Publications by authors named "Gabriele Simonini"

137 Publications

Amoxicillin Adverse Cutaneous Reaction Versus Post Streptococcal Vasculitis: Lymphocyte Transformation Test Solved the Question.

Pediatr Infect Dis J 2021 Nov 30. Epub 2021 Nov 30.

From the Allergy Unit, Department of Pediatrics, Meyer Children's University Hospital Department of Clinical and Experimental Medicine, University of Florence Rheumatology Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy.

In children, skin rashes are a frequent manifestation of infectious diseases, or they could also be the result of a drug hypersensitivity reaction, especially after antibiotic intake. We report the case of a 5-year-old girl investigated for a suspected post streptococcal vasculitis where differential diagnosis was improved by an allergy work-up and confirmed by lymphocyte transformation test.
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http://dx.doi.org/10.1097/INF.0000000000003420DOI Listing
November 2021

Chronic Recurrent Multifocal Osteomyelitis Associated with Crohn Disease: A Potential Role of Exclusion Diet? Comment on Starz et al. The Modification of the Gut Microbiota via Selected Specific Diets in Patients with Crohn's Disease. 2021, , 2125.

Nutrients 2021 Nov 10;13(11). Epub 2021 Nov 10.

Pediatric Gastroenterology Unit, Maggiore Hospital, Azienda USL, 40133 Bologna, Italy.

The efficacy of diet and its influence on gut microbiome composition has been largely demonstrated in inflammatory bowel disease (IBD). Little is known about its potential in the management of extraintestinal manifestations. We report a successful application of Crohn disease exclusion diet (CDED) in association with infliximab and methotrexate, as salvage therapy in a child affected by chronic recurrent multifocal osteomyelitis (CRMO) and Crohn disease (CD) resistant to optimized therapy. Both intestinal and bone symptoms remitted after the application of CDED. Diet may have acted on common microbic inciting agents that trigger both intestinal and bone inflammation, supporting the role of microbiota in the pathogenesis of IBD-associated extraintestinal manifestations. Our experience suggests the potential benefit of CDED in association with combined therapy in resistant patients affected by CD and extraintestinal manifestations.
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http://dx.doi.org/10.3390/nu13114005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617979PMC
November 2021

A nationwide study on Sydenham's chorea: Clinical features, treatment and prognostic factors.

Eur J Paediatr Neurol 2021 Nov 6;36:1-6. Epub 2021 Nov 6.

Pediatric Rheumatology, Pediatric University Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy.

Objectives: Sydenham's Chorea (SC) is a neuropsychiatric disorder and a major manifestation of acute rheumatic fever. The erroneous assumption that SC is a benign and self-limiting disease, has led to a lack of high-quality scientific evidence of the therapeutical and prognostic features of SC.

Study Design: We retrospectively analyzed the medical records of patients <18-years old with SC in 17 Italian pediatric centers. Recorded data included clinical, instrumental and laboratory parameters. Prognostic risk factors including treatment regimens were assessed with univariate and multivariate sub-analysis.

Results: We included 171 patients with SC. 66% had generalized chorea, and 34% hemichorea. 81% had carditis (subclinical in 65%). Additional neurological symptoms were reported in 60% of the patients, mainly dysarthria and dysgraphia. 51% had neuropsychiatric symptoms at onset, which persisted after 12 months in 10%. Among psychiatric manifestations, the most common was anxiety disorder/depression (77%). Neurological remission was reached by 93% of the patients at 6 months; 9% relapsed. Patients were treated as follows: 11% penicillin alone, 37% immunomodulatory therapy, 16% symptomatic drugs (i.e. anti-seizure medication, dopamine antagonists) and 37% both symptomatic and immunomodulatory treatment. Neurological outcome did not differ between groups. Patients receiving symptomatic drugs had a higher risk of relapse on multivariate analysis (p = 0.045).

Conclusions: Treatment of SC was largely heterogeneous. Based on our results, immunomodulatory therapy did not show higher efficacy at medium term, although it was associated to a slightly lower risk of relapse compared to symptomatic therapy. Longitudinal studies are needed to assess specific risk factors and best treatment options.
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http://dx.doi.org/10.1016/j.ejpn.2021.11.002DOI Listing
November 2021

The Role of Anti-IL-1 Treatment in MIS-C Patients.

Expert Opin Biol Ther 2021 Nov 26:1-5. Epub 2021 Nov 26.

Rheumatology Unit, Meyer Children's University Hospital, Firenze, Italy.

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http://dx.doi.org/10.1080/14712598.2022.2006631DOI Listing
November 2021

Cerebral venous thrombosis in a child with Behçet's disease: a complication to bear in mind also in children.

Clin Exp Rheumatol 2021 Sep-Oct;39 Suppl 132(5):141-142. Epub 2021 Oct 6.

Rheumatology Unit, NEUROFARBA Department, Meyer Children's Hospital, University of Florence, Italy.

