Publications by authors named "Clara Malattia"

75 Publications

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 EFSUMB Guidelines and Recommendations for Musculoskeletal Ultrasound - Part II: Joint Pathologies, Pediatric Applications, and Guided Procedures.

Ultraschall Med 2021 Nov 3. Epub 2021 Nov 3.

Department of Anaesthesiology and Intensive Care Medicine, Cork University Hospital and University College Cork, Cork, Ireland.

The second part of the Guidelines and Recommendations for Musculoskeletal Ultrasound (MSUS), produced under the auspices of EFSUMB, following the same methodology as for Part 1, provides information and recommendations on the use of this imaging modality for joint pathology, pediatric applications, and musculoskeletal ultrasound-guided procedures. Clinical application, practical points, limitations, and artifacts are described and discussed for every joint or procedure. The document is intended to guide clinical users in their daily practice.
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http://dx.doi.org/10.1055/a-1640-9183DOI Listing
November 2021

The EFSUMB Guidelines and Recommendations for Musculoskeletal Ultrasound - Part I: Extraarticular Pathologies.

Ultraschall Med 2021 Sep 3. Epub 2021 Sep 3.

Paediatric Imaging Department, "Reine Fabiola" Children's University Hospital, Université Libre de Bruxelles, Brussels, Belgium.

The first part of the guidelines and recommendations for musculoskeletal ultrasound, produced under the auspices of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB), provides information about the use of musculoskeletal ultrasound for assessing extraarticular structures (muscles, tendons, entheses, ligaments, bones, bursae, fasciae, nerves, skin, subcutaneous tissues, and nails) and their pathologies. Clinical applications, practical points, limitations, and artifacts are described and discussed for every structure. After an extensive literature review, the recommendations have been developed according to the Oxford Centre for Evidence-based Medicine and GRADE criteria and the consensus level was established through a Delphi process. The document is intended to guide clinical users in their daily practice.
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http://dx.doi.org/10.1055/a-1562-1455DOI Listing
September 2021

Predictive value of MRI in patients with juvenile idiopathic arthritis in clinical remission.

Arthritis Care Res (Hoboken) 2021 Jul 19. Epub 2021 Jul 19.

Università degli Studi di Genova, Dipartimento di Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Genova, Italy.

Objectives: To define the prevalence of MRI subclinical synovitis in a large cohort of JIA patients in clinical remission and to evaluate its predictive value in terms of disease flare and joint deterioration.

Methods: Ninety patients with clinically inactive JIA who underwent a contrast-enhanced (CE) MRI of a previously affected joint were retrospectively included. Each joint was evaluated for synovitis, tenosynovitis and bone marrow oedema (BMO). Baseline and follow-up radiographs were assessed to evaluate structural damage progression.

Results: CE-MRI was acquired in 45 wrists, 30 hips, 13 ankles and 2 knees. Subclinical synovitis was detected in 59/90 (65.5%) patients and BMO in 42/90 (46.7%) patients. Fifty-seven out of 90 (63.3%) patients experienced a disease flare during follow-up. Forty-four out of 59 (74.6%) patients with subclinical synovitis experienced a disease flare versus 13/31 (41.9%) patients with no residual synovitis on MRI (p=0.002). The presence of subclinical synovitis was the best predictor of disease flare on multivariable regression analysis (HR= 2.45; p=0.003). Baseline and follow-up radiographs were available for 54 patients; 17/54 (31.5%) patients experienced radiographic damage progression. BMO (HR=4.40; p=0.045) and age > 17 years (HR= 3.51; p=0.04) were strong predictors of joint damage progression in the multivariable analysis.

Conclusions: MRI-detected subclinical inflammation was present in a large proportion of patients with JIA despite clinical remission. Subclinical synovitis and BMO have been shown to play a role in predicting the risk of disease relapse and joint deterioration, with potential implications for patients' management.
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http://dx.doi.org/10.1002/acr.24757DOI Listing
July 2021

Cutaneous mucinosis of infancy: a rare case of joint involvement.

Pediatr Rheumatol Online J 2021 Jun 29;19(1):99. Epub 2021 Jun 29.

Department of "Clinica Pediatrica e Reumatologia", IRCCS Giannina Gaslini, Genoa, Italy.

Background: Primary cutaneous mucinosis are a heterogeneous group of diseases characterized by the deposition of glycosaminoglycans in the dermis and the follicles. These diseases are rare in children therefore their diagnosis and management are still challenging. Joint involvement has been reported in patients with secondary cutaneous mucinosis and, rarely, in primary mucinosis. We describe a case of Cutaneous Mucinosis of Infancy with joint involvement.

