Publications by authors named "Fabrizio De Benedetti"

133 Publications

Monocytes From Patients With Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis Are Hyperresponsive to Interferon Gamma.

Front Immunol 2021 17;12:663329. Epub 2021 Mar 17.

Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Objective: To investigate the activation of the IFNγ signaling pathway in monocytes of patients with secondary hemophagocytic lymphohistiocytosis (sHLH)/macrophage activation syndrome (MAS) and to evaluate whether levels of phosphorylated STAT1 represent a biomarker for the identification of patients at early stages of the disease.

Methods: Fresh whole blood samples from pediatric patients with active sHLH/MAS, not receiving (n=10) and receiving glucocorticoids (n=14) at time of sampling, were prospectively collected. As disease control groups, patients with active systemic juvenile idiopathic arthritis (sJIA) without MAS, patients with sHLH/MAS in remission and patients with other rheumatic diseases were also sampled. Whole blood cells were left unstimulated or stimulated with increasing concentrations of IFNγ for 10 minutes and the intracellular Tyrosine (701)-phosphorylated STAT1 (pSTAT1) levels were evaluated in monocytes by flow cytometry.

Results: Monocytes from untreated sHLH/MAS patients showed significantly higher basal levels of pSTAT1 compared to those observed in monocytes from glucocorticoid-treated sHLH/MAS patients and from all the other disease controls. In addition, a significant increase in responsiveness to IFNγ, as assessed by increased levels of pSTAT1 following stimulation, was observed in monocytes from untreated sHLH/MAS patients. pSTAT1 levels in monocytes distinguished patients with sHLH/MAS not treated with glucocorticoids from patients with active sJIA or with other rheumatic diseases [AUC, 0.93; 95% confidence interval 0.85-1.00, p<0.001]. Statistically significant correlations between mRNA levels in whole blood cells, circulating IFNγ levels and pSTAT1 levels in sHLH/MAS monocytes were found.

Conclusion: Our data demonstrating higher basal levels of pSTAT1 as well as a hyperreactivity to IFNγ stimulation in monocytes from patients with sHLH/MAS point to perturbations in the activation of downstream IFNγ signaling pathway as a contributor to the hyperinflammation occurring in these patients. Finally, the observation that glucocorticoids affect pSTAT1 levels , makes it difficult to consider the measurement of pSTAT1 levels as a biomarker to identify patients at early stages of sHLH/MAS in clinical practice.
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http://dx.doi.org/10.3389/fimmu.2021.663329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010171PMC
March 2021

Case Report: Pansclerotic Morphea-Clinical Features, Differential Diagnoses and Modern Treatment Concepts.

Front Immunol 2021 9;12:656407. Epub 2021 Mar 9.

Pediatric Dermatology Unit, Department of Pediatrics and Dermatology and Venereology, University Hospital Lausanne and University of Lausanne, Lausanne, Switzerland.

Pansclerotic morphea (PSM) is a rare skin disease characterized by progressive stiffening of the skin with or without the typical superficial skin changes usually seen in morphea (localized scleroderma). Standard therapy, consisting of a combination of systemic glucocorticoids and methotrexate or mycophenolate mofetil, does rarely stop disease progression, which may lead to severe cutaneous sclerosis and secondary contractures. Little is known about the efficacy of newer biologicals such as abatacept, a fusion protein antibody against CTLA-4, or tocilizumab, a fully humanized IL-6R antibody, in the treatment of this pathology. We present the case of an 8 years old girl with an unusual, progressive stiffening of the skin, which was eventually diagnosed as pansclerotic morphea. A treatment with systemic glucocorticoids and methotrexate combined with tocilizumab led to a good clinical response within 2 months after initiation. In this paper, we discuss differential diagnoses to be considered and this new promising treatment option based on a case review of the literature.
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http://dx.doi.org/10.3389/fimmu.2021.656407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985437PMC
March 2021

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

Arthritis Rheumatol 2021 06 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

Subcutaneous dosing regimens of tocilizumab in children with systemic or polyarticular juvenile idiopathic arthritis.

Rheumatology (Oxford) 2021 Jan 28. Epub 2021 Jan 28.

Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Objectives: To determine subcutaneous-tocilizumab (SC-TCZ) dosing regimens for systemic juvenile idiopathic arthritis (sJIA) and polyarticular JIA (pJIA).

Methods: In two 52-week phase 1 b trials, SC-TCZ (162 mg/dose) was administered to sJIA patients every week or every 2 weeks (every 10 days before interim analysis) and to pJIA patients every 2 weeks or every 3 weeks with body weight ≥30 kg or < 30 kg, respectively. Primary endpoints were pharmacokinetics, pharmacodynamics and safety; efficacy was exploratory. Comparisons were made to data from phase 3 trials with intravenous-tocilizumab (IV-TCZ) in sJIA and pJIA.

