay between Notch and autoinflammatory diseases, trying to identify the role of this signaling route in the context of these disorders.

Objective: The new classification criteria for the hereditary recurrent fever (HRF) syndrome [cryopyrin-associated periodic syndrome (CAPS), TNF-α receptor-associated periodic syndrome (TRAPS), FMF and mevalonate kinase deficiency] have been published recently. These criteria define two core sets of criteria for each HRF: mixed criteria, including genetic and clinical variables, and clinical criteria, relying on clinical variables only. Our aim was to validate the criteria for HRF in an independent cohort, the JIR Cohort database, an international repository of systemic inflammatory diseases., Methods: We enrolled patients with HRF, periodic fever, adenitis, pharyngitis and aphthous stomatitis syndrome (PFAPA) and syndrome of undefined recurrent fever (SURF). A score ranging from zero to two was attributed to their respective genotypes: zero (no mutation), one (non-confirmatory genotype) or two (confirmatory genotype). The criteria were applied to all patients based on genotype scoring. The treating physician's diagnosis served as the gold standard for the determination of specificity., Results: We included 455 patients. The classification criteria showed excellent specificity for CAPS and TRAPS (98% specificity each), fair specificity for FMF (88%), but poor specificity for mevalonate kinase deficiency (58%). Sub-analysis showed excellent accuracy of the mixed criteria for all four HRFs. Misclassification was mainly attributable to clinical criteria sets, with false-positive patients in all four HRF clinical criteria sets., Conclusion: This study represents the final validation step of the HRF classification criteria as recommended by the ACR. Genetic data appear to be necessary to classify patients with HRF correctly., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Monogenic autoinflammatory diseases present with systemic inflammation with the involvement of multiple organs. With the help of modern molecular genetic techniques a large number of diseases with previously unknown pathomechanisms have been described in recent years. This knowledge can be utilized to group autoinflammatory diseases according to the signalling pathways involved and thus provide a better understanding of these entities.

Autoinflammation as a distinct disease category was first reported in 1999 as a group of monogenic disorders characterized by recurrent episodes of systemic and organ-specific inflammation, known as periodic fever syndromes. Since this original description, the focus has shifted considerably to the inclusion of complex multifactorial conditions with an autoinflammatory basis. Furthermore, the boundaries of what are considered to be autoinflammatory disorders are constantly evolving and currently encompass elements of immunodeficiency and autoimmunity. Notable developments in the intervening 20 years include substantial progress in understanding how the different inflammasomes are activated, how infection is sensed by the innate immune system and how intracellular signalling systems are consequently activated and integrated with many different cellular functions in the autoinflammatory process. With these developments, the field of autoinflammation is moving from a gene-centric view of innate immune-mediated disease towards a systems-based concept, which describes how various convergent pathways, including pyrin and the actin cytoskeleton, protein misfolding and cellular stress, NF-κB dysregulation and interferon activation, contribute to the autoinflammatory process. The development and adoption of a systems-based concept of systemic autoinflammatory diseases is anticipated to have implications for the development of treatments that target specific components of the innate immune system.

Autoinflammatory disorders (AIDs) are a subgroup of immune-mediated syndromes that result from a primary dysfunction of the innate immune system. AIDs can be either monogenic or polygenic diseases. Unlike organspecific AIDs, systemic AIDs are characterized by fever and/or elevation of acute-phase reactants. This review aims to describe the most common adult-onset systemic AIDs, focusing mostly on polygenic and mixed-pattern diseases which are expected to be more prevalent in adult patients than monogenic AIDs overall. The literature was searched in Medline database. Organ-specific or childhood-onset systemic AIDs were excluded. AIDs were divided in three distinct groups: mixed-pattern, polygenic and adult-onset monogenic AIDs. Most adult-onset AIDs are polygenic but late-onset disease is not rare among monogenic AIDs such as familial Mediterranean fever (FMF). The diagnosis of systemic AIDs in adults is often delayed due to several factors and sometimes it is only established when amyloidosis or other complications are present. Therefore, it probably makes sense to primarily exclude common AIDs in adult patients with fever of unknown origin (and probably different presentations such as polyserositis) since a high prevalence of adult-onset Still's disease or FMF is usually expected. Colchicine, nonsteroidal anti-inflammatory drugs, steroids, immunosuppressive agents, interleukin-1 inhibitors and tumor necrosis factor antagonists constitute common therapeutic options for systemic AIDs.

