Defining criteria for disease activity states in systemic juvenile idiopathic arthritis based on the systemic Juvenile Arthritis Disease Activity Score.

OBJECTIVE: To develop and validate cutoff values in the systemic Juvenile Arthritis Disease Activity Score 10 (sJADAS10) that distinguish the states of inactive disease (ID), minimal disease activity (MiDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with systemic juvenile idiopathic arthritis (sJIA), based on subjective disease state assessment by the treating pediatric rheumatologist. METHODS: The cutoffs definition cohort was composed of 400 patients enrolled at 30 pediatric rheumatology centers in 11 countries. Using the subjective physician rating as an external criterion, 6 methods were applied to identify the cutoffs: mapping, calculation of percentiles of cumulative score distribution, Youden index, 90% specificity, maximum agreement, and ROC curve analysis. Sixty percent of the patients were assigned to the definition cohort and 40% to the validation cohort. Cutoff validation was conducted by assessing discriminative ability. RESULTS: The sJADAS10 cutoffs that separated ID from MiDA, MiDA from MoDA, and MoDA from HDA were ≤ 2.9, ≤ 10, and > 20.6. The cutoffs discriminated strongly among different levels of pain, between patients with or without morning stiffness, and between patients whose parents judged their disease status as remission or persistent activity/flare or were satisfied or not satisfied with current illness outcome. CONCLUSION: The sJADAS cutoffs revealed good metrologic properties in both definition and validation cohorts, and are therefore suitable for use in clinical trials and routine practice.

Defining criteria for disease activity states in juvenile dermatomyositis based on the Juvenile Dermatomyositis Activity Index.

OBJECTIVES: To develop and validate the cut-offs in the Juvenile DermatoMyositis Activity Index (JDMAI) to distinguish the states of inactive disease (ID), low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA) in children with juvenile dermatomyositis (JDM). METHODS: For cut-off definition, data from 139 patients included in a randomised clinical trial were used. Among the six versions of the JDMAI, JDMA1 (score range 0-40) and JDMAI2 (score range 0-39) were selected. Optimal cut-offs were determined against external criteria by calculating different percentiles of score distribution and through receiver operating characteristic curve analysis. External criteria included the modified Pediatric Rheumatology International Trials Organization (PRINTO) criteria for clinically ID in JDM (for ID) and PRINTO levels of improvement in the clinical trial (for LDA and HDA). MDA cut-offs were set at the score interval between LDA and HDA cut-offs. Cut-off validation was conducted by assessing construct and discriminative ability in two cohorts including a total of 488 JDM patients. RESULTS: The calculated JDMAI1 cut-offs were ≤2.4 for ID, ≤6.6 for LDA, 6.7-11 for MDA and >11 for HDA. The calculated JDMAI2 cut-offs were ≤5.2 for ID, ≤8.5 for LDA, 8.6-11.3 for MDA and >11.3 for HDA. The cut-offs discriminated strongly among disease activity states defined subjectively by caring physicians and parents, parents' satisfaction or non-satisfaction with illness outcome, levels of pain, fatigue, physical functional impairment and physical well-being. CONCLUSIONS: Both JDMAI1 and JDMAI2 cut-offs revealed good metrologic properties in validation analyses and are, therefore, suited for application in clinical practice and research.

Clinical features, treatment and outcomes of Italian children with enthesitis-related arthritis and juvenile psoriatic arthritis: a cross-sectional cohort study.

