Publications by authors named "Antonella Insalaco"

72 Publications

Early Treatment and IL1RN Single-Nucleotide Polymorphisms Affect Response to Anakinra in Systemic Juvenile Idiopathic Arthritis.

Arthritis Rheumatol 2021 Jun 2;73(6):1053-1061. Epub 2021 May 2.

Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

Objective: To evaluate the impact of early treatment and IL1RN genetic variants on the response to anakinra in systemic juvenile idiopathic arthritis (JIA).

Methods: Response to anakinra was defined as achievement of clinically inactive disease (CID) at 6 months without glucocorticoid treatment. Demographic, clinical, and laboratory characteristics of 56 patients were evaluated in univariate and multivariate analyses as predictors of response to treatment. Six single-nucleotide polymorphisms (SNPs) in the IL1RN gene, previously demonstrated to be associated with a poor response to anakinra, were genotyped by quantitative polymerase chain reaction (qPCR) or Sanger sequencing. Haplotype mapping was performed with Haploview software. IL1RN messenger RNA (mRNA) expression in whole blood from patients, prior to anakinra treatment initiation, was assessed by qPCR.

Results: After 6 months of anakinra treatment, 73.2% of patients met the criteria for CID without receiving glucocorticoids. In the univariate analysis, the variable most strongly related to the response was disease duration from onset to initiation of anakinra treatment, with an optimal cutoff at 3 months (area under the curve 84.1%). Patients who started anakinra treatment ≥3 months after disease onset had an 8-fold higher risk of nonresponse at 6 months of treatment. We confirmed that the 6 IL1RN SNPs were inherited as a common haplotype. We found that homozygosity for ≥1 high-expression SNP correlated with higher IL1RN mRNA levels and was associated with a 6-fold higher risk of nonresponse, independent of disease duration.

Conclusion: Our findings on patients with systemic JIA confirm the important role of early interleukin-1 inhibition and suggest that genetic IL1RN variants predict nonresponse to therapy with anakinra.
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http://dx.doi.org/10.1002/art.41612DOI Listing
June 2021

Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients.

J Allergy Clin Immunol Pract 2021 02 18;9(2):803-818.e11. Epub 2020 Nov 18.

Pediatric Pulmonology Department and Reference Center for Rare Lung Disease RespiRare, Trousseau University Hospital, AP-HP Sorbonne Université, Paris, France.

Background: Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD).

Objective: To describe a cohort of patients with SAVI.

Methods: Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out.

Results: Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good.

Conclusion: The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies.
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http://dx.doi.org/10.1016/j.jaip.2020.11.007DOI Listing
February 2021

Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis.

N Engl J Med 2021 01 16;384(1):31-41. Epub 2020 Nov 16.

From the Center for the Diagnosis and Treatment of Pericardial Diseases, Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland (A.L.K., P.C.); University Cardiology, Cardiovascular, and Thoracic Department, Azienda Ospedaliero-Universitaria (AOU) Città della Salute e della Scienza di Torino and University of Turin, Turin (M.I.), the Department of Biomedical and Clinical Science, University of Milan, Fatebenefratelli Hospital, Milan (A.B.), and the Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome (A.I.) - all in Italy; Pauley Heart Center, Virginia Commonwealth University, Richmond (A.A.); Kiniksa Pharmaceuticals, Lexington, MA (F.F., A.P., J.F.P.); the Cardiology Unit, University of Vermont Medical Center, Burlington (M.L.); the Cardiovascular Clinical Research Institute, Lady Davis Carmel Medical Center and the Technion-Israel Institute of Technology, Haifa, Israel (B.S.L.); the Minneapolis Heart Institute, Abbott Northwestern Hospital, Minneapolis (D.L.), and the Division of Cardiovascular Ultrasound, Department of Cardiovascular Medicine, Mayo Clinic, Rochester (S.A.L.) - both in Minnesota; the Monash Cardiovascular Research Centre, Victorian Heart Institute, Monash University, Clayton, VIC, Australia (S.J.N.); and Kiniksa Pharmaceuticals, Hamilton, Bermuda (A.W.).

Background: Interleukin-1 has been implicated as a mediator of recurrent pericarditis. The efficacy and safety of rilonacept, an interleukin-1α and interleukin-1β cytokine trap, were studied previously in a phase 2 trial involving patients with recurrent pericarditis.

Methods: We conducted a phase 3 multicenter, double-blind, event-driven, randomized-withdrawal trial of rilonacept in patients with acute symptoms of recurrent pericarditis (as assessed on a patient-reported scale) and systemic inflammation (as shown by an elevated C-reactive protein [CRP] level). Patients presenting with pericarditis recurrence while receiving standard therapy were enrolled in a 12-week run-in period, during which rilonacept was initiated and background medications were discontinued. Patients who had a clinical response (i.e., met prespecified response criteria) were randomly assigned in a 1:1 ratio to receive continued rilonacept monotherapy or placebo, administered subcutaneously once weekly. The primary efficacy end point, assessed with a Cox proportional-hazards model, was the time to the first pericarditis recurrence. Safety was also assessed.