Until now, the diagnosis of familial Mediterranean fever (FMF) was based on validated subsets of clinical criteria, but recently new Eurofever/PRINTO classification criteria concerning genetic analyses were proposed. The study aimed to compare the performances of three validated diagnostic criteria (Tel-Hashomer, Livneh, pediatric criteria) and new Eurofever/PRINTO classification criteria. The medical charts of study and control groups were reviewed retrospectively. Patients were evaluated for three diagnostic criteria and new Eurofever/PRINTO classification criteria. Control group consists of patients with other autoinflammatory diseases. A total of 1291 patients were classified into three groups according to their mutations: group 1: 447 patients with homozygous mutations; group 2: 429 patients with compound heterozygous mutations; and group 3: 415 patients with one heterozygous mutation. Similar diagnostic utility was found according to Livneh criteria between groups. But, proportion of patients fulfilling Tel-Hashomer and pediatric criteria was higher in groups 1 and 2. According to Eurofever/PRINTO criteria, 98.2% of patients with homozygous mutations, 94.2% of patients with compound heterozygous mutations and 80.2% of patients with heterozygous mutations were classified as FMF. In control group, 99.2% of them fulfilled the Livneh criteria, 66.9% met the pediatric criteria and 0.8% satisfied the Tel-Hashomer criteria, while none of control patients met the Eurofever/PRINTO classification criteria. Performances of three validated diagnostic criteria and new Eurofever/PRINTO classification criteria for FMF were similar and provide high utility in diagnosing/classifying patients with homozygous and compound heterozygous mutations. However, both Eurofever/PRINTO classification criteria and Tel-Hashomer criteria had significantly lower performance in heterozygous patients.

The periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an auto-inflammatory condition characterized by recurrent episodes of fever accompanied by aphthosis, cervical adenitis, and pharyngitis. Diagnosis of PFAPA could be challenging due to clinic overlap with familial Mediterranean fever (FMF). An international consensus has been established recently, to define a new set of classification criteria for PFAPA syndrome. We aimed to evaluate the performance of recently proposed PFAPA criteria, to assess their utility in FMF regions. Patients diagnosed with PFAPA syndrome, FMF, and juvenile idiopathic arthritis (JIA) were included. Two investigators blindly evaluated all of patients for the newly proposed PFAPA criteria. A total of 542 patients (322 with PFAPA syndrome, 118 FMF and 102 JIA) were evaluated. Mean age of patients was 6.6 ± 2.81, 12.75 ± 3.9, and 12.42 ± 4.8 years for PFAPA, FMF, and JIA, respectively. We found quite high sensitivity (89.7%) but insufficient specificity of newly proposed PFAPA criteria (69.5%). When applied to control patients separately, specificity was found to be 61% and 79.4% for FMF and JIA patients, respectively. Positive predictive value was 81%, while negative predictive value was 82%. Recently proposed PFAPA criteria have satisfactory sensitivity, but its specificity is still under expectation. There is a need for a distinctive criterion between PFAPA syndrome and FMF, in FMF endemic regions, e.g., cryptic tonsillitis rapidly responsive to single dose of glucocorticoids. Further studies with higher patients' number in different regions are needed.

Periodic Fever, Aphthous Stomatitis, Pharyngitis and Cervical Adenitis (PFAPA) syndrome is the most common autoinflammatory disorder among children in many parts of the world and an important differential diagnosis in children presenting with recurrent fever episodes. Commonly, PFAPA has an onset under the age of 5 years. Fever episodes in PFAPA usually last 3-6 days and are associated with one or more of the cardinal symptoms aphthous stomatitis, pharyngitis and cervical adenitis. The fever episodes typically recur with an interval of 3-6 weeks, often with a striking regularity. During the episodes, the patient has elevated inflammatory variables such as CRP and serum amyloid A (SAA) and may sometimes have additional symptoms such as abdominal pain, nausea and leg pain. Between the fever episodes, the patient is typically free of symptoms with normalized inflammatory variables and grows normally. Awareness and recognition of PFAPA is key to providing the patient with adequate treatment and avoiding misdiagnosis.