OBJECTIVES: Limited information is available on the clinical features, treatment modalities and outcomes of the juvenile idiopathic arthritis (JIA) categories of enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA). This study was aimed to describe the characteristics of Italian children with ERA and JPsA and to compare them with those of patients with the other categories of JIA. METHODS: Patients were part of a multinational sample included in a study aimed to investigate the prevalence of disease categories, treatment approaches, and disease status in patients from across different geographical areas (EPOCA Study). All patients underwent a retrospective assessment, based on the review of clinical chart, and a cross-sectional evaluation, which included assessment of physician- and parent-reported outcomes and laboratory tests, and recording of ongoing therapies. RESULTS: Of the 9081 children with JIA enrolled in the EPOCA Study, 1300 were recruited at 18 paediatric rheumatology centres in Italy. 45 (3.5%) had ERA and 49 (3.8%) had JPsA. Several remarkable differences in demographic features and frequency of articular and extra-articular manifestations, disease damage, impairment in physical function and health-related quality of life, school-related problems, comorbidities, and ongoing treatments were observed between ERA and JPsA and the other JIA categories. CONCLUSIONS: We described the characteristics of Italian children with ERA and JPsA and highlighted their peculiarities and their differences from the other JIA subsets. These data provide useful insights for future revisions of JIA classification and a benchmarking against which the features from other cohorts may be compared.

Skin manifestations help identifying different phenotypes of paediatric SAPHO syndrome.

OBJECTIVES: to evaluate whether the heterogeneous skin manifestations might influence the disease presentation and outcome of a cohort of SAPHO children. METHODS: the clinical, serological, imaging and therapeutic data of 14 SAPHO patients, followed between 2001 and 2022 at the Unit for Autoinflammatory diseases at the Gaslini Hospital, were reviewed. According to their cutaneous manifestations, patients were divided into 2 groups: the acne-hidradenitis suppurativa (HS) and the Palmo-Plantar Pustulosis (PPP) group. Data were retrieved from the Eurofever database. RESULTS: all patients presented bone involvement characterized by Chronic Recurrent multifocal Osteomyelitis (CRMO): 8 patients presented acne-HS while 6 patients had PPP. In the PPP group, all patients were female, characterized by a prepuberal disease onset with osteoarticular manifestations, followed by the appearance of PPP in the following 6 months. This group responded well to the treatments. In the acne-HS group, 7/8 patients were male: the disease onset was characterized by skin manifestations in pubertal age, followed by osteoarticular manifestations in the following year. This group presented a severe refractory skin disease that required in most cases the addition of biological therapies. A literature review confirmed our data highlighting the association males-acne-puberal age and female-PPP-prepuberal age. CONCLUSION: paediatric SAPHO patients should be mainly stratified according to their skin involvement. In fact, our data suggest that two different skin phenotypes may be identified in SAPHO: the first is constituted by prepuberal females with PPP and a prevalent osteoarticular involvement, while the second by puberal males with a difficult-to-treat acne-HS.

Treat-to-Target in Pediatric Rheumatic Diseases.

PURPOSE OF REVIEW: To summarize the current evidence on the adoption of the treat-to-target (T2T) strategy in pediatric rheumatic diseases (PRD). RECENT FINDINGS: The recent advances in the management of PRD have markedly increased the ability to achieve disease remission. Complete disease quiescence is regarded as the ideal therapeutic goal because its attainment leads to lesser long-term damage and physical disability, and to optimization of quality of life. Studies in adult rheumatic diseases have shown that patient outcomes are improved if complete suppression of the inflammatory process is aimed for by frequent adjustments of therapy according to quantitative indices. This approach, which underlies the T2T concept, has been applied in strategic trials in rheumatoid arthritis (RA). Furthermore, recommendations for the T2T have been issued for RA and other adult rheumatic diseases. There is currently a growing interest for the introduction of T2T in PRD, and recommendations for treating juvenile idiopathic arthritis (JIA) to target were promulgated. A similar initiative has been undertaken for childhood-onset systemic lupus erythematosus. Preliminary therapeutic studies have explored the T2T design in JIA. The T2T strategy is a modern therapeutic approach that holds the promise of improving the outcomes in patients with PRD.

Juvenile Psoriatic Arthritis: Myth or Reality? An Unending Debate.