Results: A total of 86 patients with pericarditis pain and an elevated CRP level were enrolled in the run-in period. During the run-in period, the median time to resolution or near-resolution of pain was 5 days, and the median time to normalization of the CRP level was 7 days. A total of 61 patients underwent randomization. During the randomized-withdrawal period, there were too few recurrence events in the rilonacept group to allow for the median time to the first adjudicated recurrence to be calculated; the median time to the first adjudicated recurrence in the placebo group was 8.6 weeks (95% confidence interval [CI], 4.0 to 11.7; hazard ratio in a Cox proportional-hazards model, 0.04; 95% CI, 0.01 to 0.18; P<0.001 by the log-rank test). During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group. In the run-in period, 4 patients had adverse events leading to the discontinuation of rilonacept therapy. The most common adverse events with rilonacept were injection-site reactions and upper respiratory tract infections.

Conclusions: Among patients with recurrent pericarditis, rilonacept led to rapid resolution of recurrent pericarditis episodes and to a significantly lower risk of pericarditis recurrence than placebo. (Funded by Kiniksa Pharmaceuticals; RHAPSODY ClinicalTrials.gov number, NCT03737110.).
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http://dx.doi.org/10.1056/NEJMoa2027892DOI Listing
January 2021

Chronic nonbacterial osteomyelitis - clinical and magnetic resonance imaging features.

Pediatr Radiol 2021 02 9;51(2):282-288. Epub 2020 Oct 9.

Section of Pediatric Radiology, University Hospital of North Norway, 9019, Tromsø, Norway.

Background: Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disorder. Little information exists on the use of imaging techniques in CNO.

Materials And Methods: We retrospectively reviewed clinical and MRI findings in children diagnosed with CNO between 2012 and 2018. Criteria for CNO included unifocal or multifocal inflammatory bone lesions, symptom duration >6 weeks and exclusion of infections and malignancy. All children had an MRI (1.5 tesla) performed at the time of diagnosis; 68 of these examinations were whole-body MRIs including coronal short tau inversion recovery sequences, with additional sequences in equivocal cases.

Results: We included 75 children (26 boys, or 34.7%), with mean age 10.5 years (range 0-17 years) at diagnosis. Median time from disease onset to diagnosis was 4 months (range 1.5-72.0 months). Fifty-nine of the 75 (78.7%) children presented with pain, with or without swelling or fever, and 17 (22.7%) presented with back pain alone. Inflammatory markers were raised in 46/75 (61.3%) children. Fifty-four of 75 (72%) had a bone biopsy. Whole-body MRI revealed a median number of 6 involved sites (range 1-27). Five children (6.7%) had unifocal disease. The most commonly affected bones were femur in 46 (61.3%) children, tibia in 48 (64.0%), pelvis in 29 (38.7%) and spine in 20 (26.7%). Except for involvement of the fibula and spine, no statistically significant differences were seen according to gender.

Conclusion: Nearly one-fourth of the children presented with isolated back pain, particularly girls. The most common sites of disease were the femur, tibia and pelvic bones. Increased inflammatory markers seem to predict the number of MRI sites involved.
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http://dx.doi.org/10.1007/s00247-020-04827-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846524PMC
February 2021

Movement disorders in ADAR1 disease: Insights from a comprehensive cohort.

Parkinsonism Relat Disord 2020 Aug 30;79:100-104. Epub 2020 Aug 30.

Department of Systems Medicine, University of Roma Tor Vergata, Rome, Italy; Department of Neurosciences, IRCCS Bambino Gesù Children's Hospital, Rome, Italy. Electronic address:

ADAR1 variants are associated to rare and heterogenous neurological conditions, including Aicardi-Goutières syndrome type 6, bilateral striatal necrosis, and dyschromatosis symmetrica hereditaria. Movement disorders (MDs) commonly occur in ADAR1-related diseases although a complete overview on the phenomenology has not been provided yet. Here, a cohort of 57 patients with ADAR1-related diseases, including 3 unpublished patients and 54 previously reported cases, was reviewed. Data on demographics, clinical features of MDs, genetics and biomarkers were collected and descriptive statistics, group analysis for genotype and logistic regression were run. Manifestations of MD characterized the onset of ADAR1-related disease in 60% of patients. Specifically, dystonia occurred in 39% of cases, even as severe status dystonicus, while prevalence of other MDs was lower. Patients often presented brain lesions (>90%) and progressive disease course (43%), fatal in some cases. Clinical presentation and outcome differed among patients with distinct genotype. This review shows that phenomenology of MDs in ADAR1-related diseases is wide and heterogeneous, although a severe motor syndrome (often characterized by dystonia) secondary to brain lesions represents the most common manifestation. Waiting for future development of disease-modifying treatments, an appropriate symptomatic intervention is crucial for ADAR1 patients. Accordingly, a deeper knowledge of phenomenology is fundamental.
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http://dx.doi.org/10.1016/j.parkreldis.2020.08.039DOI Listing
August 2020

Clinical Features at Onset and Genetic Characterization of Pediatric and Adult Patients with TNF- Receptor-Associated Periodic Syndrome (TRAPS): A Series of 80 Cases from the AIDA Network.

