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Objectives: We present the first case of a Majeed syndrome in a girl of central-European ancestry., Methods: : Patient's medical records were reviewed. A NGS panel for autoinflammatory diseases was performed and the mutation was confirmed by Sanger analysis. Freshly isolated monocytes were activated with LPS +/- ATP. The concentration of inflammatory cytokines was assessed in monocytes supernatants., Results: A 2-year-old girl presented with pain in the lower limbs, increase of acute phase reactants and persistent microcytic anaemia. The MRI showed bilateral STIR hyper-intensity of the spongy osseous tissue of femur, tibia, radius, ulna, and astragalus. Bone marrow analysis revealed increased trilinear cellularity with signs of dyserythropoietic anaemia. NGS panel detected the presence of two novel compound heterozygous mutations in the LPIN2 gene, confirmed by Sanger analysis. Treatment with anakinra was started with a prompt resolution of the clinical picture. Increased kinetics and concentration of IL-1β was observed in the patient's monocytes compared with healthy controls, with a marked drop following the start of therapy. About six months after the start of the therapy, resolution of MRI findings, microcytic anaemia and dyserythropoiesis at bone marrow aspirate was observed., Conclusion: We describe the first case of Majeed syndrome in a patient of central-European ancestry. The functional test on circulating monocytes before and after therapy with anakinra confirmed pathogenicity of the mutation and the role of LPIN2 in the NLRP3 inflammasome activation. Anti-IL1 agents were effective, leading not only to the resolution of bone lesion but also to an improvement of dyserythropoiesis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: Granulomatosis with polyangiitis (GPA) is an ANCA-associated vasculitis. The 2022 ACR/EULAR-endorsed classification criteria for GPA was derived using data only from adult patients. We aimed to assess the performance of the ACR/EULAR classification criteria for GPA in paediatric patients and compare it with the EULAR/Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology European Society (PReS)-endorsed Ankara 2008 criteria for GPA., Methods: Retrospective data of paediatric patients with GPA in 20 centres from 9 countries were evaluated. The diagnosis of GPA was made according to the expert opinion. The sensitivity, specificity, positive predictive value, and negative predictive value of the criteria sets were evaluated., Results: The study included 77 patients with GPA and 108 controls [IgA vasculitis (n = 44), Takayasu's arteritis (n = 20), microscopic polyangiitis (n = 16), polyarteritis nodosa (n = 14), Behçet's disease (n = 12), eosinophilic granulomatosis with polyangiitis (n = 1) and Cogan's syndrome (n = 1)] with a median age of 17.8 and 15.2 years, respectively. Among patients with GPA, constitutional symptoms (85.7%) and ENT involvement (79.2%) were the most common presentations. In the GPA group, 73 patients fulfilled the Ankara 2008 criteria and 69 the ACR/EULAR classification criteria. Sensitivities of the Ankara 2008 criteria and the ACR/EULAR classification criteria were 94.8% and 89.6%, while specificities were 95.3% and 96.3%, respectively. No significant difference was found between sensitivities and specificities of both classification criteria (P = 0.229 and P = 0.733, respectively)., Conclusion: In children, both the ACR/EULAR and EULAR/PRINTO/PReS Ankara 2008 classification criteria for GPA perform well and similarly., (© Crown copyright 2023.)