Case Presentation: An healthy 5-year-old boy showed acute arthritis of the left knee and left elbow confirmed by ultrasound. Laboratory tests were within normal range. Symptoms disappeared after a course of nonsteroid anti-inflammatory drugs. One year later, the knee swelling reappeared; juvenile idiopathic arthritis was diagnosed and intra-articular steroid injection was performed. Due to persistence of arthritis of the knee he was admitted to our hospital. On physical examination variable skin-colored lesions were observed, which had been in existence for over 2 years. We performed a skin biopsy that showed an interstitial mucine deposition in the reticular dermis. Cutaneous Mucinosis of Infancy was diagnosed.

Discussion And Conclusions: Cutaneous Mucinosis of Infancy is a persistent dermatosis with benign prognosis and no treatment is generally required. Our case report is particularly interesting because it is the first in which joint involvement has been reported in CMI, a disorder that has so far been described as limited to skin involvement. Further studies will be necessary in order to clarify the pathogenesis of joint involvement in primary mucinosis.
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http://dx.doi.org/10.1186/s12969-021-00590-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243549PMC
June 2021

Failure of first anti-TNF agent in Takayasu's arteritis: to switch or to swap?

Clin Exp Rheumatol 2021 Mar-Apr;39 Suppl 129(2):129-134. Epub 2021 Mar 5.

Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy.

Objectives: Biologic drugs (bDMARD), especially TNF-α-inhibitors (TNFi), are used in refractory Takayasu's arteritis (TAK) patients. Up to 23% of patients are switched to a different bDMARD because of inefficacy. No data are available on which strategy is more efficient after TNFi failure. The aim of our study is to evaluate whether a switch or swap strategy should be preferred in TAK patients failing TNFis.

Methods: TAK patients treated with a second bDMARD after the failure of the first TNFi were identified from 3 referral centres. Patients were classified as switch if treated with a different TNFi, and swap if treated with a non-TNFi bDMARD. Baseline features were evaluated. Efficacy and safety of the second bDMARD at 6 and 12 months were assessed and a comparison between switch and swap patients was made.

Results: Twenty-four TAK patients were identified. Eleven patients (46%) were switched and 13 patients (54%) were swapped (12 to tocilizumab, 1 to ustekinumab). Baseline features of patients in the 2 groups were comparable. At 12 months, the second bDMARD was suspended in 4 switch (36%) and in 5 swap (42%) patients. Second biologic drug survival and relapse-free survival were equivalent between the two groups at 6 and 12 months. A vascular worsening was observed in 4 switch (40%) and 2 swap (25%) patients. Severe infections, myocardial infarction, ischemic stroke or cancer were recorded in no patient.

Conclusions: Our retrospective study suggests that in first-line TNFi failure TAK patients both switch and swap strategies can be considered suitable approaches.
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May 2021

Underlying CTLA4 Deficiency in a Patient With Juvenile Idiopathic Arthritis and Autoimmune Lymphoproliferative Syndrome Features Successfully Treated With Abatacept-A Case Report.

J Pediatr Hematol Oncol 2021 Nov;43(8):e1168-e1172

Haematology Unit.

Background: Functional variants of the cytotoxic T-lymphocyte antigen-4 (CTLA4) could contribute to the pathogenesis of disorders characterized by abnormal T-cell responses.

Case Presentation: We report a case of a 13-year-old girl who first presented with polyarticular juvenile idiopathic arthritis poorly responsive to treatment. During the following years the patient developed cytopenias, chronic lymphoproliferation, high values of T-cell receptor αβ+ CD4- CD8- double-negative T cells and defective Fas-mediated T cells apoptosis. Autoimmune lymphoproliferative syndrome was diagnosed and therapy with mycophenolate mofetil was started, with good hematological control. Due to the persistence of active polyarthritis, mycophenolate mofetil was replaced with sirolimus. In the following months the patient developed hypogammaglobulinemia and started having severe diarrhea. Histologically, duodenitis and chronic gastritis were present. Using the next generation sequencing-based gene panel screening, a CTLA4 mutation was detected (p.Cys58Serfs*13). At the age of 21 the patient developed acute autoimmune hemolytic anemia; steroid treatment in combination with abatacept were started with clinical remission of all symptoms, even arthritis.