Mediators Inflamm 2020 7;2020:8562485. Epub 2020 Aug 7.

Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Siena, Italy.

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) 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 ( < 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 < 0.01 and < 0.05, respectively), while abdominal pain was present in 84% of children and in 25% of adults ( < 0.01). Abdominal pain was significantly associated also to the presence of HP mutations ( < 0.01), while oral aphthosis was more frequently found in the LP variant group ( < 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 ( < 0.01) and to the persistence of steadily elevated inflammatory markers during asymptomatic periods ( < 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 ( < 0.05). Both NSAIDs and colchicine were used as monotherapy more frequently in the LP group compared to the HP group ( < 0.01). Biologic agents were prescribed to 49 (61%) patients; R92Q subjects were more frequently on NSAIDs monotherapy than other patients ( < 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 ( < 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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http://dx.doi.org/10.1155/2020/8562485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428902PMC
August 2020

Dysregulation in B-cell responses and T follicular helper cell function in ADA2 deficiency patients.

Eur J Immunol 2021 01 28;51(1):206-219. Epub 2020 Aug 28.

Unità Operativa Semplice Dipartimentale Centro Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy.

Adenosine deaminase 2 deficiency (DADA2) is an autoinflammatory disease characterized by inflammatory vasculopathy, early strokes associated often with hypogammaglobulinemia. Pure red cell aplasia, thrombocytopenia, and neutropenia have been reported. The defect is due to biallelic loss of function of ADA2 gene, coding for a protein known to regulate the catabolism of extracellular adenosine. We therefore investigated immune phenotype and B- and T-cell responses in 14 DADA2 patients to address if ADA2 mutation affects B- and T-cell function. Here, we show a significant decrease in memory B cells, in particular class switch memory, and an expansion of CD21 B cells in DADA2 patients. In vitro stimulated B lymphocytes were able to secrete nonfunctional ADA2 protein, suggesting a cell intrinsic defect resulting in an impairment of B-cell proliferation and differentiation. Moreover, CD4 and CD8 T cells were diminished; however, the frequency of circulating T follicular helper cells was significantly increased but they had an impairment in IL-21 production possibly contributing to an impaired B cell help. Our findings suggest that ADA2 mutation could lead to a B-cell intrinsic defect but also to a defective Tfh cell function, which could contribute to the immunodeficient phenotype reported in DADA2 patients.
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http://dx.doi.org/10.1002/eji.202048549DOI Listing
January 2021

High prevalence of rare FBLIM1 gene variants in an Italian cohort of patients with Chronic Non-bacterial Osteomyelitis (CNO).

Pediatr Rheumatol Online J 2020 Jul 10;18(1):55. Epub 2020 Jul 10.

University of Trieste, Trieste, Italy.

Background: FBLIM1 gene has been recently demonstrated to be involved in the pathogenesis of bone sterile inflammation. The aim of the study is to evaluate the prevalence of FBLIM1 gene variants in a cohort of 80 Italian patients with Chronic Non-bacterial Osteomyelitis (CNO).

Methods: The coding regions of FBLIM1 gene were sequenced in a cohort of 80 patients with CNO using DNA extracted from blood lymphocytes, and PCR products were sequenced. Only rare (global MAF < 2%), coding variants detected were considered. Clinical evaluation of patients with rare variants and those without was performed. Fisher's exact test was used to compare categorical and ordinal data, and Student's t-test was used to analyze continuous data.

Results: Eighteen out of 80 patients (~ 22%) presented at least one rare coding variant in FBLIM1. Eight patients presented a variant never associated before with CNO. All patients presented classical features of CNO and no statistical difference between patients with presence of FBLMI1 variants and those without were found in terms of clinical manifestation, treatment, and outcome.

Conclusion: Considering the high frequency of rare variants in our CNO cohort, our data seem to confirm a possible role of FBLIM1 in the pathogenesis of CNO suggesting that CNO is a disorder of chronic inflammation and imbalanced bone remodeling.
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http://dx.doi.org/10.1186/s12969-020-00447-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350626PMC
July 2020

Role of Colchicine Treatment in Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS): Real-Life Data from the AIDA Network.

Mediators Inflamm 2020 27;2020:1936960. Epub 2020 May 27.

Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Italy.

