<Emphasis Type="Italic">The Eurofever Project</Emphasis>: towards better care for autoinflammatory diseases

Autoinflammatory diseases are a group of diseases characterized by inflammatory attacks. The monogenic forms of these diseases are also classified as the hereditary periodic fever syndromes. All are characterized by attacks of fever along with certain clinical features and high acute phase reactants. Most of these monogenic diseases are associated with hereditary disorders of the interleukin-1 pathway. The most common autoinflammatory disease is familial Mediterranean fever. The other rather common monogenic diseases are the tumor necrosis factor receptor-associated periodic syndrome, hyperimmunoglobulinemia D with periodic fever syndrome, and cryopyrin-associated periodic fever syndromes (CAPS). However, a number of multifactorial diseases such as Behçet disease are now also categorized under the topic of autoinflammatory diseases. The main features and management of these diseases will be reviewed. Finally, we introduce the “Eurofever” project, aimed to increase awareness and education for the aforementioned diseases. We conclude that the pediatrician should be aware of the features and management of autoinflammatory diseases since all present with fever—the most common symptom of pediatric practice.     

Tumor necrosis factor receptor-associated periodic syndrome

Tumoral necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominantly inherited disease belonging to the hereditary periodic fever syndromes, which are the main subgroup among systemic autoinflammatory diseases. TRAPS is characterized by prolonged and recurrent inflammatory attacks associated with fever and an acute phase reaction. Articular, cutaneous, ocular and abdominal symptoms may also be present. We describe the case of a 4-year-old boy with recurrent inflammatory episodes, fever and cutaneous symptoms who was diagnosed with TRAPS. We review the clinical and laboratory findings, genetic diagnosis, and treatment approach in this disease.     

Periodic fevers and autoinflammatory conditions

Autoinflammatory syndromes (AIS) are a spectrum of immune-mediated disorders that typically present in childhood with recurrent fevers, high inflammatory markers and systemic involvement. The quintessential periodic fever is familial Mediterranean fever, which is relatively common in Middle Eastern populations, but in general, these conditions are rare and diagnostically challenging. As a group of conditions they are typified by a delay in diagnosis of several years with repeated hospital visits, unnecessary investigations and treatment, impact on quality of life and an increased risk of the most severe complication of systemic AA amyloidosis.The purpose of this review is to help clinicians suspect and diagnose AIS in children presenting with (recurrent) fevers or multisystem inflammation of unknown aetiology after common causes such as infection and autoimmune diseases have been excluded. We will identify when to consider AIS through a systematic approach of pattern recognition. We will discuss the presentation and differential diagnosis of recurrent fevers in neonates (the cryopyrinopathies), in childhood (hereditary periodic fevers) and pathognomonic rashes associated with AIS. Although, by no means exhaustive, we will also discuss other forms of AIS and provide an overview of the principles of treatment of AIS.     

Consensus Document on the differential diagnosis and therapeutic approach to recurrent fever by the Paediatric Infectology Society and the Paediatric Rheumatology Society

Recurrent fever is a relatively common problem during childhood. Diagnosis is often easy and related to mild viral infections. However a small proportion of these cases originate from an underlying non-infectious process that is generally difficult to diagnose. In this paper we describe the differential diagnosis of recurrent or periodic fever versus other processes, with especial attention to autoinflammatory disorders (AD). AD are alterations of innate immunity, and they have been recently classified as an immunodeficiency. Anyhow, since infections are not present, these processes are different to the classic primary immunodeficiency. An important part of AD is of known genetic aetiology. The symptoms originate from an underlying inflammatory process and can have different clinical expressions. One of the most relevant groups is the hereditary syndromes of periodic fever. This group of diseases associates recurrent fever and several clinical symptoms with a relative periodicity, separated by intervals free or almost free of symptoms. We include the diagnostic criteria for some processes as well as the characteristics that should, eventually, lead to a genetic study. Although treatment should be individualised, we also include some general recommendations.     