Conclusions: Targeted immunologic screening and appropriate genetic tests could help in the diagnosis of a specific genetically mediated immune dysregulation syndrome, allowing to select those patients who can take advantage of target therapy, as in the case of abatacept in CTLA4 deficiency.
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http://dx.doi.org/10.1097/MPH.0000000000002120DOI Listing
November 2021

Current status of MR imaging of juvenile idiopathic arthritis.

Best Pract Res Clin Rheumatol 2020 12 3;34(6):101629. Epub 2020 Dec 3.

Department of Diagnostic Imaging, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Imaging, University of Toronto, Toronto, ON, Canada. Electronic address:

Juvenile idiopathic arthritis (JIA) is the most common chronic arthropathy in the pediatric population. Although the diagnosis is essentially clinical for many affected joints, MR imaging has become an important tool for the assessment of joints that are difficult to evaluate clinically, such as temporomandibular and sacroiliac joints, and for screening of inflammatory changes in the entire body by whole body MRI (WBMRI) assessment. The utilization of MR imaging is challenging in the pediatric population given the need for discrimination between pathological and physiological changes in the growing skeleton. Several multicentric multidisciplinary organizations have made major efforts over the past decades to standardize, quantify, and validate scoring systems to measure joint changes both cross-sectionally and longitudinally according to rigorous methodological standards. In this paper, we (1) discuss current trends for the diagnosis and management of JIA, (2) review challenges for detecting real pathological changes in growing joints, (3) summarize the current status of standardization of MRI protocols for data acquisition and the quantification of joint pathology in JIA by means of scoring systems, and (4) outline novel MR imaging techniques for the evaluation of anatomy and function of joints in JIA. Optimizing the role of MRI as a robust biomarker and outcome measure remains a priority of future research in this field.
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http://dx.doi.org/10.1016/j.berh.2020.101629DOI Listing
December 2020

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

J Rheumatol 2021 06 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

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

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

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

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

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

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

Università degli Studi di Genova, Genoa, Italy.

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

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

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

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

Trial Registration: Trial registration numbers and dates: TENDER, NCT00642460 (March 19, 2008); CHERISH, NCT00988221 (October 1, 2009).
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http://dx.doi.org/10.1186/s13075-020-02303-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488325PMC
September 2020

Ultrasound imaging in paediatric rheumatology.

Best Pract Res Clin Rheumatol 2020 12 25;34(6):101570. Epub 2020 Aug 25.

UOC Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, Genoa, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal Infantile Sciences (DINOGMI) University of Genoa, Italy.

The role of ultrasound imaging in the diagnosis and monitoring of paediatric rheumatic diseases with special emphasis on recent scientific work regarding the evidence base and standardization of this technique is being reviewed. An overview of the most important practical aspects for the use of musculoskeletal ultrasound in a clinical setting is also provided. Huge scientific efforts and advances in recent years illustrate the increasing importance of musculoskeletal ultrasound in pediatric rheumatology. Several studies focused on setting an evidence-based standard for the ultrasound appearance of healthy and normal joints in children of all age groups. Physiologic vascularization and ossification were two main aspects of these studies. Other publications demonstrate that ultrasound imaging is also an important and useful tool to detect pathology as synovitis, tenosynovitis or enthesitis in children and to monitor pediatric patients with rheumatic conditions. Important practical aspects include training in the use of correct ultrasound techniques, as well as knowledge and experience of normal pediatric sonoanatomy and the appearance of pathological findings on ultrasound.
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http://dx.doi.org/10.1016/j.berh.2020.101570DOI Listing
December 2020

Linking Joint Impairment and Gait Biomechanics in Patients with Juvenile Idiopathic Arthritis.

Ann Biomed Eng 2019 Nov 20;47(11):2155-2167. Epub 2019 May 20.

Department of Mechanical Engineering, University of Sheffield, Sheffield, UK.

Juvenile Idiopathic Arthritis (JIA) is a paediatric musculoskeletal disease of unknown aetiology, leading to walking alterations when the lower-limb joints are involved. Diagnosis of JIA is mostly clinical. Imaging can quantify impairments associated to inflammation and joint damage. However, treatment planning could be better supported using dynamic information, such as joint contact forces (JCFs). To this purpose, we used a musculoskeletal model to predict JCFs and investigate how JCFs varied as a result of joint impairment in eighteen children with JIA. Gait analysis data and magnetic resonance images (MRI) were used to develop patient-specific lower-limb musculoskeletal models, which were evaluated for operator-dependent variability (< 3.6°, 0.05 N kg and 0.5 BW for joint angles, moments, and JCFs, respectively). Gait alterations and JCF patterns showed high between-subjects variability reflecting the pathology heterogeneity in the cohort. Higher joint impairment, assessed with MRI-based evaluation, was weakly associated to overall joint overloading. A stronger correlation was observed between impairment of one limb and overload of the contralateral limb, suggesting risky compensatory strategies being adopted, especially at the knee level. This suggests that knee overloading during gait might be a good predictor of disease progression and gait biomechanics should be used to inform treatment planning.
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http://dx.doi.org/10.1007/s10439-019-02287-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838035PMC
November 2019