Objective: To analyze the potential role of colchicine monotherapy in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) in terms of control of clinical and laboratory manifestations.

Methods: Patients with TRAPS treated with colchicine monotherapy were retrospectively enrolled; demographic, clinical and therapeutic data were collected and statistically analysed after having clustered patients according to different times at disease onset, penetrance of mutations, dosage of colchicine, and different disease manifestations.

Results: 24 patients (14 males; 15 with pediatric disease onset) treated with colchicine monotherapy were enrolled. Colchicine resulted in a complete response in 3 (12.5%) cases, partial response in 14 (58.3%) patients, and lack of response in 7 (29.2%) patients. There were not significant differences in colchicine response between pediatric and adult disease onset ( = 0.42), between low- and high-penetrance mutations ( = 0.62), and according to different dosages ( = 0.66). No significant differences were identified in the frequency of specific disease manifestations between patients experiencing any response to colchicine and patients with lack of response.

Conclusions: Colchicine monotherapy is useful in a low percentage of TRAPS patients; nevertheless, it could be attempted in patients with milder phenotypes and at a lower risk of developing reactive amyloidosis.
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http://dx.doi.org/10.1155/2020/1936960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273368PMC
May 2020

Blood-based test for diagnosis and functional subtyping of familial Mediterranean fever.

Ann Rheum Dis 2020 07 20;79(7):960-968. Epub 2020 Apr 20.

VIB Center for Inflammation Research, Zwijnaarde, Belgium

Background And Objective: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) worldwide. The disease is caused by mutations in the gene encoding the inflammasome sensor Pyrin. Clinical diagnosis of FMF is complicated by overlap in symptoms with other diseases, and interpretation of genetic testing is confounded by the lack of a clear genotype-phenotype association for most of the 340 reported variants. In this study, the authors designed a functional assay and evaluated its potential in supporting FMF diagnosis.

Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with Pyrin-associated autoinflammation with an FMF phenotype (n=43) or with autoinflammatory features not compatible with FMF (n=8), 10 asymptomatic carriers and 48 healthy donors. Sera were obtained from patients with distinct AIDs (n=10), and whole blood from a subset of patients and controls. The clinical, demographic, molecular genetic factors and other characteristics of the patient population were assessed for their impact on the diagnostic test read-out. Interleukin (IL)-1β and IL-18 levels were measured by Luminex assay.

Results: The ex vivo colchicine assay may be performed on whole blood or PBMC. The functional assay robustly segregated patients with FMF from healthy controls and patients with related clinical disorders. The diagnostic test distinguished patients with classical FMF mutations (M694V, M694I, M680I, R761H) from patients with other mutations and variants (K695R, P369S, R202Q, E148Q) that are considered benign or of uncertain clinical significance.

Conclusion: The ex vivo colchicine assay may support diagnosis of FMF and functional subtyping of Pyrin-associated autoinflammation.
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http://dx.doi.org/10.1136/annrheumdis-2019-216701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307214PMC
July 2020

Prevalence of cranial involvement in a cohort of Italian patients with chronic non-bacterial osteomyelitis.

Clin Exp Rheumatol 2020 Mar-Apr;38(2):366-369. Epub 2020 Jan 29.

University of Trieste, and Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy.

Objectives: Chronic non-bacterial osteomyelitis (CNO) is a non-infectious inflammatory disease characterised by uni- or multi-focal bone lytic lesions. CNO mainly affects metaphysis of long bones, pelvis and shoulder girdle. Neurocranium lesions are extremely rare. The objective of the study is to describe the prevalence and clinical manifestations of CNO patients with neurocranium involvement in an Italian cohort of CNO patients.

Methods: This is a retrospective study. Medical records of patients with CNO admitted to eight paediatric rheumatology centres were reviewed.

Results: Among 86 patients with CNO enrolled in the study, three of them were female and presented neurocranium involvement - multifocal lesions. Two out of the 3 patients were completely asymptomatic for cranial involvement, while one of the 3 complained of cranial bossing. Cranial involvement was detected with bone scintigraphy and then confirmed by magnetic resonance imaging and/or computed tomography. Two patients presented fever and two with skin manifestations. Laboratory inflammatory markers were increased in two of them. All patients underwent bone biopsy confirming the diagnosis. They all received NSAIDs. Two patients received corticosteroids and then methotrexate and achieved clinical remission, while one patient received pamidronate.

Conclusions: This is the first report of neurocranium involvement in a cohort of patients affected by CNO. In our cohort no patient showed significant signs attributable to cranial involvement.
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April 2020

The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis.

PLoS One 2019 17;14(12):e0226043. Epub 2019 Dec 17.