Background: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA., Methods: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria., Results: The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98)., Conclusion: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Provisional evidence-based classification criteria for hereditary periodic fever (HPF) have been recently developed. However, no consensus on how to combine clinical criteria, laboratory tests, and results of molecular analysis has been reached. The objective of this study is to understand which variables physicians consider important for the classification of patients with HPF., Methods: Two Delphi surveys were sent to health professionals in the field of autoinflammation. In the first open survey, 124 researchers could list all the variables they consider useful for the diagnosis of each monogenic periodic fever. The variables could be of any type and each researcher could complete the survey for 1 or more diseases. In the second survey, 162 researchers were asked to select, from a list of items coming from the first survey, the 10 top variables and to rank them by assigning a score from 10 to 1., Results: The response rates to the Delphi surveys were 85% for the first session and 87% for the second. The variables selected for each disease (corresponding to the third quartile, considering the total score obtained by the variables after the second Delphi survey) were 21 for mevalonate kinase deficiency, 22 for cryopyrinopathies, 18 for familial Mediterranean fever, and 20 for tumor necrosis factor receptor-associated periodic fever syndrome. A positive genetic test reached the top rank in all the HPF., Conclusion: Our process led to the identification of those features considered the most important as candidate variables to be included in a new set of evidence-based classification criteria for HPF.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a complex autoinflammatory disease with a clinical phenotype characterised by recurrent episodes of fever, systemic inflammation and symptoms and signs depicted in disease acronym. Although PFAPA is the most common autoinflammatory disease among children in many parts of the world, the condition is still an enigma, which include the regular episodes, the prompt responses to corticosteroids, the genetic bases for the familial clustering and therapeutic effects of tonsillectomy. This review explores PFAPA syndrome with the aim of describing the current clinical and scientific understanding of the condition., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Autoinflammatory diseases are characterized by innate immunity abnormalities. In autoinflammatory diseases (AID), inflammatory blood biomarkers are elevated during crisis without infection and usually without autoantibodies. The first 4 described AID were familial Mediterranean fever, cryopyrin-associated periodic fever syndrome (CAPS) or NLRP3-associated autoinflammatory disease (NRLP3-AID), mevalonate kinase deficiency (MKD) and TNFRSF1A-receptor associated periodic fever syndrome (TRAPS). Since their description 20 years ago, and with the progresses of genetic analysis, many new diseases have been discovered; some with recurrent fever, others with predominant cutaneous symptoms or even immune deficiency. After describing the 4 historical recurrent fevers, some polygenic inflammatory diseases will also be shortly described such as Still disease and periodic fever with adenitis, pharyngitis and aphtous (PFAPA) syndrome. To better explore AID, some key anamnesis features are crucial such as the family tree, the age at onset, crisis length and organs involved in the clinical symptoms. An acute phase response is mandatory in crisis., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The systemic autoinflammatory disorders (SAIDs) are associated with dysregulation of the innate immune system, affecting pro-inflammatory cytokines and apoptosis pathways. The spectrum of SAIDs continues to grow with over 30 different disorders identified to date. The main indication for genetic referral is when a patient presents with clinical symptoms consistent with one or more of the SAIDs. Thus, in making a referral for DNA screening, clinical information that supports the choice for screening of one or more SAIDs genes is required. Many of the SAIDs can display overlapping, partial or atypical symptoms, which makes the differential diagnosis extremely difficult and thus heavily dependent on genetic testing. Various attempts have been aimed at improving the efficiency of SAIDs diagnosis by proposing a set of clinical criteria to guide the genetic analysis of the SAIDs. In the last decade, due to application of the next-generation sequencing (NGS) the genetic diagnosis in patients with SAIDs have greatly improved; novel diseases and disease-associated genes have been identified and remarkable progress has been made in the genetic characterization of the undiagnosed patients and the sporadic cases. To date more than 800 variants have been recorded on the Infevers database, an online repository for DNA changes in genes associated with SAIDs (http://fmf.igh.cnrs.fr/ISSAID/infevers/). Recently, it has been updated with the new guidelines for classification of genetic variants pathogenicity in the in four most recognised SAIDs genes: MEFV, TNFRSF1A, NLRP3 and MVK., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Diagnosis of Periodic Fever, Aphthous stomatitis, Pharyngitis and Cervical Adenitis (PFAPA) syndrome is currently based on the modified Marshall's criteria, but no validated evidence based classification criteria for PFAPA has been established so far., Methods: A multistep process, based on the Delphi and Nominal Group Technique was conducted. After 2 rounds of e-mail Delphi survey involving 21 experts in autoinflammation we obtained a list of variables that were discussed in an International Consensus Conference. Variables reaching the 80% of consensus between participants were included in the new classification criteria. In the second phase the new classification criteria and the modified Marshall's criteria were applied on a cohort of 80 pediatric PFAPA patients to compare their performance., Results: The Delphi Survey was sent to 22 participants, 21 accepted to participate. Thirty variables were obtained from the survey and have been discussed at the Consensus Conference. Through the Nominal Group Technique we obtained a new set of classification criteria. These criteria were more restrictive in respect to the modified Marshall's criteria when applied on our cohort of patients., Conclusion: Our work led us to identify a new set of classification criteria for PFAPA syndrome, but they resulted to be too restrictive to be applied in daily clinical practice for the diagnosis of PFAPA.

