Publications by authors named "Rolando Cimaz"

289 Publications

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

Targeting immune checkpoints in juvenile idiopathic arthritis: accumulating evidence.

Pediatr Res 2021 Jul 16. Epub 2021 Jul 16.

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

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http://dx.doi.org/10.1038/s41390-021-01650-zDOI Listing
July 2021

Long Term Experience in Patients With JIA-Associated Uveitis in a Large Referral Center.

Front Pediatr 2021 28;9:682327. Epub 2021 Jun 28.

Department of Ophthalmology, San Raffaele Scientific Institute, University Vita-Salute, Milan, Italy.

To describe demographic, clinical and therapeutic findings of a large cohort of patients with JIA-associated uveitis in a nationwide referral pediatric rheumatology and uveitis center in Northern Italy. Retrospective study of 125 patients with JIA-associated uveitis followed from 2009 to 2019. Demographic and rheumatologic features including JIA ILAR classification, age at onset, and laboratory data were recorded. Ocular findings collected were: anatomic location of uveitis, laterality, type, recurrence rate, visual acuity, ocular complications, and local therapy. Systemic therapy with conventional and biologic immunosuppressants, occurrence of adverse events, and duration of treatments were recorded. One hundred and twenty-five patients with JIA-associated uveitis were followed for a meantime of 9.2 (±1.7) years. Oligoarticular JIA was present in 92.8% of patients and anterior uveitis in 96%. The most common ocular complications recorded in our sample were posterior synechiae (37.6%), cataract (20.8%), band keratopathy (19.2%), glaucoma (7.2%), and macular edema (5.6%). Conventional immunosuppressants were used in 75.2% of patients with a mean duration of 9.1 years (±5.4), while biologics were administered in 47.2% of them for a period of 5.4 years. Adverse events (AE) were seen in 23% of patients being treated with Methotrexate, in 10.4% of patients treated with Adalimumab, in 38.5% of patients in therapy with Infliximab, and in 14.3% of patients being treated with Tocilizumab. No AE were reported in patients treated with Golimumab, Certolizumab, Abatacept and Rituximab. An aggressive treatment approach for patients with JIA-associated uveitis ensured a low number of ocular complications with a good safety profile.
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http://dx.doi.org/10.3389/fped.2021.682327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273291PMC
June 2021

Serum calprotectin (S100A8/9), clinical and ultrasound assessment in patients with juvenile idiopathic arthritis.

Clin Exp Rheumatol 2021 Jun 8. Epub 2021 Jun 8.

Paediatric Rheumatology, ASST G. Pini-CTO, Milan, and Department of Clinical Sciences and Community Health, and Research Center for Adult and Paediatric Rheumatic Diseases, University of Milan, Italy.

Objectives: To explore the association between serum S100A8/9 (calprotectin), clinical and ultrasound (US) assessment in juvenile idiopathic arthritis (JIA) patients.

Methods: A total of 30 well-characterised consecutive patients (18 female) with non-systemic JIA and 20 age-matched healthy controls were included. Serum and plasma samples obtained the same day of the clinical and sonographical assessment were tested for calprotectin levels by ELISA. Clinical status was defined using Wallace criteria. Ultrasonographic B-mode and power Doppler (PD) assessment of 44 joints for each subject was performed.

Results: Clinically active disease was present in 14 patients, while 16 patients were active according to US evaluation. We found no differences in the serum/plasma calprotectin levels in clinically active disease group [29.6 (5.4-198.1) ng/ml; 12.6 (2.8-65.8) ng/ml] as compared with inactive disease group [24.8 (14.1-204.3); 12.7 (3.4-65.1)] (p=0.73; p=0.29). There was also no difference between US active disease [29.8 (5.4-204.3); 12.9 (2.8-65.8)] and US inactive disease [24.8 (12.1-197.1); 11.7 (3.4-44.2)] with regard to the serum/plasma calprotectin levels (p=0.83; p=1.0). Serum/plasma calprotectin levels correlated moderately with C-reactive protein (CRP) (Spearman r=0.44, p=0.01; Spearman r=0.56, p=0.0021).