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October 2021

Ocular involvement in monogenic autoinflammatory disease.

Autoimmun Rev 2021 Nov 9;20(11):102944. Epub 2021 Sep 9.

Rheumatology Unit, Meyer Children's University Hospital, NEUROFARBA Department, University of Florence, Florence, Italy. Electronic address:

Objective: Monogenic Autoinflammatory diseases (AIDs) are a broad spectrum of rare hereditary diseases whose ocular involvement has not been well characterized yet. This systematic review aims to provide an overview of the current knowledge about ocular findings in AIDs.

Methods: A systematic literature review was conducted using 2 electronic databases, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. A combination of AIDs and ophthalmology-related search terms were used. All articles were screened by 2 independent reviewers for title, abstract and full text level. We included solely studies that investigated ocular findings in AIDs.

Results: 198 papers of 4268 records were retained. Data about 1353 patients with a diagnosis of autoinflammatory disease and ocular involvement were collected (680 CAPS, 211 FMF, 138 TRAPS, 238 Blau, 32 MKD, 21 SIFD, 7 Aicardi Goutières, 3 CANDLE, 8 DADA2, 9 HA20, 6 APLAID). Conjunctivitis was significantly more frequent in CAPS (p < 0.00001), uveitis in Blau, MKD, HA20 and CANDLE (p < 0.00001), papillitis/papilledema in CAPS (p < 0.00001), optic neuritis in Aicardi and DADA2 (p < 0.008), retinal vasculitis in FMF (p < 0.00001), progressive reduction in choroidal thickness in FMF and DADA2 (p < 0.00001), periorbital oedema in TRAPS (p < 0.00001) and retinitis in SIFD (p < 0.00001). Among AIDs with uveitis, granulomatous inflammation was more common in Blau syndrome (p < 0.00001).

Conclusion: This systematic literature review characterized the ocular involvement of several AIDs, and the present data may encourage to consider a timely ophthalmological screening program for these rare diseases.
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http://dx.doi.org/10.1016/j.autrev.2021.102944DOI Listing
November 2021

A peptide-based anti-Adalimumab antibody assay to monitor immune response to biologics treatment in juvenile idiopathic arthritis and childhood chronic non-infectious uveitis.

Sci Rep 2021 08 12;11(1):16393. Epub 2021 Aug 12.

Interdepartmental Laboratory of Peptide and Protein Chemistry and Biology, Department of NeuroFarBa, University of Florence, Sesto Fiorentino, Italy.

Immune response to biologics treatment, while widely reported, yet fails to correlate with clinical outcomes and assay to assay comparison is often not possible. Hence, we developed a new peptide based-detection assay to stratify pediatric patients with juvenile idiopathic arthritis (JIA) or chronic non-infectious uveitis (CNU) and monitor anti-drug antibodies (ADAbs) formed as part of an immune response to treatment with the fully human monoclonal therapeutic antibody Adalimumab. Adalimumab derived synthetic peptides were optimized for maximum immunogenicity and were tested by SP-ELISA on a development cohort of 18 JIA and CNU treated patients. The two best performing peptides able to differentiate patient groups were selected for evaluation with a larger scale ELISA testing on a total of 29 sera from pediatric patients with JIA or CNU. The results of this peptide-based assay were compared to an in-house developed SPR biosensor ADAbs assay and a commercially available bridging ELISA. The first peptide, termed HC3, was able to positively detect ADAbs in 7 out of the 29 sera, while the second peptide, called LC3, was able to detect ADAbs in 11 out of 29 sera in the evaluation group. Following statistical data evaluation, it has been found that the detection of ADAbs using the peptide-based ELISA assay positively correlates with disease progression and remission. Two synthetic peptides derived from Adalimumab may provide a beneficial tool to clinicians for monitoring patient response to such treatment and taking informed decisions for treatment alternatives.
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http://dx.doi.org/10.1038/s41598-021-95920-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360964PMC
August 2021

Moving from nature to nurture: a systematic review and meta-analysis of environmental factors associated with juvenile idiopathic arthritis.

Rheumatology (Oxford) 2021 Aug 11. Epub 2021 Aug 11.

Department of Paediatric Rheumatology, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

Objectives: JIA is the most common paediatric rheumatic disease, thought to be influenced by both genetics and the environment. Identifying environmental factors associated with disease risk will improve knowledge of disease mechanism and ultimately benefit patients. This review aimed to collate and synthesise the current evidence of environmental factors associated with JIA.

Methods: Four databases (MEDLINE, Embase, Web of Science and Cumulative Index to Nursing and Allied Health Literature) were searched from inception to January 2020. Study quality was rated using the Newcastle-Ottawa Scale. Pooled estimates for each environmental factor were generated using a random-effects, inverse-variance method, where possible. The remaining environmental factors were synthesised in narrative form.