Juvenile psoriatic arthritis (JPsA) accounts for 1-7% of all cases of juvenile idiopathic arthritis (JIA) and its definition has been a matter of controversy among pediatric rheumatologists for many years. The traditional attribution of JPsA to the spondyloarthropathy group was challenged in the early 1990s, whereas the recent demonstrations of its heterogenous nature have led to questions about its identification as a distinct category in JIA classification. It has been shown that children with the phenotype of JPsA can be divided in two subgroups, one presenting with the features of early-onset ANA-positive JIA, and another that belongs to the spectrum of spondyloarthropathies. The few studies that have compared the clinical characteristics and genetic determinants of JPsA with those of the other JIA categories have obtained contrasting findings. The debate on the categorization of JPsA as a distinct entity within JIA classification is still ongoing and has prompted the revision of its current classification.

Standardized nailfold capillaroscopy in children with rheumatic diseases: a worldwide study.

OBJECTIVES: To standardly assess and describe nailfold videocapillaroscopy (NVC) assessment in children and adolescents with juvenile rheumatic and musculoskeletal diseases (jRMD) vs healthy controls (HCs). MATERIAL AND METHODS: In consecutive jRMD children and matched HCs from 13 centres worldwide, 16 NVC images per patient were acquired locally and read centrally per international consensus standard evaluation of the EULAR Study Group on Microcirculation in Rheumatic Diseases. A total of 95 patients with JIA, 22 with JDM, 20 with childhood-onset SLE (cSLE), 13 with juvenile SSc (jSSc), 21 with localized scleroderma (lSc), 18 with MCTD and 20 with primary RP (PRP) were included. NVC differences between juvenile subgroups and HCs were calculated through multivariable regression analysis. RESULTS: A total of 6474 images were assessed from 413 subjects (mean age 12.1 years, 70.9% female). The quantitative NVC characteristics were significantly lower or higher in the following subgroups compared with HCs: for density: lower in jSSc, JDM, MCTD, cSLE and lSc; for dilations: higher in jSSc, MCTD and JDM; for abnormal shapes: higher in JDM and MCTD; for haemorrhages: higher in jSSc, MCTD, JDM and cSLE. The qualitative NVC assessment of JIA, lSc and PRP did not differ from HCs, whereas the cSLE and jSSc, MCTD, JDM and cSLE subgroups showed more non-specific and scleroderma patterns, respectively. CONCLUSIONS: This analysis resulted from a pioneering registry of NVC in jRMD. The NVC assessment in jRMD differed significantly from HCs. Future prospective follow-up will further elucidate the role of NVC in jRMD.

Emerging therapies for juvenile arthritis: agents in early clinical trials.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory rheumatic condition in childhood. The management of JIA has been revolutionized thanks to the development of new powerful drugs and the possibility to conduct controlled clinical trials with support from legislative initiatives and availability of international collaborative networks. Trials are still needed in children because we now have new drugs related to specific JIA category. AREAS COVERED: The review is centered on the latest achievements in the field, focusing on new investigational drugs which are currently or have been recently tested for JIA treatment, encompassing agents in early phase of clinical development. EXPERT OPINION: Despite the tremendous improvement witnessed in the field of JIA treatment in the past 20 years, there are still many unmet needs to be prioritized. Studies on disease pathogenesis will hopefully help in the identification of new treatment targets for individual JIA categories, that could possibly favor a stricter disease control and contribute to solve the issue of refractory JIA. Novel strategies aimed at the prevention of the risk of long-term joint damage are also desirable, as well as the discovery of predictive biomarkers for treatment efficacy and safety in the individual patient.

Drivers of non-zero physician global scores during periods of inactive disease in juvenile idiopathic arthritis.

