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Background: To derive a list of opportunistic infections (OI) through the analysis of the juvenile idiopathic arthritis (JIA) patients in the Pharmachild registry by an independent Safety Adjudication Committee (SAC). Methods: The SAC (3 pediatric rheumatologists and 2 pediatric infectious disease specialists) elaborated and approved by consensus a provisional list of OI for use in JIA. Through a 5 step-procedure, all the severe and serious infections, classified as per MedDRA dictionary and retrieved in the Pharmachild registry, were evaluated by the SAC by answering six questions and adjudicated with the agreement of 3/5 specialists. A final evidence-based list of OI resulted by matching the adjudicated infections with the provisional list of OI. Results: A total of 772 infectious events in 572 eligible patients, of which 335 serious/severe/very severe non-OI and 437 OI (any intensity/severity), according to the provisional list, were retrieved. Six hundred eighty-two of 772 (88.3%) were adjudicated as infections, of them 603/682 (88.4%) as common and 119/682 (17.4%) as OI by the SAC. Matching these 119 opportunistic events with the provisional list, 106 were confirmed by the SAC as OI, and among them infections by herpes viruses were the most frequent (68%), followed by tuberculosis (27.4%). The remaining events were divided in the groups of non-OI and possible/patient and/or pathogen-related OI. Conclusions: We found a significant number of OI in JIA patients on immunosuppressive therapy. The proposed list of OI, created by consensus and validated in the Pharmachild cohort, could facilitate comparison among future pharmacovigilance studies. © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

A few studies have reported the safety profile of interleukin (IL)-1 blockers from real life. The aim of this study is to describe anakinra (ANA) and canakinumab (CAN) safety profile in children and adults, based on data from a real-life setting. Demographic, clinical, and therapeutic data from patients treated with ANA and CAN were retrospectively collected and analyzed. Four hundred and seventy five patients were enrolled; ANA and CAN were prescribed in 421 and 105 treatment courses, respectively. During a mean follow-up of 24.39 ± 27.04 months, 89 adverse events (AE) were recorded; 13 (14.61%) were classified as serious AE (sAE). The overall estimated rate of AE and sAE was 8.4 per 100 patients/year. Safety concerns were more frequent among patients aged ≥ 65 years compared with patients < 16 years (p = 0.002). No differences were detected in the frequency of safety concerns between monotherapy and combination therapy with immunosuppressants (p = 0.055), but a significant difference was observed when injection site reactions were excluded from AE (p = 0.01). No differences were identified in relation to gender (p = 0.462), different lines of biologic therapy (p = 0.775), and different dosages (p = 0.70 ANA; p = 0.39 CAN). The overall drug retention rate was significantly different according to the occurrence of safety concerns (p value < 0.0001); distinguishing between ANA and CAN, significance was maintained only for ANA (p < 0.0001 ANA; p > 0.05 CAN). Treatment duration was the only variable associated with onset of AE (OR = 0.399 [C.I. 0.250–0.638], p = 0.0001). ANA and CAN have shown an excellent safety profile; the risk for AE and sAE tends to decrease over time from the start of IL-1 inhibition.

To assess the efficacy of monoclonal anti-tumour necrosis factor (TNF)-α agents in patients with anterior uveitis (AU) in terms of decrease of recurrences, variation of visual acuity and steroid sparing effect and to identify any demographic, clinical or therapeutic variables associated with a sustained response to monoclonal TNF-α inhibitors.Data from patients suffering from AU treated with adalimumab, infliximab, golimumab or certolizumab pegol were retrospectively collected and statistically analysed.Sixty-nine patients (22 males, 47 females), corresponding to 101 eyes, were enrolled. The mean follow-up period was 29.25±23.51 months. The rate of ocular flares decreased from 42.03 events/100 patients/year recorded during the 12 months preceding the start of TNF-α inhibitors to 2.9 flares/100 patients/year after the start of treatment (p0.0001). The overall decrease in ocular flares was 93.1%. No statistically significant changes were identified in the best corrected visual acuity during the follow-up period (p0.99). The number of patients treated with corticosteroids at baseline was significantly higher compared with that referred to the 12-month evaluation (p0.001) and to the last follow-up visit (p=0.006). Concomitant treatment with conventional disease-modifying anti-rheumatic drugs (cDMARDs) represented the sole clinical, demographic or therapeutic variable associated with long-term treatment duration (p=0.045, R2=0.87).Monoclonal TNF-α inhibitors induce a remarkable decrease in the recurrence of AU during a long-term follow-up period and lead to a significant steroid sparing effect along with stabilisation of visual acuity. Concomitant treatment with cDMARDs represented the sole variable associated with treatment duration in the long-term.

Clinical research is needed to identify patients with axial spondyloarthritis (axSpA) who are more likely to be responsive to interleukin (IL)-17 inhibition.To evaluate short-term efficacy of secukinumab in the management of axSpA.Twenty-one patients (7 males, 14 females) with axSpA were consecutively treated with secukinumab. Laboratory and clinical assessments were based on erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Data were recorded at baseline and at a 3 month follow-up visit.The study was comprised of 21 patients. Both BASDAI and ASDAS-CRP showed a statistically significant reduction between the baseline and the 3 month visit (P0.0001 and P = 0.0005, respectively). During the laboratory assessment, ESR showed a significant decrease (P = 0.008) while CRP improvement did not reach statistical significance (P = 0.213). No statistical significance was observed between patients treated with secukinumab 150 mg vs. 300 mg in BASDAI (P=0.99), ASDAS-CRP (P = 0.69), ESR (P = 0.54), and CRP (P = 0.56). No significant differences emerged between the BASDAI (P = 0.15), ASDAS-CRP (P = 0.09), and CRP (P = 0.15) rates in biologic-naïve patients and those previously failing tumor necrosis factor-α inhibition. Conversely, ESR decrease was significantly higher in the biologic-naïve subgroup (P = 0.01). No adverse events were reported.Secukinumab has proven remarkable short-term effectiveness, regardless of the biologic treatment line. A dosage of 150 mg proved to be appropriate in the clinical and laboratory management of axSpA.

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.