Results: This review includes 66 environmental factors from 39 studies (11 cohort and 28 case-control studies) over 45 years. Study sample sizes ranged from 41 to 1.9 million participants. Eight environmental factors from ten studies were meta-analysed. Caesarean section delivery was associated with increased JIA risk (pooled OR 1.11, 95% CI: 1.01-1.22). Conversely, presence (vs absence) of siblings (pooled OR 0.60, 95% CI: 0.44-0.81) and maternal prenatal smoking (pooled OR 0.70, 95% CI: 0.58-0.84) were associated with decreased JIA risk.

Conclusion: This review identifies several environmental factors associated with JIA and demonstrates the huge breadth of environmental research undertaken over five decades. We also highlight the challenges of combining data collected over this period due to limited between study comparability, evolution in healthcare and social practices, and changing environment, which warrant consideration when planning future studies.
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http://dx.doi.org/10.1093/rheumatology/keab627DOI 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

OBSIDIAn - real world evidence of Originator to BioSImilar Drug switch in juvenile idiopathic arthritis.

Rheumatology (Oxford) 2021 Jul 17. Epub 2021 Jul 17.

Rheumatology Unit, Meyer Children's University Hospital; Florence, Italy.

Objectives: Limited data about use of biosimilars are available in children with Juvenile Idiopathic Arthritis (JIA). This study therefore aimed to evaluate long-term efficacy and safety of switching from etanercept (ETA) and adalimumab (ADA) originators to their biosimilars, in children with JIA, in a real-world setting.

Methods: This is a retro-prospective non-interventional multicentre Italian comparative cohort study. Medical charts of JIA children treated with biosimilars of ETA or ADA were included. Efficacy and safety of TNF-inhibitors therapy was evaluated at last follow-up during originator and at 3, 6 and 12 months following the switch to biosimilar.

Results: 59 children (42 female, median age at onset 88 months) were treated with biosimilar of ETA (21) and ADA (38). Forty-five switched from the originator to the BIO (17 ETA, 28 ADA). At time of switch, 12/17 patients on ETA and 18/28 on ADA were in remission. No significant difference has been found at 3, 6 and 12 months after the switch. Ten patients discontinued biosimilars due to disease remission (4 ETA, 3 ADA), family willing (1 ETA), occurrence of burning at injection site (1 ETA), and persistent activity (1 ADA). No statistically significant difference was observed between originator and BIOs, nor between originator and BIOs, and between ADA and ETA in time to disease remission achievement, time to relapse and number of patients who experienced AE.

Conclusion: Our real-life results seem to confirm the efficacy and safety profile of switching from originator of ADA and ETA to their respective BIOs also in paediatric patients with JIA.
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http://dx.doi.org/10.1093/rheumatology/keab572DOI Listing
July 2021

Gastrointestinal involvement in IgA vasculitis: a single-center 11-year study on a cohort of 118 children.

Clin Rheumatol 2021 Dec 17;40(12):5041-5046. Epub 2021 Jul 17.

Pediatric Unit, Department of Health Sciences, Meyer Children's University Hospital, Viale Pieraccini 24, 50139, Florence, Italy.

Introduction And Objectives: Immunoglobulin A vasculitis (IgAV), the most common childhood vasculitis, is associated with gastrointestinal (GI) involvement in 50-75% of cases. The aim of this study was to describe the characteristics of GI involvement in a cohort of hospitalized children with IgAV.

Methods: We retrospectively evaluated patients hospitalized for IgAV at Meyer Children's University Hospital, from January 2010 to December 2020. The children's families were interviewed by phone and asked about disease relapses.

Results: In the study period, 118 children had GI involvement, corresponding to 75% of children hospitalized for IgAV. Their median age was 7 years (interquartile range 6-9). The most frequent GI manifestations were abdominal pain (96%), bleeding (71%, mostly occult), vomiting (58%), and diarrhea (17%). GI complications, observed in 18%, were intussusception (14%), appendicitis (3%), gallbladder hydrops (2%), and ileal perforation (1%). Abdomen ultrasound, performed in all cases, was abnormal in 68%. Abdomen X-ray, performed in 19 patients, showed pathologic findings in 84% of them. Selected children with severe manifestations also underwent abdomen computed tomography (2/118; 2%) and GI endoscopy (5/118; 4%). Steroids were used in 80 (67.8%) cases. The use of second- and third-line therapies was necessary in three cases. Relapses, investigated in 80 cases (68%), occurred in 21% of them. Key Points • The present retrospective study describes a cohort of 118 patients hospitalized for gastrointestinal (GI) involvement in immunoglobulin A vasculitis (IgAV) at a tertiary care children's hospital from January 2010 to December 2020. • The most frequent GI manifestations were abdominal pain (96%), vomiting (58%), and diarrhea (17%). GI bleeding was reported in 71% of children, and it was occult in most cases. • GI complications, occurring in 18% of cases, were intussusception (14%), appendicitis (3%), gallbladder hydrops (2%), and ileal perforation (1%). • Steroid treatment has been successfully used in severe GI manifestations; however, our data do not support its association with low relapse risk.