Monogenic autoinflammatory disorders are an increasingly heterogeneous group of conditions characterised by innate immune dysregulation. Improved genetic sequencing in recent years has led not only to the discovery of a plethora of conditions considered to be 'autoinflammatory', but also the broadening of the clinical and immunological phenotypic spectra seen in these disorders. This review outlines the classification strategies that have been employed for monogenic autoinflammatory disorders to date, including the primary innate immune pathway or the dominant cytokine implicated in disease pathogenesis, and highlights some of the advantages of these models. Furthermore, the use of the term 'autoinflammatory' is discussed in relation to disorders that cross the innate and adaptive immune divide. The utilisation of next-generation sequencing (NGS) in this population is examined, as are potential in vivo and in vitro methods of modelling to determine pathogenicity of novel genetic findings. Finally, areas where our understanding can be improved are highlighted, such as phenotypic variability and genotype-phenotype correlations, with the aim of identifying areas of future research., (© 2018 The Author(s).)

The discovery of new autoinflammatory syndromes and novel mutations has advanced at breakneck speed in recent years. Part 2 of this review focuses on vasculitis syndromes and the group of histiocytic and macrophage activation syndromes. We also include a table showing the mutations associated with these autoinflammatory syndromes and treatment alternatives., (Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Monogenic autoinflammatory diseases are a heterogeneous emergent group of conditions that are currently under intensive study. We review the etiopathogenesis of these syndromes and their principal manifestations. Our aim is to propose a classification system based on the clinicopathologic features of typical skin lesions for routine clinical use in dermatology. Our focus is on diagnosis in pediatric practice given that this is the period when the signs and symptoms of these syndromes first appear. In Part 1 we discuss the course of urticaria-like syndromes, which include cryopyrin-associated periodic conditions and hereditary periodic fever syndromes. Pustular syndromes are also covered in this part. Finally, we review the range of therapies available as well as the genetic mutations associated with these autoinflammatory diseases., (Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

The spectrum of systemic autoinflammatory disorders broadens continually. In part, this is due to the more widespread application of massive parallel sequencing, helping with novel gene discovery in this and other areas of rare diseases. Some of the conditions that have been described fit neatly into a conventional idea of autoinflammation. Others, such as interferon-mediated autoinflammatory diseases, are broadening the concept which we consider to be autoinflammatory disorders. There is also a widening of the clinical phenotypes associated with certain genetic mutations, as genetic testing is used more regularly and increasing numbers of patients are screened. It is also increasingly evident that both autoinflammatory and autoimmune problems are frequently seen as complications of primary immunodeficiency disorders. The aim of this review is to provide an update on some recently discovered conditions and to discuss how these disorders help to define the concept of autoinflammation. The review will also cover recent discoveries in the biology of innate-immune-mediated inflammation and describe how this has provided the biological rationale for using anti-interleukin-1 therapies in the treatment of many such conditions. Finally, we discuss the importance of recognising somatic mutations as causes of autoinflammatory clinical phenotypes and provide practical advice on how this could be tackled in everyday clinical practice., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Autoinflammatory diseases are hyperinflammatory, immune dysregulatory conditions that typically present in early childhood with fever and rashes and disease-specific patterns of organ inflammation. This review provides a historic background of autoinflammatory disease research, an overview of the currently genetically defined autoinflammatory diseases, and insights into treatment strategies derived from understanding of the disease pathogenesis. The integrative assessment of autoinflammatory conditions led to the identification of innate pro-inflammatory cytokine 'amplification loops' as the cause of the systemic and organ-specific disease manifestations, which initially centered around increased IL-1 production and signaling. More recently, additional innate pro-inflammatory cytokine amplification loops resulting in increased Type I IFN, IL-17, IL-18, or IL-36 signaling or production have led to the successful use of targeted therapies in some of these conditions. Clinical findings such as fever patterns, type of skin lesions, genetic mutation testing, and the prevalent cytokine abnormalities can be used to group autoinflammatory diseases., (Published 2016. This article is a U.S. Government work and is in the public domain in the USA.)

