Publications by authors named "Francesca Minoia"

40 Publications

Development and Preliminary Validation of an Electromyography-Scoring Protocol for the Assessment and Grading of Muscle Involvement in Patients With Juvenile Idiopathic Inflammatory Myopathies.

Pediatr Neurol 2021 Aug 6;124:6-10. Epub 2021 Aug 6.

Pediatric Rheumatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Introduction: We performed a pilot study in order to investigate the feasibility of an electromyography (EMG)-scoring protocol for the assessment of disease activity in juvenile idiopathic inflammatory myopathies (JIIM).

Methods: Children with JIIM followed up in a tertiary-level care center underwent standardized clinical, laboratory, and EMG assessment. An EMG-scoring protocol was devised by a consensus panel including a pediatric neurophysiologist and two pediatric rheumatologists, based on a combined score obtained as the sum of (1) the presence of denervation signs (fibrillation potentials) and (2) motor unit remodeling (mixed pattern of short- and long-duration motor unit action potentials). The EMG-scoring protocol was then validated following the Outcome Measures in Rheumatoid Arthritis Clinical Trials filter for outcome measures in rheumatology and the consensus-based standards for the selection of health measurement instruments methodology.

Results: Thirteen children (77% females) were included in the study, with a median age of 10 years (interquartile range: 7-17 years) and median disease duration of 11.8 months (interquartile range: 2.1-44.5). A total of 39 EMG examinations were evaluated. A strong positive association between a standardized tool for muscle strength assessment and the combined score was observed. No significant associations were found with both creatine kinase and erythrocyte sedimentation rate levels.

Discussion: Our EMG-scoring protocol is the first standardized and reproducible tool for the neurophysiologic evaluation and grading of muscle involvement in patients with JIIM and could provide relevant additional information in the assessment and follow-up of these rare conditions.
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http://dx.doi.org/10.1016/j.pediatrneurol.2021.07.017DOI Listing
August 2021

CANAKINUMAB IN SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS: REAL-LIFE DATA FROM A RETROSPECTIVE ITALIAN COHORT.

Rheumatology (Oxford) 2021 Aug 3. Epub 2021 Aug 3.

Division of Rheumatology, ERN RITA center, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy.

Objective: To evaluate in real-life the effectiveness and safety of canakinumab in Italian patients with systemic juvenile idiopathic arthritis (sJIA).

Methods: A retrospective multicentre study of children with sJIA was performed. Clinical features, laboratory parameters and adverse events were collected at baseline, after 6 and 12 months from starting canakinumab. The effectiveness primary outcome was clinical inactive disease (CID) off glucocorticoids (GCs) treatment at 6 months.

Results: A total of 80 children were analyzed from 15 Italian centers. Of the 12 patients who started canakinumab in CID while receiving anakinra, all maintained CID. Of the 68 with active disease at baseline, 57.4% achieved CID off GCs at 6 months and 63.8% at 12 months. In univariate analysis, the variables significantly related with non-response were number of active joints (NAJ) ≥5, history of macrophage activation syndrome (MAS) and disease duration. Multivariate analysis confirmed the association with non-response of NAJ ≥5 (OR 6.37 (95%CI 1.69-24.02), p= 0.006) and history of MAS (OR 3.53 (95%CI 1.06-11.70), p= 0.039). No serious adverse events were recorded in this series. There were two cases of MAS during canakinumab, leading to a rate of 2.9 episodes per 100 patient year.

Conclusion: We confirm, in real-life, the efficacy of canakinumab in sJIA in a multicentric cohort. History of MAS and higher NAJ were associated with lower probability of achieving clinical inactive disease.
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http://dx.doi.org/10.1093/rheumatology/keab619DOI Listing
August 2021

Cytokine storm syndrome in a young patient with cystic fibrosis.

Pediatr Pulmonol 2021 Oct 22;56(10):3435-3437. Epub 2021 Jul 22.

Cystic Fibrosis Regional Reference Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

We report the case of a patient with cystic fibrosis (CF) presenting with a full-blown cytokine storm syndrome probably triggered by infection. This condition is rare and the diagnosis can be particularly difficult in patients with a complex chronic disease such as CF. However, timely recognition and appropriate treatment in the early stages are key to avoiding a potentially fatal course.
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http://dx.doi.org/10.1002/ppul.25579DOI Listing
October 2021

Juvenile idiopathic arthritis in Harlequin ichthyosis, a rare combination or the clinical spectrum of the disease? Report of a child treated with etanercept and review of the literature.