Results: Study participants were 51 sJIA patients and 52 pJIA patients aged 1-17 years who received SC-TCZ. Steady-state minimum TCZ concentration (Ctrough) >5th percentile of that achieved with IV-TCZ was achieved by 49 (96%) sJIA and 52 (100%) pJIA patients. In both populations, pharmacodynamic markers of disease were similar between body weight groups. Improvements in Juvenile Arthritis Disease Activity Score-71 were comparable between SC-TCZ and IV-TCZ. By week 52, 53% of sJIA patients and 31% of pJIA patients achieved clinical remission on treatment. Safety was consistent with that of IV-TCZ except for injection site reactions, reported by 41.2% and 28.8% of sJIA and pJIA patients, respectively. Infections were reported in 78.4% and 69.2% of patients, respectively. Two sJIA patients died; both deaths were considered related to TCZ.

Conclusion: SC-TCZ provides exposure and risk/benefit profiles similar to those of IV-TCZ. Subcutaneous administration provides an alternative administration route that is more convenient for patients and caregivers and that has potential for in-home use.

Trial Registration: ClinicalTrials.gov, NCT01904292 and NCT01904279.
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http://dx.doi.org/10.1093/rheumatology/keab047DOI Listing
January 2021

Defining colchicine resistance/intolerance in patients with familial Mediterranean fever: a modified-Delphi consensus approach.

Rheumatology (Oxford) 2020 Dec 17. Epub 2020 Dec 17.

Division of Paediatric Rheumatology, Department of Paediatrics and Autoinflammation Reference Center Tuebingen, University Hospital Tuebingen, Tuebingen, Germany.

Objectives: Colchicine is the main treatment for familial Mediterranean fever (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 pediatric 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 8 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.
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http://dx.doi.org/10.1093/rheumatology/keaa863DOI Listing
December 2020

Hyperinflammation in Two Severe Acute Respiratory Syndrome Coronavirus 2-Infected Adolescents Successfully Treated With the Interleukin-1 Inhibitor Anakinra and Glucocorticoids.

Front Pediatr 2020 30;8:576912. Epub 2020 Nov 30.

Academic Department of Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

In severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) critically ill adults, hyperinflammation plays a key role in disease progression. The clinical manifestations of SARS-CoV-2 infection among children are much less severe compared with adult patients and usually associated with a good prognosis. However, hyperinflammation in SARS-CoV-2-infected pediatric patients has been described as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 or as Kawasaki-like disease but is still little known, and optimal management has to be defined. The World Health Organization (WHO) on the 15th of May 2020 has developed a preliminary case definition for multisystem inflammatory disorder in children and adolescents with coronavirus disease 2019 (COVID-19) and stated for an urgent need to collect data on this condition. Here, we report two adolescent patients affected by COVID-19 presenting with multisystem inflammatory disorder, 3-4 weeks after the first symptoms of SARS-CoV-2 infection, treated with the interleukin-1 receptor antagonist anakinra and glucocorticoids with good clinical response. We report two patients chronically ill appearing, with high fever, severe gastrointestinal involvement, and increased biomarkers of inflammation onset 3-4 weeks after paucisymptomatic SARS-CoV-2 infection. They had no lung involvement, but abdominal ultrasound and CT scan showed thickening of the bowel wall. SARS-CoV-2 PCR was positive on ileum biopsy in both patients, whereas it was negative on other common sampled sites. They have been admitted to the pediatric intensive care unit and have been treated with a combination of anakinra 6-8 mg/kg/day i.v. and a standard dose of methylprednisolone 2 mg/kg/day in addition to lopinavir/ritonavir 400 mg q12h and low molecular weight heparin 100 UI/kg q12h with good clinical response.
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http://dx.doi.org/10.3389/fped.2020.576912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734022PMC
November 2020

A rare cause of multiple airways narrowing in a 15-year-old girl.

Thorax 2021 02 3;76(2):205-207. Epub 2020 Dec 3.

Pediatric Pulmonology & Respiratory Intermediate Care Unit, Sleep and Long-Term Ventilation Unit, Department of Pediatrics, Bambino Gesu Pediatric Hospital Department of Paediatrics, Roma, Italy.

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http://dx.doi.org/10.1136/thoraxjnl-2020-216102DOI Listing
February 2021

Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis.

Front Genet 2020 18;11:937. Epub 2020 Sep 18.