Conclusions: The present study describes a large pediatric cohort of GI involvement in IgAV. Steroid treatment should be used when GI manifestations are severe. The association of steroid use with relapse risk is not currently established.
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http://dx.doi.org/10.1007/s10067-021-05863-9DOI Listing
December 2021

Establishing core domain sets for Chronic Nonbacterial Osteomyelitis (CNO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO): A report from the OMERACT 2020 special interest group.

Semin Arthritis Rheum 2021 08 7;51(4):957-961. Epub 2021 Jun 7.

Pediatric Rheumatology, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.

Objective: A working group was established to develop a core domain set (CDS) for Chronic Nonbacterial Osteomyelitis (CNO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO) following the OMERACT filter 2.1.

Methods: A scoping review to identify disease-related manifestations was performed, followed by a special interest group (SIG) session at OMERACT2020 to begin the CNO/SAPHO CDS framework.

Results: Candidate items were identified from the scoping review and most fell under Life Impact and Pathophysiology Manifestation core areas. A SIG agreed on the need to develop a CDS for CNO and SAPHO (100%) and for children and adults (91%).

Conclusion: Based on candidate items identified, qualitative research and Delphi surveys will be performed as next steps.
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http://dx.doi.org/10.1016/j.semarthrit.2021.05.015DOI Listing
August 2021

Successful treatment of adalimumab in a child with Vogt-Koyanagi-Harada: which is the best available systemic treatment?

Clin Exp Rheumatol 2021 Nov-Dec;39(6):1453-1454. Epub 2021 Jun 8.

Rheumatology Unit, Meyer Children's University Hospital, Florence, and Neurofarba Department, University of Florence, Italy.

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June 2021

The Development of Extra-Articular Manifestations in Children With Enthesitis-Related Arthritis: Natural Course or Different Disease Entity?

Front Med (Lausanne) 2021 13;8:667305. Epub 2021 May 13.

Rheumatology Unit, Meyer Children Hospital of Florence, University of Florence, Florence, Italy.

Enthesitis-related Arthritis (ERA) is a specific category of juvenile idiopathic arthritis (JIA) characterized by axial and/or peripheral arthritis, and enthesitis, although other different extra-articular manifestations may encompass its clinical spectrum. In order to examine if ERA-JIA with extra-articular involvement may represent a different entity from ERA without extra-articular involvement, we performed a retrospective, observational, monocentric study, in a cohort of ERA patients followed between 2001 and September 2020 at the Pediatric Rheumatology Unit of Meyer Children Hospital of Florence. We analyzed the demographic, clinical, laboratory and imaging data at the disease onset, as well as after 3, 6, and 12 months follow up. We have enrolled 53 patients, 33 males. At the time of diagnosis, average age was 10.9 years, 53 patients had active arthritis and 25 active enthesitis. The middle foot involvement was present in 20 patients. Twenty-five children achieved clinical remission on medication. Extra-articular manifestations were observed in 14 patients, of whom 3 had inflammatory bowel disease, 5 uveitis, one uveitis associated with Crohn disease, 4 SAPHO syndrome, one celiac disease. The cohort was stratified according to the presence/absence of extra-articular manifestations. It was observed that middle foot involvement was more frequent in patients with no extra-articular manifestations (18/39 vs. 2/14; χ = 4.45, = 0.05). Additionally, patients presenting extra-articular manifestation needed more frequently (12/14 vs. 21/39, χ= 4.45, = 0.05), and preciously (months: 3.7 ± 5.4 vs. 16.7 ± 26.5, = 0.02), treatment with biologic agents. Finally, these patients achieved belatedly (months: 31.6 ± 32.3 vs. 22.9 ± 18.3, = 0.01) and less frequently (3/14 vs. 22/39; χ= 5.50, = 0.03) the clinical remission on medication. Eventually, extra-articular involvement inversely correlated with the middle-foot arthritis (ρ -0.29, = 0.03), the chance to achieve remission on medication (ρ -0.31 e = 0.02), as well as the chance to keep overall remission, with and without medication (ρ -0.28, = 0.04). In our cohort, children diagnosed with ERA-JIA at the onset of disease and then developed extra-articular manifestations show the absence of middle foot involvement and worse prognosis with an early need for the use of biologic agents, and overall low chance to achieve remission.
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http://dx.doi.org/10.3389/fmed.2021.667305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155293PMC
May 2021

"Environmental risk factors associated with juvenile idiopathic arthritis associated uveitis: a systematic review of the literature".

J Ophthalmic Inflamm Infect 2021 May 24;11(1):15. Epub 2021 May 24.

Department of Paediatric Rheumatology, Bristol Royal Hospital for Children, Bristol, UK.