An image-based kinematic model of the tibiotalar and subtalar joints and its application to gait analysis in children with Juvenile Idiopathic Arthritis.

J Biomech 2019 03 9;85:27-36. Epub 2019 Jan 9.

Department of Mechanical Engineering and INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, United Kingdom.

In vivo estimates of tibiotalar and the subtalar joint kinematics can unveil unique information about gait biomechanics, especially in the presence of musculoskeletal disorders affecting the foot and ankle complex. Previous literature investigated the ankle kinematics on ex vivo data sets, but little has been reported for natural walking, and even less for pathological and juvenile populations. This paper proposes an MRI-based morphological fitting methodology for the personalised definition of the tibiotalar and the subtalar joint axes during gait, and investigated its application to characterise the ankle kinematics in twenty patients affected by Juvenile Idiopathic Arthritis (JIA). The estimated joint axes were in line with in vivo and ex vivo literature data and joint kinematics variation subsequent to inter-operator variability was in the order of 1°. The model allowed to investigate, for the first time in patients with JIA, the functional response to joint impairment. The joint kinematics highlighted changes over time that were consistent with changes in the patient's clinical pattern and notably varied from patient to patient. The heterogeneous and patient-specific nature of the effects of JIA was confirmed by the absence of a correlation between a semi-quantitative MRI-based impairment score and a variety of investigated joint kinematics indexes. In conclusion, this study showed the feasibility of using MRI and morphological fitting to identify the tibiotalar and subtalar joint axes in a non-invasive patient-specific manner. The proposed methodology represents an innovative and reliable approach to the analysis of the ankle joint kinematics in pathological juvenile populations.
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http://dx.doi.org/10.1016/j.jbiomech.2018.12.041DOI Listing
March 2019

Microbiome Analytics of the Gut Microbiota in Patients With Juvenile Idiopathic Arthritis: A Longitudinal Observational Cohort Study.

Arthritis Rheumatol 2019 06 29;71(6):1000-1010. Epub 2019 Apr 29.

Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Objective: To assess the composition of gut microbiota in Italian and Dutch patients with juvenile idiopathic arthritis (JIA) at baseline, with inactive disease, and with persistent activity compared to healthy controls.

Methods: In a multicenter, prospective, observational cohort study, fecal samples were collected at baseline from 78 Italian and 21 Dutch treatment-naive JIA patients with <6 months of disease duration and compared to 107 geographically matched samples from healthy children. Forty-four follow-up samples from patients with inactive disease and 25 follow-up samples from patients with persistent activity were analyzed. Gut microbiota composition was determined by 16S ribosomal RNA-based metagenomics. Alpha- and β-diversity were computed, and log ratios of relative abundance were compared between patients and healthy controls using random forest models and logistic regression.

Results: Baseline samples from Italian patients showed reduced richness compared to healthy controls (P < 0.001). Random forest models distinguished between Italian patient baseline samples and healthy controls and suggested differences between Dutch patient samples and healthy controls (areas under the curve >0.99 and 0.71, respectively). The operational taxonomic units (OTUs) of Erysipelotrichaceae (increased in patients), Allobaculum (decreased in patients), and Faecalibacterium prausnitzii (increased in patients) showed different relative abundance in Italian patient baseline samples compared to controls after controlling for multiple comparisons. Some OTUs differed between Dutch patient samples and healthy controls, but no evidence remained after controlling for multiple comparisons. No differences were found in paired analysis between Italian patient baseline and inactive disease samples.

Conclusion: Our findings show evidence for dysbiosis in JIA patients. Only patient/control status, age, and geographic origin appear to be drivers of the microbiota profiles, regardless of disease activity stage, inflammation, and markers of autoimmunity.
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http://dx.doi.org/10.1002/art.40827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593809PMC
June 2019

Effect of the Inclusion of the Metacarpophalangeal Joints on the Wrist Magnetic Resonance Imaging Scoring System in Juvenile Idiopathic Arthritis.