In recent years interest has grown on the applications of polymer physics to model chromatin folding in order to try to make sense of the complexity of experimental data emerging from new technologies such as Hi-C or GAM, in a principled way. Here we review the methods employed to efficiently implement Molecular Dynamics computer simulations of polymer models, focusing in particular on the String&Binders Switch (SBS) model. The constant improvement of such methods and computer power is returning increasingly more accurate insights on the structure and molecular mechanisms underlying the spatial organization of chromosomes in the cell nucleus. We aim to provide an account of the state of the art of computational techniques employed in this type of investigations and to review recent applications of such methods to the description of real genomic loci, such as the Sox9 locus in mESC.

An apparently unprovoked recurrent inflammation is the quintessential hallmark of autoinflammatory diseases (AIDs), a large and heterogeneous group of disorders in which there is poor regulation of the innate immune system with no clearly demonstrated autoimmune machinery involvement. Innate immunity pathways are diverse and our understanding of their molecular composition and function is continuously expanding. The impaired immune responses we observe in monogenic AIDs, mostly in the hereditary periodic fever syndromes, is officiated by target molecules of microbial origin (pathogen-associated molecular patterns) and also host molecules (danger-associated molecular patterns). Further crucial components of innate immune mechanisms that contribute differently in the deregulated inflammatory patterns of different AIDs include Toll-like receptors, Nod-like receptors, scaffolding proteins (such as the caspase recruitment domain of proteins), cytosolic DNA-sensing molecules, inflammatory multi-protein complexes (referred to as inflammasomes), complement system, and others. In recent years, the knowledge of protean molecular pathways responsible for the most common monogenic AIDs has expanded, in parallel with very recent extraordinary technological advances, allowing the identification and characterisation of some unknown aspects of the innate immunity. This review will list and describe the most common monogenic febrile syndromes belonging to AIDs and will focus on current insights dealing with their pathologic processes.

OBJECTIVE: Mevalonate kinase deficiency (MKD) is a rare metabolic disease characterized by recurrent inflammatory episodes. This study was undertaken to describe the genotype, phenotype, and response to treatment in an international cohort of MKD patients. METHODS: All MKD cases were extracted from the Eurofever registry (Executive Agency for Health and Consumers project no. 2007332), an international, multicenter registry that retrospectively collects data on children and adults with autoinflammatory diseases. RESULTS: The study included 114 MKD patients. The median age at onset was 0.5 years. Patients had on average 12 episodes per year. Most patients had gastrointestinal symptoms (n = 112), mucocutaneous involvement (n = 99), lymphadenopathy (n = 102), or musculoskeletal symptoms (n = 89). Neurologic symptoms included headache (n = 43), cerebellar syndrome (n = 2), and mental retardation (n = 4). AA amyloidosis was noted in 5 patients, almost twice as many as expected from findings in previous cohorts. Macrophage activation syndrome occurred in 1 patient. Patients were generally well between attacks, but 10-20% of the patients had constitutional symptoms, such as fatigue, between fever episodes. Patients with p.V377I/p.I268T compound heterozygosity had AA amyloidosis significantly more often. Patients without a p.V377I mutation more often had severe musculoskeletal involvement. Treatment with nonsteroidal antiinflammatory drugs relieved symptoms. Steroids given during attacks, anakinra, and etanercept appeared to improve symptoms and could induce complete remission in patients with MKD. CONCLUSION: We describe the clinical and genetic characteristics of 114 MKD patients, which is the largest cohort studied so far. The clinical manifestations confirm earlier reports. However, the prevalence of AA amyloidosis is far higher than expected.

Item does not contain fulltext 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.

Fevers recurring at a nearly predictable rate every 3-8 weeks are the signature symptom of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome, an acquired autoinflammatory disorder which recurs in association with at least one sign among aphthous stomatitis, pharyngitis, and/or cervical lymph node enlargement without clinical signs related to upper respiratory airways or other localized infections. The disease usually has a rather benign course, although it might relapse during adulthood after a spontaneous or treatment-induced resolution in childhood. The number of treatment choices currently available for PFAPA syndrome has grown in recent years, but data from clinical trials dedicated to this disorder are limited to small cohorts of patients or single case reports. The response of PFAPA patients to a single dose of corticosteroids is usually striking, while little data exist for treatment with cimetidine and colchicine. Preliminary interesting results have been published with regard to vitamin D supplementation in PFAPA syndrome, while inhibition of interleukin-1 might represent an intriguing treatment for PFAPA patients who have not responded to standard therapies. Tonsillectomy has been proven curative in many studies related to PFAPA syndrome, although the evidence of its efficacy is not widely shared by different specialists, including pediatricians, rheumatologists and otorhynolaryngologists.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome is a non-Mendelian autoinflammatory disorder until now considered to be specifically limited to paediatric age. Recently, an increasing number of reports seems to suggest that PFAPA syndrome, diagnosed by the Marshall criteria revised by Thomas et al., can also affect adults.The Marshall/Thomas criteria have been applied to 989 adult patients presenting for recurrent fever episodes: all patients enrolled were reviewed for demographic, clinical, and therapeutic data. Infectious, neoplastic, autoimmune and other autoinflammatory diseases were ruled out.We identified 30 adult patients (19 males, 11 females) with a suspected PFAPA syndrome: their mean age at disease onset was 33.75±14.01 years, mean age at diagnosis 39.1±14.39 years, and mean body temperature peak 39.5±0.7°C. In addition, the mean frequency of febrile episodes was 11.58±8.97 per year. More precisely, patients complained of pharyngitis (77%), cervical adenitis (73%), asthenia (63%), arthralgia (67%), oral aphthosis (50%), myalgia (54%), cephalalgia (43%), abdominal pain (27%), nausea/vomiting (17%), periorbital pain (17%), and arthritis (10%). Six out of 30 (20%) patients had suffered from PFAPA syndrome also during childhood, and the disease had reappeared in adulthood.We provide the largest monocentric cohort of patients diagnosed with a suspected PFAPA syndrome in adulthood confirming that this syndrome can occur also during adulthood; moreover, due to the medical history of our patients and based on our experience, PFAPA syndrome might relapse during adulthood after a temporary remission reached in the course of paediatric age.