Division of Rheumatology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Aim of this study was to investigate the activation of the IFNγ pathway in the affected liver and in the blood of patients with secondary hemophagocytic lymphohistiocytosis (sHLH). To this purpose, the mRNA expression levels of IFNG and IFNγ-inducible genes as well as Tyrosine (701)-phosphorylated signal transducer and activator of transcription 1 (STAT1) protein levels were evaluated in the liver and in peripheral blood mononuclear cells (PBMCs) of three patients with sHLH with predominant liver involvement. The mRNA expression levels of IFNG and IFNγ-inducible genes were markedly higher in patient livers compared to control livers and to one disease control liver. Conversely, slight differences in the expression levels of Type I IFN-inducible genes and other classical inflammatory cytokine genes were found. Further supporting the activation of the IFNγ pathway, higher protein levels of phosphorylated and total STAT1 were detected in patient livers compared to control livers. When the expression of the same genes analysed in liver tissues was evaluated in PBMCs collected from 2 out of 3 patients before the liver biopsy, we found that mRNA levels of IFNγ-inducible genes were markedly increased. Accordingly, high circulating levels of IFNγ-inducible CXCL9 were observed in patients. Altogether, these data demonstrate the selective and marked up-regulation of the IFNγ pathway in the liver tissue and blood of patients with active sHLH. Finally, we show that measurement of circulating CXCL9 levels and evaluation of IFNγ-inducible gene expression levels in PBMCs may represent a new valid tool to better identify patients with suspected HLH with predominant liver involvement.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226043PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917341PMC
April 2020

A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function.

J Exp Med 2019 12 10;216(12):2778-2799. Epub 2019 Oct 10.

Baylor-Hopkins Center for Mendelian Genomics, Houston, TX.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival.
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http://dx.doi.org/10.1084/jem.20190147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888978PMC
December 2019

Anakinra Drug Retention Rate and Predictive Factors of Long-Term Response in Systemic Juvenile Idiopathic Arthritis and Adult Onset Still Disease.

Front Pharmacol 2019 23;10:918. Epub 2019 Aug 23.

Division of Rheumatology, Department of Pediatric Medicine, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.

Only a few studies have reported long-term efficacy of interleukin (IL)-1 inhibition in systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still disease (AOSD). Herein we report on the effectiveness of anakinra (ANA), expressed in terms of drug retention rate (DRR), and evaluate the predictive factors of drug survival in a cohort of patients with sJIA and AOSD. This is a multicenter study reviewing retrospectively the medical records from 61 patients with sJIA and 76 with AOSD, all treated with ANA in 25 Italian tertiary referral centers. The cumulative retention rate of ANA at 12-, 24-, 48-, and 60-month of follow-up was 74.3%, 62.9%, 49.4%, and 49.4%, respectively, without any significant differences between sJIA and AOSD patients ( = 0.164), and between patients treated in monotherapy compared with the subgroup coadministered with conventional disease-modifying antirheumatic drugs (cDMARDs) ( = 0.473). On the other hand, a significant difference in DRR was found between biologic-naïve patients and those previously treated with biotechnologic drugs ( = 0.009), which persisted even after adjustment for pathology ( = 0.013). In the regression analysis, patients experiencing adverse events (AEs) {hazards ratio (HR) = 3.029 [confidence interval (CI) 1.750-5.242], < 0.0001} and those previously treated with other biologic agents [HR = 1.818 (CI 1.007-3.282), = 0.047] were associated with a higher HR of ANA discontinuation. The median treatment delay was significantly higher among patients discontinuing ANA ( < 0.0001). Significant corticosteroid-sparing ( = 0.033) and cDMARD-sparing effects ( < 0.0001) were also recorded. Less than one-third of our cohort developed AEs, and 85% were deemed mild in nature, with 70% of them involving the skin. Our findings display an overall excellent DRR of ANA on the long run for both sJIA and AOSD, that may be further optimized by closely monitoring patient's safety issues and employing this IL-1 inhibitor as a first-line biologic as early as possible. Moreover, ANA allowed a significant drug-sparing effect and showed an overall good safety profile.
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http://dx.doi.org/10.3389/fphar.2019.00918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715768PMC
August 2019

The activating p.Ser466Arg change in STAT1 causes a peculiar phenotype with features of interferonopathies.

Clin Genet 2019 12 4;96(6):585-589. Epub 2019 Sep 4.