J Rheumatol 2018 11 15;45(11):1581-1587. Epub 2018 Aug 15.

From the Clinica Pediatrica e Reumatologia, and the Department of Pediatric Radiology, Istituto Giannina Gaslini, Genoa, Italy; Pediatric Rheumatology, Universitair Medisch Centrum (UMC) Utrecht, Wilhelmina Children's Hospital, Utrecht, the Netherlands; Unité romande de rhumatologie pédiatrique, Centre Hospitalier Universitaire Vaudois, Lausanne; Pediatric Department of Southern Switzerland, Bellinzona, Switzerland; Department of Pediatric Radiology, Haukeland University Hospital and Department of Clinical Medicine, Bergen, Norway; Department of Pediatric Rheumatology, Amsterdam Rheumatology and Immunology Center Reade, Amsterdam, the Netherlands; Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università degli studi di Genova, Genoa, Italy.

Objective: To extend the magnetic resonance imaging (MRI) score for assessment of wrist synovitis in juvenile idiopathic arthritis (JIA) by inclusion of the metacarpophalangeal (MCP) joints, and to compare the metric properties of the original and the extended score.

Methods: Wrist MRI of 70 patients with JIA were scored by 3 independent readers according to (1) the wrist component of the rheumatoid arthritis MRI synovitis score (comprising distal radioulnar, radiocarpal, and combined midcarpal and carpometacarpal joints); and (2) an extended score including the MCP joints. Thirty-eight patients had a 1-year MRI followup. The concordance between the readers [intraclass correlation coefficient (ICC), 95% limits of agreement (LOA), and weighted Cohen's κ], correlations with clinical variables (Spearman's ϱ), and the sensitivity to change [standardized response mean (SRM)] were calculated for both scores.

Results: The interreader agreement was moderate for the original score (ICC 0.77; 95% CI 0.68-0.84) and good for the extended score (ICC 0.86; 95% CI 0.80-0.91). Using 95% LOA, the aggregate score variability was less favorable with relatively wide LOA. Weighted Cohen's κ of the individual joints indicated good agreement for the original score and good to excellent agreement for the extended score. Correlations with clinical variables reflecting disease activity improved for the extended score and its SRM was higher compared to that of the original score.

Conclusion: The extended score showed better reliability, construct validity, and sensitivity to change than the original. Inclusion of the MCP joints should be considered for a more accurate assessment of disease activity and treatment efficacy in JIA.
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http://dx.doi.org/10.3899/jrheum.171246DOI Listing
November 2018

The role of imaging in juvenile idiopathic arthritis.

Expert Rev Clin Immunol 2018 08 20;14(8):681-694. Epub 2018 Jul 20.

c Direzione Scientifica Istituto Giannina Gaslini , Genova Italy.

Introduction: The prognosis of juvenile idiopathic arthritis (JIA) has changed dramatically due to the availability of novel drugs. Prompt diagnosis and treatment are essential to prevent permanent joint damage. As a result, methods to improve JIA diagnosis and prognosis are of high priority to tailor treatment strategies and maximize their efficacy. Musculoskeletal ultrasound and magnetic resonance imaging are more sensitive than clinical examination and radiography in the detection of joint involvement and might play a substantial role to optimize the management of JIA. Areas covered: This review compiles an inventory of potential uses of imaging studies in the modern practice of pediatric rheumatology, together with a critical analysis of the major challenges that are still to be addressed. Imaging appearance of normal growth-related changes of the musculoskeletal system will be discussed. Expert commentary: Knowledge of the evolving patterns of skeletal maturity is paramount to define pathological findings and avoid misinterpretations. Establishing a novel radiological algorithm for a rational use of imaging in JIA is of high priority to allow a speedier integration of imaging into the clinical workflow and decision-making process.
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http://dx.doi.org/10.1080/1744666X.2018.1496019DOI Listing
August 2018

Prediction of inactive disease in juvenile idiopathic arthritis: a multicentre observational cohort study.

Rheumatology (Oxford) 2018 10;57(10):1752-1760

Paediatric Rheumatology, Istituto Giannina Gaslini, Genoa, Italy.

Objectives: To predict the occurrence of inactive disease in JIA in the first 2 years of disease.

Methods: An inception cohort of 152 treatment-naïve JIA patients with disease duration <6 months was analysed. Potential predictors were baseline clinical variables, joint US, gut microbiota composition and a panel of inflammation-related compounds in blood plasma. Various algorithms were employed to predict inactive disease according to Wallace criteria at 6-month intervals in the first 2 years. Performance of the models was evaluated using the split-cohort technique. The cohort was analysed in its entirety, and separate models were developed for oligoarticular patients, polyarticular RF negative patients and ANA positive patients.

