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Autoinflammatory Syndromes De Sanctis et al. Italian Journal of Pediatrics 2010, 36:57 http://www.ijponline.net/content/36/1/57 ITALIAN JOURNAL OF PEDIATRICS REVIEW Open Access Autoinflammatory syndromes: diagnosis and management Sara De Sanctis*, Manuela Nozzi, Marianna Del Torto, Alessandra Scardapane, Stefania Gaspari, Giuseppina de Michele, Luciana Breda, Francesco Chiarelli Abstract During the last decades the description of autoinflammatory syndromes induced great interest among the scienti- fic community. Mainly rheumatologists, immunologists and pediatricians are involved in the discovery of etiopatho- genesis of these syndromes and in the recognition of affected patients. In this paper we will discuss the most important clues of monogenic and non-genetic inflammatory syndromes to help pediatricians in the diagnosis and treatment of these diseases. Introduction fever (FMF), hyper IgD syndrome (HIDS), tumor necro- The first time that a periodic disease was mentioned in sis factor receptor associated autoinflammatory syn- the medical literature was in 1802 when Heberden drome (TRAPS), cryopyrin associated periodic described a condition characterized by recurrent abdom- syndromes (CAPS), Blau syndrome and pyogenic sterile inal pain, thoracic pain and painful extremities. Later arthritis pyoderma gangrenosum and acne syndrome several syndromes with recurrent episodes of fever and (PAPA). Some of these genes are still available for the inflammatory symptoms were recognized, some of molecular diagnosis, especially in patients with familial which with Mendelian inheritance pattern [1,2]. The recurrence or with highly suggestive clues. Gattorno and term hereditary recurrent fever syndrome was associated collegues identified major clinical clues to predict the to this group of syndromes; attacks begin early, usually possibility of a genetic alteration in a suspected autoin- before 10 years of age and recur with irregular intervals flammatory syndrome. Early onset, family history of per- of time [3]. During the past decade, the term “autoin- iodic fever, thoracic and abdominal pain, diarrhea and flammatory syndromes” was introduced by Kastner to oral aphtous ulcers represent the most relevant clues to include all those disorders that did not fit into classical predict the possibility of a positive genetic test. The groups of immune-mediated diseases, and characterized authors also proposed a flow chart based on the clinical by recurrent fever associated with rheumatologic symp- profile of patients with suspected autoinflammatory syn- toms involving joints, skin, muscles, and eyes. The main dromes with the purpose to identify patients with effec- difference with autoimmune diseases is that neither tive need of a genetic analysis. Thanks to this method, autoantigens nor autoantibodies are involved. Autoin- the number of genetic tests and relative costs have been flammatory syndromes are associated to a disregulation significantly reduced [4]. of the innate immune response with subsequent epi- To date few periodic syndromes remain of unknown sodes of acute spontaneous inflammation [3]. This con- origin like PFAPA syndrome (periodic fever, aphtous cept was initially assigned to the hereditary recurrent stomatitis, pharyngitis and adenitis), characterized by fevers but now is expanding to a broad number of periodic fever attacks with early onset, of non-infective disorders. origin, with benign prognosis in the absence of familial Thanks to the advanced techniques in genetics, to inheritance [5] and Majeed syndrome, characterized by date many genes have been recognized in the pathogen- recurrent multifocal osteomyelitis (CRMO), congenital esis of periodic syndromes like familial Mediterranean dyserithropoietic anemia, and neutrophilic dermatosis. Epidemiological data about inflammatory diseases are poor; generally they are quite rare diseases. No gender * Correspondence: [email protected] Department of Pediatrics, University of Chieti, Via Vestini 5, 66100 Chieti, Italy prevalence has been described; only some reports © 2010 De Sanctis et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. De Sanctis et al. Italian Journal of Pediatrics 2010, 36:57 Page 2 of 7 http://www.ijponline.net/content/36/1/57 recorded mild predominance in males for FMF [6]. The episodes may mimic acute appendicitis and many prevalence of other autoinflammatory syndromes is patients have undergone appendicectomy [11]. Chest lower than FMF, but not yet quantified. pain because of pleuric or pericardial involvement There are not specific and standardized therapies for occurs in 33-53% of subjects. Patients with pleural invol- the acute