Objective. Pharmacogenomics is considered as the new frontier to predict the response to treatments and it can also be based on the comparison of family members being treated for the same condition. No data are available on the impact of anti-tumour necrosis factor (TNF)-α therapies in members of the same family with ankylosing spondylitis (AS). Methods. We describe three motherdaughter couples concordant for AS and HLA-B27, both treated with TNF-α inhibitors, for whom the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP were evaluated during a follow-up of 24 months. Results. All patients manifested improvements of all scores, but the daughters had a more prominent effect achieving faster complete disease remission. Conclusion. We hypothesise that longer standing chronic inflammation and older age may cause a less prompt and effective response to treatment in SA when compared with their genetically related controls.

Autoinflammatory and autoimmune disorders are characterized by chronic activation of the immune system, which leads to systemic self-directed inflammation in genetically predisposed individuals. Mutations in inflammasome-related proteins have been associated with autoinflammatory disorders, and the link between inflammasome and autoimmune disorders is becoming increasingly clear. As researchers learn more about these two areas, other disorders that were once thought to be autoimmune are now being considered autoinflammatory, or as having at least an autoinflammatory component. This review depicts the role of interleukin-1 as "Ariadne's thread" on the path through the labyrinth of autoinflammatory and autoimmune disorders and emphasizes the blurred boundary between innate and adaptive immune systems.

Tumour necrosis factor-receptor associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder characterised by recurrent episodes of long-lasting fever and inflammation in different regions of the body, as musculo-skeletal system, skin, gastrointestinal tube, serosal membranes and eye. Inflammatory attacks usually start in the pediatric age with initial corticosteroid-responsiveness. Most reported cases of TRAPS involve patients of European ancestry and diagnosis can be formulated by the combination of genetic analysis and a compatible phenotype. Its prognosis is strictly dependent on the appearance of amyloidosis, secondary to uncontrolled relapsing inflammation. Thanks to a better understanding of its pathogenesis, the disease is now managed with anti-interleukin (IL)-1 antagonists, rather than corticosteroids or tumour necrosis factor (TNF) inhibitors. The aim of this review is to describe the current understanding and advances of TRAPS genetic basis, pathogenesis and management options by integrating the most recent data in the medical literature.

The pathophysiology of PFAPA syndrome, mainly characterised by regularly recurring periodic fevers associated with aphthous stomatitis, pharyngitis and/or lymphadenitis, and mostly occurring in the paediatric setting, resembles an acquired autoinflammatory disease. The description of PFAPA syndrome in adult patients is largely increasing.To recognise PFAPA syndrome in a group of adult patients evaluated for recurrent fevers in our Rheumatology Unit.To apply current diagnostic criteria for PFAPA syndrome in a group of 359 adults with unexplained recurrent fevers monitored in our Unit between January 2007 and June 2011.We have found 17 out of 359 patients fulfilling the diagnosis of PFAPA syndrome: these patients (10 males, 7 females) were Caucasian with a mean age of 33.3±9.5 years, had recurrent febrile episodes begun at a mean age of 25.9±8.3 years and a mean number of episodes of 8.3±5.2 per year with a mean duration of 5.5±1.8 days. In particular, 7/17 patients had the 3 cardinal signs, the other 10 had a combination of 2 signs. Corticosteroids were given in 14/17 patients; tonsillectomy was performed in 9/17 patients: corticosteroid responsiveness and tonsillectomy efficacy were observed respectively in 11 and 2 patients.Our case highlights the importance of considering PFAPA syndrome in adults presenting with unexplained recurrent fevers and symptoms commonly encountered in general medical practice.

We present a five-year-old boy with an unremarkable medical history who was incidentally found to have bradycardia and electrocardiographic signs of right axial deviation. Initial echocardiogram showed left displacement of the cardiac apex with slight enlargement of the right ventricle, while frontal chest radiograph showed a lucent area between the aorta and pulmonary artery. Cardiac magnetic resonance imaging finally revealed a partial left pericardial agenesis and abnormal displacement of the heart into the left hemithorax.

Objective: Polyarteritis nodosa (PAN) is a rare vasculitis in childhood and poor information is known about its long-term outcome. Our aim was to describe the clinical features, at onset and during the disease course, of childhood- onset PAN and identify a potential correlation with persistent organ damage and worse outcome in a cohort of paediatric patients with a confirmed diagnosis of PAN. Methods: A retrospective collection of demographic and clinical data of 52 Caucasian children diagnosed with PAN, fulfilling the EULAR/PRES diagnostic criteria, recruited from eight paediatric rheumatologic centres and one transition unit, was performed. A statistical correlation was made between clinical involvement at onset or during the overall disease course and patients' final outcome. Results: Data from 52 patients (31 males, 21 females) were collected: their mean age at onset was 7.9 years (median 6.3) and mean follow-up period was 6.2 years (median 5.4). At the last follow-up visit, 27 patients (51.9%) were off therapy in clinical remission, 17 (32.7%) were in clinical remission while on medication, and 6 (11.6%) had a persistent or relapsing disease course. Two patients (3.8%) deceased because of severe cerebral involvement. Cranial nerve palsy during the disease course was significantly correlated with a worse prognosis (p=0.011). The presence of nephrogenic hypertension at onset and seizures during the disease course were significantly associated with the development of irreversible organ damage (p= 0.040 and 0.011, respectively). Conclusion: Childhood PAN is a severe disease with substantial risk of long-term morbidities. In our cohort of patients the worst outcome was significantly correlated with renal and neurological involvement. © Clinical and Experimental Rrheumatology 2014.

Objective: Cryopyrin-associated periodic syndromes (CAPS) are a group of chronic, relapsing autoinflammatory disorders which may be complicated by systemic AA amyloidosis. The aim of our study was to evaluate serum amyloid protein A (SAA) level in CAPS patients treated with Interleukin-1 beta (IL-1β) antagonist and to correlate its level with treatment response. Methods: All patients of CAPS Italian Register treated with IL-1β inhibitor were enrolled. SAA levels before starting therapy, and at last visit were evaluated. Patients were then divided in complete responders and partial responders. Results: Twenty-five patients were enrolled. SAA level before starting therapy was increased (median 118.5 mg/L, IQR 96.4-252.8; normal value < 6.4 mg/L), while at last visit SAA was significantly reduced (median 4.3 mg/L, IQR 2.3-12.7) (p < 0.001). However 12 patients still presented SAA levels beyond normal range, 10/25 patients (40%) showed a complete response to treatment. Conversely, 15 patients presented only a partial response, of which 12 for increased SAA value and 3 for increased CRP value. Patients with partial response had SAA values significantly higher than patients with complete response (median 12.6 mg/L; IQR 8.3-20.0 vs. 2.7 mg/L; IQR 1.6-4.1, p < 0.001). Conclusion: Our results confirm the long term efficacy of anti IL-1β treatment in CAPS and the decrease of SAA levels; however 48% of patients still presented SAA elevation despite treatment. The real risk of these patients in developing amyloidosis is not clear but the persistent increase of SAA needs a close follow-up.