Introduction: Systemic juvenile idiopathic arthritis (sJIA), a multifaceted autoinflammatory disorder, can be complicated by life-threatening conditions such as macrophage activation syndrome (MAS) and interstitial lung disease (ILD). The management of these conditions presents a therapeutic challenge, underscoring the need for innovative treatment approaches., Objectives: to report the possible role of MAS825, a bispecific anti-IL1β and IL-18 monoclonal antibody, in the treatment of multi-drug-resistant sJIA., Methods: We report two patients affected by sJIA with severe and refractory MAS and high serum IL-18 levels, responding to dual blockade of IL-1β and IL-18., Results: The first patient is a 20-year-old man, presenting a severe MAS complicated by thrombotic microangiopathy, following SARS-CoV-2 infection. He was treated with MAS825, with quick improvement. Eighteen months later, the patient is still undergoing biweekly treatment with MAS825, associated with MTX, ciclosporin and low-dose glucocorticoids, maintaining good control over the systemic features of the disease.The second patient, a 10-year-old girl, presented a severe MAS case, complicated by posterior reversible encephalopathy syndrome (PRES), following an otomastoiditis. The MAS was not fully controlled despite treatment with IV high-dose glucocorticoids, anakinra and ciclosporin. She began biweekly MAS825, which led to a prompt amelioration of MAS parameters. After 10 months, the patient continues to receive MAS825 and is in complete remission., Conclusion: In light of the pivotal role of IL-1β and IL-18 in sJIA, MAS and ILD, MAS825 might represent a possible valid and safe option in the treatment of drug-resistant sJIA, especially in the presence of high serum IL-18 levels., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To assess current treatment in macrophage activation syndrome (MAS) worldwide and to highlight any areas of major heterogeneity of practice., Methods: A systematic literature search was performed in both Embase and PubMed databases. Paper screening was done by two independent teams based on agreed criteria. Data extraction was standardized following the PICO framework. A panel of experts assessed paper validity, using the Joanna Briggs Institute appraisal tools and category of evidence (CoE) according to EULAR procedure., Results: Fifty-seven papers were finally included (80% retrospective case-series), describing 1148 patients with MAS: 889 systemic juvenile idiopathic arthritis (sJIA), 137 systemic lupus erythematosus (SLE), 69 Kawasaki disease (KD) and 53 other rheumatologic conditions. Fourteen and 11 studies specified data on MAS associated to SLE and KD, respectively. All papers mentioned glucocorticoids (GCs), mostly methylprednisolone and prednisolone (90%); dexamethasone was used in 7% of patients. Ciclosporin was reported in a wide range of patients according to different cohorts. Anakinra was used in 179 MAS patients, with a favourable outcome in 83% of sJIA-MAS. Etoposide was described by 11 studies, mainly as part of HLH-94/04 protocol. Emapalumab was the only medication tested in a clinical trial in 14 sJIA-MAS, with 93% of MAS remission. Ruxolitinib was the most reported JAK-inhibitor in MAS., Conclusion: High-dose GCs together with IL-1 and IFNγ inhibitors have shown efficacy in MAS, especially in sJIA-associated MAS. However, global level of evidence on MAS treatment, especially in other conditions, is still poor and requires standardized studies to be confirmed., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: The main aim of this study was to define the best treatment option for multisystem inflammatory syndrome in children (MIS-C) and to analyse the role of anakinra., Methods: This is a multicentre retrospective cohort study. Patients were treated according to the attending physician's decision. The patients were divided into four groups on the basis of the first treatment at time of admittance: (i) IVIG, (ii) IVIG and methylprednisolone (≤2 mg/kg/day), (iii) IVIG with high-dose methylprednisolone (>2 mg/kg/day) and (iv) anakinra with or without IVIG and/or methylprednisolone. Primary outcomes were defined as the presence of at least one of the following features: death, the failure of initial treatment, meaning the need for additional treatment for clinical worsening and cardiac involvement at the end of follow-up., Results: Two hundred thirty-nine patients were recruited. At univariate analysis, persistent heart involvement at discharge was more frequent in those not receiving anakinra as initial treatment (3/21 vs 66/189; P = 0.047). After comparisons between the four treatment regimens, adjusting for the propensity score, we observed that early treatment with anakinra was associated with a lower probability of developing persistent heart disease at the end of follow-up (odds ratio: 0.6; 95% CI: 0.4-1.0)., Conclusion: We report that early treatment with anakinra is safe and very effective in patients with severe MIS-C. In addition, our study suggests that early treatment with anakinra is the most favourable option for patients with a higher risk of developing a severe disease outcome., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: to validate the PEDiatric Behçet's Disease classification criteria (PEDBD) with an evidence-based approach., Methods: 210 pediatric patients (70 Behçet's disease (BD), 40 Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis, 35 familial Mediterranean fever, 26 hyper-IgD syndrome, 22 TNF-Receptor associated Periodic fever Syndrome, 17 undefined recurrent fevers) were randomly selected from the Eurofever Registry. A set of 11 experienced clinicians/researchers blinded to the original diagnosis evaluated the patients. Using the table consensus as gold standard (agreement ≥ 80%), the PEDBD, ISG and ICBD criteria were applied to BD patients and to confounding diseases with other autoinflammatory conditions in order to define their