Conclusions: To our knowledge, this is the first study to simultaneously examine the correlation between serum/plasma calprotectin levels, clinical and US assessment in JIA. Calprotectin was not associated with the disease status in JIA patients with low number of active joints and its levels were moderately correlated with CRP. Our preliminary study needs to be extended with a larger number of patients.
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June 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

Drug survival of anakinra and canakinumab in monogenic autoinflammatory diseases: observational study from the International AIDA Registry.

Rheumatology (Oxford) 2021 May 7. Epub 2021 May 7.

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

Objectives: To investigate survival of interleukin (IL)-1 inhibitors in monogenic autoinflammatory disorders (mAID) through drug retention rate (DRR) and identify potential predictive factors of drug survival from a real-life perspective.

Patients And Methods: Multicentre retrospective study analyzing patients affected by the most common mAID treated with anakinra or canakinumab. Survival curves were analyzed with the Kaplan-Meier method. Statistical analysis included a Cox-proportional hazard model to detect factors responsible for drug discontinuation.

Results: Seventy-eight patients for a total of 102 treatment regimens were enrolled. The mean treatment duration was 29.59 months. The estimated DRR of IL-1 inhibitors at 12, 24, and 48 months of follow-up was 75.8%, 69.7% and 51.1%, respectively. Patients experiencing an adverse event had a significantly lower DRR (p = 0.019). In contrast, no significant differences were observed between biologic-naïve patients and those previously treated with biologic drugs (p = 0.985) Patients carrying high-penetrance mutations exhibited a significantly higher DRR compared with those with low-penetrance variants (p = 0.015). Adverse events were the only variable associated with a higher hazard of treatment withdrawal (HR 2.573 [CI: 1.223-5.411], p = 0.013) on regression analysis. A significant glucorticoid-sparing effect was observed (p < 0.0001).

Conclusions: IL-1 inhibitors display an excellent long-term effectiveness in terms of DRR, and their survival is not influenced by the biologic line of treatment. They display a favorable safety profile, that deserves however a close monitoring given its impact on treatment continuation. Special attention should be paid to molecular diagnosis and mutation penetrance, as patients carrying low-penetrance variants are more likely to interrupt treatment.
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http://dx.doi.org/10.1093/rheumatology/keab419DOI Listing
May 2021

Ballet foot in a boy.

Int J Rheum Dis 2021 May 7;24(5):719-720. Epub 2021 Apr 7.

ASST G.Pini-CTO, Milano, Italy.

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http://dx.doi.org/10.1111/1756-185X.14106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252499PMC
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

Acute Rheumatic Fever: Where Do We Stand? An Epidemiological Study in Northern Italy.

Front Med (Lausanne) 2021 24;8:621668. Epub 2021 Feb 24.

Department of Pediatrics, Desio Hospital, Azienda Socio Sanitaria Territoriale Monza, Monza, Italy.

Acute rheumatic fever (ARF) is a non-septic complication of group A β-hemolytic streptococcal (GAS) throat infection. Since 1944, ARF diagnosis relies on the Jones criteria, which were periodically revised. The 2015 revision of Jones criteria underlines the importance of knowing the epidemiological status of its own region with updated data. This study aims to describe ARF features in a retrospective cohort retrieved over a 10-year timespan (2009-2018) and to report the annual incidence of ARF among children in the Province of Monza-Brianza, Lombardy, Italy during the same period. This is a multicentric cross-sectional/retrospective study; 70 patients (39 boys) were diagnosed with ARF. The median age at diagnosis was 8.5 years (range, 4-14.2 years). Overall, carditis represented the most reported major Jones criteria followed by arthritis and chorea (40, 27, and 20 cases, respectively). In order to calculate the annual incidence of ARF, only children resident in the Province of Monza-Brianza were included in this part of the analysis. Therefore, 47 patients aged between 5 and 14 years were identified. The median incidence during the study time was 5.7/100,000 (range, 2.8-8.3/100,000). In the Province of Monza-Brianza, we found an incidence rate of ARF among children aged 5-14 years constantly above the threshold of low-risk area as defined in the 2015 revision of Jones criteria. Therefore, the diagnosis of ARF should be based on the moderate-high-risk set of Jones criteria. However, given the burden of secondary prophylaxis, expert opinion is advisable when the diagnosis of ARF is uncertain.
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http://dx.doi.org/10.3389/fmed.2021.621668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943448PMC
February 2021

Whole-body MRI in paediatric undefined inflammatory conditions.