To assess the efficacy of anti-tumour necrosis factor (TNF)-α agents in the treatment of refractory uveitic macular oedema (UME).Patients with refractory UME treated with TNF-α blockers were retrospectively enrolled. Central macular thickness (CMT) was assessed at optical coherence tomography (OCT) at the start of TNF-α inhibition, after 3 and 12 months, and at the last follow-up visit.Thirty-six patients (56 eyes with UME) were enrolled. The mean follow-up period was 29.9±40.8 (4-184) months. A statistically significant decrease was observed in the frequency of UME (p0.0001) and in the mean CMT values (p0.0001) during the study period. Best corrected visual acuity improved in 35 eyes (62.5%), remained stable in 12 eyes (21.4%), reduced in 9 eyes (16.1%). The mean corticosteroid dosage significantly decreased during the study period (p=0.016).TNF-α inhibitors represent a useful treatment in patients with severe or resistant UME.

Behçet's disease (BD) is an inflammatory disorder potentially leading to life- and sight-threatening complications. No laboratory marker correlating with disease activity or predicting the occurrence of disease manifestations is currently available.To determine an association between serum amyloid-A (SAA) levels and disease activity via the BD Current Activity Form (BDCAF), to evaluate disease activity in relation to different SAA thresholds, to examine the association between single organ involvement and the overall major organ involvement with different SAA thresholds, and to assess the influence of biologic therapy on SAA levels.We collected 95 serum samples from 64 BD patients. Related demographic, clinical, and therapeutic data were retrospectively gathered.No association was identified between SAA levels and BD disease activity (Spearman's rho = 0.085, P = 0.411). A significant difference was found in the mean BDCAF score between patients presenting with SAA levels200 mg/L and those with SAA levels200 mg/L (P = 0.027). SAA levels200 mg/L were associated with major organ involvement (P = 0.008). A significant association was found between SAA levels150 mg/dl and ocular (P = 0.008), skin (P = 0.002), and mucosal (P = 0.012) manifestations. Patients undergoing biologic therapies displayed more frequently SAA levels200 mg/L vs. patients who were not undergoing biologic therapies (P = 0.012).Although SAA level does not represent a biomarker for disease activity, it might be a predictor of major organ involvement and ocular disease relapse at certain thresholds in patients with BD.

Several studies have demonstrated that Helicobacter pylori (H. pylori) eradication does not affect metabolic control in diabetic patients. The prevalence of H. pylori infection and reinfection rate in adult diabetic patients seems to be higher than in controls.To evaluate the reinfection rate of H. pylori three years after a standard eradicating treatment and the late effect of eradication upon metabolic control in young diabetic patients.We enrolled 75 diabetic patients and 99 controls, from previous our studies in which we had evaluated H. pylori infection. In all subjects we re-evaluated the presence of H. pylori by means of 13C-Urea Breath Test, metabolic control and the prevalence of gastrointestinal symptoms. The effect of age, sex and socio-economic factors on H. pylori reinfection were also evaluated.The prevalence of H. pylori infection was higher in diabetic patients (17/69, 24%) than in dyspeptic controls of similar age, gender and socio-economical status after three years of follow-up. The reinfection rate was higher in diabetic patients than in controls. Multivariate analysis confirmed that age and socio-economical status were independently associated with H. pylori reinfection.Young patients with diabetes present a higher risk of H. pylori gastric reinfection than controls. In addition, age and mean annual income are associated with reinfection.

The aim of the study was to evaluate the efficacy of golimumab (GOL) and certolizumab pegol (CZP) as additional treatment options for the treatment of uveitis.Patients with longstanding uveitis receiving either GOL or CZP were retrospectively evaluated in terms of frequency of ocular flares, drug survival, changes in best corrected visual acuity (BCVA) and steroid-sparing effect.Twenty-one patients (30 eyes), 17 of whom being female, were enrolled in the study; 16 out of 21 patients had been previously treated with other tumour necrosis factor (TNF)-α blockers. A significant reduction in ocular flares (from 128.6 bouts for 100 patients-year to 42.9 events for 100 patients-year) was observed between the 12 months prior to the start of GOL or CZP and the 12 months thereafter (p=0.01). The 36-month drug survival was 54.5% for CZP and 50.0% for GOL with no statistically significant differences between the two biologic agents. No differences were detected concerning BCVA values and the mean corticosteroid intake between baseline and the last follow-up. The safety profile was excellent.GOL and CZP represent effective and safe treatment choices for patients with uveitis also when unsuccessfully treated with other anti-TNF-α drugs, permitting a significant reduction in the frequency of ocular flares and preserving visual function with a good long-term retention rate.

Aim of these revised recommendations for the general management of Kawasaki disease is to encourage its prompter recognition and warrant the most appropriate therapy, based on ascertained scientific data, raising awareness of the complications related to misdiagnosis or delayed treatment. A set of 20 synthetic operative statements is herein provided, including the definition of Kawasaki disease, its protean presentations, clinical course and seminal treatment modalities of all disease phases. The application of these recommendations should improve prognosis of Kawasaki disease and prevent the progression to permanent vascular abnormalities, thereby diminishing morbidity and mortality.

Familial Mediterranean fever (FMF) is characterized by self limited episodes of fever and polyserositis.1 MEFV gene en codes for a protein named Pyrin, which plays a pivotal role in the activation and secretion of IL-1.2 Daily colchicine is highly effective in preventing attacks in this disorder in a dose-related fashion.3 Many definitions of colchicine resistance are available in the literature. The European League Against Rheumatism (EULAR) guidelines defined resistance as one or more attacks per month in compliant patients who had been receiving the maxi mally tolerated dose for at least 6 months.4 A similar definition was confirmed by a recent consensus among experts.5 In the present national multicentric longitudinal study, we analyze the impact of colchicine treatment on disease activity and quality of life in real life in pediatric and adult patients with FMF.