Pediatr Rheumatol Online J 2021 Jun 3;19(1):80. Epub 2021 Jun 3.

Pediatric Rheumatology, Pediatric Medium Intensity Care Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Via della Commenda, 9, 20122, Milan, Italy.

Background: Harlequin ichthyosis (HI) is the most severe phenotype of autosomal recessive congenital ichthyosis. Juvenile Idiopathic Arthritis (JIA) represents a heterogenous group of disorders all sharing the clinical manifestation of chronic arthritis. Association of HI and chronic arthritis has been reported in few cases.

Case Presentation: We report the case of a child with HI who developed a severe form of chronic polyarthritis during the first years of life, treated with repeated multiple joint injections, methotrexate and etanercept with good response and without any adverse events.

Conclusion: The reported case and the literature review highlighted the presence of a peculiar severe seronegative polyarthritis with early onset in a series of patients with HI, suggesting that polyarthritis may be a specific manifestation of HI, rather than a rare combination of two separate conditions.
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http://dx.doi.org/10.1186/s12969-021-00571-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173856PMC
June 2021

Thrombotic Microangiopathy Associated with Macrophage Activation Syndrome: A Multinational Study of 23 Patients.

J Pediatr 2021 Aug 7;235:196-202. Epub 2021 Apr 7.

IRCCS Istituto Giannina Gaslini, Genoa, Italy; Università degli Studi di Genova, Genoa, Italy; Sechenov First Moscow State Medical University, Moscow, Russian Federation.

Objective: To describe the clinical characteristics, treatment, and outcomes of a multinational cohort of patients with macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA).

Study Design: International pediatric rheumatologists were asked to collect retrospectively the data of patients with the co-occurrence of MAS and TMA. Clinical and laboratory features of patients with systemic juvenile idiopathic arthritis (sJIA)-associated MAS and TMA were compared with those of an historical cohort of patients with sJIA and MAS.

Results: Twenty-three patients with MAS and TMA were enrolled: 17 had sJIA, 2 systemic lupus erythematosus, 1 juvenile dermatomyositis, 1 mixed connective tissue disease, and 2 undifferentiated connective tissue disease. Compared with the historical cohort of MAS, patients with sJIA with coexistent MAS and TMA had higher frequencies of renal failure and neurologic involvement, hemorrhage, jaundice, and respiratory symptoms, as well as more severe anemia and thrombocytopenia, higher levels of alanine aminotransferase, lactate dehydrogenase, bilirubin and D-dimer, and lower levels of albumin and fibrinogen. They also required admission to the intensive care unit more frequently. Among patients tested, complement abnormalities and reduced ADAMTS13 activity were observed in 64.3% and 44.4% of cases, respectively. All patients received glucocorticoids. Treatment for TMA included plasma-exchange, eculizumab, and rituximab.

Conclusions: The possible coexistence of MAS and TMA in rheumatic diseases may be underrecognized. This association should be considered in patients with MAS who develop disproportionate anemia, thrombocytopenia, and lactate dehydrogenase increase, or have multiorgan failure.
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http://dx.doi.org/10.1016/j.jpeds.2021.04.004DOI Listing
August 2021

Anakinra combined with methylprednisolone in patients with severe COVID-19 pneumonia and hyperinflammation: An observational cohort study.

J Allergy Clin Immunol 2021 Feb 19;147(2):561-566.e4. Epub 2020 Nov 19.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Infectious Disease Unit, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Centre for Multidisciplinary Research in Health Science, University of Milan, Milan, Italy.

Background: Immunomodulants have been proposed to mitigate severe acute respiratory syndrome coronavirus 2-induced cytokine storm, which drives acute respiratory distress syndrome in coronavirus disease 2019 (COVID-19).

Objective: We sought to determine efficacy and safety of the association of IL-1 receptor antagonist anakinra plus methylprednisolone in severe COVID-19 pneumonia with hyperinflammation.

Methods: A secondary analysis of prospective observational cohort studies was carried out at an Italian tertiary health care facility. COVID-19 patients consecutively hospitalized (February 25, 2020, to March 30, 2020) with hyperinflammation (ferritin ≥1000 ng/mL and/or C-reactive protein >10 mg/dL) and respiratory failure (oxygen therapy from 0.4 FiO Venturi mask to invasive mechanical ventilation) were evaluated to investigate the effect of high-dose anakinra plus methylprednisolone on survival. Patients were followed from study inclusion to day 28 or death. Crude and adjusted (sex, age, baseline PaO:FiO ratio, Charlson index, baseline mechanical ventilation, hospitalization to inclusion lapse) risks were calculated (Cox proportional regression model).