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

We describe a 2 year old boy with two previously undescribed frameshift mutations in the interferon (IFN)α/β receptor 2 () gene presenting with hemophagocytic lymphohistiocytosis (HLH) following measles-mumps-rubella vaccination. Functional analyses show the absence of response to type I IFN in the patient's cells, as revealed by the lack of phosphorylation of STAT1 and the lack of induction of interferon-stimulated genes upon stimulation with IFNα. HLH has been reported in patients with inborn errors of type I IFN-mediated immune responses following vaccination with live-attenuated viruses. The relation between HLH and defective type I IFN-mediated responses is unclear. We show that in patient's natural killer (NK) cells stimulated with IFNα the expected increase in degranulation and inhibition of IFNγ production were affected. These data support a role for NK cell function dysregulation and lack of inhibition of IFNγ production as contributors to the development of HLH in patients with impaired type I IFN signaling.
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http://dx.doi.org/10.3389/fgene.2020.00937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531586PMC
September 2020

Fused Omics Data Models Reveal Gut Microbiome Signatures Specific of Inactive Stage of Juvenile Idiopathic Arthritis in Pediatric Patients.

Microorganisms 2020 Oct 6;8(10). Epub 2020 Oct 6.

Department of Laboratories, Unit of Parasitology and Area of Genetics and Rare Diseases, Unit of Human Microbiome, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Herein, we evaluated the relationship between the gut microbiome (GM) and disease phenotype by an integrated omics fused approach. In a multicenter, observational cohort study, stools from Italian JIA patients were collected at baseline, active, and inactive disease stages, and their GM compared to healthy controls (CTRLs). The microbiota metabolome was analyzed to detect volatile- and non-volatile organic compounds (VOCs); the data were fused with operational taxonomic units (OTUs) from 16S RNA targeted-metagenomics and classified by chemometric models. Non-VOCs did not characterize JIA patients nor JIA activity stages compared to CTRLs. The core of VOCs, (Ethanol, Methyl-isobutyl-ketone, 2,6-Dimethyl-4-heptanone and Phenol) characterized patients at baseline and inactive disease stages, while the OTUs represented by Ruminococcaceae, Lachnospiraceae and Clostridiacea discriminated between JIA inactive stage and CTRLs. No differences were highlighted amongst JIA activity stages. Finally, the fused data discriminated inactive and baseline stages versus CTRLs, based on the contribution of the invariant core of VOCs while Ruminococcaceae concurred for the inactive stage versus CTRLs comparison. In conclusion, the GM signatures enabled to distinguish the inactive disease stage from CTRLs.
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http://dx.doi.org/10.3390/microorganisms8101540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650812PMC
October 2020

IgM on the surface of T cells: a novel biomarker of pediatric-onset systemic lupus erythematosus.

Pediatr Nephrol 2021 Apr 6;36(4):909-916. Epub 2020 Oct 6.

Division of Nephrology, Department of Pediatric Subspecialties, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Children with systemic lupus erythematosus (SLE) frequently have kidney involvement. Lupus nephritis sometimes presents alone, without systemic SLE features, representing the so-called full-house nephropathy (FHN). Distinguishing patients with SLE or FHN has therapeutic and prognostic implications.

Methods: In this retrospective observational study, we determined the presence of IgM on the surface of T cells (T cell IgM) by flow cytometry and characterized its ability in distinguishing SLE and FHN patients in a large pediatric cohort (n = 84). Fifty-seven patients with SLE (≥ 4 SLICC criteria at disease onset or during the follow-up) and 27 patients with FHN (3 or less SLICC criteria) were enrolled.

Results: Elevated T cell IgM levels were found in 24/25 SLE patients in active phase of disease and in 29/45 SLE patients in remission. In contrast, among FHN patients, only 1/9 presented this characteristic in active phase of disease and 0/20 in remission. Compared with standardized SLICC laboratory parameters, i.e., autoantibody titers and hypocomplementemia, T cell IgM positivity showed an extremely high sensitivity and specificity for the diagnosis of SLE, with the highest area under the curve (0.97, p < 0.001) by receiver operating characteristic analysis, similar to ANA (0.96, p < 0.001) and anti-dsDNA (0.90, p < 0.001) autoantibodies.

Conclusions: Altogether, our data indicate that T cell IgM intensity may be a useful tool to correctly classify patients with lupus nephritis as SLE or FHN since disease onset.
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http://dx.doi.org/10.1007/s00467-020-04761-7DOI Listing
April 2021

Efficacy and Safety of Tocilizumab for Polyarticular-Course Juvenile Idiopathic Arthritis in the Open-Label Two-Year Extension of a Phase III Trial.

Arthritis Rheumatol 2021 03 9;73(3):530-541. Epub 2021 Feb 9.

IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Objective: To report the 2-year efficacy and safety of tocilizumab (TCZ) in patients with polyarticular-course juvenile idiopathic arthritis (JIA).