Background: Juvenile idiopathic arthritis associated uveitis (JIA-U) is the most common extra-articular manifestation of juvenile idiopathic arthritis (JIA) and carries considerable risk to vision. The aim of this systematic review was to synthesise evidence of environmental risk factors for JIA-U and identify risk factors which may be modifiable or used to stratify JIA patients.

Methods: This systematic review was carried out in accordance with PRISMA guidelines. Four online databases - Cumulative Index of Nursing and Allied Health Literature, Web of Science, MEDLINE and Embase - were searched from database inception to 12th August 2020. Identified studies were screened by two independent reviewers against pre-defined inclusion and exclusion criteria. Data was extracted from all primary studies meeting inclusion criteria and independently checked.

Results: We identified three studies from 895 unique records which met the inclusion criteria, each examining a different environmental risk factor. This systematic review includes 973, predominantly female, participants with JIA across these three studies. The use of allergy medication or documentation of "allergy"/"allergic" in the medical records was associated with an increased risk of JIA-U in all models presented. Vitamin D sufficiency was associated with reduced risk of JIA-U. There was insufficient evidence to support an association between seasonality and JIA-U.

Conclusions: This review identifies a potential role for allergy and vitamin D in JIA-U. It also illustrates the paucity of data regarding environmental risk factors for JIA-U and highlights the need for further research to both identify additional risk factors and replicate existing findings.
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http://dx.doi.org/10.1186/s12348-021-00247-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141477PMC
May 2021

Early anti IL-1 treatment replaces steroids in refractory Kawasaki disease: clinical experience from two case reports.

Ther Adv Musculoskelet Dis 2021 29;13:1759720X211002593. Epub 2021 Mar 29.

NEUROFARBA Department, University of Florence, Rheumatology Unit, Meyer Children's University Hospital, Florence, Viale Gaetano Pieraccini, 24, Firenze, 50139, Italy.

Refractory Kawasaki disease (KD) is related to a major risk of coronary arteries abnormalities and its treatment is not standardized. In this regard, anakinra (ANA), an interleukin (IL)-1 receptor antagonist, represents an emerging therapeutic option. We report two cases of children, diagnosed with KD, nonresponsive to two doses of intravenous immunoglobulins, successfully treated with ANA, without a prior use of steroids. Patient 2 developed a coronary dilatation, that improved significantly after ANA therapy. Our experience highlights IL-1 blockade effectiveness in reducing KD inflammation and suggests ANA adoption as second-line therapy, with a timesaving and steroid-sparing strategy. Our results, combined with the evidence of the IL-1 key role in KD and coronary arteritis pathogenesis and to the recent clinical evidence reported by the KAWAKINRA trial, encourage an earlier recourse to ANA in patients with refractory KD, in order to fight inflammation, and to treat and prevent the development of coronary artery aneurysms. Further studies are needed to better define the place of IL-1 blockade in KD step-up treatment.
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http://dx.doi.org/10.1177/1759720X211002593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010843PMC
March 2021

Biological drugs in paediatric COVID-19 infection: what patients, which drug, how much and how long.

Clin Exp Rheumatol 2021 May-Jun;39(3):697-699. Epub 2021 Mar 25.

Neurofarba Department, University of Florence, Rheumatology Unit, Meyer Children's University Hospital, Firenze, Italy.

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May 2021

Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: results from a national, multicenter survey.

Pediatr Rheumatol Online J 2021 Mar 16;19(1):29. Epub 2021 Mar 16.

University of Trieste, Piazzale Europa, 2, Trieste, Italy.

Background: There is mounting evidence on the existence of a Pediatric Inflammatory Multisystem Syndrome-temporally associated to SARS-CoV-2 infection (PIMS-TS), sharing similarities with Kawasaki Disease (KD). The main outcome of the study were to better characterize the clinical features and the treatment response of PIMS-TS and to explore its relationship with KD determining whether KD and PIMS are two distinct entities.

Methods: The Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD (Kawasaki Disease Group - KDG) or KD-like (Kawacovid Group - KCG) disease between February 1st 2020, and May 31st 2020. Demographic, clinical, laboratory data, treatment information, and patients' outcome were collected in an online anonymized database (RedCAP®). Relationship between clinical presentation and SARS-CoV-2 infection was also taken into account. Moreover, clinical characteristics of KDG during SARS-CoV-2 epidemic (KDG-CoV2) were compared to Kawasaki Disease patients (KDG-Historical) seen in three different Italian tertiary pediatric hospitals (Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste; AOU Meyer, Florence; IRCCS Istituto Giannina Gaslini, Genoa) from January 1st 2000 to December 31st 2019. Chi square test or exact Fisher test and non-parametric Wilcoxon Mann-Whitney test were used to study differences between two groups.