Results: A total of 120 COVID-19 patients with hyperinflammation (median age, 62 years; 80.0% males; median PaO:FiO ratio, 151; 32.5% on mechanical ventilation) were evaluated. Of these, 65 were treated with anakinra and methylprednisolone and 55 were untreated historical controls. At 28 days, mortality was 13.9% in treated patients and 35.6% in controls (Kaplan-Meier plots, P = .005). Unadjusted and adjusted risk of death was significantly lower for treated patients compared with controls (hazard ratio, 0.33, 95% CI, 0.15-0.74, P = .007, and HR, 0.18, 95% CI, 0.07-0.50, P = .001, respectively). No significant differences in bloodstream infections or laboratory alterations were registered.

Conclusions: Treatment with anakinra plus methylprednisolone may be a valid therapeutic option in COVID-19 patients with hyperinflammation and respiratory failure, also on mechanical ventilation. Randomized controlled trials including the use of either agent alone are needed to confirm these results.
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http://dx.doi.org/10.1016/j.jaci.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674131PMC
February 2021

COVID-19 multidisciplinary high dependency unit: the Milan model.

Respir Res 2020 Oct 9;21(1):260. Epub 2020 Oct 9.

IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Respiratory Unit and Cystic Fibrosis Adult Center, Via Francesco Sforza 35, 20122, Milan, Italy.

COVID-19 is a complex and heterogeneous disease. The pathogenesis and the complications of the disease are not fully elucidated, and increasing evidence shows that SARS-CoV-2 causes a systemic inflammatory disease rather than a pulmonary disease. The management of hospitalized patients in COVID-19 dedicated units is advisable for segregation purpose as well as for infection control. In this article we present the standard operating procedures of our COVID-19 high dependency unit of the Policlinico Hospital, in Milan. Our high dependency unit is based on a multidisciplinary approach. We think that the multidisciplinary involvement of several figures can better identify treatable traits of COVID-19 disease, early identify patients who can quickly deteriorate, particularly patients with multiple comorbidities, and better manage complications related to off-label treatments. Although no generalizable to other hospitals and different healthcare settings, we think that our experience and our point of view can be helpful for countries and hospitals that are now starting to face the COVID-19 outbreak.
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http://dx.doi.org/10.1186/s12931-020-01516-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545383PMC
October 2020

Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis.

Rheumatology (Oxford) 2020 Nov;59(11):3505-3514

Rheumatology Division, National Medical Research Center of Children's Health, Moscow, Russian Federation.

Objective: To develop a composite disease activity score for systemic JIA (sJIA) and to provide preliminary evidence of its validity.

Methods: The systemic Juvenile Arthritis Disease Activity Score (sJADAS) was constructed by adding to the four items of the original JADAS a fifth item that aimed to quantify the activity of systemic features. Validation analyses were conducted on patients with definite or probable/possible sJIA enrolled at first visit or at the time of a flare, who had active systemic manifestations, which should include fever. Patients were reassessed 2 weeks to 3 months after baseline. Three versions were examined, including ESR, CRP or no acute-phase reactant.

Results: A total of 163 patients were included at 30 centres in 10 countries. The sJADAS was found to be feasible and to possess face and content validity, good construct validity, satisfactory internal consistency (Cronbach's alpha 0.64-0.65), fair ability to discriminate between patients with different disease activity states and between those whose parents were satisfied or not satisfied with illness outcome (P < 0.0001 for both), and strong responsiveness to change over time (standardized response mean 2.04-2.58). Overall, these properties were found to be better than those of the original JADAS and of DAS for RA and of Puchot score for adult-onset Still's disease.

Conclusion: The sJADAS showed good measurement properties and is therefore a valid instrument for the assessment of disease activity in children with sJIA. The performance of the new tool should be further examined in other patient cohorts that are evaluated prospectively.
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http://dx.doi.org/10.1093/rheumatology/keaa240DOI Listing
November 2020

Chronic non-bacterial osteomyelitis: a retrospective international study on clinical manifestations and response to treatment.

Clin Exp Rheumatol 2020 Nov-Dec;38(6):1255-1262. Epub 2020 Aug 5.

Department of Clinical Sciences and Community Health, University of Milan, and Paediatric Rheumatology Unit, ASST G. Pini & CTO, Milan, Italy.