Results: All models analysing the cohort as a whole showed poor performance in test data [area under the curve (AUC): <0.65]. The subgroup models performed better. Inactive disease was predicted by lower baseline juvenile arthritis DAS (JADAS)-71 and lower relative abundance of the operational taxonomic unit Mogibacteriaceae for oligoarticular patients (AUC in test data: 0.69); shorter duration of morning stiffness, higher haemoglobin and lower CXCL-9 levels at baseline for polyarticular RF negative patients (AUC in test data: 0.69); and shorter duration of morning stiffness and higher baseline haemoglobin for ANA positive patients (AUC in test data: 0.72).

Conclusion: Inactive disease could not be predicted with satisfactory accuracy in the whole cohort, likely due to disease heterogeneity. Interesting predictors were found in more homogeneous subgroups. These need to be validated in future studies.
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http://dx.doi.org/10.1093/rheumatology/key148DOI Listing
October 2018

Imaging of the hip in juvenile idiopathic arthritis.

Pediatr Radiol 2018 06 8;48(6):811-817. Epub 2018 May 8.

Department of Radiology, Haukeland University Hospital, Bergen, Norway.

Hip involvement is common and estimated to occur in approximately 35-63% of children with juvenile idiopathic arthritis (JIA). It is more prevalent in the aggressive systemic subtypes, with irreversible changes occurring as early as within 5 years of diagnosis. Whilst clinical parameters and joint examination can be useful for assessing disease severity, subclinical disease is known to exist and delayed treatment may herald a lifetime of disability and pain. Early recognition of JIA changes is therefore crucial in determining treatment options. Validated scoring systems in the radiologic assessment of the hip for clinical drug trials may inform treatment outcomes, although robust tools for analysis are still lacking. This review article details the modalities utilised for imaging the hip in children with JIA with particular efforts focused upon reliability and validity in their assessment of joint disease. We conclude with a short literature review on the potential future techniques being developed for hip joint imaging in JIA.
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http://dx.doi.org/10.1007/s00247-017-4022-7DOI Listing
June 2018

Juvenile idiopathic arthritis - the role of imaging from a rheumatologist's perspective.

Pediatr Radiol 2018 06 8;48(6):785-791. Epub 2018 May 8.

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

Alongside recent advances in treatment strategies for juvenile idiopathic arthritis (JIA), paediatric rheumatologists have taken increasing interest in the use of imaging. Magnetic resonance imaging (MRI) and musculoskeletal ultrasound, by providing more detailed information on disease activity than clinical examination and conventional radiography (CR), have become helpful diagnostic and managerial tools. The growing skeleton, however, with changing appearances over time, is still challenging in the establishment of valid scoring systems for pathological changes. Defining child- and age-specific reference standards is therefore a highly prioritized issue. The aim of this article is to raise awareness among radiologists of the substantial role that imaging can play to optimize the management of JIA patients and to describe the state-of-the-art validation process of imaging as an outcome measure. A closer collaboration between radiologists and pediatric rheumatologists is crucial to define a scheduled workflow for imaging in JIA.
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http://dx.doi.org/10.1007/s00247-017-4014-7DOI Listing
June 2018

Current status of wrist imaging in juvenile idiopathic arthritis.

Pediatr Radiol 2018 06 8;48(6):801-810. Epub 2018 May 8.

Department of Radiology and Intervention Unit for Paediatric Radiology, Oslo University, Oslo, Norway.

Wrist involvement occurs in about one-quarter of patients diagnosed with juvenile idiopathic arthritis (JIA), increasing to 40% 5 years after diagnosis. The imaging appearances, both for active inflammation and permanent change, differ from those seen in adult rheumatoid arthritis; therefore, a child-specific approach is crucial for correct assessment. In this review article, we provide an update on the current status for imaging wrist JIA, with a focus on evidence-based practice.
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http://dx.doi.org/10.1007/s00247-017-4063-yDOI Listing
June 2018

A novel radiographic scoring system for growth abnormalities and structural change in children with juvenile idiopathic arthritis of the hip.

Pediatr Radiol 2018 08 1;48(8):1086-1095. Epub 2018 May 1.

Department of Pediatric Radiology, Haukeland University Hospital, Bergen, Norway.