OBJECTIVE: To investigate the frequency in which the physician provides a global assessment of disease activity (PhGA) >0 and an active joint count (AJC)=0 in children with juvenile idiopathic arthritis (JIA) and search for determinants of divergence between the two measures. METHODS: Data were extracted from a multinational cross-sectional dataset of 9966 patients who had JIA by International League of Associations for Rheumatology criteria, were recruited between 2011 and 2016, and had both PhGA and AJC recorded by the caring paediatric rheumatologist at the study visit. Determinants of discordance between PhGA>0 and AJC=0 were searched for by multivariable logistic regression and dominance analyses. RESULTS: The PhGA was scored >0 in 1647 (32.3%) of 5103 patients who had an AJC of 0. Independent associations with discordant assessment were identified for tender or restricted joint count >0, history of enthesitis, presence of active uveitis or systemic features, enthesitis-related or systemic arthritis, increased acute phase reactants, pain visual analogue scale (VAS)>0, and impaired physical or psychosocial well-being. In dominance analysis, tender joint count accounted for 35.43% of PhGA variance, followed by pain VAS>0 (17.72%), restricted joint count >0 (16.14%) and physical health score >0 (11.42%). CONCLUSION: We found that many paediatric rheumatologists did not mark a score of 0 for patients who they found not to have active joints. The presence of pain in joints not meeting the definition of active joint used in JIA was the main determinant of this phenomenon.

Disparities in the prevalence of clinical features between systemic juvenile idiopathic arthritis and adult-onset Still's disease.

OBJECTIVE: To compare clinical features and treatments of patients with systemic JIA (sIJA) and adult-onset Still's disease (AOSD). METHODS: The clinical charts of consecutive patients with sJIA by International League of Association of Rheumatology criteria or AOSD by Yamaguchi criteria were reviewed. Patients were seen at a large paediatric rheumatology referral centre or at 10 adult rheumatology academic centres. Data collected included clinical manifestations, inflammation biomarkers, systemic score, macrophage activation syndrome (MAS), parenchymal lung disease, disease course, disability, death and medications administered. RESULTS: A total of 166 patients (median age at diagnosis 5 years) with sJIA and 194 patients with AOSD (median age at diagnosis 41 years) were included. The frequency of fever, rash, arthralgia, abdominal pain, MAS, parenchymal lung disease and increased acute phase reactants and ferritin were comparable between the two cohorts. Patients with sJIA had a higher prevalence of arthritis, whereas patients with AOSD had experienced leucocytosis and extra-articular organ involvement more frequently. Patients with AOSD were given more commonly low-dose corticosteroids, whereas biologic DMARDs were administered first-line more frequently in patients with sJIA. CONCLUSION: We found remarkable disparities in the prevalence of clinical manifestations between the two illnesses, which may partly depend on their classification by different criteria.

Multisystem Inflammatory Syndrome in Children: Unique Disease or Part of the Kawasaki Disease Spectrum?

One of the most intriguing and mysterious phenomena observed during the COVID-19 pandemic has been represented by the occurrence of the multisystem inflammatory syndrome in children and adolescents (MIS-C). Patients with this condition have some overlapping signs and symptoms with those of Kawasaki disease (KD), but also display clinical features that are uncommon or less frequent in this illness, such as diarrhea, abdominal pain and myocardial involvement. The sickest patients may develop multiorgan failure and shock, usually due to myocarditis. Management is based on the administration of intravenous immunoglobulin, glucocorticoids and, in the most severe instances, anakinra. It is still debated whether MIS-C and KD represent different illnesses or are part of the same disease spectrum. The aim of the present review is to analyze critically the evidence in favor of the latter hypothesis and to provide the authors' personal interpretation of the relationship between the two conditions.

Novel biomarkers for prediction of outcome and therapeutic response in juvenile idiopathic arthritis.

INTRODUCTION: The search for biomarkers in juvenile idiopathic arthritis (JIA) is a promising and rapidly expanding field of investigation. The biomarkers identified so far may help to dissect the clinical heterogeneity of the illness, measure the level of disease activity, predict clinical remission, relapse, response to medications, course over time, complications, and forestall disease flares. AREAS COVERED: We provide a summary of the most recent advances in the development and application of biomarkers in JIA. We performed a PubMed search for significant articles combining predetermined keywords related to biomarkers in non-systemic and systemic JIA, chronic uveitis, and macrophage activation syndrome (MAS). The biomarkers available or under study are presented and discussed separately for non-systemic and systemic subtypes and for the two main disease complications, uveitis and MAS. EXPERT OPINION: The incorporation of valid and reliable biomarkers in standard clinical care may help to design better patient-tailored treatment regimens and to improve the therapeutic strategies based on the treat-to-target approach. The establishment of biomarkers that predict the risk of disease flare may lead to define the optimal modalities for treatment discontinuation after the achievement of clinical remission.