Background Behçet’s disease is a rare multi-systemic inflammatory disease with unknown etiology which involves principally oral and genital mucosa, skin and eyes. Average age at onset of the disease is about 25-30 years, but it may be diagnosed before the age of 16. It is not very rare in Italy, even though there are limited data concerning epidemiology. Aim of this study is to describe the baseline data of an Italian cohort of patients with as having BD or probable BD. Methods We described the baseline data of the first national epidemiological study on children coming from 16 Italian Pediatric Rheumatologic Centers diagnosed by the treating physicians as having Behçet’s Disease. Data on demographic characteristics, clinical features and therapy were collected. We then compared our findings to those of international pediatric cohort studies and also retrospectively evaluated the ability to diagnose BD using ISG, ICBD and, for the first time, the new PEDBD criteria. Results The study included 110 patients (62 M, 48F). Average age at onset was 8.34±4.11 years. The frequencies of signs/symptoms were: recurrent oral aphtosis 94.5%, genital ulcers 33.6%, ocular 43.6%, gastrointestinal 42.7%, musculoskeletal 42.7%, neurological 30.9% and vascular involvement 10%. Thirty-two patients (29.1%) fulfilled ISG, 78 (70.9%) ICBD, 50 (45.5%) PEDBD criteria and 31 (28%) didn’t fulfill any of them. The most frequently used treatments were colchicine and corticosteroids followed by immunosuppressants. Four patients received biologic therapy (anti TNF-α and anti-IL-1) to treat severe organ involvement. Conclusions Recurrent oral aphtosis was the most frequent clinical manifestation, followed by ocular involvement. Gastrointestinal lesions were more frequent in Italy than in non-European countries as opposed to genital ulcers. Skin, ocular and vascular manifestations had a higher frequency in males and genital ulcers in females. Constitutional symptoms were present in 44.5% and recurrent fever in one third of our population.

© 2022 Elsevier Inc.Background/objectives: Long-term efficacy and safety of tocilizumab (TCZ) in adult-onset Still's disease (AOSD) mostly derive from small case series. Herein we report a registry-based study investigating TCZ efficacy and safety in a cohort of patients with AOSD evaluated by clinical and serum inflammatory markers as well as drug retention rate analysis. Methods: This is an international multicentre study analyzing data from patients with AOSD regularly enrolled in the AIDA registry. TCZ efficacy was evaluated between baseline and last follow-up assessment in terms of changes in the Pouchot score and laboratory findings. Drug-retention rate was estimated by the Kaplan-Meier method, while Cox-regression analysis was employed to detect potential predictive factors of treatment withdrawal. Results: Data from 31 patients (15 men, 16 women) refractory to the conventional therapies and treated with TCZ were extracted from the AIDA registry. Mean ± SD time of treatment duration with TCZ was 24.32 ± 20.57 months. Median (IRQ) Pouchot score significantly decreased throughout the study period (p=0.001) with a significant difference between baseline [2.00 (4.00)] and 6 month-follow-up [0.00 (0.00)] (p=0.003) and between baseline and last follow-up assessment [0.00 (0.00)] (p=0.032), while no differences were observed between 6 month-evaluation and last follow-up assessment (p=0.823). Similarly, laboratory parameters significantly decreased from baseline to the last follow-up visit. With regard to drug survival, cumulative TCZ retention rate at 12-, 24-, and 36-month follow-up visit were 83.1%, 71.7% and 63.7%, respectively, without significant differences between biologic naïve patients and those previously treated with other biologics (p=0.329). Likewise, no significant differences were observed between chronic articular course of AOSD and other types of disease course (p=0.938) or between patients co-administered with conventional immunosuppressants and patients receiving TCZ as monotherapy (p=0.778). Cox-regression analysis identified no variable associated with a higher hazard of treatment withdrawal. Treatment was discontinued in 9 patients due to long-term remission (n=4), adverse events (n=2), loss of efficacy (n=1), non-medical reason (n=1) and unspecified cause (n=1). Mean glucocorticosteroids daily dose significantly decreased from baseline (18.36 ± 24.72 mg) to the last follow-up assessment (4.02 ± 4.99 mg, p=0.003). Conclusions: TCZ allows control of disease activity as well as normalization of serum inflammatory markers in both systemic and chronic articular form of AOSD. Additionally, TCZ displays an excellent drug retention rate while minimizing the risk of long-term exposure to corticosteroids.

INTRODUCTION: New Eurofever/PRINTO classification criteria (EPCC) for Familial Mediterranean Fever (FMF) and other recurrent fevers have been recently developed, together with the classification of the pathogenicity of MEFV variants. OBJECTIVES: To evaluate the impact in real life of both the EPCC and INSAID pathogenicity classification of MEFV variants in the large international Eurofever FMF cohort. METHODS: Baseline demographic, genetic and clinical data of FMF patients included in the Eurofever registry were evaluated. The EPCC and the 2018 INSAID classification for MEFV variants were applied in all eligible FMF patients. RESULTS: Since November 2009, clinical information was available for 1012 FMF (532 males/480 females, 827 children/185 adults) from 119 centres. Complete data were available for 887 patients in whom 623 (70.2%) satisfied EPCC (EPCC+), while 264 (29.8%) did not (EPCC-). The majority of the EPCC- patients (172, 65.1%) displayed negative or non-informative genetics (monoallelic or biallelic benign variants, monoallelic variant of unknown significance). At baseline, colchicine was used in most of EPCC+ patients (88%) and in a lower percentage of EPCC- patients (69%, p