Objectives: Chronic non-bacterial osteomyelitis (CNO) is a rare non-infectious bone inflammatory disorder; when multifocal, it is referred to as Chronic Recurrent Multifocal Osteomyelitis (CRMO). This study evaluates the demographic, clinical and radiological characteristics of a multi-centre cohort of patients with CNO/CRMO.

Methods: Demographic and clinical data of patients with an established diagnosis of CNO/CRMO followed at paediatric rheumatology centres across Europe (Italy, France, Slovenia) and India were retrospectively collected.

Results: There were no demographic differences across countries, but time to diagnosis was significantly longer in India (p=0.041). Pain was almost invariably present at disease onset; functional impairment was more frequent among Italian and Slovenian patients (p=0.001). The number of sites of bone involvement was similar between genders and countries, with long bone metaphises being the most common site. Raised acute phase reactants, detected in >50% of patients, were not associated with clinical manifestations or response to treatment. Comorbidities, evinced in 37% of patients, were equally distributed between genders and nationalities. Imaging approach was similar across countries, without any association between radiological findings and clinical manifestations. NSAIDs were almost invariably used as first-line treatment, but response rate was significantly lower in Italy (p=0.02). Methotrexate was used in 28% of case, with an overall rate of response of 82%. Health conditions and rate of permanent deformities were similar across different countries.

Conclusions: The differences in clinical presentation, radiological features and response to treatment described in this multinational cohort of CNO/CRMO might provide novel insights into this still elusive disease.
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December 2020

Successful treatment of refractory hyperferritinemic syndromes with canakinumab: a report of two cases.

Pediatr Rheumatol Online J 2020 Jul 11;18(1):56. Epub 2020 Jul 11.

Università degli Studi di Genova, Genoa, Italy.

Background: Hyperferritinemic syndromes are systemic inflammatory disorders characterized by a dysfunctional immune response, which leads to excessive activation of the monocyte-macrophage system with hypercytokinemia and may pursue a rapidly fatal course.

Case Presentation: We describe two patients of 11 and 9 years of age with hyperferritinemic syndromes, one with impending macrophage activation syndrome (MAS) and one with overt MAS, who were refractory or intolerant to conventional therapies, but improved dramatically with canakinumab.

Conclusions: Our report indicates that canakinumab may be efficacious in the management of hyperferritinemic syndromes, including MAS.
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http://dx.doi.org/10.1186/s12969-020-00450-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353681PMC
July 2020

Use of anakinra in severe COVID-19: A case report.

Int J Infect Dis 2020 Jul 11;96:607-609. Epub 2020 May 11.

Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milano, Italy; University of Milan, Italy. Electronic address:

Coronavirus disease 19 is a global healthcare emergency with a high lethality rate. Relevant inflammatory cytokine storm is associated with severity of disease, and IL1 inhibition is a cornerstone treatment for hyperinflammatory diseases. We present here the case of a patient with critical COVID-19 successfully treated with IL-1 receptor antagonist (anakinra).
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http://dx.doi.org/10.1016/j.ijid.2020.05.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211644PMC
July 2020

Ferritin to Erythrocyte Sedimentation Rate Ratio: Simple Measure to Identify Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis.

ACR Open Rheumatol 2019 Aug 13;1(6):345-349. Epub 2019 Jul 13.

University of Alabama at Birmingham.

Objective: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA). Early diagnosis is critical. Classification criteria for MAS in sJIA perform less well in the setting of cytokine-directed therapies. The goal herein was to explore a simple ratio of serum ferritin to the erythrocyte sedimentation rate (ESR) for diagnosis of MAS in the setting of sJIA, and to assess ferritin alone as a screening tool for identifying MAS of multiple etiologies.

Methods: Data from a large international cohort of sJIA patients with and without MAS, and from hospitalized patients with systemic infection (SI), were assessed for the ferritin:ESR ratio and ferritin alone to identify MAS among sJIA patients. Moreover, data from a smaller cohort of MAS patients associated with multiple etiologies and febrile hospitalized controls were explored. For both cohorts and controls, receiver operating characteristic curves (ROCs) for the ferritin:ESR ratio and ferritin alone were constructed, and areas under the curves (AUCs) were calculated. The Youden index was used to determine the optimal ferritin:ESR ratio and ferritin alone cut points for diagnosis.

Results: A ferritin:ESR ratio of 21.5 was 82% sensitive and 78% specific for diagnosing sJIA-MAS versus active sJIA without MAS. Ferritin alone with a set sensitivity of 95% (screening tool) had an 89.3% specificity of identifying all-cause MAS versus febrile hospitalized children.