Periodic fever syndromes

The term periodic fever syndrome has been used in a restricted sense to denote two diseases in which episodic fevers occur with a regular periodicity: cyclic neutropenia and the periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome. Other authors have used the term in a more general sense to encompass a larger group of disorders characterized by recurrent episodes of fever that do not necessarily follow a strictly periodic pattern. These include familial Mediterranean fever, the autosomal dominant familial fevers (also known as Hibernian fever), and the hyperimmunoglobulin D syndrome. This article follows the latter usage, and reviews recent advances in our understanding of the genetics and molecular pathology of this group of diseases, as well as their clinical characterization and treatment.     

Periodic fevers]

Periodic fever is defined as a series of unexplained febrile episodes, most often starting during childhood. The febrile episodes last usually few days, are of fixed or variable duration, and regress spontaneously, the intervals between episodes being asymptomatic. Fever is accompanied by clinical manifestations affecting peritoneal, pleural and/or mucous membranes, joints and skin. Four different etiologies are presently known. Three are hereditary diseases: familial mediterranean fever and periodic fever with hyperimmunoglobulinemia D which have a recessive autosomal transmission, and TNF receptor associated periodic syndrome or TRAPS which has a dominant autosomal transmission. One is sporadic: periodic fever with aphthous stomatitis, pharyngitis and adenopathy or PFAPA. Other etiologies are yet to be identified as many cases of periodic fever remain unexplained.     

TNF receptor-associated periodic syndrome (TRAPS): clinical aspects and physiopathology of a rare familial disease]

Hereditary periodic fever syndromes are defined as recurrent attacks of generalized inflammation for which no infectious or auto-immune cause can be identified. Minimal clinical variations, a unique biochemical-specific abnormality and the mode of genetic inheritance distinguish the four main diseases: familial Mediterranean fever, hyper-immunoglobulinemia D, TNF-receptor-associated periodic syndrome (TRAPS) and Muckle Wells syndrome. It presents with prolonged attacks of fever and severe localized inflammation. TRAPS is caused by dominantly inherited mutations in the gene encoding the first TNF receptor, which result in decreased serum levels of soluble TNF-receptor leading to inflammation due to unopposed TNF-alpha action. Corticosteroid treatment is not completely effective in most TRAPS patients. Preliminary experiences with recombinant TNF-receptor analogues in the treatment appear be promising.     

Autoinflammatory diseases in childhood,part 1: monogenic syndromes

Autoinflammatory diseases constitute a family of disorders defined by aberrant stimulation of inflammatory pathways without involving antigen-directed autoimmunity. They may be divided into monogenic and polygenic types. Monogenic autoinflammatory syndromes are those with identified genetic mutations, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency or hyperimmunoglobulin D syndrome, cryopyrin-associated periodic fever syndromes (CAPS), pyogenic arthritis pyoderma gangrenosum and acne (PAPA) syndrome, interleukin-10 and interleukin-10 receptor deficiencies, adenosine deaminase 2 deficiency and pediatric sarcoidosis. Those without an identified genetic mutation are known as polygenic and include systemic-onset juvenile idiopathic arthritis, idiopathic recurrent acute pericarditis, Behçet syndrome, chronic recurrent multifocal osteomyelitis and inflammatory bowel disease among others. Autoinflammatory disorders are defined by repeating episodes or persistent fever, rash, serositis, lymphadenopathy, arthritis and increased acute phase reactants, and thus may mimic infections clinically. Most monogenic autoinflammatory syndromes present in childhood. However, because of their infrequency, diverse and nonspecific presentation, and the relatively new genetic recognition, diagnosis is usually delayed. In this article, which is Part 1 of a two-part series, the authors update monogenic autoinflammatory diseases in children with special emphasis on imaging features that may help establish the correct diagnosis.

     

The efficacy of anakinra in an adolescent with colchicine-resistant familial Mediterranean fever

Colchicine is the treatment of choice in familial Mediterranean fever (FMF) for the prevention of both attacks and secondary amyloidosis. The overall nonresponder rate is about 5–10%. Anakinra is known to have good effectiveness in a severe autoinflammatory syndrome [chronic infantile neurological cutaneous and articular (CINCA) syndrome] and other recurrent hereditary periodic fevers. Pyrin—the protein involved in FMF—has a role in activating the proinflammatory cytokine interleukin (IL)-1β. We report the effectiveness of the addition of an IL-1-receptor inhibitor (anakinra) to colchicine in controlling the febrile attacks and acute phase response in an adolescent with FMF resistant to colchicine.     