Results: One-hundred-forty-nine cases were enrolled, (96 KDG and 53 KCG). KCG children were significantly older and presented more frequently from gastrointestinal and respiratory involvement. Cardiac involvement was more common in KCG, with 60,4% of patients with myocarditis. 37,8% of patients among KCG presented hypotension/non-cardiogenic shock. Coronary artery abnormalities (CAA) were more common in the KDG. The risk of ICU admission were higher in KCG. Lymphopenia, higher CRP levels, elevated ferritin and troponin-T characterized KCG. KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%; p = 0.04 and 71,9% vs 43,4%; p = 0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%; p < 0.0001). SARS-CoV-2 assay more often resulted positive in KCG than in KDG (75,5% vs 20%; p < 0.0001). Short-term follow data showed minor complications. Comparing KDG with a KD-Historical Italian cohort (598 patients), no statistical difference was found in terms of clinical manifestations and laboratory data.

Conclusion: Our study suggests that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD and PIMS-TS. Older age at onset and clinical peculiarities like the occurrence of myocarditis characterize this multi-inflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths.
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http://dx.doi.org/10.1186/s12969-021-00511-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962084PMC
March 2021

Gastrointestinal and hepatic involvement in paediatric systemic lupus erythematosus.

Clin Exp Rheumatol 2021 Jul-Aug;39(4):899-906. Epub 2021 Mar 2.

Liver Unit, Meyer Children's University Hospital, NEUROFARBA Department, University of Florence, Italy.

Systemic lupus erythematosus (SLE) is a multisystemic, autoimmune, inflammatory disease. Gastrointestinal (GI) involvement, extensively described in adults, is less characterised in paediatric-onset SLE (pSLE). The aim of the present narrative review was to provide a comprehensive summary and update on GI involvement in pSLE. A literature search on PubMed and EMBASE was conducted to identify original articles, reviews, case series and editorials published in English from 2000 to 31 August 2020. Based on this, we reported the prevalence, pathogenetic mechanisms, clinical issues, diagnostic tools and management of each form of GI involvement in pSLE. Lupus enteritis is the most frequent type of GI involvement in pSLE, followed by intestinal pseudo-obstruction, protein-losing enteropathy, hepatic disease and acute pancreatitis. The most common presenting GI symptoms are non-specific and include abdominal pain, anorexia, nausea, vomiting. In most cases, they are associated with other clinical and laboratory manifestations of SLE. The complications of GI involvement, including perforation and intestinal infarction, can be life-threatening. Laboratory findings and imaging studies can help to rule out non-SLE related causes for GI manifestations and to reveal typical features of the single forms of GI involvement. Early diagnosis and treatment are crucial to improve prognosis and avoid unnecessary surgery. Most SLE GI manifestations respond well to glucocorticoids and immunosuppressants. In conclusion, GI involvement is frequent in pSLE and its diagnosis and management can be a challenge for clinicians. In view of the limited available data, further studies are needed to better explore the prevalence, prognosis and treatment recommendations for GI involvement in pSLE.
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July 2021

Diagnostic challenge of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome in pediatric age: A monocentric case series.

Mod Rheumatol 2021 11 16;31(6):1228-1231. Epub 2021 Mar 16.

Rheumatology Unit, NEUROFARBA Department, Meyer Children's Hospital, University of Florence, Florence, Italy.

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http://dx.doi.org/10.1080/14397595.2021.1892264DOI Listing
November 2021

Epidemiology of systemic sclerosis: a multi-database population-based study in Tuscany (Italy).

Orphanet J Rare Dis 2021 02 17;16(1):90. Epub 2021 Feb 17.

Institute of Clinical Physiology, National Research Council, Via Moruzzi 1, Pisa, Italy.

Background: Systemic Sclerosis (SSc) is a chronic autoimmune disease with a complex pathogenesis that includes vascular injury, abnormal immune activation, and tissue fibrosis. We provided a complete epidemiological characterization of SSc in the Tuscany region (Italy), considering prevalence and incidence, survival, comorbidities and drug prescriptions, by using a multi-database population-based approach. Cases of SSc diagnosed between 1st January 2003 and 31st December 2017 among residents in Tuscany were collected from the population-based Rare Diseases Registry of Tuscany. All cases were linked to regional health and demographic databases to obtain information about vital statistics, principal causes of hospitalization, complications and comorbidities, and drug prescriptions.

Results: The prevalence of SSc in Tuscany population resulted to be 22.2 per 100,000, with the highest prevalence observed for the cases aged ≥ 65 years (33.2 per 100,000, CI 95% 29.6-37.3). In females, SSc was predominant (86.7% on the total) with an overall sex ratio F/M of 6.5. Nevertheless, males presented a more severe disease, with a lower survival and significant differences in respiratory complications and metabolic comorbidities. Complications and comorbidities such as pulmonary involvement (HR = 1.66, CI 95% 1.17-2.35), congestive heart failure (HR = 2.76, CI 95% 1.80-4.25), subarachnoid and intracerebral haemorrhage (HR = 2.33, CI 95% 1.21-4.48) and malignant neoplasms (HR = 1.63, CI 95% 1.06-2.52), were significantly associated to a lower survival, also after adjustment for age, sex and other SSc-related complications. Disease-modifying antirheumatic drugs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors were the drugs with the more increasing prevalence of use in the 2008-2017 period.