Conclusion: The ferritin:ESR ratio is a practical tool for diagnosing MAS among sJIA patients, and serum ferritin alone is a remarkable screening tool for identifying MAS among febrile hospitalized children.
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http://dx.doi.org/10.1002/acr2.11048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857981PMC
August 2019

Response to 'Application of MS score in macrophage activation syndrome patients associated with adult onset Still's disease' by Wang .

Ann Rheum Dis 2021 09 25;80(9):e146. Epub 2019 Oct 25.

UOC Clinica Pediatrica e Reumatologia, Istituto Giannina Gaslini, Genova, Italy.

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http://dx.doi.org/10.1136/annrheumdis-2019-216310DOI Listing
September 2021

Response to: 'MS score in systemic juvenile idiopathic arthritis: suitable for routine use?' by Chi .

Ann Rheum Dis 2021 07 16;80(7):e108. Epub 2019 Aug 16.

UOC Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, Genova, Italy.

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http://dx.doi.org/10.1136/annrheumdis-2019-216067DOI Listing
July 2021

Development and initial validation of the MS score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

Ann Rheum Dis 2019 10 11;78(10):1357-1362. Epub 2019 Jul 11.

Istituto Giannina Gaslini, Genova, Italy.

Objective: To develop and validate a diagnostic score that aids in identifying macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (sJIA).

Methods: The clinical and laboratory features of 362 patients with sJIA-associated MAS and 404 patients with active sJIA without evidence of MAS were collected in a multinational collaborative project. Eighty percent of the study population was used to develop the score and the remaining 20% constituted the validation sample. A Bayesian Model Averaging approach was used to assess the role of each clinical and laboratory variables in the diagnosis of MAS and to obtain the coefficients of selected variables. The final score, named MAS/sJIA (MS) score, resulted from the linear combination of these coefficients multiplied by the values of each variable. The cut-off that best discriminated MAS from active sJIA was calculated by means of receiver operating characteristic (ROC) curve analysis. Score performance was evaluated in both developmental and validation samples.

Results: The MS score ranges from -8.4 to 41.8 and comprises seven variables: central nervous system dysfunction, haemorrhagic manifestations, active arthritis, platelet count, fibrinogen, lactate dehydrogenase and ferritin. A cut-off value ≥-2.1 revealed the best performance in discriminating MAS from active sJIA, with a sensitivity of 0.85, a specificity of 0.95 and a kappa value of 0.80. The good performance of the MS score was confirmed in the validation sample.

Conclusion: The MS score is a powerful and feasible tool that may assist practitioners in making a timely diagnosis of MAS in patients with sJIA.
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http://dx.doi.org/10.1136/annrheumdis-2019-215211DOI Listing
October 2019

When neonatal inflammation does not mean infection: an early-onset mevalonate kinase deficiency with interstitial lung disease.

Clin Immunol 2019 08 13;205:25-28. Epub 2019 May 13.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, NICU, via della Commenda 12, 20122 Milan, Italy; University of Milan, Department of Clinical Sciences and Community Health, via della Commenda 12, 20122 Milan, Italy. Electronic address:

Systemic inflammation in neonates is attributable to an infection in almost all cases. When inflammation persists, an autoinflammatory disease should be promptly suspected. We report here a case of mevalonate kinase deficiency (MKD) that presented at birth with mild symptoms and signs suggestive for a perinatal infection, together with the uncommon finding of interstitial lung disease. An extensive diagnostic work-up, performed after ineffective antibiotic treatment, demonstrated high levels of mevalonic acid in urine (7024 mM/M of creatinine, normal value <0.1). Next-generation sequencing showed a rare c.709A > T (p.T237S) homozygous mutation in the MVK gene, consistent with MKD. Treatment with anakinra led to a prompt resolution of symptoms and a sharp drop in serum inflammatory markers. The patient is now six months-old, currently undergoing evaluation for hematopoietic stem-cell transplantation. To our knowledge, this is the first case of MKD presenting within the first week of life with interstitial lung disease.
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http://dx.doi.org/10.1016/j.clim.2019.05.002DOI Listing
August 2019

Extracorporeal blood purification techniques in children with hyper-inflammatory syndromes: a clinical overview.

Minerva Anestesiol 2019 May 7;85(5):531-542. Epub 2019 Feb 7.

Unit of Dialysis, Giannina Gaslini Institute, Genoa, Italy.