sensitivity, specificity and accuracy., Results: At the end of the third round, a consensus was reached in 139/210 patients (66.2%). The patients with a consensus ≥80% were classified as confirmed-BD (n = 24), and those with an agreement of 60-79% as probable-BD (n = 10). When comparing these patients with the confounding diseases group, an older age at disease onset, the presence of oral and genital ulcers, skin papulo-pustular lesions, a positive pathergy test and posterior uveitis were BD distinctive elements. The ISG, ICBD and PEDBD criteria were applied to confirmed-BD and to the confounding disease group, showing a sensitivity of 0.50, 0.79 and 0.58, a specificity of 1.00, 0.97, 0.99, and an accuracy of 0.91, 0.94 and 0.92, respectively., Conclusions: the PEDBD criteria were very specific, while the ICBD resulted to be more sensitive. The complexity of childhood BD suggests larger prospective international cohorts to further evaluate the performance of the criteria., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To compare clinical features and treatments of patients with systemic JIA (sIJA) and adult-onset Still's disease (AOSD)., Methods: The clinical charts of consecutive patients with sJIA by International League of Association of Rheumatology criteria or AOSD by Yamaguchi criteria were reviewed. Patients were seen at a large paediatric rheumatology referral centre or at 10 adult rheumatology academic centres. Data collected included clinical manifestations, inflammation biomarkers, systemic score, macrophage activation syndrome (MAS), parenchymal lung disease, disease course, disability, death and medications administered., Results: A total of 166 patients (median age at diagnosis 5 years) with sJIA and 194 patients with AOSD (median age at diagnosis 41 years) were included. The frequency of fever, rash, arthralgia, abdominal pain, MAS, parenchymal lung disease and increased acute phase reactants and ferritin were comparable between the two cohorts. Patients with sJIA had a higher prevalence of arthritis, whereas patients with AOSD had experienced leucocytosis and extra-articular organ involvement more frequently. Patients with AOSD were given more commonly low-dose corticosteroids, whereas biologic DMARDs were administered first-line more frequently in patients with sJIA., Conclusion: We found remarkable disparities in the prevalence of clinical manifestations between the two illnesses, which may partly depend on their classification by different criteria., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: To evaluate the long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency during the open label extension (weeks 41-113) of the randomized controlled CLUSTER trial., Methods: During a 72-week period, patients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks. The disease activity was evaluated every 8 weeks using physician global assessment and counting the number of flares. Concentrations of CRP and serum amyloid A protein were measured. The safety was studied by determination and classification of observed adverse events. The safety and efficacy were analysed separately in three subgroups of patients receiving a cumulative dose of less than <35 mg/kg, ≥35 to <70 mg/kg or ≥70 mg/kg., Results: Of the 74 patients who started the CLUSTER study, 66 entered Epoch 4 and 65 completed it. During the 72-week period, 42 (64%) patients experienced no flares, while 13 (20%) had one flare, as compared with a median of 12 flares per year reported at baseline. Low physician global assessment scores were seen at the end of the study for all groups with >90% reporting minimal disease activity or none at all. Median CRP concentrations were consistently equal or lower than 10 mg/l, while median serum amyloid A concentrations remained only slightly above the normal range of 10 mg/l. The study showed no new or unexpected adverse events., Conclusion: Canakinumab proved effective to control disease activity and prevent flares in mevalonate kinase deficiency during the 72-week study period. No new safety concerns were reported., Trial Registration: NCT02059291. https://clinicaltrials.gov., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To test the usefulness of an extended panel of lymphocyte subsets in combination with Oliveira's diagnostic criteria for the identification of autoimmune lymphoproliferative syndrome (ALPS) in children referred to a paediatric rheumatology centre., Methods: Patients referred from 2015 to 2018 to our rheumatology unit for an autoimmune or autoinflammatory condition were retrospectively analysed. Oliveira's required criteria [chronic lymphoproliferation and elevated double-negative T (DNT)] were applied as first screening. Flow cytometry study included double-negative CD4-CD8-TCRαβ+ T lymphocytes (DNT), CD25+CD3+, HLA-DR+CD3+ T cells, B220+ T cells and CD27+ B cells. Data were analysed with a univariate logistic regression analysis, followed by a multivariate analysis. Sensitivity and specificity of the Oliveira's required criteria were calculated., Results: A total of 264 patients were included in the study and classified as: (i) autoimmune diseases (n = 26); (ii) juvenile idiopathic arthritis (JIA) (35); (iii) monogenic systemic autoinflammatory disease (27); (iv) periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (100); (v) systemic undefined recurrent fever (45); (vi) undetermined-systemic autoinflammatory disease (14); or (vii) ALPS (17). Oliveira's required criteria displayed a sensitivity of 100% and specificity of 79%. When compared with other diseases the TCRαβ+B220+ lymphocytes were significantly increased in ALPS patients. The multivariate analysis revealed five clinical/laboratory parameters positively associated to ALPS: splenomegaly, female gender, arthralgia, elevated DNT and TCRαβ+B220+ lymphocytes., Conclusions: Oliveira's required criteria are useful for the early suspicion of ALPS. TCRαβ+B220+ lymphocytes should be added