Conclusions: The multi-database approach is important in the investigation of rare diseases where it is often difficult to provide accurate epidemiological indicators. A population-based registry can be exploited in synergy with health databases, to provide evidence related to disease outcomes and therapies and to assess the burden of disease, relying on a large cohort of cases. Building an integrated archive of data from multiple databases linking a cohort of patients to their comorbidities, clinical outcomes and survival, is important both in terms of treatment and prevention.
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http://dx.doi.org/10.1186/s13023-021-01733-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890847PMC
February 2021

Whole-body MRI in pediatric undefined inflammatory conditions.

Pediatr Int 2021 Nov 4;63(11):1282-1288. Epub 2021 Oct 4.

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.

Background: Whole-body magnetic resonance imaging (WBMRI) is a multiregional imaging technique suitable for investigating the extent of multisystemic diseases without exposure to radiation, with a high sensitivity to bone alterations. The aim of our study was to evaluate the role of WBMRI in the workup of children with non-specific musculoskeletal features and non-indicative laboratory and instrumental data, who were suspected to have a rheumatologic disease.

Methods: We retrospectively analyzed medical records, including laboratory tests and radiological data of 34 children who had been evaluated due to non-specific musculoskeletal manifestations, for which a WBMRI was prescribed.

Results: We included 34 children, 19 females and 15 males, mean age 10 years (range 2-16 years), with the following clinical features: diffuse arthralgia (12 children), persistent fever (2 children), persistent fever and diffuse arthralgia (20 children). Serologic inflammatory markers were increased in 29/34 patients. Twenty-five children had already received X-ray and / or ultrasound before WBMRI, with a negative / uninformative result. WBMRI was performed 3-6 weeks (median, 3.5 weeks) after the initial presentation of symptoms. In 22/34 (65%) children, WBMRI revealed some abnormalities that supported the final diagnosis. Twelve out of 34 children (35%) were be affected by chronic recurrent multifocal osteomyelitis.

Conclusions: WBMRI is helpful in pediatric rheumatology for the differential diagnosis of undefined inflammatory conditions. It appears to be a promising tool, especially in the detection of multifocal bone lesions. The diagnosis that mainly benefits from WBMRI in our series is chronic recurrent multifocal osteomyelitis. WBMRI can also help in excluding neoplastic diseases.
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http://dx.doi.org/10.1111/ped.14650DOI Listing
November 2021

Childhood multisystem inflammatory syndrome associated with COVID-19 (MIS-C): a diagnostic and treatment guidance from the Rheumatology Study Group of the Italian Society of Pediatrics.

Ital J Pediatr 2021 Feb 8;47(1):24. Epub 2021 Feb 8.

Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini and DINOGMI, Università di Genova, Via Gerolamo Gaslini 5, 16147, Genoa, Italy.

Background: Italy was the first Western country to be hit by the SARS-CoV-2 epidemic. There is now mounting evidence that a minority of children infected with SARS-CoV2 may experience a severe multisystem inflammatory syndrome, called Multisystem inflammatory Syndrome associated with Coronavirus Disease 2019 (MIS-C). To date no universally agreed approach is available for this disease. MAIN BODY: as Italy is now facing a second hity of COVID-19 cases, we fear a recrudescence of MIS-C cases. We have, therefore, decided to prepare a report that will help clinicians to face this novel and challenging disease. We propose a diagnostic algorithm, to help case definition and guide work-up, and a therapeutic approach. MIS-C should be promptly recognized, based on the presence of systemic inflammation and specific organ involvement. Early treatment is crucial, and it will be based on the combined use of corticosteroids, high-dose immunoglobulins and anti-cytokine treatments, depending on the severity of the disease. Ancillary treatments (such as. aspirin and thrombo-profilaxis) will be also discussed.

Conclusions: we propose a document that will help physicians to diagnose and treat MIS-C patients. Given the level of evidence available and the methodology used, this document should not be interpreted as a guideline; the final decision about the optimal management should still be taken by the caring physician, on an individual basis.
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http://dx.doi.org/10.1186/s13052-021-00980-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868856PMC
February 2021

Cervical arthritis as early manifestation of enthesitis-related arthritis complicated by uveitis.

J Paediatr Child Health 2021 Sep 22;57(9):1531-1532. Epub 2020 Dec 22.

Division of Pediatric Rheumatology, AOU Anna Meyer, Firenze, Italy.

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http://dx.doi.org/10.1111/jpc.15315DOI Listing
September 2021

Changing evidence over time: updated meta-analysis regarding anti-TNF efficacy in childhood chronic uveitis.

Rheumatology (Oxford) 2021 02;60(2):568-587

Rheumatology Unit, NEUROFARBA Department, Meyer Children's Hospital, University of Florence, Florence, Italy.