Data on clinical applications of blood purification techniques in children are scarce. The aim of this review is to offer a clinical overview, as complete as possible, on blood purification in children with hyper-inflammatory syndromes (HS). A review of the literature using the PubMed, EMBASE, Web of Science, and Scopus databases, on the most recent data about blood purification in children was conducted until June 2018. Except for three randomized controlled trials (RCTs) on plasma exchange, no RCTs, but only observational studies or case reports were found regarding other blood purification techniques in children. High-volume hemofiltration in two non-randomized trials did not significantly reduce 28-day mortality in children. PE was not associated with reduced mortality in pediatric patients with septic shock, but the small number of patients enrolled is an important limitation. The use of polymixin B and other adsorbing columns in children with septic shock and HS is increasing, but results are still limited by the observational nature of the studies. Based on the low-level of available evidence, no conclusions can be drawn regarding the efficacy and safety of blood purification in children. Further research with more clinically robust data is needed to determine the impact of different extracorporeal blood purification techniques in this pediatric population.
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http://dx.doi.org/10.23736/S0375-9393.19.13189-6DOI Listing
May 2019

Predictors of Effectiveness of Anakinra in Systemic Juvenile Idiopathic Arthritis.

J Rheumatol 2019 04 15;46(4):416-421. Epub 2019 Jan 15.

From the Università degli Studi di Genova, and the Istituto Giannina Gaslini, Genoa; Fondazione Institute for Research and Health Care (IRCCS) Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy; Instituto de Criança - Faculty of Medicine of the University of São Paulo (FMUSP), São Paulo, Brazil.

Objective: To seek predictors of therapeutic response to the interleukin (IL)-1 inhibitor anakinra in children with systemic-onset juvenile idiopathic arthritis (sJIA).

Methods: The clinical charts of all patients with sJIA who were newly treated with anakinra at our center between 2004 and 2017 were reviewed retrospectively. Predictors included baseline demographic, clinical, and laboratory variables as well as previous or concomitant therapies. The effectiveness of anakinra was assessed at 1 year after treatment start. Complete clinical response (CCR) was defined as absence of fever, physician's global assessment ≤ 1, count of active joints ≤ 1, negative C-reactive protein, and ≥ 75% reduction of corticosteroid dose. According to the intention-to-treat principle, patients who had anakinra discontinued before 1 year for any reasons other than disease remission were classified as nonresponders. Statistics included univariate and multivariable analyses.

Results: Of the 62 patients included in the study, 24 (39%) met the criteria for CCR at 1 year, whereas 38 (61%) did not. On multivariable analysis, independent correlations with achievement of CCR were identified for shorter disease duration, lower active joint count, higher ferritin level, and greater activity of systemic manifestations. The area under the curve of the model was 0.83.

Conclusion: Our findings help to delineate the clinical profile of patients with sJIA who are more likely to benefit from IL-1 blockade. They also underscore the need for studies aimed at examining the therapeutic role of early IL-1 inhibition and to identify biomarkers predicting response to either IL-1 or IL-6 antagonists.
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http://dx.doi.org/10.3899/jrheum.180331DOI Listing
April 2019

CD70 Deficiency due to a Novel Mutation in a Patient with Severe Chronic EBV Infection Presenting As a Periodic Fever.

Front Immunol 2017 29;8:2015. Epub 2018 Jan 29.

Clinica Pediatria e Reumatologia, Istituto Giannina Gaslini, Genova, Italy.

Primary immunodeficiencies with selective susceptibility to EBV infection are rare conditions associated with severe lymphoproliferation. We followed a patient, son of consanguineous parents, referred to our center for recurrent periodic episodes of fever associated with tonsillitis and adenitis started after an infectious mononucleosis and responsive to oral steroid. An initial diagnosis of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome was done. In the following months, recurrent respiratory infections and episodes of keratitis were also observed, together with a progressive reduction of immunoglobulin levels and an increase of CD20 cells. Cell sorting and EBV PCR showed 25,000 copies for 100,000 leukocytes with predominant infection of B lymphocytes. Lymph node's biopsy revealed reactive lymphadenopathy with paracortical involvement consistent with a chronic EBV infection. Molecular analysis of , and genes did not detect any pathogenic mutation. The patients underwent repeated courses of anti-CD20 therapy with only a partial control of the disease, followed by stem cell transplantation with a complete normalization of clinical and immunological features. Whole exome sequencing of the trio was performed. Among the variants identified, a novel loss of function homozygous c.163-2A>G mutation of the gene, affecting the exon 2 AG-acceptor splice site, fit the expected recessive model of inheritance. Indeed, deficiency of both CD27, and, more recently, of its ligand CD70, has been reported as a cause of EBV-driven lymphoproliferation and hypogammaglobulinemia. Cell surface analysis of patient-derived PHA-T cell blasts and EBV-transformed lymphoblastoid cell lines confirmed absence of CD70 expression. In conclusion, we describe a case of severe chronic EBV infection caused by a novel mutation of CD70 presenting with recurrent periodic fever.
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http://dx.doi.org/10.3389/fimmu.2017.02015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796890PMC
January 2018

Filling the Gap: Toward a Disease Activity Tool for Systemic Juvenile Idiopathic Arthritis.