Pediatr Int 2021 Feb 10. Epub 2021 Feb 10.

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

Background: Whole Body Magnetic Resonance Imaging (WBMRI) is a multiregional imaging technique suitable to investigate 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, suspected to have a rheumatologic disease.

Methods: We retrospectively analysed medical records, including laboratory tests and radiological data of 34 children who have 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 resulted increased in 29/34 patients. Twenty-five children had already performed 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 (34%) resulted to be affected by chronic recurrent multifocal osteomyelitis (CRMO).

Conclusions: WBMRI is helpful in paediatric rheumatology in 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 was CRMO. WBMRI can also help in excluding neoplastic diseases.
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http://dx.doi.org/10.1111/ped.14650DOI Listing
February 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

Pediatric Antiphospholipid Syndrome: from Pathogenesis to Clinical Management.

Curr Rheumatol Rep 2021 01 28;23(2):10. Epub 2021 Jan 28.

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

Purpose Of Review: Elucidating the pathogenic mechanisms mediated by antiphospholipid antibodies (aPL) might exert important clinical implications in pediatric antiphospholipid syndrome (APS).

Recent Findings: aPL are traditionally regarded as the main pathogenic players in APS, inducing thrombosis via the interaction with fluid-phase and cellular components of coagulation. Recent APS research has focused on the role of β2 glycoprotein I, which bridges innate immunity and coagulation. In pediatric populations, aPL should be screened in appropriate clinical settings, such as thrombosis, multiple-organ dysfunction, or concomitant systemic autoimmune diseases. Children positive for aPL tests often present non-thrombotic non-criteria manifestations or asymptomatic aPL positivity. In utero aPL exposure has been suggested to result in developmental disabilities, warranting long-term follow-up. The knowledge of the multifaceted nature of pediatric APS should be implemented to reduce the risk of underdiagnosing/undertreating this condition. Hopefully, recent pathogenic insights will open new windows of opportunity in the management of pediatric APS.
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http://dx.doi.org/10.1007/s11926-020-00976-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843475PMC
January 2021

Revised recommendations of the Italian Society of Pediatrics about the general management of Kawasaki disease.

Ital J Pediatr 2021 Jan 25;47(1):16. Epub 2021 Jan 25.

Bambino Gesù Children's Hospital, Rome, Italy.

Aim of these revised recommendations for the general management of Kawasaki disease is to encourage its prompter recognition and warrant the most appropriate therapy, based on ascertained scientific data, raising awareness of the complications related to misdiagnosis or delayed treatment. A set of 20 synthetic operative statements is herein provided, including the definition of Kawasaki disease, its protean presentations, clinical course and seminal treatment modalities of all disease phases. The application of these recommendations should improve prognosis of Kawasaki disease and prevent the progression to permanent vascular abnormalities, thereby diminishing morbidity and mortality.
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http://dx.doi.org/10.1186/s13052-021-00962-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830049PMC
January 2021

Absence of Association Between Abatacept Exposure and Initial Infection in Patients With Juvenile Idiopathic Arthritis.

J Rheumatol 2021 Jul 15;48(7):1073-1081. Epub 2021 Jan 15.

A. Martini, MD, IRCCS Istituto G Gaslini, Clinica Pediatrica e Reumatologia, Genoa, Italy and Università di Genova, Genoa, Italy.

Objective: To assess the relationship between infection risk and abatacept (ABA) exposure levels in patients with polyarticular-course juvenile idiopathic arthritis (pJIA) following treatment with subcutaneous (SC) and intravenous (IV) ABA.