Methods: Patients ages 2-17 years with active polyarticular-course JIA, in whom treatment with methotrexate was unsuccessful, received 16 weeks of open-label intravenous TCZ in part 1 (once every 4 weeks: 8 mg/kg or 10 mg/kg for body weight [BW] <30 kg; 8 mg/kg for BW ≥30 kg). Assessments were based on the JIA-American College of Rheumatology (ACR) response (defined as percentage of improvement in ≥3 of the 6 JIA core response variables [CRVs]). Patients with at least a JIA-ACR30 response (defined as ≥30% improvement in ≥3 of the 6 JIA CRVs without worsening in >1 of the remaining JIA CRVs by >30%) at week 16 were randomly assigned (1:1) to receive TCZ or placebo in part 2. Patients remained in part 2 until either week 40 or the occurrence of JIA flare. Upon starting part 3, all patients received open-label TCZ. At week 104 of the study, efficacy was assessed using JIA-ACR50/70/90 response rates (defined as 50%, 70%, or 90% improvement, respectively), achievement of inactive disease, and the Juvenile Arthritis Disease Activity Score in 71 joints (JADAS-71). Safety was assessed in the all-exposure population per 100 patient-years of exposure.

Results: Overall, 188 patients entered part 1, 166 patients entered part 2, and 160 patients entered part 3. By week 104, among the 188 patients in the modified intent-to-treat group who received TCZ, JIA-ACR50/70/90 response rates were 80.3%/77.1%/59.6%, respectively, the median JADAS-71 score decreased from 3.6 at week 40 to 0.7 at week 104, 51.1% of patients had achieved inactive disease, and 31 of 66 patients who had been receiving glucocorticoids discontinued them. Adverse event (AE) and serious AE rates were 406.5 per 100 patient-years and 11.1 per 100 patient-years, respectively. The infection rate was 151.4 per 100 patient-years, and the serious infection rate was 5.2 per 100 patient-years.

Conclusion: Patients treated with TCZ for polyarticular-course JIA showed high-level disease control for up to 2 years. The TCZ safety profile was consistent with that previously reported.
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http://dx.doi.org/10.1002/art.41528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986602PMC
March 2021

Tocilizumab may slow radiographic progression in patients with systemic or polyarticular-course juvenile idiopathic arthritis: post hoc radiographic analysis from two randomized controlled trials.

Arthritis Res Ther 2020 09 10;22(1):211. Epub 2020 Sep 10.

Università degli Studi di Genova, Genoa, Italy.

Background: Few clinical trials have investigated the prevention of radiographic progression in children with juvenile idiopathic arthritis treated with antirheumatic drugs. This study aimed to investigate radiographic progression in patients with systemic juvenile idiopathic arthritis (sJIA) and patients with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with the anti-interleukin-6 receptor antibody tocilizumab for 2 years in the TENDER and CHERISH randomized controlled trials, respectively.

Methods: Standard radiographs of both wrists and both hands in the posteroanterior view were obtained within 4 weeks of baseline and were repeated at weeks 52 ± 4 and 104 ± 4 in both trials. All films were scored by two independent readers using the adapted Sharp-van der Heijde (aSH) and Poznanski scoring methods. Although the Poznanski score indicates bone growth limitation or cartilage growth decrease, which are not the same as joint space narrowing in rheumatoid arthritis, its change reflects damage to cartilage. Therefore, impairment in the Poznanski score as well as the aSH score was considered as a measure of structural joint damage. Radiographic progression was defined as worsening of radiographic scores beyond the smallest detectable difference.

Results: Poznanski and aSH scores were available at baseline and at one or more postbaseline time points for 33 and 47 of 112 sJIA patients and 61 and 87 of 188 pcJIA patients, respectively, providing a representative subset of the study populations. The inter-reader and intra-reader agreement intra-class correlation coefficient was > 0.8. Median baseline Poznanski and aSH scores, respectively, were - 2.4 and 24.6 for sJIA patients and - 1.5 and 8.0 for pcJIA patients. Compared with baseline, aSH scores remained stable for all sJIA patients at week 52, whereas 9.4% of sJIA patients had radiographic progression according to Poznanski scores at week 52; at 104 weeks, radiographic progression according to aSH and Poznanski scores was observed in 5.4% and 11.5%, respectively. In pcJIA patients, radiographic progression from baseline at 52 weeks and at 104 weeks was 12.5% and 2.9%, respectively, using aSH scoring and 6.5% and 4%, respectively, using Poznanski scoring.

Conclusion: Tocilizumab may delay radiographic progression in children with sJIA and children with pcJIA.

Trial Registration: Trial registration numbers and dates: TENDER, NCT00642460 (March 19, 2008); CHERISH, NCT00988221 (October 1, 2009).
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http://dx.doi.org/10.1186/s13075-020-02303-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488325PMC
September 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

Functional Ability and Health-Related Quality of Life in Randomized Controlled Trials of Tocilizumab in Patients With Juvenile Idiopathic Arthritis.

Arthritis Care Res (Hoboken) 2020 Jul 23. Epub 2020 Jul 23.