J Rheumatol 2018 01;45(1):3-5

Istituto Giannina Gaslini and Università degli Studi di Genova, Genoa, Italy.

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http://dx.doi.org/10.3899/jrheum.170703DOI Listing
January 2018

Development and Initial Validation of the Macrophage Activation Syndrome/Primary Hemophagocytic Lymphohistiocytosis Score, a Diagnostic Tool that Differentiates Primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome.

J Pediatr 2017 10 12;189:72-78.e3. Epub 2017 Aug 12.

Karolinska University Hospital, Stockholm, Sweden.

Objective: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis.

Study Design: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples.

Results: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from <1% for a score of <11 to >99% for a score of  ≥123. A cutoff value of ≥60 revealed the best performance in discriminating pHLH from MAS.

Conclusion: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.
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http://dx.doi.org/10.1016/j.jpeds.2017.06.005DOI Listing
October 2017

Biologics in juvenile idiopathic arthritis: a narrative review.

Eur J Pediatr 2017 Sep 20;176(9):1147-1153. Epub 2017 Jul 20.

Istituto Giannina Gaslini and Università degli Studi di Genova, Genoa, Italy.

In the past years, pediatric rheumatology has seen a revolution in the treatments for rheumatic diseases, particularly juvenile idiopathic arthritis. Even if nonsteroidal anti-inflammatory drugs (NSAID), intra-articular corticosteroids (IAC) injections, and methotrexate remain the mainstay of the treatment for JIA patients, in aggressive disease, these treatments may be not sufficient to reach disease remission and to prevent long-term disability. Comprehension of immunological mechanisms involved in the pathogenesis of the diseases allowed to conceive new drugs targeting specific steps of the immune response. Several cytokines, like TNF alpha and IL-1, represent a very interesting target for biologic therapies. Due to the efficacy of these therapies, nowadays, "disease remission" in pediatric rheumatology is more and more frequent, especially in juvenile idiopathic arthritis patients, and the long-term outcomes have been significantly improved. Crucial to these advancements have been multicenter controlled clinical trials and long-term safety monitoring.

Conclusions: Research in pediatric rheumatology has resulted in dramatic advances in diseases management. Biologic treatments have improved physical and functional outcomes and quality of life of patients with rheumatic disease. What is Known: • NSAID, intra-articular injection of corticoids, and methotrexate are the mainstay in treatment of JIA. • In aggressive JIA, these treatments may be not sufficient to reach disease remission and to prevent long term disability. What is New: • In recent years, management of JIA has significantly improved with the development of biologic therapies that allowed children with arthritis to reach a normal growth and to achieve a good long-term functional outcome.
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http://dx.doi.org/10.1007/s00431-017-2960-6DOI Listing
September 2017

Effect of Biologic Therapy on Clinical and Laboratory Features of Macrophage Activation Syndrome Associated With Systemic Juvenile Idiopathic Arthritis.

Arthritis Care Res (Hoboken) 2018 03 30;70(3):409-419. Epub 2018 Jan 30.

Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio.

Objective: To assess performance of the 2016 macrophage activation syndrome (MAS) classification criteria for patients with systemic juvenile idiopathic arthritis (JIA) who develop MAS while treated with biologic medications.

Methods: A systematic literature review was performed to identify patients with MAS while being treated with interleukin (IL)-1 and IL-6 blocking agents. Clinical and laboratory information was compared to a large previously compiled historical cohort.

Results: Eighteen publications were identified, and after removing duplicates, 35 patients treated with canakinumab and 49 patients with tocilizumab were available for analysis; 5 anakinra-treated patients were excluded due to limited numbers. MAS classification criteria were less likely to classify tocilizumab-treated patients as having MAS compared to the historical cohort or canakinumab-treated patients (56.7%, 78.5%, and 84%, respectively; P < 0.01). Patients who developed MAS while treated with canakinumab trended towards lower ferritin at MAS onset than the historical cohort (4,050 versus 5,353 ng/ml; P = 0.18) but had no differences in other cardinal clinical or laboratory features. In comparison, patients who developed MAS while treated with tocilizumab were less likely febrile and had notably lower ferritin levels (1,152 versus 5,353 ng/ml; P < 0.001). Other features of MAS were more pronounced in patients treated with tocilizumab, including lower platelet counts, lower fibrinogen, and higher aspartate aminotransferase levels. Mortality rates for patients with MAS treated with tocilizumab or canakinumab were not significantly different from the historical cohort.