Background There is mounting evidence on the existence of a Pediatric Inflammatory Multisystem Syndrome-temporally associated to SARS-CoV-2 infection (PIMS-TS), sharing similarities with Kawasaki Disease (KD). The main outcome of the study were to better characterize the clinical features and the treatment response of PIMS-TS and to explore its relationship with KD determining whether KD and PIMS are two distinct entities. Methods The Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD (Kawasaki Disease Group – KDG) or KD-like (Kawacovid Group - KCG) disease between February 1st 2020, and May 31st 2020. Demographic, clinical, laboratory data, treatment information, and patients’ outcome were collected in an online anonymized database (RedCAP®). Relationship between clinical presentation and SARS-CoV-2 infection was also taken into account. Moreover, clinical characteristics of KDG during SARS-CoV-2 epidemic (KDG-CoV2) were compared to Kawasaki Disease patients (KDG-Historical) seen in three different Italian tertiary pediatric hospitals (Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste; AOU Meyer, Florence; IRCCS Istituto Giannina Gaslini, Genoa) from January 1st 2000 to December 31st 2019. Chi square test or exact Fisher test and non-parametric Wilcoxon Mann-Whitney test were used to study differences between two groups. Results One-hundred-forty-nine cases were enrolled, (96 KDG and 53 KCG). KCG children were significantly older and presented more frequently from gastrointestinal and respiratory involvement. Cardiac involvement was more common in KCG, with 60,4% of patients with myocarditis. 37,8% of patients among KCG presented hypotension/non-cardiogenic shock. Coronary artery abnormalities (CAA) were more common in the KDG. The risk of ICU admission were higher in KCG. Lymphopenia, higher CRP levels, elevated ferritin and troponin-T characterized KCG. KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%; p = 0.04 and 71,9% vs 43,4%; p = 0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%; p Conclusion Our study suggests that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD and PIMS-TS. Older age at onset and clinical peculiarities like the occurrence of myocarditis characterize this multi-inflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths.

This study explores demographic, clinical, and therapeutic features of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a cohort of 80 patients recruited from 19 Italian referral Centers. Patients’ data were collected retrospectively and then analyzed according to age groups (disease onset before or after 16 years) and genotype (high penetrance (HP) and low penetrance (LP) TNFRSF1A gene variants). Pediatric- and adult-onset were reported, respectively, in 44 and 36 patients; HP and LP variants were found, respectively, in 32 and 44 cases. A positive family history for recurrent fever was reported more frequently in the pediatric group than in the adult group (p<0.05). With reference to clinical features during attacks, pericarditis and myalgia were reported more frequently in the context of adult-onset disease than in the pediatric age (with p<0.01 and p<0.05, respectively), while abdominal pain was present in 84% of children and in 25% of adults (p<0.01). Abdominal pain was significantly associated also to the presence of HP mutations (p<0.01), while oral aphthosis was more frequently found in the LP variant group (p<0.05). Systemic amyloidosis occurred in 25% of subjects carrying HP variants. As concerns laboratory features, HP mutations were significantly associated to higher ESR values (p<0.01) and to the persistence of steadily elevated inflammatory markers during asymptomatic periods (p<0.05). The presence of mutations involving a cysteine residue, abdominal pain, and lymphadenopathy during flares significantly correlated with the risk of developing amyloidosis and renal impairment. Conversely, the administration of colchicine negatively correlated to the development of pathologic proteinuria (p<0.05). Both NSAIDs and colchicine were used as monotherapy more frequently in the LP group compared to the HP group (p<0.01). Biologic agents were prescribed to 49 (61%) patients; R92Q subjects were more frequently on NSAIDs monotherapy than other patients (p<0.01); nevertheless, they required biologic therapy in 53.1% of cases. At disease onset, the latest classification criteria for TRAPS were fulfilled by 64/80 (80%) patients (clinical plus genetic items) and 46/80 (57.5%) patients (clinical items only). No statistically significant differences were found in the sensitivity of the classification criteria according to age at onset and according to genotype (p<0.05). This study describes one of the widest cohorts of TRAPS patients in the literature, suggesting that the clinical expression of this syndrome is more influenced by the penetrance of the mutation rather than by the age at onset itself. Given the high phenotypic heterogeneity of the disease, a definite diagnosis should rely on both accurate working clinical assessment and complementary genotype.

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Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome is a mysterious disorder characterized by periodically recurrent fevers, oropharyngeal inflammation, and adenitis, which mainly affects children, though in very recent times, it has been also recognized in adulthood. We enrolled 115 unrelated pediatric and adult patients with history of periodic fevers who fulfilled the current diagnostic criteria for PFAPA syndrome in three Italian referral centers and highlighted differences between children and adults. Eighty-five children and 30 adults were evaluated: the frequency of flares was significantly higher in pediatric cases, while febrile attack duration was significantly longer in adults. Clockwork periodicity of fever and recurrent pharyngitis were more frequently observed in childhood, but no differences were identified for aphthosis and cervical adenopathy. Conversely, joint symptoms, myalgia, headache, fatigue, ocular signs, and rashes were more common in adults. The simultaneous occurrence of two or three cardinal PFAPA signs did not show any statistical difference between the groups, while the occurrence of only one cardinal manifestation was more frequent in adults. Corticosteroids were effective in 98.82% of children and 88.2% of adults. Tonsillectomy was rarely performed, resulting effective in only two patients. Our data illustrate the clinical overlap between pediatric and adult cases of PFAPA syndrome. Adults are characterized by a wider repertoire of inflammatory signs, suggesting that onset in adulthood might leave the disease misdiagnosed. Clinicians, not only pediatricians, should take into account this clinical entity in every patient of whatever age suffering from recurrent fevers of unknown origin.

OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from 99% for a score of =123. A cutoff value of =60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.

Summary Background Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy. Methods We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m 2 ; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70. Findings Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event. Interpretation Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis. Funding Italian Agency of Drug Evaluation.

An increased white blood cell count is a hallmark of active Kawasaki syndrome (KS) and has been suggested as a risk factor for cardiovascular morbidity by several investigators. Morphologic analysis of polymorphonuclear cells (PMNs) represents an accessible tool that is worth validating prospectively in a larger study to predict KS severity and poor response to intravenous immunoglobulin. More precisely, PMNs might be culprits in the development of KS and its complications, but they are not the only cells involved in this systemic vasculitis: further in-depth analysis will probably unravel the tangled pathogenesis of KS and find new targets for a more specific therapy.