Pediatric and Rheumatology Clinic, PRINTO, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Objective: Evaluate changes in health-related quality of life (HRQOL) and disability in children with systemic juvenile idiopathic arthritis (sJIA) or polyarticular juvenile idiopathic arthritis (pJIA) treated with tocilizumab.

Methods: Secondary analyses of two double-blind, placebo-controlled trials of intravenous tocilizumab in children with active sJIA or pJIA were conducted. Patient-reported outcomes of disability (Childhood Health Assessment Questionnaire [CHAQ]), HRQOL (Child Health Questionnaire-Parent Form-50 [CHQ-P50]; health concepts, physical summary score [CHQ-P50-PhS]; psychosocial summary score [CHQ-P50-PsS]), pain, and well-being (100-mm visual analog scale [VAS]) were measured at weeks 0 and 12 (sJIA), 16 and 40 (pJIA), and 104.

Results: 112 sJIA and 188 pJIA patients entered the trials. At week 16, pJIA patients' mean ± SD CHAQ decreased from 1.39 ± 0.74 at baseline to 0.67 ± 0.65 (P < 0.001). At week 12, sJIA patients' mean CHQ-P50-PhS improved more with tocilizumab than placebo (7.3 ± 10.2 vs 2.4 ± 10.6; P < 0.05). Almost all mean CHQ-P50 health concept scores, CHQ-P50-PsS, and CHQ-P50-PhS improved (P ≤ 0.002) by week 104 for patients with sJIA. pJIA and sJIA patients showed significant (P < 0.001) reductions in disability (mean CHAQ scores: -1.09 ± 0.71; -1.17 ± 0.80), improvements in well-being (-43.76 ± 26.61; -51.53 ± 23.57), and decreases in pain (-41.56 ± 31.06; -51.26 ± 26.79); 92.9%/96.8% of tocilizumab-treated pJIA/sJIA patients reported no more than minimal pain (VAS ≤35 mm) at week 104.

Conclusion: Tocilizumab treatment was associated with significantly reduced disability and pain and improved HRQOL in sJIA and pJIA patients.
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http://dx.doi.org/10.1002/acr.24384DOI Listing
July 2020

Long-term efficacy and safety of canakinumab in patients with colchicine-resistant familial Mediterranean fever: results from the randomised phase III CLUSTER trial.

Ann Rheum Dis 2020 10 22;79(10):1362-1369. Epub 2020 Jun 22.

Université de Paris Sud-Saclay, Le Kremlin Bicêtre, France.

Objectives: To evaluate the long-term efficacy and safety of canakinumab to treat patients with colchicine-resistant familial Mediterranean fever (crFMF) during Epoch 4 (weeks 41 to 113) of the CLUSTER study.

Methods: Patients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks during a 72-week period. We evaluated disease activity every 8 weeks using the physician global assessment (PGA) of disease activity, counting the number of flares, and measuring concentrations of C reactive protein (CRP) and serum amyloid A (SAA). Safety was studied by determination and classification of observed adverse events (AEs). We analysed safety and efficacy separately in two subgroups of patients receiving a cumulative dose of less than 2700 mg, or equal or more than 2700 mg.

Results: Of the 61 patients that started the CLUSTER study, 60 entered Epoch 4 and 57 completed it. During the 72-week period, 35/60 (58.3%) patients experienced no flares, and 23/60 (38.3%) had one flare, as compared with a median of 17.5 flares per year reported at baseline. PGA scores indicated no disease activity for the majority of patients throughout the study. Median CRP concentrations were always lower than 10 mg/L, while median SAA concentrations remained over the limit of normal (10 mg/L) but under the 30 mg/L threshold. No new or unexpected AEs were reported.

Conclusion: crFMF patients treated with canakinumab during 72 weeks experienced a minimal incidence of flares and good control of clinical disease activity, with no new safety concerns reported.
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http://dx.doi.org/10.1136/annrheumdis-2020-217419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509527PMC
October 2020

An Inflammatory Profile Correlates With Decreased Frequency of Cytotoxic Cells in Coronavirus Disease 2019.

Clin Infect Dis 2020 11;71(16):2272-2275

National Institute for Infectious Diseases Lazzaro Spallanzani, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.

Increased production of inflammatory cytokines and myeloid-derived suppressor cells occurs in patients with coronavirus disease 2019. These inversely correlated with perforin-expressing natural killer (NK) and CD3+ T cells. We observed a lower number of perforin-expressing NK cells in intensive care unit (ICU) patients compared with non-ICU patients, suggesting an impairment of the immune cytotoxic arm as a pathogenic mechanism.
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http://dx.doi.org/10.1093/cid/ciaa577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239202PMC
November 2020

Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis.