Autoinflammatory disease (AID) is a newly proposed category of disorders characterized by unprovoked episodes of inflammation without any infectious or autoimmune evidence. We aimed to characterize the clinical and genetic features of patients who had recurrent fever and multi-system inflammation but remain unclassified for any established AIDs. Medical records of 1,777 patients who visited our Rheumatology Clinic between March 2009 and December 2010 were reviewed to identify those who met the following criteria; 1) presence of fever, 2) inflammation in two or more organ systems, 3) recurrent nature of fever or inflammation, 4) no evidence of infection or malignancy, 5) absence of high titer autoantibodies, and 6) failure to satisfy any classification criteria for known AIDs. Genotyping was performed for common missense variants in MEFV, NOD2/CARD15, and TNFRSF1A. A small number of patients (17/1,777, 0.95%) were identified to meet the above criteria. Muco-cutaneous and musculoskeletal features were most common, but there was a considerable heterogeneity in symptom combination. Although they did not satisfy any established classification criteria for AIDs, substantial overlap was observed between the clinical spectrum of these patients and known AIDs. According to the newly proposed Eurofever criteria for periodic fevers, eleven of them were classified as TNF receptor-associated periodic syndrome and two as mevalonate kinase deficiency. However, no examined genetic variants including those in TNFRSF1A were found in these patients. A new set of classification criteria needs to be developed and validated for Asian patients with unclassified AIDs.

Objective: Our aims were to validate the pediatric diagnostic criteria in a large international registry and to compare them with the performance of previous criteria for the diagnosis of familial Mediterranean fever (FMF)., Methods: Pediatric patients with FMF from the Eurofever registry were used for the validation of the existing criteria. The other periodic fevers served as controls: mevalonate kinase deficiency (MKD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS), aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA), and undefined periodic fever from the same registry. The performances of Tel Hashomer, Livneh, and the Yalcinkaya-Ozen criteria were assessed., Results: The FMF group included 339 patients. The control group consisted of 377 patients (53 TRAPS, 45 MKD, 32 CAPS, 160 PFAPA, 87 undefined periodic fevers). Patients with FMF were correctly diagnosed using the Yalcinkaya-Ozen criteria with a sensitivity rate of 87.4% and a specificity rate of 40.7%. On the other hand, Tel Hashomer and Livneh criteria displayed a sensitivity of 45.0 and 77.3%, respectively. Both of the latter criteria displayed a better specificity than the Yalcinkaya-Ozen criteria: 97.2 and 41.1% for the Tel Hashomer and Livneh criteria, respectively. The overall accuracy for the Yalcinkaya-Ozen criteria was 65 and 69.6% (using 2 and 3 criteria), respectively. Ethnicity and residence had no effect on the performance of the Yalcinkaya-Ozen criteria., Conclusion: The Yalcinkaya-Ozen criteria yielded a better sensitivity than the other criteria in this international cohort of patients and thus can be used as a tool for FMF diagnosis in pediatric patients from either the European or eastern Mediterranean region. However, the specificity was lower than the previously suggested adult criteria.

Autoinflammatory syndrome is characterized by: 1) episodes of seemingly unprovoked inflammation, 2) the absence of a high titer of autoantibodies or auto-reactive T cells, and 3) an inborn error of innate immunity. In this decade, many autoinflammatory syndromes have been reported in Japan, and so many Japanese physicians have become aware of this syndrome. Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. The main monogenic autoinflammatory syndromes are familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), cryopyrin-associated periodic syndrome (CAPS), Blau syndrome, and syndrome of pyogenic arthritis with pyoderma gangrenosum and acne (PAPA). We diagnosed these syndromes as clinical manifestations and performed genetic screening. Many serum cytokines are elevated in patients with autoinflammatory syndrome, but this is not disease-specific. The pathogeneses of many autoinflammatory syndromes are known to be related to inflammasomes, which are multiprotein complexes that serve as a platform for caspase 1 activation and interleukin-1β(IL-1β) and IL-18 maturation. Especially, NLRP3 inflammasomes may play a crucial role in the initiation and progression of FMF and CAPS. Recently, it was reported that NETs (neutrophil extracellular traps) derived from neutrophils may also play an important role in the pathogenesis of FMF. In the future, we hope to discover new clinical examinations which can provide evidence of inflammasome activation independent of genetic screening. In this issue, I introduce autoinflammatory syndromes and discuss the pathogenesis and clinical examination of these syndromes.