Conclusion: These findings show substantial alterations in MAS features that may limit utility of defined criteria for diagnosis of systemic JIA patients treated with biologic agents.
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http://dx.doi.org/10.1002/acr.23277DOI Listing
March 2018

Critical role of STIR MRI in early detection of post-streptococcal periostitis with dysproteinaemia (Goldbloom's syndrome).

Clin Exp Rheumatol 2017 May-Jun;35(3):516-517. Epub 2017 Mar 23.

2nd Department of Paediatrics, Giannina Gaslini Institute, Genova, Italy.

Objectives: In 1966, Goldbloom et al. described two children who developed a peculiar clinical picture characterized by intermittent daily bone pain in the lower limbs, fever spikes, increased acute phase reactants and dysproteinaemia. The syndrome occurred two weeks after a group A β-haemolytic streptococcus infection. So far, only a few cases have been reported in the medical literature in English.

Methods: We report two further cases of Goldbloom's syndrome with a review of the literature in English.

Results: Our two patients lived in the same Italian region and presented their syndrome onset a week apart. Early use of STIR MRI revealed an atypical metaphyseal hyperintensity in the femurs and tibias. X-ray showed periosteal hyperostosis. A short cycle of corticosteroids led to rapid recovery of symptoms and disappearance of bone changes.

Conclusions: The reported cases highlight a likely under-recognised post-streptococcal inflammatory periosteal reaction and emphasise the diagnostic utility of the newer imaging modalities.
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August 2017

Widening the Heterogeneity of Leigh Syndrome: Clinical, Biochemical, and Neuroradiologic Features in a Patient Harboring a NDUFA10 Mutation.

JIMD Rep 2017 1;37:37-43. Epub 2017 Mar 1.

Rare Diseases Unit, Istituto Giannina Gaslini, Genoa, Italy.

Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder, characterized by a wide clinical and genetic heterogeneity, and is the most frequent disorder of mitochondrial energy production in children. Beside its great variability in clinical, biochemical, and genetic features, LS is pathologically uniformly characterized by multifocal bilateral and symmetric spongiform degeneration of the basal ganglia, brainstem, thalamus, cerebellum, spinal cord, and optic nerves. Isolated complex I deficiency is the most common defect identified in Leigh syndrome. In 2011, the first child with a mutation of NDUFA10 gene, coding for an accessory subunits of complex I, was described. Here, we present an additional description of a child with Leigh syndrome harboring a homozygous mutation in NDUFA10, providing insights in clinical, biochemical, and neuroradiologic features for future earlier recognition.
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http://dx.doi.org/10.1007/8904_2017_9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740043PMC
March 2017

IL-1 Inhibition in Systemic Juvenile Idiopathic Arthritis.

Front Pharmacol 2016 6;7:467. Epub 2016 Dec 6.

Pediatric Rheumatology, Istituto Giannina GasliniGenova, Italy; Pediatria II, Università degli Studi di GenovaGenova, Italy.

Systemic juvenile idiopathic arthritis (sJIA) is the form of childhood arthritis whose treatment is most challenging. The demonstration of the prominent involvement of interleukin (IL)-1 in disease pathogenesis has provided the rationale for the treatment with biologic medications that antagonize this cytokine. The three IL-1 blockers that have been tested so far (anakinra, canakinumab, and rilonacept) have all been proven effective and safe, although only canakinumab is currently approved for use in sJIA. The studies on IL-1 inhibition in sJIA published in the past few years suggest that children with fewer affected joints, higher neutrophil count, younger age at disease onset, shorter disease duration, or, possibly, higher ferritin level may respond better to anti-IL-1 treatment. In addition, it has been postulated that use of IL-1 blockade as first-line therapy may take advantage of a "window of opportunity," in which disease pathophysiology can be altered to prevent the occurrence of chronic arthritis. In this review, we analyze the published literature on IL-1 inhibitors in sJIA and discuss the rationale underlying the use of these medications, the results of therapeutic studies, and the controversial issues.
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http://dx.doi.org/10.3389/fphar.2016.00467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5138234PMC
December 2016
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