Dipartimento Pediatrie Specialistiche, U. O. Reumatologia, Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Signal Transducer and Activator of Transcription 1 (STAT1) is a DNA-binding signal transducer that regulates transcription of specific genes in response to IFNγ and IFNα/β stimulation. Loss-of-function mutations impairing STAT1 activity are known to confer susceptibility to intracellular bacterial and viral diseases. Conversely, the few known activating mutations of STAT1 allow predisposition to chronic mucocutaneous candidiasis disease, and occur in patients with combined immunodeficiency and defective Th1 and Th17 responses. Here, we report on a de novo gain-of-function (GoF) STAT1 mutation (c.1398C>G, p.Ser466Arg) identified by exome sequencing in an individual with brain calcification, arthritis, recurrent pericarditis, leukopenia, thrombocytopenia and low C3 levels, a phenotype resembling an interferonopathy. The Ser466Arg change affects a highly conserved residue located in the DNA binding domain of the protein and the amino acid substitution was documented to have an activating role both in vitro and in vivo. Altogether, clinical features and functional studies are compatible with hyperactivation of the Interferon pathways, highlighting a role of STAT1 GoF mutation in clinical phenotypes fitting interferonopathies.
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http://dx.doi.org/10.1111/cge.13632DOI Listing
December 2019

Clinical characteristics and genetic analyses of 187 patients with undefined autoinflammatory diseases.

Ann Rheum Dis 2019 10 5;78(10):1405-1411. Epub 2019 Jul 5.

Center for Autoinflammatory Diseases and Immunodeficiency, IRCCS Instituto Giannina Gaslini, Genoa, Italy

Objectives: To describe the clinical characteristics, treatment response and genetic findings in a large cohort of patients with undefined systemic autoinflammatory diseases (SAIDs).

Methods: Clinical and genetic data from patients with undefined SAIDs were extracted from the Eurofever registry, an international web-based registry that retrospectively collects clinical information on patients with autoinflammatory diseases.

Results: This study included 187 patients. Seven patients had a chronic disease course, 180 patients had a recurrent disease course. The median age at disease onset was 4.3 years. Patients had a median of 12 episodes per year, with a median duration of 4 days. Most commonly reported symptoms were arthralgia (n=113), myalgia (n=86), abdominal pain (n=89), fatigue (n=111), malaise (n=104) and mucocutaneous manifestations (n=128). In 24 patients, relatives were affected as well. In 15 patients, genetic variants were found in autoinflammatory genes. Patients with genetic variants more often had affected relatives compared with patients without genetic variants (p=0.005). Most patients responded well to non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine and anakinra. Complete remission was rarely achieved with NSAIDs alone. Notable patterns were found in patients with distinctive symptoms. Patients with pericarditis (n=11) were older at disease onset (33.8 years) and had fewer episodes per year (3.0/year) compared with other patients. Patients with an intellectual impairment (n=8) were younger at disease onset (2.2 years) and often had relatives affected (28.6%).

Conclusion: This study describes the clinical characteristics of a large cohort of patients with undefined SAIDs. Among these, patients with pericarditis and intellectual impairment appear to comprise distinct subsets.
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http://dx.doi.org/10.1136/annrheumdis-2018-214472DOI Listing
October 2019

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome.

J Clin Immunol 2019 07 29;39(5):476-485. Epub 2019 May 29.

U.O.C. Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Objectives: Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib.

Methods: We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis.

Results: We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease.

Conclusions: We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.
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http://dx.doi.org/10.1007/s10875-019-00645-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086512PMC
July 2019

An unusual presentation of purine nucleoside phosphorylase deficiency mimicking systemic juvenile idiopathic arthritis complicated by macrophage activation syndrome.

Pediatr Rheumatol Online J 2019 May 22;17(1):25. Epub 2019 May 22.

Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Piazza S. Onofrio 4, 00165, Rome, Italy.

Background: Systemic juvenile idiopathic arthritis (sJIA) is an inflammatory condition that presents with fever, rash and arthritis. At onset systemic features are predominant and the diagnosis may be a challenge. Secondary hemophagocytic lymphohistiocytosis (sHLH) forms may be associated with different disorders, including rheumatic diseases, and this form is called macrophage activation syndrome (MAS). CXCL9 levels, a chemokine induced by IFNγ, are significantly elevated in patients with sHLH or MAS and are correlated with laboratory features of disease activity. High levels of IL-18 have been reported in patients with MAS during sJIA, as well as in some patients with sHLH and IL-18 is indeed known to induce IFNγ production.

Findings: We report a patient with a clinical presentation highly suggestive for systemic juvenile idiopathic arthritis (sJIA) onset complicated by MAS, and was later diagnosed with purine nucleoside phosphorylase (PNP)-deficiency with HLH. Some unusual features appeared when HLH was controlled and further investigations provided the correct diagnosis. Serum CXCL9 and IL-18 levels were found markedly elevated at disease onset, during the active phase of MAS and decreased progressively during the course.

Conclusion: The reported case underlines the potential difficulties in discriminating sJIA from other causes of systemic inflammation. Furthermore, this supports the notion that especially in young children with a sJIA-like disease other mimicking conditions should be actively sought for. CXCL9 and IL-18 levels suggested that patients with PNP-deficiency may have a subclinical activation of the IFNγ pathway and indeed they are predisposed to develop sHLH.
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http://dx.doi.org/10.1186/s12969-019-0328-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532153PMC
May 2019

Drug Retention Rate and Predictive Factors of Drug Survival for Interleukin-1 Inhibitors in Systemic Juvenile Idiopathic Arthritis.