Short-lived systemic inflammatory reactions arising from disrupted rules in the innate immune system are the operating platforms of hereditary autoinflammatory disorders (HAIDs). Multiple organs may be involved and aseptic inflammation leading to disease-specific phenotypes defines most HAIDs. Lungs are infrequently involved in children with HAIDs: the most common pulmonary manifestation is pleuritis in familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), respectively caused by mutations in the MEFV and TNFRSF1A genes, while interstitial lung disease can be observed in STING-associated vasculopathy with onset in infancy (SAVI), caused by mutations in the TMEM173 gene. The specific pleuropulmonary diseases may range from sub-clinical abnormalities during inflammatory flares of FMF and TRAPS to a severe life-threatening disorder in children with SAVI.

Background: Data from routine clinical practice are needed to further define the efficacy and safety of biologic medications in children with juvenile idiopathic arthritis (JIA). The aim of this analysis was to investigate the disease status, reasons for discontinuation and adverse events in Italian JIA patients treated with etanercept (ETN). Methods: In 2013, all centers of the Italian Pediatric Rheumatology Study Group were asked to make a census of patients given ETN after January 2000. Patients were classified in three groups: group 1 = patients still taking ETN; group 2 = patients discontinued from ETN for any reasons; group 3 = patients lost to follow-up while receiving ETN. All three groups received a retrospective assessment; patients in group 1 also underwent a cross-sectional assessment. Results: 1038 patients were enrolled by 23 centers: 422 (40.7%) were in group 1, 462 (44.5%) in group 2, and 154 (14.8%) in group 3. Median duration of ETN therapy was 2.5 years. At cross-sectional assessment, 41.8% to 48.6% of patients in group 1 met formal criteria for inactive disease, whereas 52.4% of patients in group 2 and 55.8% of patients in group 3 were judged in clinical remission by their caring physician at last visit. A relatively greater proportion of patients with systemic arthritis were discontinued or lost to follow-up. Parent evaluations at cross-sectional visit in group 1 showed that 52.4% of patients had normal physical function, very few had impairment in quality of life, 51.2% had no pain, 76% had no morning stiffness, and 82.7% of parents were satisfied with their child's illness outcome. Clinically significant adverse events were reported for 27.8% of patients and ETN was discontinued for side effects in 9.5%. The most common adverse events were new onset or recurrent uveitis (10.2%), infections (6.6%), injection site reactions (4.4%), and neuropsychiatric (3.1%), gastrointestinal (2.4%), and hematological disorders (2.1%). Ten patients developed an inflammatory bowel disease and 2 had a malignancy. One patient died of a fulminant streptococcal sepsis. Conclusions: Around half of the patients achieved complete disease quiescence under treatment with ETN. The medication was overall well tolerated, as only one quarter of patients experienced clinically significant adverse events and less than 10% had treatment discontinued for toxicity.

Kawasaki syndrome (KS) is the most relevant cause of heart disease in children living in developed countries. Intravenous immunoglobulin (IVIG) has a preventive function in the formation of coronary artery abnormalities and a poor strictly-curative action in established coronary damage. More than two decades ago, the Harada score was set to assess which children with KS should be subject to administration of IVIG, evaluating retrospectively a large cohort of patients with regard to age, sex and laboratory data. Nowadays, high dose IVIG is administered to all children with a confirmed diagnosis of KS, but a tool for predicting non-responsiveness to the initial infusion of IVIG has not been found. The prediction of IVIG resistance is a crucial issue, as recognising these high-risk patients should consent the administration of an intensified initial treatment in combination with IVIG in order to prevent coronary injuries. Few reports have focused on factors, referring to both clinical parameters and laboratory data at the onset of KS, in order to predict which patients might be IVIG non-responsive. We have analysed three different risk scores which were formulated to predict IVIG resistance in Japanese children with typical KS, but their application in non-Japanese patients or in those with incomplete and atypical patterns of the disease has been studied in a fragmentary way. Overall, our analysis showed that early and definite ascertainment of likely IVIG non-responders who require additional therapies reducing the development of coronary artery involvement in children with KS is still a challenge.

A complex web of dynamic relationships between innate and adaptive immunity is now evident for many autoinflammatory and autoimmune disorders, the first deriving from abnormal activation of innate immune system without any conventional danger triggers and the latter from self-/non-self-discrimination loss of tolerance, and systemic inflammation. Due to clinical and pathophysiologic similarities giving a crucial role to the multifunctional cytokine interleukin-1, the concept of autoinflammation has been expanded to include nonhereditary collagen-like diseases, idiopathic inflammatory diseases, and metabolic diseases. As more patients are reported to have clinical features of autoinflammation and autoimmunity, the boundary between these two pathologic ends is becoming blurred. An overview of monogenic autoinflammatory disorders, PFAPA syndrome, rheumatoid arthritis, type 2 diabetes mellitus, uveitis, pericarditis, Behçet’s disease, gout, Sjögren’s syndrome, interstitial lung diseases, and Still’s disease is presented to highlight the fundamental points that interleukin-1 displays in the cryptic interplay between innate and adaptive immune systems.

Group A Streptococcus (GAS) strains are lately classified on the basis of sequence variations in the emm gene encoding the M protein, but despite the high number of distinct emm genotypes, the spectrum of phenotypes varying from invasive suppurative to non-suppurative GAS-related disorders has still to be defined. The relationship of GAS types with the uprising of acute rheumatic fever (ARF), a multisystemic disease caused by misdirected anti-GAS response in predisposed people, is also obscure. Studies published over the last 15. years were retrieved from PubMed using the keywords: ". Streptococcus pyogenes" or "group A Streptococcus" and "acute rheumatic fever": the prevalence of peculiar emm types across different countries of the world is highly variable, depending on research designs, year of observation, country involved, patients' age, and gender. Most studies revealed that a relatively small number of specific emm/M protein types can be considered "rheumatogenic", as potentially characterized by the possibility of inducing ARF, with remarkable differences between developing and developed countries. The association between emm types and post-streptococcal manifestations is challenging, however surveillance of disease-causing variants in a specific community with high rate of ARF should be reinforced with the final goal of developing a potential primary prophylaxis against GAS infections.