in the diagnostic work-up of patients referred to the paediatric rheumatology unit for a suspected autoimmune or autoinflammatory condition, providing a relevant support in the early diagnosis of ALPS., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Mevalonic aciduria represents the most severe form of mevalonate kinase deficiency (MKD). Patients with mevalonic aciduria have an incomplete response even to high doses of anti-cytokine drugs such as anakinra or canakinumab and stem cell transplantation (SCT) represents a possible therapy for this severe disease., Methods: We report the first two children affected by severe MKD who received haploidentical α/β T-cell and B-cell depleted SCT. Both patients received a treosulfan-based conditioning regimen and one received a second haploidentical-SCT for secondary rejection of the first., Results: Both patients obtained a stable full donor engraftment with a complete regression of clinical and biochemical inflammatory signs, without acute organ toxicity or acute and chronic GvHD. In both, the urinary excretion of mevalonic acid remained high post-transplant in the absence of any inflammatory signs., Conclusion: Haploidentical α/β T-cell and B-cell depleted SCT represents a potential curative strategy in patients affected by MKD. The persistence of urinary excretion of mevalonic acid after SCT, probably related to the ubiquitous expression of MVK enzyme, suggests that these patients should be carefully monitored after SCT to exclude MKD clinical recurrence. Prophylaxis with anakinra in the acute phase after transplant could represent a safe and effective approach. Further biological studies are required to clarify the pathophysiology of inflammatory attacks in MKD in order to better define the therapeutic role of SCT., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Henoch-Schönlein purpura (HScP) may present in children with severe, occasionally refractory, gastrointestinal (GI) involvement. The use of corticosteroids (CSs) is commonplace in the management of the disease, but to date no standardized protocol is available and, although rare, resistance to CS therapy may be challenging to clinicians. IVIG has been proposed as an effective alternative to CSs, but to date no controlled trial has been conducted to ascertain their real efficacy. We share our personal experience of successful IVIG treatment in two cases of GI HScP, comparing it with similar experiences reported in literature., Methods: Retrospective clinical data collection, comparison with available literature., Results: We describe two children with severe HScP GI vasculitis refractory to high-dose intravenous CSs that responded rapidly to IVIG administration, with complete recovery within a few days. Patient characteristics and response to IVIG administration were comparable to those of other previously reported cases., Conclusion: Our observation confirms that IVIG may be useful in the treatment of CS-resistant HScP-related GI vasculitis in children, and highlights the need for more structured research, including a randomized trial against CSs, in order to ascertain their real effectiveness., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Colchicine is the main treatment for FMF. Although a number of individuals with FMF are intolerant/resistant to colchicine, there is no standard definition of colchicine resistance/intolerance. We developed a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF that may serve as a guide for clinicians and health authorities., Methods: A set of statements was identified using a modified-Delphi consensus-based approach. The process involved development of an initial colchicine resistance/intolerance-related questionnaire derived from a systematic literature review. The questionnaire, which was completed by an international panel of 11 adult and paediatric rheumatologists with expertise in FMF, was analysed anonymously. The results informed draft consensus statements that were discussed by a round-table expert panel, using a nominal group technique to agree on the selection and wording of the final statements., Results: Consensus among the panel was achieved on eight core statements defining colchicine resistance/intolerance in patients with FMF. A definition of resistance was agreed upon that included recurrent clinical attacks (average one or more attacks per month over a 3-month period) or persistent laboratory inflammation in between attacks. Other core statements recognize the importance of assessing treatment adherence, and the impact of active disease and intolerance to colchicine on quality of life., Conclusion: Based on expert opinion, a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF were identified to help guide clinicians and health authorities in the management of patients with FMF., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The number of innate immune system disorders classified as systemic autoinflammatory diseases (SAID) has increased in recent years. More than 70% of patients with clinical manifestations of SAID did not receive a molecular diagnosis, thus being classed as so-called undifferentiated or undefined SAID (uSAID). The aim of the present study was to evaluate a next-generation sequencing (NGS)-based clinically oriented protocol in patients with uSAID., Methods: We designed a NGS panel that included 41 genes clustered in seven subpanels. Patients with uSAID were classified into different groups according to their clinical features and sequenced for the coding portions of the 41 genes., Results: Fifty patients were enrolled in the study. Thirty-four patients (72%) displayed recurrent fevers not consistent with a PFAPA phenotype. Sixteen patients displayed a chronic inflammatory disease course. A total of 100 gene variants were found (mean 2 per patient; range 0-6), a quarter of which affected suspected genes. Mutations with a definitive diagnostic impact were detected in two patients. Patients