Background: Approximately 20-50% of children with juvenile idiopathic arthritis (JIA) have hip involvement within 6 years of diagnosis. Scoring systems for hip-related radiographic changes are lacking.

Objective: To examine precision of potential radiographic variables and to suggest a scoring system.

Materials And Methods: We reviewed a set of 75 pelvic radiographs from 75 children with JIA hip involvement across two European centres. We assessed findings of (1) destructive change and (2) growth abnormality, according to a pre-defined scoring system. All radiographs were scored independently by two sets of radiologists. One set scored the radiographs a second time. We used kappa statistics to rate inter- and intra-observer variability.

Results: Assessment of erosions of the femoral head, femoral neck and the acetabulum showed moderate to good agreement for the same reader (kappa of 0.5-0.8). The inter-reader agreement was, however, low (kappa of 0.1-0.3). There was moderate to high agreement for the assessment of femoral head flattening (kappa of 0.6-0.7 for the same reader, 0.3-0.7 between readers). Joint space narrowing showed moderate to high agreement both within and between observers (kappa of 0.4-0.8). Femoral neck length and width measurements, the centrum-collum-diaphysis angle, and trochanteric-femoral head lengths were relatively precise, with 95% limits of agreement within 10-15% of the observer average.

Conclusion: Several radiographic variables of destructive and growth abnormalities in children with hip JIA have reasonable reproducibility. We suggest that future studies on clinical validity focus on assessing only reproducible radiographic variables.
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http://dx.doi.org/10.1007/s00247-018-4136-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061460PMC
August 2018

ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum.

Eur J Paediatr Neurol 2018 Jul 12;22(4):725-728. Epub 2018 Apr 12.

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

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by fragmented and mineralized elastic fibers in the mid-dermis of the skin, eye, digestive tract and cardiovascular system. Clinical presentation includes typical skin lesions, ocular angioid streaks, and multisystem vasculopathy. The age of onset varies considerably from infancy to old age, but the diagnosis is usually made in young adults due to frequent absence of pathognomonic skin and ocular manifestations in early childhood. We report two children with PXE presenting with isolated multisystem vasculopathy and early-onset stroke. In the first patient, diagnosis was delayed until typical dermatologic alterations appeared; in the second patient, next-generation sequencing (NGS) study led to early diagnosis and specific follow-up, underlying the crucial role in idiopathic pediatric stroke of early genetic testing using NGS-based panels.
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http://dx.doi.org/10.1016/j.ejpn.2018.04.002DOI Listing
July 2018

Innovative Research Design to Meet the Challenges of Clinical Trials for Juvenile Dermatomyositis.

Curr Rheumatol Rep 2018 04 10;20(5):29. Epub 2018 Apr 10.

Università degli Studi di Genova, Genoa, Italy.

Purpose Of Review: This paper aims to provide a summary of the recent therapeutic advances and the latest research on outcome measures for clinical trials in juvenile dermatomyositis (JDM).

Recent Findings: Recent randomized controlled trials (RCTs) have demonstrated the superiority of the combination of prednisone with methotrexate over other conventional therapies and the potential effectiveness of rituximab in refractory cases. A multinational project has led to develop new criteria for the definition of minimal, moderate, and major improvement in future JDM clinical trials. This effort has been paralleled by the establishment of criteria for clinically inactive disease. The validation of the first composite disease activity score for JDM is in progress. The new outcome measures will increase the reliability of assessment of clinical response in JDM clinical trials and foster future multinational RCTs aimed to investigate novel treatment strategies for refractory forms of JDM.
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http://dx.doi.org/10.1007/s11926-018-0734-4DOI Listing
April 2018

Imaging in juvenile idiopathic arthritis - international initiatives and ongoing work.

Pediatr Radiol 2018 06 13;48(6):828-834. Epub 2018 Jan 13.

Department of Radiology, Haukeland University Hospital, Bergen, Norway.

Imaging is increasingly being integrated into clinical practice to improve diagnosis, disease control and outcome in children with juvenile idiopathic arthritis. Over the last decades several international groups have been launched to standardize and validate different imaging techniques. To enhance transparency and facilitate collaboration, we present an overview of ongoing initiatives.
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http://dx.doi.org/10.1007/s00247-017-4054-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953998PMC
June 2018

Ultrasound changes in synovial abnormalities induced by treatment in juvenile idiopathic arthritis.

Clin Exp Rheumatol 2018 Mar-Apr;36(2):329-334. Epub 2017 Nov 28.