Autoinflammatory syndrome is characterized by: 1) episodes of seemingly unprovoked inflammation, 2) the absence of a high titer of autoantibodies or auto-reactive T cells, and 3) an inborn error of innate immunity. In this decade, many autoinflammatory syndromes have been reported in Japan, and so many Japanese physicians have become aware of this syndrome. Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. The main monogenic autoinflammatory syndromes are familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), cryopyrin-associated periodic syndrome (CAPS), Blau syndrome, and pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. We diagnosed these syndromes as clinical manifestations and performed genetic screening. Many serum cytokines are elevated in patients with autoinflammatory syndrome, but this is not disease-specific. The pathogeneses of many autoinflammatory syndromes are known to be related to inflammasomes, which are multiprotein complexes that serve as a platform for caspase 1 activation and interleukin-1β (IL-1β) and IL-18 muturation. Especially, NLRP3 inflammasomes may play a crucial role in the intiation and progression of FMF and CAPS. In the future, we hope to discover new clinical examinations which can provide evidence of inflammasome activation independent of genetic screening. In this issue, I introduce autoinflammatory syndromes and discuss the diagnosis and clinical examination of these syndromes.

The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be 'gold standard' on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Most of the autoinflammatory diseases (AID) are orphan diseases with recurrent episodes of systemic inflammation. Fever and exanthema are leading features. Given the ongoing elucidation of pathogenic causes and hence therapeutic approaches, we provided a review of the current literature of AID., (© Georg Thieme Verlag KG Stuttgart · New York.)

The notion of 'autoinflammatory' disease was introduced at the end of the 1990s, and, since then, this concept has rapidly evolved. As a result, multiple definitions of autoinflammatory disease, and classifications of conditions encompassed by these definitions, have been proposed; this succession highlights advances that have been made in understanding of the innate immune system, and especially the roles of IL-1β and the inflammasome in autoinflammtory conditions. However, the definitions and classifications that have been suggested to date face a number of structure and content issues. We therefore propose another, more clinically-oriented, definition: autoinflammatory diseases are diseases with clinical signs of inflammation, associated with elevated levels of acute-phase reactants, which are attributable to dysfunction of the innate immune system, genetically-determined or triggered by an endogenous factor. From this foundation, we propose a clinically-based classification of autoinflammatory diseases, and go on to discuss how immunological diseases as a whole, including autoimmune diseases, can be appropriately located within a continuum only if the classification process is multidimensional. For this purpose, we appeal to the philosophical concepts of family resemblance and signature.

Over 15 years have passed since the discovery of the first autoinflammatory gene, MEFV, responsible for familial Mediterranean fever. The identification of another gene, TNFRSF1A, in 1999 led to the concept of autoinflammation which characterises rheumatological conditions triggered by a defective innate immunity. Substantive progress has been made since then with the identification of 18 autoinflammatory genes accounting for up to 24 disease entities showing overlapping symptoms. The accumulation of studies reporting patients with missing or excess mutations as compared with expected numbers favours the hypothesis that these diseases are distributed along a continuum ranging from monogenic to multifactorial conditions, rather than featuring only classical modes of inheritance. Moreover, the probable interactions of environmental and epigenetic factors further obscure our understanding of the mechanisms underlying the phenotypic expression of patients. This review explores the history of autoinflammatory gene discovery, discusses the nosological disparities stemming from the clinical versus pathophysiological definition of autoinflammatory diseases and summarises various inheritance patterns. This review calls for a consistent disease nomenclature and presents a reconciling hypothesis which places different sequence variants within the autoinflammatory disease continuum. Integrating these new concepts should help to facilitate communication between health professionals and promote personalised patient care.

Systemic autoinflammatory diseases are a group of inherited disorders of the innate immune system characterized by seemingly unprovoked inflammation recurring at variable intervals and involving skin, serosal membranes, joints, and gastrointestinal apparatus, with reactive amyloidosis as a possible severe long-term complication. Recent advances in genetics and molecular biology have improved our understanding of the pathogenesis of these diseases, including familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes, and hereditary pyogenic and granulomatous disorders: the vast majority of these conditions are related to the activation of the interleukin-1 pathway, which results in (or from?) a common unifying pathogenetic mechanism. Their diagnostic identification derives from the combination of clinical data, evaluation of acute phase reactants, clinical efficacy in response to specific drugs, and recognition of specific mutations in the relevant genes, although genetic tests may be unconstructive in some cases. This review will discuss clinical and laboratory clues useful for a diagnostic approach to systemic autoinflammatory diseases.