with genetically negative recurrent fevers displayed a prevalent gastrointestinal, skin and articular involvement. Patients responded to steroids on demands (94%) and colchicine, with a response rate of 78%., Conclusion: Even with a low molecular diagnostic rate, a NGS-based approach is able to provide a final diagnosis in a proportion of uSAID patients with evident cost-effectiveness. It also allows the identification of a subgroup of genetically negative patients with recurrent fever responding to steroid on demand and colchicine., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Chronic non-bacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disorder characterized by sterile bone osteolytic lesions. The aim of this study was to evaluate the demographic data and clinical, instrumental and therapeutic features at baseline in a large series of CNO/CRMO patients enrolled in the Eurofever registry., Methods: A web-based registry collected retrospective data on patients affected by CRMO/CNO. Both paediatric and adult centres were involved., Results: Complete baseline information on 486 patients was available (176 male, 310 female). The mean age of onset was 9.9 years. Adult onset (>18 years of age) was observed in 31 (6.3%) patients. The mean time from disease onset to final diagnosis was 1 year (range 0-15). MRI was performed at baseline in 426 patients (88%), revealing a mean number of 4.1 lesions. More frequent manifestations not directly related to bone involvement were myalgia (12%), mucocutaneous manifestations (5% acne, 5% palmoplantar pustulosis, 4% psoriasis, 3% papulopustular lesions, 2% urticarial rash) and gastrointestinal symptoms (8%). A total of 361 patients have been treated with NSAIDs, 112 with glucocorticoids, 61 with bisphosphonates, 58 with MTX, 47 with SSZ, 26 with anti-TNF and 4 with anakinra, with a variable response., Conclusion: This is the largest reported case series of CNO patients, showing that the range of associated clinical manifestations is rather heterogeneous. The study confirms that the disease usually presents with an early teenage onset, but it may also occur in adults, even in the absence of mucocutaneous manifestations., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To provide a rationale for anti-IL-1 treatment in pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) by defining whether IL-1β secretion is enhanced; requires NLRP3; and correlates with proline-serine-threonine phosphatase-interacting protein 1 mutations, disease activity and/or the clinical picture in PAPA., Methods: Monocytes were isolated from 13 patients and 35 healthy donors and studied at baseline and following activation. Secretion pattern of IL-1β, IL-1α, IL-1Ra, IL-6, IL-18 and TNF-α was assessed in supernatants by ELISA. The NLRP3 requirement for IL-1β secretion was investigated by silencing technique in PAPA and healthy donor monocytes. Long-term follow-up (mean 26 months, range 4-38) was performed in five patients enrolled in an anti-IL-1 regimen., Results: IL-1β secretion in PAPA is increased, requires NLRP3 and correlates with disease activity. Patients with a history of osteoarticular flares release more IL-1β, IL-6 and TNF-α compared with those with predominant cutaneous recurrences. Monocytes from patients in anti-IL-1 treatment dramatically reduced IL-1β secretion after ex vivo activation, and long-term follow-up demonstrated decreased frequency of flares and normalization of acute phase reactants in all the patients. A straightforward correlation between genotype and IL-1β signalling was not observed suggesting that factors other than mutation itself may play a role in regulating IL-1β secretion and response to treatment in PAPA., Conclusion: PAPA patients with active lesions display increased NLRP3-mediated IL-1β secretion, and long-term efficacy of IL-1 blockade was demonstrated. Even if other mechanisms related to the complex proline-serine-threonine phosphatase-interacting protein 1 protein networking might play additional roles, this study further supports the potential of IL-1 blockade as an effective therapeutic strategy in PAPA syndrome., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: The aims of this study were to describe the clinical features of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) and identify distinct phenotypes in a large cohort of patients from different countries., Methods: We established a web-based multicentre cohort through an international collaboration within the periodic fevers working party of the Pediatric Rheumatology European Society (PReS). The inclusion criterion was a diagnosis of PFAPA given by an experienced paediatric rheumatologist participating in an international working group on periodic fever syndromes., Results: Of the 301 patients included from the 15 centres, 271 had pharyngitis, 236 cervical adenitis, 171 oral aphthosis and 132 with all three clinical features. A total of 228 patients presented with additional symptoms (131 gastrointestinal symptoms, 86 arthralgias and/or myalgias, 36 skin rashes, 8 neurological symptoms). Thirty-one patients had disease onset after 5 years and they reported more additional symptoms. A positive family history for recurrent fever or recurrent tonsillitis was found in 81 patients (26.9%). Genetic testing for monogenic periodic fever syndromes was performed on 111 patients, who reported fewer occurrences of oral aphthosis or additional symptoms. Twenty-four patients reported symptoms (oral aphthosis and malaise) outside the flares. The CRP was >50 mg/l in the majority (131/190) of the patients tested during the fever., Conclusion: We describe the largest cohort of PFAPA patients presented so far. We confirm that PFAPA may present with varied clinical manifestations and we show the limitations of the commonly used diagnostic criteria. Based on detailed analysis of this cohort, a consensus definition of PFAPA with better-defined criteria should be proposed.