attacks of fever. On the other way long term vement may have shallow breathing and dyspnoea. Mus- treatment is available, effective in reducing the number culo-skeletal involvement is frequent and characterized and intensity of attacks and preventing severe complica- by myalgia, arthritis and/or arthralgia. Arthritis occurs tions like amyloidosis. in about 25 to 41% of cases [10]. It may be divided into Acute attacks, especially in FMF, usually need a com- three groups: 1) asymmetrical non destructive arthritis, bination of drugs like non steroidal anti-inflammatory in which one or two joints are swollen (most frequent drugs (NSAIDs) and analgetics. by knees, ankles, and wrists) 2) chronic destructive The proven effectiveness of anti IL-1 drugs in many arthritis, including sacroiliitis, 3) migratory polyarthritis. autoinflammatory disorders made these drugs as first Splenomegaly and scrotal pain may be present in pre- line choice in long-term treatment. pubertal children during attacks. Thirty per cent of patients experience painful erysipela-like skin lesions Familial Mediterranean fever (FMF) usually on the distal extremities. A number of other dif- FMF, first described in 1945 by Siegal, is the most com- ferent cutaneous manifestations such as Henoch-Schön- mon autoinflammatory syndrome. It is an autosomal lein purpura and polyarteritis nodosa can also occur recessive inherited condition, prevalent among people of during fever episodes [2,10,11]. Mediterranean descent (Arabs, Turks, Armenians, non- Laboratory investigations during acute attacks are non- Ashkenazi and Sephardic Jews) but may affect any eth- specific: leukocyte count, sedimentation rate and C-reac- nic group [7]; its prevalence is high among Sephardic tive protein (CRP) are often elevated during flares [2]. Jews (100-400 every 100000 inhabitants) and quite low Amyloidosis is the most significant complication of in west Europeans (2.5 per 100000) [3]. FMF and may result in a progressive accumulation of FMF is caused by mutations in the MEFV (MEditerra- serum amyloid A protein (SAA) mainly in the kidney. nean FeVer) gene, located on the short arm of chromo- The most common clinical manifestation of amyloidosis some 16 (16p13.3). At least 100 disease-linked is the development of proteinuria that may lead to renal mutations in the MEFV gene have been described, the failure. Patients are frequently normotensive and do not most being clustered in the 10th exon of this gene. The present hematuria. Before the advent of colchicine, the MEFV gene encodes for a protein of 781 aminoacids prevalence of amyloidosis among FMF patients was high known as pyrin (or marenostrin). Pyrin is primarily ranging from 60% to 80% [12]. Renal involvement is expressed in neutrophils, eosinophils, monocytes, den- usually observed after a variable time from disease dritic cells and fibroblasts. Wild-type pyrin suppresses onset. In few patients (less than 1%), renal amyloidosis inflammasome-mediated IL-1b production. Furthermore, may represent the first manifestation of the disease [6]. wild-type pyrin plays an antiapoptotic role through inhi- Acute attacks of FMF usually respond to a combina- bition of NF-kB nuclear trascription factor [8]. The tion of non-steroidal anti-inflammatory drugs (NSAIDs) most commonly reported mutations of MEFV gene are and analgesics. Colchicine is the treatment of choice for M694V, M680I and V726A. The presence of M694V FMF. It greatly reduces the frequency and intensity of mutation has been associated with more severe disease clinical attacks and prevents the development of renal course and in particular with the development of amy- amyloidosis. In adults the dose is 1 mg/day. In children loidosis [9]. the starting dose should be ≤0.5 mg/day for children FMF is clinically characterized by recurrent attacks of below 5 years of age, 1 mg/day for children 5-10 years, high spiking fever with associated serositis that usually and 1.5 mg/day for children above 10 years. Dosage can last 1-3 days and subside spontaneously. Frequency of be increased in a stepwise fashion up to a maximum of attacks is highly variable and asymptomatic periods last- 2 mg/day [2]. Only 5% of patients are non responders. ing a few years have been reported [3]. Triggers may Lack of response to colchicine is often caused by poor include stress, menstrual cycle, exercise and subclinical adherence to treatment [3]. infections [7]. Recurrent fever may be the only manifes- Biologic treatments (anti TNF-a,antiIL-1b)have tation in childhood [10]. Abdominal pain is present in been proposed in non responsive patients, although 95% of cases and is associated with board-like
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