Methods: Data from 2 published studies (ClinicalTrials.gov: NCT01844518, NCT00095173) of ABA treatment in pediatric patients were analyzed. One study treated patients aged 2-17 years with SC ABA and the other treated patients aged 6-17 years with IV ABA. Association between serum ABA exposure measures and infection was evaluated using Kaplan-Meier plots of probability of first infection vs time on treatment by ABA exposure quartiles and log-rank tests. Number of infections by ABA exposure quartiles was investigated.

Results: Overall, 343 patients were included in this analysis: 219 patients received SC ABA and 124 patients received IV ABA. Overall, 237/343 (69.1%) patients had ≥ 1 infection over 24 months. No significant difference in time to first infection across 4 quartiles of ABA exposure levels was observed in the pooled ( = 0.45), SC (2-5 yrs: = 0.93; 6-17 yrs: = 0.48), or IV ( = 0.50) analyses. Concomitant use of methotrexate and glucocorticoids (at baseline and throughout) with ABA did not increase infection risk across the ABA exposure quartiles. There was no evidence of association between number of infections and ABA exposure quartiles. No opportunistic infections related to ABA were reported.

Conclusion: In patients aged 2-17 years with pJIA, no evidence of association between higher levels of exposure to IV ABA or SC ABA and incidence of infection was observed.
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http://dx.doi.org/10.3899/jrheum.200154DOI Listing
July 2021

Brainstem Auditory Evoked Potentials and Visual Potentials in Kawasaki Disease: An Observational Monocentric Study.

Front Pediatr 2020 7;8:581780. Epub 2020 Dec 7.

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

Kawasaki Disease is a systemic vasculitis, particularly involving coronary arteries. Rare involvement of other vascular districts is described, as central nervous system arteries, leading to a vasculitic neuropathy. Sensorineural hearing loss and alterations of evoked potentials are uncommonly reported complications. In an observational monocentric study, 59 children (37 males; 22 females; mean age: 2.7 ± 2.2 years) with documented Kawasaki Disease were enrolled. No risk factors for hearing loss and/or neurological impairment were identified in the cohort. Brainstem auditory evoked potentials and visual evoked potentials were correlated with clinical, hamatological and radiological data, evaluated in the acute phase of the Kawasaki Disease, and during the follow-up. Evoked potentials were altered in 39/59 patients (66%): of these, 27/39 (69%) showed altered IV and V waves and/or III-V interwave latencies of brainstem auditory evoked potentials; 4/39 (10%) showed pathological visual evoked potentials; 8/39 (21%) had abnormalities of both brainstem auditory evoked potentials and visual evoked potentials. No permanent deafness was reported. Abnormalities in visual evoked potentials were not significantly correlated with coronary artery lesions; however, the presence of abnormalities of brainstem auditory evoked potentials were associated with the risk of coronary artery lesions.
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http://dx.doi.org/10.3389/fped.2020.581780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750363PMC
December 2020

Case Report: Infantile Ischemic Stroke and Antiphospholipid Antibodies, Description of Four Cases.

Front Pediatr 2020 24;8:596386. Epub 2020 Nov 24.

Azienda Socio Sanitaria Territoriale G-Pini, Milan, Italy.

Antiphospholipid syndrome (APS) is a rare condition in childhood, but even more in the neonatal age. Most neonatal cases are considered a passively acquired autoimmune disease, due to a transplacental passage of maternal antiphospholipid antibodies (aPL) from mothers with primary or secondary APS or, more often, from asymptomatic aPL carriers. Exceedingly unusual is the neonatal production of aPL. We present four infants with presumed perinatal stroke in presence of increased and persistent aPL levels, even after 6 months of life, opening the window on a gray zone related to the origin of these antibodies (maternal or neonatal) and on their role in the pathogenesis of stroke.
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http://dx.doi.org/10.3389/fped.2020.596386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732433PMC
November 2020

Antigen-driven PD-1 TOX BHLHE40 and PD-1 TOX EOMES T lymphocytes regulate juvenile idiopathic arthritis in situ.