Objective: To investigate the expression and release of HLA-G and HLA-E in JIA., Methods: Soluble (s)HLA-G and HLA-E were measured in sera from 58 JIA patients and 54 healthy donors. Surface expression of HLA-G, HLA-E and immunoglobulin-like transcript (ILT)2 and ILT4, two receptors for HLA-G, was assessed on T, B cells and monocytes from peripheral blood (PB) and SF of 12 JIA patients and from PB of 12 controls., Results: Serum sHLA-G concentration was significantly lower in patients than in controls. Both sHLA-G and sHLA-E were detected in SF and sHLA-E concentration in SF was higher in extended oligoarticular/polyarticular than in limited oligoarticular JIA. Patients compared with controls showed: (i) down-regulation of HLA-E and ILT2 expression on T cells; (ii) up-regulation of HLA-E expression on B cells and monocytes; and (iii) down-regulation of ILT4 expression on monocytes. Comparing JIA patients' SF and PB we found: (i) up-regulation of HLA-E and ILT2 expression in T and B cells and monocytes; and (ii) down-regulation of ILT4 expression in monocytes. ILT4 was up-regulated in monocytes from oligoarticular extended/polyarticular compared with oligoarticular limited JIA., Conclusions: A lower concentration of sHLA-G in sera may predispose to JIA, as observed for other autoimmune diseases. sHLA-E concentration in SF correlate with the number of affected joints. Higher ILT2 expression on SF cell populations compared with PB may be related to high sHLA-G concentration in SF. Higher HLA-E expression in SF than in PB cell populations may protect them from NK cytolysis.

Objective: To set-up an international cohort of patients suspected with Behçet's disease (BD). The cohort is aimed at defining an algorithm for definition of the disease in children., Methods: International experts have defined the inclusion criteria as follows: recurrent oral aphthosis (ROA) plus one of following-genital ulceration, erythema nodosum, folliculitis, pustulous/acneiform lesions, positive pathergy test, uveitis, venous/arterial thrombosis and family history of BD. Onset of disease is <16 years, disease duration is ≤3 years, future follow-up duration is ≥4 years and informed consent is obtained. The expert committee has classified the included patients into: definite paediatric BD (PED-BD), probable PED-BD and no PED-BD. Statistical analysis is performed to compare the three groups of patients. Centres document their patients into a single database., Results: At January 2010, 110 patients (56 males/54 females) have been included. Mean age at first symptom: 8.1 years (median 8.2 years). At inclusion, 38% had only one symptom associated with ROA, 31% had two and 31% had three or more symptoms. A total of 106 first evaluations have been done. Seventeen patients underwent the first-year evaluation, and 36 had no new symptoms, 12 had one and 9 had two. Experts have examined 48 files and classified 30 as definite and 18 as probable. Twenty-six patients classified as definite fulfilled the International Study Group criteria. Seventeen patients classified as probable did not meet the international criteria., Conclusion: The expert committee has classified the majority of patients in the BD group although they presented with few symptoms independently of BD classification criteria.