N Engl J Med 2020 05;382(19):1811-1822

From the Department of Pediatrics, Sapienza, University of Rome (F.L.), and the Department of Pediatric Hematology-Oncology (F.L.) and Division of Rheumatology (F.D.B.), IRCCS Bambino Gesù Children's Hospital, Rome, Pediatric Hematology-Oncology, Woman and Child Hospital, Azienda Ospedaliera Universitaria Integrata, Verona (S.C.), the Pediatric Hematology-Oncology Unit, Department of Pediatrics, University of Milano-Bicocca, Monza Brianza per il Bambino e la sua Mamma Foundation, Monza (C.R.), the Clinic of Pediatric Hematology-Oncology, University Hospital of Padova, Padua (M.-C.P.), and the Division of Pediatric Onco-Hematology, Regina Margherita Hospital, Turin (F.F.) - all in Italy; the Divisions of Immunobiology and Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics (M.B.J.), and the Division of Rheumatology (A.G.), Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine (M.B.J.) - all in Cincinnati; the Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston (C.A.); the Department of Hematology, Great Ormond Street Hospital for Children, London (A.R.); the Department of Pediatric Hematology-Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston (B.D.); the Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora (T.P.G.); the Departments of Pediatric Hematology-Oncology and Hematology and Oncology, Fundación para la Investigación Biomédica Hospital Infantil Universitario Niño Jesús, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid (J.S.), and the Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d'Hebron, Barcelona (J.-L.D.D.); the Department of Pediatric Hematology and Oncology, University Children's Hospital, Muenster, Germany (M.A.); the Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ (M.H.); NovImmune, Plan-les-Ouates, Switzerland (G.L., M.B., C.M.); and MnS Modelling and Simulation, Dinant, Belgium (P.J.).

Background: Primary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality.

Methods: We investigated the efficacy and safety of emapalumab (a human anti-interferon-γ antibody), administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving patients who had received conventional therapy before enrollment (previously treated patients) and previously untreated patients who were 18 years of age or younger and had primary hemophagocytic lymphohistiocytosis. The patients could enter a long-term follow-up study until 1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year after the last dose of emapalumab, if transplantation was not performed. The planned 8-week treatment period could be shortened or extended if needed according to the timing of transplantation. The primary efficacy end point was the overall response, which was assessed in the previously treated patients according to objective clinical and laboratory criteria.

Results: At the cutoff date of July 20, 2017, a total of 34 patients (27 previously treated patients and 7 previously untreated patients) had received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40% (P = 0.02 and P = 0.005, respectively). In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis.

Conclusions: Emapalumab was an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis. (Funded by NovImmune and the European Commission; NI-0501-04 and NI-0501-05 ClinicalTrials.gov numbers, NCT01818492 and NCT02069899.).
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http://dx.doi.org/10.1056/NEJMoa1911326DOI Listing
May 2020

Translating IL-6 biology into effective treatments.

Nat Rev Rheumatol 2020 06 23;16(6):335-345. Epub 2020 Apr 23.

Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.

In 1973, IL-6 was identified as a soluble factor that is secreted by T cells and is important for antibody production by B cells. Since its discovery more than 40 years ago, the IL-6 pathway has emerged as a pivotal pathway involved in immune regulation in health and dysregulation in many diseases. Targeting of the IL-6 pathway has led to innovative therapeutic approaches for various rheumatic diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, giant cell arteritis and Takayasu arteritis, as well as other conditions such as Castleman disease and cytokine release syndrome. Targeting this pathway has also identified avenues for potential expansion into several other indications, such as uveitis, neuromyelitis optica and, most recently, COVID-19 pneumonia. To mark the tenth anniversary of anti-IL-6 receptor therapy worldwide, we discuss the history of research into IL-6 biology and the development of therapies that target IL-6 signalling, including the successes and challenges and with an emphasis on rheumatic diseases.
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http://dx.doi.org/10.1038/s41584-020-0419-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178926PMC
June 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

On the Alert for Cytokine Storm: Immunopathology in COVID-19.

Arthritis Rheumatol 2020 07 10;72(7):1059-1063. Epub 2020 May 10.

Boston Children's Hospital, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.

Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.
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http://dx.doi.org/10.1002/art.41285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262347PMC
July 2020

Dynamic Contrast-Enhanced MRI Confirms Rapid And Sustained Improvement Of Rheumatoid Arthritis Induced By Tocilizumab Treatment: An Italian Multicentre Study.

Biologics 2020 11;14:13-21. Epub 2020 Feb 11.

Rheumatology Unit, L. Sacco University Hospital, Milan, Italy.

Objective: This open-label study evaluated the effects of combined tocilizumab (TCZ) and disease-modifying antirheumatic drugs (DMARDs) on magnetic resonance imaging (MRI) changes in synovial membrane enhancement, bone marrow edema (BME), and erosions in the wrist and hand joints of rheumatoid arthritis (RA) patients inadequately responding to DMARDs alone.