Eur J Immunol 2021 Apr 2;51(4):915-929. Epub 2021 Feb 2.

Deutsches Rheuma-Forschungszentrum (DRFZ), Institute of the Leibniz Association, Berlin, Germany.

T lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro-inflammatory cytokines upon re-stimulation in vitro. Further, a significant genetic linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA). However, the functions of T lymphocytes in established disease remain elusive. Here we dissect the transcriptional and the clonal heterogeneity of synovial T lymphocytes in JIA patients by single-cell RNA sequencing combined with T cell receptor profiling on the same cells. We identify clonally expanded subpopulations of T lymphocytes expressing genes reflecting recent activation by antigen in situ. A PD-1 TOX EOMES population of CD4 T lymphocytes expressed immune regulatory genes and chemoattractant genes for myeloid cells. A PD-1 TOX BHLHE40 population of CD4 , and a mirror population of CD8 T lymphocytes expressed genes driving inflammation, and genes supporting B lymphocyte activation in situ. This analysis points out that multiple types of T lymphocytes have to be targeted for therapeutic regeneration of tolerance in arthritis.
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http://dx.doi.org/10.1002/eji.202048797DOI Listing
April 2021

Childhood Sjogren's syndrome: An Italian case series and a literature review-based cohort.

Semin Arthritis Rheum 2020 Nov 21. Epub 2020 Nov 21.

ASST G.Pini-CTO, Via Gaetano Pini 9, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, and Research Center for Adult and Pediatric Rheumatic Diseases, University of Milan, Via della Commenda 19, 20122 Milan, Italy.

Objective: Sjogren's syndrome (SS) is a chronic autoimmune disease with a highly variable presentation. This study aims to describe childhood SS (cSS) features to help guide clinicians in their consideration of and workup for cSS.

Methods: We retrospectively reviewed medical records of patients with cSS referred to three Italian pediatric rheumatology centers from 2015 to 2019 and we conducted a literature review of cSS. Statistical analysis was performed to detect associations between clinical/laboratory features.

Results: We reviewed 12 cases (9 female) followed in 3 Italian centers and 240 cases (191 female) in the published literature reporting individual information. The median age at disease onset was 10 years for both cohorts. The most frequently reported clinical SS-specific feature was parotitis in both cohorts (67% each). Extraglandular manifestations were very common and joint involvement was the most frequent. In the cluster analysis, we identified a significant association between parotitis and younger patients (< 11 years). We verified the presence of the main SS features (exocrine gland inflammation, exocrine gland dysfunction, and presence of autoantibodies) in the Italian cohort and the literature review-based cohort: 92% and 80% of the cohorts, respectively, had at least 2/3 main characteristics.

Conclusion: We described cSS features with relative frequencies and we found that parotid involvement was related to cSS in younger patients. The majority of patients showed various combinations of exocrine gland inflammation, exocrine gland dysfunction, and presence of autoantibodies giving a theoretical basis for future research to pave the way for the development of cSS specific diagnostic criteria.
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http://dx.doi.org/10.1016/j.semarthrit.2020.11.004DOI Listing
November 2020

Development and Testing of Reduced Versions of the Manual Muscle Test-8 in Juvenile Dermatomyositis.

J Rheumatol 2021 Jun 15;48(6):898-906. Epub 2020 Nov 15.

C. Malattia, MD, PhD, A. Consolaro, MD, PhD, UOC Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini and Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DiNOGMI), Università degli Studi di Genova, Genoa, Italy.

Objective: To develop and test shortened versions of the Manual Muscle Test-8 (MMT-8) in juvenile dermatomyositis (JDM).

Methods: Construction of reduced tools was based on a retrospective analysis of individual scores of MMT-8 muscle groups in 3 multinational datasets. The 4 and 6 most frequently impaired muscle groups were included in MMT-4 and MMT-6, respectively. Metrologic properties of reduced tools were assessed by evaluating construct validity, internal consistency, discriminant ability, and responsiveness to change.