Objective: To determine the capability and reliability of dynamic contrast-enhanced MRI (DCE-MRI) in the assessment of disease activity in juvenile idiopathic arthritis (JIA)., Methods: DCE-MRI of the clinically more affected wrist or hip joints was undertaken in 21 patients, coupled with standard clinical assessment and biochemical analysis. Synovial inflammation was assessed by computing the maximum level of synovial enhancement (ME), the maximum rate of enhancement (MV) and the rate of early enhancement (REE) from the enhancement curves generated from region of interest independently delineated by two readers in the area of the ME. Correlations between dynamic parameters and clinical measures of disease activity, and static MRI synovitis score were investigated., Results: In patients with wrist arthritis, REE correlated with the wrist swelling score (r(s) = 0.72), ESR (r(s) = 0.69), pain assessment scale (r(s) = 0.63) and childhood HAQ (r(s) = 0.60). In patients with hip arthritis, ME correlated with the hip limitation of motion (r(s) = 0.69). Static MRI synovitis score based on post-gadolinium enhancement correlated with MV (r(s) = 0.63) in patients with wrist arthritis and with ME (r = 0.68) in those with hip arthritis. The inter-reader agreement assessed by intra-class correlation coefficient (ICC) for ME, MV and REE (ICC = 0.98, 0.97 and 0.84, respectively) was excellent., Conclusions: DCE-MRI represents a promising method for the assessment of disease activity in JIA, especially in patients with wrist arthritis. As far as we know, this study is the first to demonstrate the feasibility, reliability and construct validity of DCE-MRI in JIA. These results should be confirmed in large-scale longitudinal studies in view of its further application in therapeutic decision making and in clinical trials.

Objectives: Recent laboratory and clinical data suggest that two prototype autoimmune diseases, systemic lupus erythematosus and rheumatoid arthritis are mainly driven by distinct cytokines, interferon (IFN)-alpha and tumour necrosis factor (TNF)-alpha, respectively. We here investigated the presence and characteristics of natural type I IFN-producing cells (IPCs), as well as IFN-alpha and TNF-alpha expression at sites of inflammation in juvenile idiopathic arthritis (JIA)., Methods: Peripheral blood (PB) and synovial fluid (SF) mononuclear cells (MNCs) (n = 25 each) from JIA patients with active disease were studied. IPCs were identified as BCDA-2(+)CD123(+)HLA-DR(+)CD45RA(+) cells, and dendritic cells (DCs) as CD11c(+)CD14(-/low)lin(-) cells by flow cytometry. IPCs and DCs were analysed for Toll-like receptor-7 and -9 mRNA expression by real-time polymerase chain reaction. IFN-alpha was measured by enzyme-linked immunosorbent assay in serum, SF and in supernatants of influenza virus-infected, cultured IPCs. Synovial tissues of n = 6 additional JIA patients were analysed by immunohistochemistry using mAbs against CD123, IFN-alpha, TNF-alpha, CD3, CD19 and CD138., Results: IPCs were enriched in SF MNCs compared with PB MNCs in all JIA patients. Influenza-induced, but no spontaneous IFN-alpha release was detected from SF IPCs, and serum and SF IFN-alpha levels were not elevated. Nonetheless, in synovial tissue IFN-alpha producing cells accumulated at inflammatory lymph-follicular-like structures, while TNF-alpha producing cells were mostly found at the lining and sublining layers., Conclusions: These data suggest that besides TNF-alpha-expressing cells, IFN-alpha-producing IPCs are involved in initiation, maintenance or regulation of the inflammatory response in JIA.

Objective: We report the experience of the Italian Registry of patients affected by chronic infantile neurological, cutaneous, articular (CINCA) syndrome. The clinical and genetic features of 12 unrelated Italian patients with CINCA syndrome are described, focusing on the possible influence of the presence of CIAS1/cryopyrin mutations on the phenotype of the disease and on its prognosis., Methods: The clinical features of 12 Italian CINCA patients were evaluated. Genomic DNA of the patients was sequenced using specific primers for CIAS1 and ASC genes., Results: Our patients shared typical CINCA characteristics and, sometimes, remarkable perinatal events, peculiar of CIAS1-mutated patients. Seven patients carried CIAS1 missense mutation, localized within the nucleotide binding domain of cryopyrin. Four previously described mutations and three new heterozygous CIAS1 missense mutations were identified. ASC gene, encoding for a direct interactor of cryopyrin, was not mutated in Italian CINCA patients. Finally, we reported the efficacy and safety of anti-IL1 therapy (Anakinra) in seven patients with a particularly severe CINCA phenotype., Conclusion: Despite some common signs-used as syndrome hallmarks-we observed a high variability in symptoms, genetic results and outcomes in Italian CINCA patients. In contrast with other authors, we cannot find out any correlation between mutations in CIAS1 and CINCA severity, but we underlined the concomitance of perinatal events and mental retardation only in CIAS1 mutated subjects. Finally, we confirmed the efficacy of Anakinra treatment, both in CIAS1-mutated and non-mutated patients.