CINCA/NOMID syndrome was first reported in 1981, identified as a new disease in 1987 and the main cause discovered in 2001, when mutations in the CIAS1 gene modifying the structure of the protein cryopirin were found in those patients (although other factors seem to play a role). Together with the major symptoms that characterized the syndrome, neurological, cutaneous and articular manifestations, others have been added which seem to be quite constant among CINCA/NOMID diagnosed patients: pre and perinatal symptoms, morfological changes, outbreaks of fever and biological abnormalities which reveal a persistent inflammatory background. The radiological studies have been able to identify the physis as the origin of the osteoarticular malformations seen in this syndrome. Diferential diagnosis includes diseases with similar onset at the neonatal period or infancy: systemic onset juvenile idiopathic athritis, periodic fever associated with mevalonate kinase deficiency, deficiency of IL-1 receptor antagonist (DIRA) and Muckle-Wells syndrome., (Copyright © 2011 Elsevier España S.L. All rights reserved.)

Objective: Auto-inflammatory diseases (AIDs) are characterized by recurrent self-limiting systemic inflammation. In a multicentre effort, we set out to register genetic, epidemiological and clinical features as well as prognostic factors of these diseases by prospective longitudinal and long-term documentation, in order to define novel AIDs and to better understand treatment responses and outcome., Methods: In 2009, a federally funded clinical and research consortium (AID-Net) was established, including an online registry for AIDs (http://www.aid-register.uk-essen.de). Inclusion criteria are disease-associated mutations for hereditary periodic fever syndromes [FMF, hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), TNF receptor 1-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndrome (CAPS)], or, alternatively, clinically confirmed AID, systemic-onset JIA (SoJIA) and periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome with unknown genetic background. Patients were recruited to the registry and patient material was deposited in biomaterial banks (DNA/serum). In addition, basic research projects were initiated that focus on molecular mechanisms of AID., Results: During the first 9 months, 117 patients (65 males, 52 females; age 1-21 years) have been recorded and classified as FMF (n=84), HIDS (n=1), TRAPS (n=3) and CAPS (n=1); clinically confirmed AID (n=5); SoJIA (n=22); and PFAPA (n=1). One hundred and fifty blood samples of 18 patients were included in biomaterial banks., Conclusion: Recruitment and follow-up of patients with AID will enable us to comprehensively address the correlation between clinical and epidemiological data, genetics and biomarkers. The translational approach may help to identify genetic or inflammatory markers relevant for the course and outcome of diseases.

Autoinflammatory syndromes are characterised by recurrent or persistent inflammation with no increase in the antibody titers or antigen-specific T lymphocytes, and absence of infection. Initially, they included the hereditary periodic fever syndromes, a group of innate immune system monogenic diseases characterised by recurrent febrile episodes, with different characteristics, duration and interval, accompanied by other symptoms. Secondary amyloidosis is a complication in this group. The advances in the last few years has led to the identification of susceptible genes, new proteins, and characterising mechanisms and pathogenic routes that have led to an improvement in the diagnosis and establishing more effective treatments. Among these routes, are the changes in the inflammasome components, a group of cytoplasmic proteins that regulate the production of several inflammatory response mediators. The initial group of monogenic autoinflammatory diseases have increased in the last few years, due to including several polygenic hereditary diseases., (Copyright © 2011 Elsevier España S.L. All rights reserved.)

Familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS) belong to the cryopyrin-associated periodic syndromes (CAPS) with CIAS1 gene mutations as a common molecular basis. Patients with FCAS have the least severe clinical phenotype but are characterized by the development of symptoms induced by a generalized exposure to cold appearing during the first months of childhood. It is important to make differential diagnosis between FCAS and acquired cold urticaria (ACU) and familial atypical cold urticaria (FACU). Muckle-Wells syndrome is characterized by recurrent fever and urticarial rash, progressive sensorineural deafness and the development of secondary amyloidosis, but it is not considered the most severe disease of this group. Sensorineural deafness and amyloidosis are the two major complications of MWS and determine poor prognosis of the disease., (Copyright © 2011 Elsevier España S.L. All rights reserved.)