Results: Neck flexors, hip extensors, hip abductors, and shoulder abductors were included in MMT-4, whereas MMT-6 also included elbow flexors and hip flexors. Both shortened tools revealed strong correlations with MMT-8 and other muscle strength measures. Correlations with other JDM outcome measures were in line with predictions. Internal consistency was good (0.88-0.96) for both MMT-4 and MMT-6. Both reduced tools showed strong ability to discriminate between disease activity states, assessed by the caring physician or a parent ( < 0.001), and between patients whose parents were satisfied or not satisfied with illness course ( < 0.001). Responsiveness to change (assessed by both standardized response mean and relative efficiency) of MMT-4 and, to a lesser degree, MMT-6, was slightly superior to that of MMT-8.

Conclusion: Overall, the metrologic performance of MMT-4 and MMT-6 was comparable to that of the other established muscle strength tools, which indicates that they may be suitable for use in clinical practice and research, including clinical trials. The measurement properties of these tools should be further tested in other patient populations and evaluated prospectively.
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http://dx.doi.org/10.3899/jrheum.200543DOI Listing
June 2021

Patients with juvenile idiopathic arthritis on TNF inhibitors exposed to COVID-19 family members.

Semin Arthritis Rheum 2020 12 2;50(6):1214-1215. Epub 2020 Oct 2.

ASST G.Pini-CTO, Via Gaetano Pini 9, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, and Research Center for Adult and Pediatric Rheumatic Diseases, University of Milan, Via della Commenda 19, 20122 Milan, Italy.

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http://dx.doi.org/10.1016/j.semarthrit.2020.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531912PMC
December 2020

Management of Juvenile idiopathic arthritis-associated uveitis duringthe COVID-19 pandemic in a pediatric referral center in Lombardy.

Ocul Immunol Inflamm 2020 Nov 25;28(8):1305-1307. Epub 2020 Sep 25.

Department of Pediatric Rheumatology, ASST G. Pini , Milan, Italy.

Italy was the first European country to be affected by the SARS-CoV-2 pandemic. In this scenario, we had to face a new clinical approach in our Pediatric Rheumatology Unit for the management of patients affected by juvenile idiopathic arthritis (JIA)-associated uveitis. During the lockdown (phase 1), the weekly outpatient clinic was discontinued and telephone consultations were set up. A toll-free telephone number was instituted for emergencies. None of our children with JIA-associated uveitis was advised to stop the ongoing immunosuppressant systemic therapy. We had no cases of COVID-19 infection and uveitis activity was under control in all but two out of 125 patients, which was comparable with the pre-COVID-19 situation. During phase 2 of the pandemic, hospital and ambulatory rearrangements were made to minimize the risk of SARS-CoV-2 infection. Overall, during the first 4 weeks of phase 2, we did not notice an increased number of patients with uveitis activity.
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http://dx.doi.org/10.1080/09273948.2020.1800752DOI Listing
November 2020

Anakinra for Treatment-Resistant Kawasaki Disease: Evidence from a Literature Review.

Paediatr Drugs 2020 Dec;22(6):645-652

ASST G-Pini, Milan, Italy.

Kawasaki disease (KD) is one of the most common vasculitides of childhood and the main cause of acquired heart disease in developed countries. Intravenous immunoglobulin (IVIG) in association with aspirin represents the main treatment for KD. However, 10-20% of patients fail to respond to standard treatment and have an increased risk of cardiac complications. There is currently no accepted protocol for treatment of resistant cases. Several authors highlighted the role of interleukin-1 (IL-1) as a mediator of inflammation in KD and suggested the possibility of using IL-1 or its receptor as a target of therapy. The use of IL-1 inhibitors in patients with KD has been reported in the scientific literature, but data are largely limited to individual case reports and small case series. We summarized the scientific literature related to the use of anakinra, analyzing preclinical and clinical data. Thirty-eight patients have been described so far, most of them with KD-related complications. Twenty-two were described in case reports and case series, while 16 were patients from the completed KAWAKINRA phase IIa study. Almost all patients received clinical benefit, and no relevant side effects were noted. Based on this evidence, in our opinion, anakinra may be considered as an option after the failure of the first IVIG infusion, especially in patients with coronary involvement.
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http://dx.doi.org/10.1007/s40272-020-00421-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471561PMC
December 2020