Objective: The aim of the study was to evaluate the pattern of the lymphoid organization in the synovial tissue of patients affected with juvenile idiopathic arthritis (JIA)., Methods: A total of 40 JIA patients who underwent synoviectomy or synovial biopsies were enrolled. The mean age at surgery was 15.1 yrs (range 6-30 yrs) and the mean disease duration was 6.7 yrs (range 3 months to 22.2 yrs). Tissue specimens were grouped according to the following criteria: (i) diffuse perivascular infiltrate without lymphoid organization, (ii) T cell-B cell aggregates with or without germinal centre reaction., Results: Synovial tissues from 12 JIA patients did not show any sign of lymphoid organization, whereas 28 patients displayed a variable number of T-B cell aggregates. Typical features consistent with a germinal centre reaction were present in two JIA patients only. Lymphoid organization in JIA patients did not correlate with the duration and severity of the disease or with the degree of synovial inflammation, but did positively correlate with the presence of anti-nuclear antibodies. Moreover, a diffuse lymphocyte infiltration was significantly related to the presence of an acute phase of inflammation and the presence of lymphoid aggregates correlated with the degree of plasma cells infiltration., Conclusions: Lymphoid neogenesis in JIA represents a phase in the immunopathological process that characterize the development of inflammatory synovitis. It is not related to disease activity or severity, but appears to be more frequent in patients with circulating anti-nuclear antibodies.

Objective: To evaluate the synovial expression of osteopontin (OPN) and its possible correlation with the degree of synovial angiogenesis in human chronic idiopathic arthritis., Methods: Forty-five patients with active juvenile idiopathic arthritis (JIA) were studied. All patients underwent SF aspiration before steroid injection. A paired plasma sample was collected from 22 JIA patients. Plasma from 15 age-matched healthy subjects was used as control. Plasma and SF were tested by ELISA for OPN and vascular endothelial growth factor (VEGF). Synovial tissue was obtained at synovectomy from 10 JIA patients. Immunohistochemistry was performed according to a standard technique with anti-OPN, anti-CD68, anti-CD31 anti-VEGF and anti-alpha(v)beta(3) antibodies., Results: OPN levels were significantly higher in SF than in paired plasma samples (P<0.001). The same pattern was observed for VEGF (P<0.001). A positive correlation between OPN and VEGF concentrations was found in SF (r = 0.6, P = 0.001). In synovial tissue, OPN was expressed at the level of the lining and sublining layers with a distribution similar to that observed for VEGF. OPN expression in the lining layer correlated with the number of vessels present in the areas underlying the sublining layer., Conclusions: Synovial expression of OPN correlates with parameters of angiogenesis in JIA. These data support, in human disease, the possible role of OPN in the vascularization of inflamed synovial tissue, as previously shown in OPN-deficient animal models of arthritis.

Objective: To evaluate the role of vascular endothelial growth factor (VEGF) in the pathogenesis of local joint inflammation in juvenile idiopathic arthritis (JIA)., Methods: Sera from 50 patients affected with JIA and 10 age-matched healthy controls were tested with a commercial ELISA for VEGF. Corresponding synovial fluid (SF) concentrations of VEGF and p75 soluble tumour necrosis factor receptor (sTNFR) were evaluated in 20 active JIA patients., Results: Serum concentrations of VEGF were significantly higher in patients with active polyarticular disease than in patients with active and inactive oligoarticular disease and healthy controls. In JIA patients, serum concentrations of VEGF displayed a significant correlation with a number of clinical and laboratory parameters of disease activity. VEGF concentrations in SF were significantly higher than those detected in corresponding sera. Moreover, a clear correlation was found between corresponding SF and serum VEGF concentrations. In SF, VEGF showed a strong positive correlation with p75 sTNFR., Conclusions: Concentrations of VEGF in SF in patients with JIA are higher than corresponding serum concentrations, suggesting that this pro-angiogenic factor may have a major role in the outgrowth of hyperplastic pannus and tissue damage at the site of tissue inflammation.