Systemic autoinflammatory diseases are a group of inherited disorders of the innate immunity characterized by the recurrence of febrile attacks lasting from few hours to few weeks and multi-district inflammation of different severity involving skin, serosal membranes, joints, gastrointestinal tube and central nervous system. The vast majority of these conditions is caused by mutations in genes involved in the control of inflammation and apoptosis mechanisms. The group includes familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes, hereditary pyogenic and granulomatous disorders. Their diagnostic identification derives from the combination of clinical and biohumoral data, though can be sometimes confirmed by genotype analysis.

TNF receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder characterized by recurrent febrile attacks. TRAPS is associated with mutation in the gene encoding TNF Receptor I (TNFRI) and seven mutations have been reported in Japan. Molecular modeling experiments indicate that the mutant TNFRI accumulates intracellularly in the endoplasmic reticulum due to misfolding and activates MAP kinase (MAPK) through induction of mitochondrial reactive oxygen species production. MAPK activation is further enhanced by the stimulation through toll-like receptor, resulting in the enhanced proinflammatory cytokine production. Febrile attacks last 21 days on average and occur every one to several months. Myalgia, erythematous macular rash, abdominal pain, conjunctivitis, periorbital edema, chest pain and arthralgia are commonly seen during the attacks. Glucocorticoid is effective in decreasing the severity and duration of the febrile attacks. Soluble TNF receptor etanercept, IL-1 receptor antagonist Anakinra(TM) and IL-6 receptor antagonist tocilizumab are effective in some patients. Japanese study group of TRAPS conducted national survey to make new diagnostic criteria in 2010.

Systemic autoinflammatory diseases encompass different rare clinical entities characterized by recurrent acute inflammatory episodes secondary to a dysregulated inflammatory process. Since their first clinical descriptions, the Mendelian hereditary nature of some of them became evident, with their genetic and molecular basis being recently elucidated. There are disease-causing mutations in genes encoding for different proteins involved in the innate immune response and inflammation. Herein, we will introduce the reader to an updated review of the main clinical, physiopathological and therapeutic features of the different hereditary systemic autoinflammatory diseases., (Copyright © 2010 Elsevier España, S.L. All rights reserved.)

Introduction: Autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high titers of autoantibodies or antigen-specific T cells, and derive from genetic variants of the innate immune system. This study characterized a cohort of patients with similar phenotypes and nucleotide oligomerization domain 2 (NOD2) gene mutations., Methods: Diagnostically challenging patients with the following clinical and genetic characteristics were prospectively studied between January 2009 and April 2011: periodic fever, dermatitis, polyarthritis, serositis, negative serum autoantibodies and additional positive NOD2 IVS8+158 gene mutation. Genetic testing for gene mutations of NOD2, tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS) and familial Mediterranean fever (FMF) was performed., Results: All seven patients with the disease were Caucasians, with four being male. The mean age at disease onset was 40.7 years and disease duration was 3.2 years. These patients characteristically presented with periodic fever, dermatitis and inflammatory polyarthritis. There were gastrointestinal symptoms in three patients, granulomas of the skin and gut in two, and recurrent chest pain in two, with one having pleuritis and pericarditis. Three patients had sicca-like symptoms. Five patients had increased acute phase reactants. All seven patients had negative tests for autoantibodies but carried the NOD2 gene mutation IVS8+158 with four having concurrent R702W mutation., Conclusions: Our cohort may represent a new disease category of autoinflammatory disease with characteristic clinical phenotypes and genotypes. It may somewhat resemble pediatric Blau's syndrome.

Autoinflammatory diseases are a group of monogenic inflammatory diseases with an early onset in childhood. Previously these diseases were summarized as"periodic fever syndromes." Included in this spectrum are familial Mediterranean fever, mevalonate kinase deficiency, and tumor necrosis factor receptor-associated disease. They are characterized by periodic or recurrent episodes of systemic inflammation causing fever, accompanied by rash, serositis, lymphadenopathy, arthritis, and other clinical manifestations. The other large group of autoinflammatory diseases consists of the cryopyrin-associated periodic syndromes, which include the cryopyrinopathies. The mildest form is familial cold-associated syndrome, a more severe form is Muckle-Wells syndrome, and the most severe is neonatal-onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular syndrome. These are characterized by chronic or recurrent systemic inflammation associated with various clinical presentations, including urticaria-like rash, arthritis, sensorineural deafness, and central nervous system and bone involvement. In our review we focus on the clinical presentation of these diseases.