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

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

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

This study explores demographic, clinical, and therapeutic features of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a cohort of 80 patients recruited from 19 Italian referral Centers. Patients' data were collected retrospectively and then analyzed according to age groups (disease onset before or after 16 years) and genotype (high penetrance (HP) and low penetrance (LP) gene variants). Pediatric- and adult-onset were reported, respectively, in 44 and 36 patients; HP and LP variants were found, respectively, in 32 and 44 cases. A positive family history for recurrent fever was reported more frequently in the pediatric group than in the adult group ( < 0.05). With reference to clinical features during attacks, pericarditis and myalgia were reported more frequently in the context of adult-onset disease than in the pediatric age (with < 0.01 and < 0.05, respectively), while abdominal pain was present in 84% of children and in 25% of adults ( < 0.01). Abdominal pain was significantly associated also to the presence of HP mutations ( < 0.01), while oral aphthosis was more frequently found in the LP variant group ( < 0.05). Systemic amyloidosis occurred in 25% of subjects carrying HP variants. As concerns laboratory features, HP mutations were significantly associated to higher ESR values ( < 0.01) and to the persistence of steadily elevated inflammatory markers during asymptomatic periods ( < 0.05). The presence of mutations involving a cysteine residue, abdominal pain, and lymphadenopathy during flares significantly correlated with the risk of developing amyloidosis and renal impairment. Conversely, the administration of colchicine negatively correlated to the development of pathologic proteinuria ( < 0.05). Both NSAIDs and colchicine were used as monotherapy more frequently in the LP group compared to the HP group ( < 0.01). Biologic agents were prescribed to 49 (61%) patients; R92Q subjects were more frequently on NSAIDs monotherapy than other patients ( < 0.01); nevertheless, they required biologic therapy in 53.1% of cases. At disease onset, the latest classification criteria for TRAPS were fulfilled by 64/80 (80%) patients (clinical plus genetic items) and 46/80 (57.5%) patients (clinical items only). No statistically significant differences were found in the sensitivity of the classification criteria according to age at onset and according to genotype ( < 0.05). This study describes one of the widest cohorts of TRAPS patients in the literature, suggesting that the clinical expression of this syndrome is more influenced by the penetrance of the mutation rather than by the age at onset itself. Given the high phenotypic heterogeneity of the disease, a definite diagnosis should rely on both accurate working clinical assessment and complementary genotype.
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http://dx.doi.org/10.1155/2020/8562485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428902PMC
July 2021

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

Periodic fever syndromes and the autoinflammatory diseases (AIDs).

J Transl Autoimmun 2020 17;3:100031. Epub 2019 Dec 17.

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

Innate immune system represents the ancestral defense against infectious agents preserved along the evolution and species; it is phylogenetically older than the adaptive immune system, which exists only in the vertebrates. Cells with phagocytic activity such as neutrophils, macrophages, and natural killer (NK) cells play a key role in innate immunity. In 1999 Kastner et al. first introduced the term "autoinflammation" describing two diseases characterized by recurrent episodes of systemic inflammation without any identifiable infectious trigger: Familial Mediterranean Fever (FMF) and TNF Receptor Associated Periodic Syndrome (TRAPS). Autoinflammatory diseases (AIDs) are caused by self-directed inflammation due to an alteration of innate immunity leading to systemic inflammatory attacks typically in an on/off mode. In addition to inflammasomopathies, nuclear factor (NF)-κB-mediated disorders (also known as Rhelopathies) and type 1 interferonopathies are subjects of more recent studies. This review aims to provide an overview of the field with the most recent updates (see "Most recent developments in.." paragraphs) and a description of the newly identified AIDs.
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http://dx.doi.org/10.1016/j.jtauto.2019.100031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388371PMC
December 2019

Pharmacotherapy for juvenile spondyloarthritis: an overview of the available therapies.