Periodic Fever: A Review on Clinical,Management and Guideline for Iranian Patients - Part II

Periodic fever syndromes are a group of diseases characterized by episodes of fever with healthy intervals between febrile episodes. In the first part of this paper, we presented a guideline for approaching patients with periodic fever and reviewed two common disorders with periodic fever in Iranian patients including familial Mediterranean fever (FMF) and periodic fever syndromes except for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA). In this part, we review other autoinflammatory disorders including hyper IgD, tumor necrosis factor receptor–associated periodic syndrome (TRAPS), cryopyrin associated periodic syndromes, autoinflammatory bone disorders and some other rare autoinflammatory disorders such as Sweet’s and Blau syndromes. In cryopyrin associated periodic syndromes group, we discussed chronic infantile neurologic cutaneous and articular (CINCA) syndrome, Muckle-Wells syndrome and familial cold autoinflammatory syndrome. Autoinflammatory bone disorders are categorized to monogenic disorders such as pyogenic arthritis, pyoderma ;gangraenosum and acne (PAPA) syndrome, the deficiency of interleukine-1 receptor antagonist (DIRA) and Majeed syndrome and polygenic background or sporadic group such as chronic recurrent multifocal osteomyelitis (CRMO) or synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome are classified in sporadic group. Other autoinflammatory syndromes are rare causes of periodic fever in Iranian system registry. Key Words: Periodic Fever; Hyper IgD; TRAPS; Autoinflammatory Bone Disorder; Cryopyrin Associated Periodic Syndromes; Sweet’s Syndrome; Blau Syndrome     

Heredit?re rekurrierende Fiebersyndrome (HRF)

Background

Hereditary recurrent fever (HRF) syndromes are autoinflammatory diseases (AID) characterized by recurrent, self-limiting and systemic inflammation and are accompanied by a dysregulation of innate immunity.

Methods

The federally funded clinical and research consortium AID-Net recruits clinical data of patients with HRF syndromes in an online registry (http://www.aid-register.uk-essen.de) and analyzes blood samples for genetic and biomarkers testing.

Results

A total of 202 patients have been recorded in the AID registry: Familial Mediterranean fever (FMF, n=177), TNF receptor 1-associated periodic syndrome (TRAPS, n=17), cryopyrin-associated periodic syndrome (CAPS, n=6) and hyperimmunoglobulinemia D and periodic fever syndrome (HIDS, n=2). Attacks of recurrent fever with multiple systemic involvement (e.g. skin, joints and abdomen) were common for all HRFs. Ethnic origin, increased inflammation parameters and disease-associated mutations were important for diagnosis. A widespread lack of knowledge on HRFs and lacking functional laboratory tests led to a delay in correct diagnosis of between 2.5 and 9 years.

Conclusion

Rare forms of HRF are largely unknown in spite of typical symptoms. The national and international cooperation AID-Net combines basic and clinical research on epidemiology, clinical and immunological features as well as molecular genetics and identification of new diseases.     

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??Periodic fever-aphthous stomatitis-pharyngitis-adenitis??PFAPA?? syndrome is the most frequent cause of recurrent fevers in childhood and presents with the cardinal symptoms of periodic fever??aphthous stomatitis??pharyngitis??and adenitis typically before 5 years old. The pathogenesis of PFAPA is still unknown and theories about the pathogenesis of PFAPA include faulty innate immunologic response with dysregulated T-cell activation. The potential hereditary nature of PFAPA is still disputed and the Mediterranean fever??MEFV?? gene mutation??implicated in familial Mediterranean fever??FMF????has a possible association with PFAPA. It appears to modify disease severity. Diagnostic criteria include the traditional clinical signs??as well as the following biomarkers??elevated C-reactive protein??vitamin D??CD64??C-X-C motif ligand 10??CXCL10?? and other nonspecific inflammatory mediators. Because PFAPA is self-limited and benign??there is no certain treatment model. Treatment for PFAPA includes a single dose of corticosteroids??tonsillectomy??and most recently??interleukin 1 inhibitors. Treatment options must be specific to the patient. More large cohort studies are needed to explore the inhereditary nature and specific biomarkers of PFAPA??to standardize the diagnosis and treatment process in order to improve the life quality of the children.     