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

Objectives: To investigate the capacity of ultrasound (US) to detect improvement of synovial abnormalities induced by treatment in juvenile idiopathic arthritis (JIA).

Methods: Eighty-three joints (33 knees, 22 tibiotalar, 10 wrists, 9 elbows, 9 subtalar joints) of 33 patients with new-onset JIA were assessed by US at study entry and 6 months after a therapeutic intervention. Each joint was scored for grey-scale (GS) and power Doppler (PD) abnormalities according to a 4-point semiquantitative scale. Pre- and post-treatment US scores were compared and the sensitivity to change of GSUS and PDUS was estimated. Clinical response was assessed using the ACR paediatric (ACRp) response criteria.

Results: Seventeen patients (51.5%) underwent intra-articular corticosteroid injection (IACI) only, 15 (45.5%) were given IACI and systemic medications, and 1 (3.0%) was started with systemic therapy alone. Both GSUS and PDUS scores improved significantly (p<0.0001) from baseline to follow-up. US revealed strong sensitivity to change with standardised response mean for GSUS and PDUS of 2.44 and 1.23, respectively. At the follow-up visit, 13/20 (65.0%) joints with residual US abnormalities were judged in remission on clinical grounds. Six/21 (28.6%) patients who were ACRp90 responders did not display complete resolution of synovial abnormalities on US.

Conclusions: US is a sensitive tool to assess therapeutic response in patients with JIA. Subclinical disease on US is common in joints with clinically-defined remission. An ACRp90 response may not be coupled with complete resolution of synovial abnormalities on US. Further studies are needed to establish the impact of US on therapeutic decision-making in JIA.
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June 2018

Imaging of Childhood Vasculitis.

Radiol Clin North Am 2017 Sep 23;55(5):1131-1143. Epub 2017 Jun 23.

Radiologia III, IRCCS San Martino-IST, DISSAL, Università di Genova, Via Pastore 1, I-16132, Genova, Italy. Electronic address:

Pediatric vasculitides are rare conditions that can represent a diagnostic challenge because symptoms are usually aspecific and variable. Symptoms are related to the size of the involved vessel, extension of disease, and organs affected. The outcome is closely linked to an early diagnosis and proper treatment. Diagnostic imaging allows visualization of the involvement of large-size and medium-size vessels and assesses end-organ changes and response to therapy, thus playing a pivotal role in the diagnosis and treatment. This article explores the general features of pediatric vasculitis and discusses the imaging approach and the most common diagnostic findings.
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http://dx.doi.org/10.1016/j.rcl.2017.05.001DOI Listing
September 2017

Biologics in juvenile idiopathic arthritis: a narrative review.

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

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

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

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

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study.

Ann Rheum Dis 2017 10 18;76(10):1648-1656. Epub 2017 May 18.

Division of Human Genetics, G. Gaslini Institute, Genova, Italy.

Objectives: To analyse the prevalence of mutations in patients diagnosed with early onset livedo reticularis and/or haemorrhagic/ischaemic strokes in the context of inflammation or polyarteritis nodosa (PAN). Forty-eight patients from 43 families were included in the study.

Methods: Direct sequencing of was performed by Sanger analysis. Adenosine deaminase 2 (ADA2) enzymatic activity was analysed in monocyte isolated from patients and healthy controls incubated with adenosine and with or without an ADA1 inhibitor.

Results: Biallelic homozygous or compound heterozygous mutations were detected in 15/48 patients. A heterozygous disease-associated mutation (p.G47V) was observed in two affected brothers. The mean age of onset of the genetically positive patients was 24 months (6 months to 7 years). Ten patients displayed one or more cerebral strokes during their disease course. Low immunoglobulin levels were detected in six patients. Thalidomide and anti-TNF (tumour necrosis factor) blockers were the most effective drugs. Patients without mutations had a later age at disease onset, a lower prevalence of neurological and skin manifestations; one of these patients displayed all the clinical features of adenosine deaminase 2deficiency (DADA2) and a defective enzymatic activity suggesting the presence of a missed mutation or a synthesis defect.

Conclusions: DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.
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http://dx.doi.org/10.1136/annrheumdis-2016-210802DOI Listing
October 2017

Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial.

Lancet 2017 03 3;389(10072):909-916. Epub 2017 Feb 3.

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

Background: Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy.

Methods: We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70.

Findings: Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event.

Interpretation: Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis.

Funding: Italian Agency of Drug Evaluation.
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http://dx.doi.org/10.1016/S0140-6736(17)30065-XDOI Listing
March 2017
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