Expert Opin Pharmacother 2020 Dec 29;21(17):2161-2168. Epub 2020 Jul 29.

Pediatric Rheumatology, ASST G.Pini-CTO , Milan, Italy.

Introduction: Spondyloarthropathies (SpA) represent a heterogeneous group of inflammatory arthritides with autoimmune pathogenesis that can affect both adults and children with peculiar features such as enthesitis, sacroiliac joint, and axial involvement. Since juvenile onset of SpA (JSpA) is not well codified by the current juvenile idiopathic arthritis classification, studies in this field are restricted to single categories and therefore cannot be exhaustive. This review aims to report recent advances in the treatment of JSpA.

Areas Covered: In order to assess the available therapies for JSpA, the authors have analyzed data obtained from retrospective and prospective studies, case reports, and case series, as well as from controlled trials.

Expert Opinion: Given the challenging classification of JSpA, research in this field has been restricted to single subcategories. Little is known of which patients are more likely to develop axial involvement leading to severe spinal damage. Whether TNF inhibitors are capable to prevent or stop disease progression, once started, is yet to be ascertained with structural damage still a matter for research. Therefore, trials on the efficacy of TNF inhibitors in JSpA are strongly advocated since they may help to elucidate their place as a treatment option.
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http://dx.doi.org/10.1080/14656566.2020.1796970DOI Listing
December 2020

SARS-COV-2 Infection and Kawasaki Disease: Case Report of a Hitherto Unrecognized Association.

Front Pediatr 2020 3;8:398. Epub 2020 Jul 3.

Pediatric Intermediate Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Coronavirus-associated disease (COVID-19) was firstly reported at the end of 2019. Generally, COVID-19 seems to be a less severe disease in children than in adults. According to the current literature, children account approximately for 2% of diagnosed COVID-19 cases. Northern Italy is one of the geographical areas mainly affected by the ongoing COVID-19 pandemic. We describe a pediatric patient diagnosed and treated for atypical/incomplete Kawasaki Disease (KD) complicated with paralytic ileus, who also resulted positive for SARS-COV-2.
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http://dx.doi.org/10.3389/fped.2020.00398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347899PMC
July 2020

Th17 lymphocyte-dependent degradation of joint cartilage by synovial fibroblasts in a humanized mouse model of arthritis and reversal by secukinumab.

Eur J Immunol 2021 01 9;51(1):220-230. Epub 2020 Aug 9.

Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.

How T-helper (Th) lymphocyte subpopulations identified in synovial fluid from patients with juvenile idiopathic arthritis (JIA) (Th17, classic Th1, or nonclassic Th1) drive joint damage is of great interest for the possible use of biological drugs that inhibit the specific cytokines. Our objective was to clarify the role of such Th subpopulations in the pathogenesis of articular cartilage destruction by synovial fibroblasts (SFbs), and the effect of Th17 blockage in an animal model. SFbs were isolated from healthy subjects and patients with JIA, and peripheral blood Th lymphocytes subsets were obtained from healthy subjects. Fragments of human cartilage from healthy subjects in a collagen matrix containing JIA or normal SFbs grafted underskin in SCID mice were used to measure cartilage degradation under the effects of Th supernatants. JIA SFbs overexpress MMP9 and MMP2 and Th17 induce both MMPs in normal SFbs, while nonclassic Th1 upregulate urokinase plasminogen activator (uPA) activity. In vitro invasive phenotype of normal SFbs is stimulated with conditioned medium of Th17 and nonclassic-Th1. In the in vivo "inverse wrap" model, normal SFbs stimulated with supernatants of Th17-lymphocytes and nonclassic Th1 produced a cartilage invasion and degradation similar to JIA SFbs. Secukinumab inhibits the cartilage damage triggered by factors produced by Th17.
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http://dx.doi.org/10.1002/eji.202048773DOI Listing
January 2021
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