Methods: The efficacy of intravenous TCZ 8 mg/kg administered every four weeks for 48 weeks was evaluated on six occasions. The primary endpoints were the changes in the extent and degree of wrist synovitis as measured using the RA MRI Score (RAMRIS) and dynamic, gadolinium-enhanced 0.2T MRI (DCE-MRI). A number of different parameters of DCE-MRI were evaluated.

Results: Fifty-eight patients were treated, eight of whom (13.8%) discontinued the study prematurely. The mean RAMRIS significantly decreased after two weeks and the decrease was maintained for up to 48 weeks. By week 4, the mean RAMRIS synovitis score had significantly decreased from baseline (-0.804±1.575; p=0.018), but not the mean early enhancement (REE) or relative enhancement (RE). However, there were significant decreases in RE at week 24, in REE and N (total number of enhancing voxels)*IRE (initial rate of enhancement) at weeks 12, 24 and 48, and in N*ME (maximal enhancement) at weeks 24 and 48. Mean BME decreased from baseline to week 48, and bone erosions did not progress. The patients' clinical parameters significantly improved from baseline until week 48.

Conclusion: TCZ in combination with DMARDs improved wrist synovitis, BME and clinical parameters, without any progression in bone erosions. The RAMRIS for synovitis rapidly improved from as early as two weeks after the first TCZ infusion. (Funded by F. Hoffmann-La Roche; ACTRACE EudraCT No. 2009 012185-32).
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http://dx.doi.org/10.2147/BTT.S209873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023854PMC
February 2020

Acute rheumatic fever prophylaxis in high-income countries: clinical observations from an Italian multicentre, retrospective study.

Clin Exp Rheumatol 2020 Sep-Oct;38(5):1016-1020. Epub 2020 Jan 20.

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

Objectives: The aim of the study is to evaluate the compliance rate to secondary prophylaxis and the presence of rheumatic heart disease (RHD) in a cohort of Italian patients with acute rheumatic fever (ARF).

Methods: This is a multicentre retrospective study. The patients were divided into two groups by the presence or absence at last follow-up of RHD. Clinical features, ARF recurrences and the rate of compliance to secondary prophylaxis were evaluated.

Results: Two-hundred and ninety patients were enrolled (137 females; 153 males). Carditis at onset was present in 244 patients (84.7%). At the end of follow-up, 173 patients manifested RHD. Adherence to secondary prophylaxis was low in 26% of patients. The presence of RHD at follow-up was associated with the presence of carditis and its severity at onset (p=0.001), but it was not related to secondary prophylaxis adherence (p=NS). No association between prophylaxis adherence and ARF recurrence was found (p=NS) nor between ARF recurrence and RHD at the end of follow-up (p=NS).

Conclusions: Poor adherence to secondary prophylaxis does not seem to be associated with increased risk of RHD in developed countries. Further studies are needed to confirm our data in a larger population.
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October 2020

Is fibrodysplasia ossificans progressiva an interleukin-1 driven auto-inflammatory syndrome?

Pediatr Rheumatol Online J 2019 Dec 21;17(1):84. Epub 2019 Dec 21.

Pediatric Rheumatology Unit, Department of Pediatrics, Meir Medical Center, 59 Tchernichovsky St., 4428164, Kfar Saba, Israel.

Background: Fibrodysplasia ossificans progressiva (FOP) is the most catastrophic form of heterotopic ossification, due to ongoing intracellular signaling through the bone morphogenic protein pathway. The paroxysmal appearance of inflammatory lumps and elevated inflammatory markers during flares, suggest that FOP is an auto-inflammatory disease. Based on evidence, demonstrating a role for interleukin-1β (IL-1β) in other forms of heterotopic ossification, we hypothesized that treating FOP patients with anti-IL-1 agents could help lower the rate of FOP paroxysms and/or limit the symptoms and residual lesions.

Case Presentation: A 13.5-year-old Arab boy was diagnosed with FOP. Treatment with anti-inflammatory drugs did not change the disease course. New lumps appeared in a rate of approximately one every 8 days. Treatment with the anti-IL-1 agents anakinra and canakinumab resulted in significantly lower rate of paroxysms (every 22-25 days, of which almost all involved only 2 existing lumps), as well as shorter duration. High levels of IL-1β were found in the patient's plasma samples, collected during a paroxysm that appeared 8 weeks after the last canakinumab dose. In contrast, IL-1β plasma levels were undetectable in the previous three plasma samples, obtained while he was treated with anti-IL-1 agents.

Conclusions: Our data demonstrate the efficacy of anti-IL-1 agents in the treatment of a patient with FOP. Results showing the marked increase in IL-1β plasma levels during a paroxysm support a role for IL-1β in the pathogenesis of FOP and further provide the rationale for the use of anti-IL-1 agents in FOP treatment.
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http://dx.doi.org/10.1186/s12969-019-0386-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925442PMC
December 2019

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

Increased Circulating Levels of Interleukin-6 Affect the Redox Balance in Skeletal Muscle.