Front Pharmacol 2018 8;9:1526. Epub 2019 Jan 8.

Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.

Few studies have reported the drug retention rate (DRR) of biologic drugs in juvenile idiopathic arthritis (JIA), and none of them has specifically investigated the DRR of interleukin (IL)-1 inhibitors on systemic JIA (sJIA). This study aims to describe IL-1 inhibitors DRR and evaluate predictive factors of drug survival based on data from a real-world setting concerning sJIA. Medical records from sJIA patients treated with anakinra (ANA) and canakinumab (CAN) were retrospectively analyzed from 15 Italian tertiary referral centers. Seventy seven patients were enrolled for a total of 86 treatment courses. The cumulative retention rate of the IL-1 inhibitors at 12-, 24-, 48-, and 60-months of follow-up was 79.9, 59.5, 53.5, and 53.5%, respectively, without any statistically significant differences between ANA and CAN ( = 0.056), and between patients treated in monotherapy compared to the subgroup co-administered with conventional immunosuppressors ( = 0.058). On the contrary, significant differences were found between biologic-naive patients and those previously treated with biologic drugs ( = 0.038) and when distinguishing according to adverse events (AEs) occurrence ( = 0.04). In regression analysis, patients pre-treated with other biologics (HR = 3.357 [CI: 1.341-8.406], = 0.01) and those experiencing AEs (HR = 2.970 [CI: 1.186-7.435], = 0.020) were associated with a higher hazard ratio of IL-1 inhibitors withdrawal. The mean treatment delay was significantly higher among patients discontinuing IL-1 inhibitors ( = 0.0002). Our findings suggest an excellent overall DRR for both ANA and CAN that might be further augmented by paying attention to AEs and employing these agents as first-line biologics in an early disease phase.
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http://dx.doi.org/10.3389/fphar.2018.01526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331484PMC
January 2019

Variable Clinical Phenotypes and Relation of Interferon Signature with Disease Activity in ADA2 Deficiency.

J Rheumatol 2019 05 15;46(5):523-526. Epub 2019 Jan 15.

From the Division of Rheumatology, and the Unit of Medical Genetics, Laboratory of Cytogenetics and Molecular Genetics, Institute for Research and Health Care (IRCCS), Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Objective: An upregulation of type I interferon (IFN) stimulated genes [IFN score (IS)] was described in patients with adenosine deaminase 2 deficiency (DADA2). We describe the clinical course of 5 such patients and the role of IS as a marker of disease activity and severity.

Methods: Expression levels of IS were determined by quantitative real-time PCR.

Results: Five white patients were identified as carrying mutations. The IS before treatment was elevated in 4 out of 5 patients and decreased after treatment.

Conclusion: Our data confirm the high variability of DADA2 and suggest type I IS as a biomarker of disease activity.
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http://dx.doi.org/10.3899/jrheum.180045DOI Listing
May 2019

In silico validation of the Autoinflammatory Disease Damage Index.

Ann Rheum Dis 2018 11 4;77(11):1599-1605. Epub 2018 Aug 4.

Paediatric Pneumology and Immunology and Interdisciplinary Centre for Social Paediatrics, Charite University Medicine Berlin, Berlin, Germany.

Introduction: Autoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting.

Methods: The ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an 'observer-nested-within-subject' design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach's alpha.

Results: The ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items.

Conclusion: The ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies.
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http://dx.doi.org/10.1136/annrheumdis-2018-213725DOI Listing
November 2018

Safety profile of the interleukin-1 inhibitors anakinra and canakinumab in real-life clinical practice: a nationwide multicenter retrospective observational study.

Clin Rheumatol 2018 Aug 17;37(8):2233-2240. Epub 2018 May 17.

Department of Medical and Biological Sciences, Rheumatology Clinic, University of Udine, Udine, Italy.

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.
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http://dx.doi.org/10.1007/s10067-018-4119-xDOI Listing
August 2018

Correction to: A national cohort study on pediatric Behçet's disease: cross-sectional data from an Italian registry.

Pediatr Rheumatol Online J 2018 04 23;16(1):29. Epub 2018 Apr 23.

Pediatric Rheumatology Unit, AOU Meyer, University of Florence, Florence, Italy.

Following publication of the original article [1], the authors reported that the names of two institutional authors - EUROFEVER and the Paediatric Rheumatology International Trials Organisation (PRINTO) - had been unintentionally omitted in the final online version of the manuscript. The corrected author list is shown in this Correction..
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http://dx.doi.org/10.1186/s12969-018-0241-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911960PMC
April 2018

A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience.

Eur J Hum Genet 2018 07 23;26(7):960-971. Epub 2018 Apr 23.