Autoinflammatorische Syndrome im Kindesalter

Systemic autoinflammatory diseases are a group of hereditary and non-hereditary diseases of the innate immune system, characterized by inflammation with no apparent cause, recurrence at irregular intervals and manifestation on the skin, mucous membranes, joints, bone, gastrointestinal tract, blood vessels and the central nervous system (CNS). Amyloidosis and other possibly severe long-term complications are important. Advances in genetics and molecular biology have improved 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 syndrome and improved others. The vast majority of these diseases are based on activation of the interleukin-1 (IL-1) pathway, so that inhibition of IL?1 provides a therapeutic option. Other syndromes are characterized by a granulomatous inflammation. Newer autoinflammatory diseases, such as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) and stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) are, however, driven by interferons.     

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??Cryopyrin-associated periodic syndromes??CAPS????also known as cryopyrinopathy??includes three kinds of diseases??familial cold autoinflammatory syndrome??FCAS????Muckle-Wells syndrome??MWS?? and neonatal onset multisystem inflammatory disease??NOMID??/chronic infantile neurological cutaneous and articular syndrome??CINCA??. CAPS are autosomal dominant disorders caused by mutations in the NLRP3??NOD-like receptor 3??also named CIAS1????located in chromosomal position 1q44 and encoding the cryopyrin protein. The clinical characteristics of CAPS are recurrent systemic inflammation??manifested with fever??arthralgia and urticaria??and may affect multiple systems and organs??such as skin??muscles??bones??joints??eyes??ears and central nervous system??CNS??. The severity of the 3 subtypes from mild to severe was FACS??MWS and NOMID/CINCA respectively. Interleukin??IL??-1 inhibitor could effectively control the progress of the disease??and should be applied as soon as possible after definite diagnosis.     

冷炎素相关周期热综合征

冷炎素相关周期热综合征（CAPS）也称为冷炎素病, 包括3种疾病： 家族性寒冷性自身炎症综合征（FCAS）、Muckle-Wells 综合征（MWS）、 新生儿多系统炎性疾病或慢性婴儿神经皮肤关节综合征（NOMID/CINCA）。为常染色体显性遗传病, 基因位于染色体1q44的NLRP3, 也称为CIAS1, 编码细胞内NOD样受体（NLRs）家族成员之一的NALP3, 即cryopyrin。其临床特征是反复发作的多系统炎症,主要表现为发热、关节痛及荨麻疹,可累及皮肤、肌肉、骨骼、关节、眼、耳以及中枢神经系统,3种亚型的病情从轻到重分别为FCAS、MWS和NOMID/CINCA;白细胞介素（IL）-1抑制剂可有效地控制病情进展,应尽早应用。     

Familial mediterranean fever: revisiting an ancient disease

Familial Mediterranean fever (FMF) is an auto-inflammatory disease characterised by periodic attacks of fever and serositis. Recent genetic and epidemiological research have highlighted the importance of this disease. FMF is the most frequent periodic fever syndrome and is transmitted in an autosomal recessive fashion. The disease is caused by mutations in the gene on the short arm of chromosome 16, coding for the protein "pyrin". Pyrin is mainly expressed in neutrophils and monocytes and is among the proteins involved in the interleukin-1 inflammatory pathway. The recurrent attacks of fever are accompanied by severe abdominal pain, arthritis and/or chest pain along with a marked increase in acute phase reactants. Among these, serum amyloid A protein is especially important since it is the precursor of the amyloid A fibrils deposited in secondary renal amyloidosis. Renal amyloidosis has a grave prognosis. Differential diagnosis from other periodic fever syndromes is especially important in western European countries. Among these hyper IgD syndrome is common in Netherlands and the tumour necrosis factor receptor-associated periodic syndrome is especially common among Scottish and Irish families. Mutation analysis of the gene may be helpful in diagnosing FMF; however, if this is not possible, a trial of colchicine is a helpful diagnostic tool. The indications for life-long colchicine treatment should be discussed with the family. CONCLUSION: Familial mediterranean fever and other auto-inflammatory syndromes should be suspected in children with recurrent febrile attacks. Early diagnosis will save the child from unnecessary work-up and kidney involvement.     