Objective: To summarize evidence regarding efficacy of anti-TNFα in childhood chronic uveitis, refractory to common DMARDs.

Methods: An updated systematic search was conducted between November 2012 and January 2020. Studies investigating the efficacy of anti-TNFα therapy, in children of ages <16 years, as the first biologic treatment for childhood chronic uveitis, refractory to topical and/or systemic steroid and at least one DMARD were eligible for inclusion. The primary outcome measure was the improvement of intraocular inflammation according to Standardization of Uveitis Nomenclature Working Group criteria. A combined estimate of the proportion of children responding to etanercept (ETA), infliximab (INF), and adalimumab (ADA) was determined.

Results: We identified 1677 articles of which 37 articles were eligible. Three were randomized controlled trials, one on ETA and two on ADA, and were excluded from pooled analysis. From the observational studies, a total of 487 children were identified: 226 received ADA, 213 INF and 48 ETA. The proportion of responding children was 86% (95% CI: 76%, 95%) for ADA, 68% (95% CI: 50%, 85%) for INF and 36% (95% CI: 9%, 67%) for ETA. Pooled analysis showed clear differences (χ2 = 32.2, P < 0.0001): ADA and INF were both significantly superior to ETA (χ2 = 26.8, P < 0.0001, and χ2 = 7.41, P < 0.006, respectively), ADA significantly superior to INF (χ2 = 13.4, P < 0.0002).

Conclusion: This meta-analysis, consistent with recent randomized controlled trial data, suggests the efficacy of ADA and INF in childhood chronic uveitis treatment. However, ADA results were superior to those of INF in this clinical setting.
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http://dx.doi.org/10.1093/rheumatology/keaa595DOI Listing
February 2021

Hypersensitivity to Rituximab in Children.

Pharmacology 2021 17;106(5-6):341-344. Epub 2020 Nov 17.

Allergy Unit, Department of Pediatrics, Meyer Children's University Hospital, Florence, Italy.

Biological agents have had an increased usage during the past years, also in pediatric population. Monoclonal antibodies can cause adverse drug reactions with different pathomechanisms, including type I IgE-mediated hypersensitivity reactions (HR). In this report, we describe 2 children who had a diagnosis of anaphylaxis to rituximab (RTX), confirmed by positive in vivo tests in both cases and elevated tryptase value in one case. We also made a review of the few cases of HR to RTX in pediatric population reported in literature and discuss differential diagnosis and utility of allergy investigations.
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http://dx.doi.org/10.1159/000511458DOI Listing
July 2021

SAPHO syndrome: the supposed trigger by isotretinoin, the efficacy of adalimumab and the specter of depressive disorder: a case report.

Ital J Pediatr 2020 Nov 13;46(1):169. Epub 2020 Nov 13.

Department of Health Science, University of Florence, Florence, Italy.

Background: SAPHO (synovitis, acne, pustolosis, hyperostosis and osteitis) syndrome is a rare autoinflammatory chronic disorder, presenting with non-infectious osteitis, sterile joint inflammation and skin manifestations including palmoplantar pustolosis and severe acne. It could be often misdiagnosed for its heterogeneous clinical presentation. Treatment is challenging and, due to the rarity of this syndrome, no randomized controlled clinical trials have been conducted. Empirical treatments, including non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antibiotics and bisphosphonates and disease-modifying anti-rheumatic drugs (DMARDs) could be quite effective. Anti-tumor necrosis factor-alpha (anti-TNF-α) agents and interleukin-1 (IL-1) antagonists have shown promising results in refractory patients. Isotretinoin, commonly used for severe acne, has been rarely described as possible trigger of osteo-articular manifestations, in particular sacroiliitis.

Case Presentation: The case of a boy, affected by acne fulminans and depression, who presented with sacroiliitis after a 10-week treatment with isotretinoin is presented. After SAPHO diagnosis, NSAIDs therapy was started but the onset of bilateral gluteal hidradenitis suppurativa required the switch to a TNF-α antagonist (Adalimumab) with the achievement of a good control of the disease. Despite specific therapy with sertraline, the patient continued to complains severe depression.

Conclusions: Our case reports a temporal association between the onset of osteo-articular symptoms and the introduction of isotretinoin, as previously described. However, this timeline is not sufficient to establish a causal role of this drug into the pathogenesis of sacroiliitis. At this regard, further studies are required. The occurrence of hidradenitis suppurativa during SAPHO course supported the introduction of TNF-α blockers with a favourable result, as reported in a few cases in literature. The association between SAPHO syndrome and depressive mood disorders is already reported. Our patient experienced severe depression whose trend seems to be independent from the course of the main disease. Currently, it is not clarified if depression could be considered reactive to the underling disease or if it forms an integral part of the autoinflammatory disorder.
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http://dx.doi.org/10.1186/s13052-020-00933-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663872PMC
November 2020
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