Laboratory of Rare and Autoinflammatory Genetic Diseases and CEREMAIA, Montpellier University Hospital, Montpellier, France.

Deficiency of adenosine deaminase 2 (DADA2) is a recently described autoinflammatory disorder. Genetic analysis is required to confirm the diagnosis. We aimed to describe the identifying symptoms and genotypes of patients referred to our reference centres and to improve the indications for genetic testing. DNA from 66 patients with clinically suspected DADA2 were sequenced by Sanger or next-generation sequencing. Detailed epidemiological, clinical and biological features were collected by use of a questionnaire and were compared between patients with and without genetic confirmation of DADA2. We identified 13 patients (19.6%) carrying recessively inherited mutations in ADA2 that were predicted to be deleterious. Eight patients were compound heterozygous for mutations. Seven mutations were novel (4 missense variants, 2 predicted to affect mRNA splicing and 1 frameshift). The mean age of the 13 patients with genetic confirmation was 12.7 years at disease onset and 20.8 years at diagnosis. Phenotypic manifestations included fever (85%), vasculitis (85%) and neurological disorders (54%). Features best associated with a confirmatory genotype included fever with neurologic or cutaneous attacks (odds ratio [OR] 10.71, p = 0.003 and OR 10.9, p < 0.001), fever alone (OR 8.1, p = 0.01), and elevated C-reactive protein (CRP) level with neurologic involvement (OR 6.63, p = 0.017). Our proposed decision tree may help improve obtaining genetic confirmation of DADA2 in the context of autoinflammatory symptoms. Prerequisites for quick and low-cost Sanger analysis include one typical cutaneous or neurological sign, one marker of inflammation (fever or elevated CRP level), and recurrent or chronic attacks in adults.
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http://dx.doi.org/10.1038/s41431-018-0130-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018671PMC
July 2018

The multifaceted presentation of chronic recurrent multifocal osteomyelitis: a series of 486 cases from the Eurofever international registry.

Rheumatology (Oxford) 2018 Jul;57(7):1203-1211

Istituto Giannina Gaslini, Pediatria II, Reumatologia, Genoa.

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.
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http://dx.doi.org/10.1093/rheumatology/key058DOI Listing
July 2018

Dealing with Chronic Non-Bacterial Osteomyelitis: a practical approach.

Pediatr Rheumatol Online J 2017 Dec 29;15(1):87. Epub 2017 Dec 29.

Pediatria 2, Istituto Gaslini, Via Gerolamo Gaslini, 5, 16148, Genoa, Italy.

Background: Chronic Non-Bacterial Osteomyelitis (CNO) is an inflammatory disorder that primarily affects children. Although underestimated, its incidence is rare. For these reasons, no diagnostic and no therapeutic guidelines exist. The manuscript wants to give some suggestions on how to deal with these patients in the every-day clinical practice.

Main Body: CNO is characterized by insidious onset of bone pain with local swelling. Systemic symptoms such as fever, skin involvement and arthritis may be sometimes present. Radiological findings are suggestive for osteomyelitis, in particular if multiple sites are involved. CNO predominantly affects metaphyses of long bones, but clavicle and mandible, even if rare localizations of the disease, are very consistent with CNO diagnosis. CNO pathogenesis is still unknown, but recent findings highlighted the crucial role of cytokines such as IL-1β and IL-10 in disease pathogenesis. Moreover, the presence of non-bacterial osteomyelitis among autoinflammatory syndromes suggests that CNO could be considered an autoinflammatory disease itself. Differential diagnosis includes infections, malignancies, benign bone tumors, metabolic disorders and other autoinflammatory disorders. Radiologic findings, either with Magnetic Resonance or with Computer Scan, may be very suggestive. For this reason in patients in good clinical conditions, with multifocal localization and very consistent radiological findings bone biopsy could be avoided. Non-Steroidal Anti-Inflammatory Drugs are the first-choice treatment. Corticosteroids, methotrexate, bisphosphonates, TNFα-inhibitors and IL-1 blockers have also been used with some benefit; but the choice of the second line treatment depends on bone lesions localizations, presence of systemic features and patients' clinical conditions.

Conclusion: CNO may be difficult to identify and no consensus exist on diagnosis and treatment. Multifocal bone lesions with characteristic radiological findings are very suggestive of CNO. No data exist on best treatment option after Non-Steroidal Anti-Inflammatory Drugs failure.
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http://dx.doi.org/10.1186/s12969-017-0216-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747935PMC
December 2017

A national cohort study on pediatric Behçet's disease: cross-sectional data from an Italian registry.

Pediatr Rheumatol Online J 2017 Dec 21;15(1):84. Epub 2017 Dec 21.

Pediatric Rheumatology Unit, AOU Meyer, University of Florence, Florence, Italy.

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.
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http://dx.doi.org/10.1186/s12969-017-0213-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740899PMC
December 2017