A prediction rule for polyarticular extension in oligoarticular-onset juvenile idiopathic arthritis.

OBJECTIVES: To search for predictors of polyarticular extension in children with oligoarticular-onset juvenile idiopathic arthritis (JIA) and to develop a prediction model for an extended course. METHODS: The clinical charts of consecutive patients with oligoarticular-onset JIA and ≥2 years of disease duration were reviewed. Predictor variables included demographic data, number and type of affected joints, presence of iridocyclitis, laboratory tests including antinuclear antibodies, and therapeutic interventions in the first 6 months. Joint examinations were evaluated to establish whether after the first 6 months of disease patients had persistent or extended course (i.e. involvement of 4 or less, or 5 or more joints). Statistics included univariable and multivariable analyses. Regression coefficients (ß) of variables that entered the best-fitting logistic regression model were converted and summed to obtain a "prediction score" for an extended course. RESULTS: A total of 480 patients with a median disease duration of 7.4 years were included. 61.2% had persistent oligoarthritis, whereas 38.8% experienced polyarticular extension. On multivariable analysis, independent correlations with extended course were identified for the presence of ≥2 involved joints and a CRP >0.8 mg/dl in the first 6 months. The prediction score ranged from 0 to 6 and its cut-off that discriminated best between patients who had or did not have polyarticular extension was >1. Sensitivity and specificity were 59.6 and 79.8, respectively. CONCLUSIONS: The number of affected joints and the CRP level in the first 6 months were the strongest predictors of polyarticular extension in our children with oligoarticular-onset JIA.

Outcome Scores in Pediatric Rheumatology.

PURPOSE OF REVIEW: Providing a summary of the latest research on outcome measures in juvenile idiopathic arthritis, childhood -onset systemic lupus erythematosus, and juvenile dermatomyositis. RECENT FINDINGS: A rational management of patients with pediatric rheumatic diseases requires the regular assessment of the level of disease activity and damage, as well as the evaluation of therapeutic response through validated and standardized outcome measures. Ideally, such tools should be simple, feasible, and easily applicable in routine care. Recently, there has been a great deal of effort to refine existing tools and devise novel outcome measures, aiming to address the various aspects of disease impact and to improve the reliability of research studies and clinical trials. The newest outcome tools in pediatric rheumatology have markedly enlarged the spectrum of health domains assessable in a standardized way, thus increasing the reliability of evaluation of clinical response and fostering future clinical trials.

Pediatric Antiphospholipid Syndrome: from Pathogenesis to Clinical Management.

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 ß2 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.

Is Anti-NXP2 Autoantibody a Risk Factor for Calcinosis and Poor Outcome in Juvenile Dermatomyositis Patients? Case Series.

Juvenile dermatomyositis (JDM) has a wide spectrum of clinical presentations. In the last decade, several myositis-specific antibodies have been identified in patients with JDM and connected with specific organ involvement or specific clinical picture. It has been published that the presence of anti-NXP2 autoantibodies presents a risk for calcinosis in patients with JDM. We aimed to investigate the prevalence of calcinosis and response to the treatment in JDM patients with anti-NXP2. In a retrospective, multinational, multicenter study, data on 26 JDM (19 F, 7 M) patients with positive anti-NXP2 were collected. The mean age at disease presentation was 6.5 years (SD 3.7), the median diagnosis delay was 4 months (range 0.5-27 months). Patients were divided into two groups (A and B) based on the presence of calcinosis, which occurred in 42% of anti-NXP2 positive JDM patients (group A). Four patients already had calcinosis at presentation, one developed calcinosis after 4 months, and 6 developed calcinosis later in the disease course (median 2 years, range 0.8-7.8). The differences in laboratory results were not statistically significant between the groups. The mean age at disease presentation (5.2/7.5 years) trended toward being younger in group A. Children with calcinosis were treated with several combinations of drugs. In four cases, rituximab and, in one case, anti-TNF alpha agents were used successfully. Disease outcome (by evaluation of the treating physician) was excellent in four, good in two, stable in two, and poor in three patients. None of the patients from group B had a poor disease outcome. In conclusion, JDM patients with anti-NXP2 are prone to develop calcinosis, especially if they present with the disease early, before 5 years of age. The development of calcinosis is associated with worse disease outcomes. The combination of several immunomodulatory drugs and biologic drugs can stop calcinosis progression; however, there are no evidence-based therapies for treating calcinosis in JDM patients.