周期性中性粒细胞减少症的诊治进展

周期性中性粒细胞减少症(cyclic neutropenia,CN)是以周期发作性的中性粒细胞减少伴反复感染为特征的遗传病,可散发或家族性发病.CN于1910年被首次报道,直到1999年才有研究者进一步发现其病因,因其发病率较低,在我国罕有报道.CN是由于嗜中性粒细胞弹性蛋白酶(ELA2或ELANE)基因突变所致,是一种罕见的常染色体显性遗传病.CN的诊断主要依据其病史和血液学特征性的周期变化.随着诊疗技术的不断发展,基因检测对于CN的确诊有一定意义.关于治疗,主要是预防感染、对症治疗和应用粒细胞集落刺激因子等.CN虽是一种血液系统疾病,但多数预后良好,并不会发生恶性血液系统疾病如白血病等.目前,临床医生对CN认识仍不足,常会漏诊,并且其发病时无明显特异性,亦常被误诊.为加强对该病的认识,提高诊治水平,明确诊疗方案,该文对CN的发病机制、临床表现、实验室检查特点、诊断及治疗进行了系统总结.     

Periodic fever syndromes

Human autoinflammatory diseases (except for the periodic fever, adenopathy, pharyngitis, aphthae syndrom) are a heterogeneous group of genetically determined diseases characterized by seemingly unprovoked inflammation, in the absence of autoimmune or infective causes. Tremendous advances in the understanding of these disorders have been seen in the last decade. This article discusses hereditary autoinflammatory syndromes that are associated with recurrent fevers.     

Etanercept plus colchicine treatment in a child with tumour necrosis factor receptor-associated periodic syndrome abolishes auto-inflammatory episodes without normalising the subclinical acute phase response

We investigated the cause of hereditary periodic fever syndrome in a Spanish child with recurrent long episodes of fever, migratory skin rash, myalgia, arthralgia, conjunctivitis and abdominal pain. Infectious and autoimmune causes were ruled out. No familial history was reported. Analysis of the tumour necrosis factor receptor superfamily 1A ( TNFRSF1A) gene identified a missense mutation (G36E) on exon 3. The absence of this variant in the patients parents and in controls identified it as a de novo disease-associated mutation. Clinical symptoms disappeared with administration of etanercept; however, levels of acute-phase reactants remained increased and could not be stabilised by the addition of colchicine. We believe that this patient gained some symptomatic relief with etanercept therapy, although not enough to completely avoid the risk of amyloidosis. Thus it is debatable whether etanercept alone or combined with other drugs, is the treatment of choice for patients with tumour necrosis factor receptor-associated periodic syndrome. Conclusion:Since there is variability in treatment responses among different patients with tumour necrosis factor receptor-associated periodic syndrome, we suggest that a systematic evaluation of acute-phase reactants, especially SAA-1, could be useful in maintaining or modifying a given therapeutic approach in these patients.Both J. I. Aróstegui and P. Solís contributed equally to this work.     

Fever tree revisited:From malaria to autoinflammatory diseases

Over the centuries the idea of recurrent fevers has mainly been associated with malaria, but many other fevers, such as typhoid and diphtheria were cause for concern. It is only in recent times, with the more severe forms of fever from infectious origin becoming less frequent or a cause for worry that we started noticing recurrent fevers without any clear infectious cause, being described as having a pathogenesis of autoinflammatory nature. The use of molecular examinations in many cases can allow a diagnosis where the cause is monogenic. In other cases, however the pathogenesis is likely to be multifactorial and the diagnostic-therapeutic approach is strictly clinical. The old fever tree paradigm developed to describe fevers caused by malaria has been revisited here to describe today's periodic fevers from the periodic fever adenitis pharyngitis aphthae syndrome to the more rare autoinflammatory diseases. This model may allow us to place cases that are yet to be identified which are likely to be of multifactorial origin.