Serum amyloid-A (SAA) is an acute phase protein, synthesized by the liver and previously investigated as a marker of disease activity in many rheumatologic disorders. Its significance in Behcet’s disease (BD), a chronic inflammatory disorder at the crossroad between autoimmune and autoinflammatory syndromes, is still unraveled. Our aim was to assess the role of SAA levels as a potential marker of disease activity in patients with BD. According to our findings, the occurrence of oral aphthosis, neurological impairment, and ocular disease is significantly associated with SAA serum levels higher than 30, 50, and 150 mg/L, respectively. We also suggest that increased SAA levels might identify a thrombotic risk in BD with previous or concurrent vascular involvement.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), formerly known as familial Hibernian fever, is the most common autosomal dominant autoinflammatory disease, resulting from mutations in the TNFRSF1A gene, encoding the 55-kD tumor necrosis factor receptor. The pathophysiologic mechanism of TRAPS remains ambiguous and only partially explained. The onset age of the syndrome is variable and the clinical scenery is characterized by recurrent episodes of high-grade fever that typically lasts 1-3 weeks, associated with migrating myalgia, pseudocellulitis, diffuse abdominal pain, appendicitis-like findings, ocular inflammatory signs, and risk of long-term amyloidosis. Fever episodes are responsive to high-dose corticosteroids, but different classes of drugs have been reported to be ineffective. The use of etanercept is unable to control systemic inflammation, while interleukin-1 blockade has been shown as effective in the control of disease activity in many patients reported so far. © 2014 Clinical Rheumatology.

Autoinflammatory disorders (AIDs) are a novel class of diseases elicited by mutations in genes regulating the homeostasis of innate immune complexes, named inflammasomes, which lead to uncontrolled oversecretion of the proinflammatory cytokine interleukin-1β. Protean inflammatory symptoms are variably associated with periodic fever, depicting multiple specific conditions. Childhood is usually the lifetime in which most hereditary AIDs start, though still a relevant number of patients may experience a delayed disease onset and receive a definite diagnosis during adulthood. As a major referral laboratory for patients with recurrent fevers, we have tested samples from 787 patients in the period September 2007–March 2014, with a total of 1,328 AID-related genes evaluated and a gene/patient ratio of 1.69. In this report, we describe our experience in the clinical approach to AIDs, highlight the most striking differences between child and adult-onset AIDs, and shed an eye-opening insight into their diagnostic process.

Item does not contain fulltext OBJECTIVE: To evaluate the response to treatment of autoinflammatory diseases from an international registry and an up-to-date literature review. METHODS: The response to treatment was studied in a web-based registry in which clinical information on anonymised patients with autoinflammatory diseases was collected retrospectively as part of the Eurofever initiative. Participating hospitals included paediatric rheumatology centres of the Paediatric Rheumatology International Trial Organisation network and adult centres with a specific interest in autoinflammatory diseases. The following diseases were included: familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF)-receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), pyogenic arthritis pustulosis acne (PAPA) syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), NLRP12-related periodic fever and periodic fever aphthosis pharyngitis adenitis (PFAPA) syndrome. Cases were independently validated by experts for each disease. A literature search regarding treatment of the abovementioned diseases was also performed using Medline and Embase. RESULTS: 22 months from the beginning of the enrolment, complete information on 496 validated patients was available. Data from the registry in combination with evidence from the literature confirmed that colchicine is the treatment of choice for FMF and IL-1 blockade for DIRA and CAPS. Corticosteroids on demand probably represent a valid therapeutic strategy for PFAPA, but also for MKD and TRAPS. Patients with poorly controlled MKD, TRAPS, PAPA or FMF may benefit from IL-1 blockade; anti-TNF treatment may represent a possible valuable alternative. CONCLUSIONS: In the absence of high-grade evidence, these results could serve as a basis for therapeutic guidelines and to identify candidate drugs for future therapeutic trials.

EULAR/PRINTO/PRES Objectives To validate the previously proposed classification criteria for Henoch-Schonlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA).Methods Step 1: retrospective/prospective webdata collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis

Objectives The aim of the study is to assess the rate of atypical manifestations at onset in pediatric systemic lupus erythematosus (SLE) and to evaluate their effect on disease outcome. Study design This is a multicenter retrospective cohort study. A manifestation was considered atypical if it was not included in the American College Rheumatology classification criteria for SLE but was reported in literature as associated with SLE. Unfavorable outcome was considered presence of organ damage in the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index at the last available evaluation. Results One hundred patients were enrolled in the study; 24% presented atypical clinical features at onset. Univariate analysis showed a significant association of worse outcome variables with the presence of atypical manifestations at onset ( P = .004), as well as renal involvement ( P = .027). A multivariate logistic regression analysis showed that atypical manifestations at onset ( P = .018), renal involvement at onset or during follow up ( P = .024), and central nervous system disease involvement during follow up ( P = .021) were independent predictors of poor prognosis. Conclusions Our data support a relatively high rate of atypical onset in pediatric SLE. Presence of atypical manifestations at presentation and early kidney disease correlate with poor outcome. Similarly, during follow-up, kidney and central nervous system diseases are associated with worse outcome.

Purpose: Aim of the present study was to validate a statistical model to predict a severe course of anterior uveitis (AU) in patients with juvenile idiopathic arthritis (JIA). Methods: Consecutive patients with newly diagnosed uveitis have been followed for at least 1 year with a standardized protocol. For each patient, demographic, clinical and laboratory characteristics, including time interval between arthritis and uveitis onset, α2-globulins level at arthritis onset, number of uveitis relapses/year, ocular complications and therapy and visual acuity, have reported. The validation procedure included the assessment of sensitivity, specificity and efficiency of previously published statistical model (Zulian et al. J Rheumatol 2002; 29: 2446–2453) in a new inception cohort of patients during a short length follow-up. Results: Sixty patients with JIA, followed at 14 paediatric rheumatology–ophthalmology centres in Italy, entered the study. The mean age at arthritis onset was 4.4 years (range 1.2–15.8 years), and the mean interval time between arthritis and uveitis onset was 1.8 years (range: 0.0–14.2 years). After the first AU, patients, followed for a mean of 3.2 years, had a mean of 2.9 uveitis relapses. Twenty-two patients (36.7%) presented at least one complication. Using a probability cut-off value = 0.7, the statistical model revealed 80% sensitivity, 58% specificity and 65% efficiency. Conclusion: The time interval between arthritis and uveitis onset resulted as the main predictor of severe course uveitis in JIA. The statistical model was able to predict the development of a severe course in 8 of 10 patients.