Oxid Med Cell Longev 2019 16;2019:3018584. Epub 2019 Nov 16.

DAHFMO-Unit of Histology and Medical Embryology, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Via A. Scarpa 14, 00161 Rome, Italy.

The extent of oxidative stress and chronic inflammation are closely related events which coexist in a muscle environment under pathologic conditions. It has been generally accepted that the inflammatory cells, as well as myofibers, are sources of reactive species which are, in turn, able to amplify the activation of proinflammatory pathways. However, the precise mechanism underlining the physiopathologic interplay between ROS generation and inflammatory response has to be fully clarified. Thus, the identification of key molecular players in the interconnected pathogenic network between the two processes might help to design more specific therapeutic approaches for degenerative diseases. Here, we investigated whether elevated circulating levels of the proinflammatory cytokine Interleukin-6 (IL-6) are sufficient to perturb the physiologic redox balance in skeletal muscle, independently of tissue damage and inflammatory response. We observed that the overexpression of circulating IL-6 enhances the generation and accumulation of free radicals in the diaphragm muscle of adult NSE/IL-6 mice, by deregulating redox-associated molecular circuits and impinging the nuclear factor erythroid 2-related factor 2- (Nrf2-) mediated antioxidant response. Our findings are coherent with a model in which uncontrolled levels of IL-6 in the bloodstream can influence the local redox homeostasis, inducing the establishment of prooxidative conditions in skeletal muscle tissue.
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http://dx.doi.org/10.1155/2019/3018584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881749PMC
April 2020

Anakinra in children and adults with Still's disease.

Rheumatology (Oxford) 2019 11;58(Suppl 6):vi9-vi22

Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Systemic juvenile idiopathic arthritis and adult-onset Still's disease are rare autoinflammatory disorders with common features, supporting the recognition of these being one disease-Still's disease-with different ages of onset. Anakinra was recently approved by the European Medicines Agency for Still's disease. In this review we discuss the reasoning for considering Still's disease as one disease and present anakinra efficacy and safety based on the available literature. The analysis of 27 studies showed that response to anakinra in Still's disease was remarkable, with clinically inactive disease or the equivalent reported for 23-100% of patients. Glucocorticoid reduction and/or stoppage was reported universally across the studies. In studies on paediatric patients where anakinra was used early or as first-line treatment, clinically inactive disease and successful anakinra tapering/stopping occurred in >50% of patients. Overall, current data support targeted therapy with anakinra in Still's disease since it improves clinical outcome, especially if initiated early in the disease course.
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http://dx.doi.org/10.1093/rheumatology/kez350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878842PMC
November 2019

NLRP2 Regulates Proinflammatory and Antiapoptotic Responses in Proximal Tubular Epithelial Cells.

Front Cell Dev Biol 2019 24;7:252. Epub 2019 Oct 24.

Department of Laboratories, Immuno-Rheumatology Research Area, Bambino Gesù Children's Hospital, Rome, Italy.

Nod-like Receptor Pyrin domain containing proteins (NLRPs) expressed by resident renal cells may contribute to the pathogenesis of multiple renal diseases. Cystinosis is a genetic disorder that affects kidney and particularly proximal tubular epithelial cells (PTEC). Here, we investigated the expression of NLRP family members in human control and cystinotic conditionally immortalized PTEC. Among all the NLRPs tested, we found that NLRP2 is highly expressed in cystinostic PTEC, but not in PTEC from healthy subjects. The NLRP2 overexpression was confirmed in primary PTEC and in kidney biopsies from cystinotic patients. In order to elucidate the role of NLRP2 in PTEC, we stably transfected control PTEC with an NLRP2-containing plasmid. We showed that NLRP2 markedly increases the production of several NF-κB regulated cytokines and chemokines. Accordingly, we demonstrated that NLRP2 interacts with IKKa and positively regulates the DNA-binding activity of p50 and p65 NF-κB, by modulating the p65 NF-κB phosphorylation status in Serine 536. Transcriptome analysis revealed that NLRP2 also upregulates the expression of profibrotic mediators and reduces that of several interferon-inducible genes. Finally, NLRP2 overexpression decreased the apoptotic cell rate. Consistently, silencing of NLRP2 by small-interfering RNA in cystinotic PTEC resulted in a significant decrease in cytokine and chemokine production as well as in an increase in the apoptosis rate. Altogether, our data reveals a previously unrecognized role for NLRP2 in regulating proinflammatory, profibrotic and antiapoptotic responses in PTEC, through NF-κB activation. Moreover, our findings unveil a novel potential mechanism involving NLRP2 overexpression in the pathogenesis of cystinosis.
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http://dx.doi.org/10.3389/fcell.2019.00252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822264PMC
October 2019

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
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