Determinants of Discordance Between Criteria for Inactive Disease and Low Disease Activity in Juvenile Idiopathic Arthritis.

OBJECTIVE: To assess concordance among criteria for inactive disease (ID) and low disease activity (LDA) in juvenile idiopathic arthritis (JIA) and to seek factors driving discordance. METHODS: The frequency of fulfillment of existing criteria was evaluated in information on 10,186 patients extracted from 3 cross-sectional data sets. Patients were divided up according to the functional phenotypes of oligoarthritis and polyarthritis. Concordance between criteria was examined using weighted Venn diagrams. The role of each individual component in explaining discordance between criteria was assessed by calculating the absolute number and percentage of instances in which the component was responsible for discrepancy between definitions. RESULTS: Criteria for ID were met by 28.6-41.1% of patients with oligoarthritis and by 24.0-33.4% of patients with polyarthritis. Criteria for LDA were met by 44.8-62.4% of patients with oligoarthritis and by 44.6-50.4% of patients with polyarthritis. There was a 57.9-62.3% overlap between criteria for ID and a 67.9-85% overlap between criteria for LDA. Parent and physician global assessments and acute-phase reactants were responsible for the majority of instances of discordance among criteria for ID (8.7-15.5%, 10.0-12.3%, and 10.8-17.3%, respectively). CONCLUSION: We found fair concordance between criteria for ID and LDA in JIA, with the main drivers of discordance for ID being physician and parent global assessments and acute-phase reactants. This observation highlights the need for further studies aimed to evaluate the impact of subjective physician and parent perception of disease remission and of laboratory measures of inflammatory activity on the definition of ID.

Analysis of arthritis flares after achievement of inactive disease with methotrexate monotherapy in juvenile idiopathic arthritis.

OBJECTIVES: To investigate the frequency of arthritis flare and factors affecting occurrence of flare in children with juvenile idiopathic arthritis (JIA) who achieved inactive disease (ID) with methotrexate (MTX) monotherapy. METHODS: A total of 217 patients were included. The modality of treatment discontinuation, time of MTX withdrawal, and disease course were examined retrospectively. For each patient, the first episode of ID after MTX start was evaluated. Patient follow-up was censored at occurrence of flare or at last visit with persistent ID. RESULTS: 170 patients (78.3%) had arthritis flare after a median of 1.6 years, whereas 47 (21.7%) maintained ID until last visit, after a median of 3 years. 54.2% of patients had discontinued MTX after ID, whereas 45.8% were still receiving MTX at the time of study censoring. Among patients who had MTX withdrawn, the median interval between ID and MTX stop was 1.5 years. Occurrence of flare was more common in patients who were still receiving MTX at study censoring than in those who had discontinued MTX (p<0.001). Most patients (78.8%) had MTX tapered over time by increasing the interval between doses. Tapering modality was comparable between patients with flare and persistent ID. Only 7.7% of the patients had a biologic DMARD started at the time of flare. CONCLUSIONS: Our results confirm that children with JIA who achieve ID with MTX monotherapy have a high risk of arthritis flare. The risk of flare was independent of withdrawal strategy. Most flare episodes were not treated with biologic therapy.