Insights into the clinical presentation of juvenile systemic lupus erythematosus: the PRAGMA monocentric cohort of 177 patients.

OBJECTIVES: The aim of this work is to describe the clinical manifestations at onset and during follow-up in a monocentric cohort of patients with juvenile systemic lupus erythematosus (jSLE) from the Paediatric Rheumatology group of the Milan area (PRAGMA). METHODS: Patients were retrospectively included in case of i) SLE diagnosis according to the 1997 American College of Rheumatology or the 2012 SLICC classification criteria and ii) disease onset before 18 years. RESULTS: Among the 177 recruited patients (155 females), haematologic involvement was the most common disease manifestation (75%), followed by joint and cutaneous involvements (70% and 57%, respectively). Renal disease was observed in 58 patients (32.8%), neurological complications in 26 cases (14.7%). Patients presented most commonly 3 clinical manifestations (32.8%), while 2 organ involvements were identified in 54 patients (30.5%) and 4 in 25 subjects (14.1%). The 49 patients with disease onset <10 years had less commonly articular involvement (p=0.02), while patients aged >14.8 years displayed less neurological manifestations (p=0.02). At a median follow-up of 118 month, the disease progressed in 93 patients, with a median of 2 new manifestations per patient. Low complement at diagnosis predicted new clinical manifestations (p=0.013 for C3 and p=0.0004 for C4). The median SLEDAI at diagnosis was 13; SLEDAI was substantially similar at 6 months, decreased at 12 months to remain stable at 18 months and further reduce at 24 months (p<0.0001). CONCLUSIONS: These data from a large jSLE monocentric cohort allow gaining further insights into a rare disease with a still high morbidity burden.

The recent evolution of ultrasound in juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common chronic joint disease in paediatric rheumatology. Over the last two decades, ultrasound (US) has emerged as a tool with the potential to enhance disease assessment and management of JIA. This imaging modality is safe and well tolerated by children and can be easily applied bedside in the clinical setting. Owing to the lack of published studies regarding the validity and reproducibility of US in JIA and the difficulties in interpreting images of children, US was initially perceived like an art rather than a science. In recent years, a great deal of efforts has been made in order to fill the gap of scientific knowledge on US between paediatric and adult rheumatology. This has yielded significant breakthroughs, such as the achievement of valuable information about the anatomical peculiarities of the growing skeleton on US, including internationally agreed definitions on B-mode and Doppler US of components for the normal joints, and the development of a standardised scanning protocol for US examination suitable for use in children. The precise role of US in JIA, however, is yet to be fully defined. Although further research regarding the use of US in joint inflammatory pathology in paediatrics is required, this imaging modality may well possess the necessary properties to pursue the best practice in the care of children with JIA in the near future. The present review provides information on the recent advances that have made the application of US increasingly promising for the management of JIA.

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.

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.

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

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/m2; 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.

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

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.

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

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.

Information technology in paediatric rheumatology.

Information technology in paediatric rheumatology has seen several exciting developments in recent years. The new multidimensional questionnaires for juvenile idiopathic arthritis, juvenile dermatomyositis, and juvenile autoinflammatory diseases integrate all major parent- and child-reported outcomes (PCROs) used in these diseases into a single tool, and provide an effective guide to manage, document change in health, assess effectiveness of therapeutic interventions, and verify the parent and child satisfaction with illness outcome. The Pharmachild registry is aimed to gain information concerning the long-term effectiveness and safety of the medications currently used in juvenile idiopathic arthritis, particularly biologic agents, through collection of prospective data in a large, multinational sample of patients. Children and their parents are directly involved in the data collection by means of the regular completion of a digital version of a multidimensional questionnaire. The Patient-Reported Outcomes Measurement Information System (PROMIS) employs modern measurement science to advance assessment of PCROs, particularly HRQL, and offers multidimensional profile measures. The conceptual link of paediatric PROMIS with adult instruments facilitates harmonisation of assessments made in children and adolescents with those carried out in young adults in the process of transition of medical care. Development of electronic versions of questionnaires that permit their completion through smartphones or touch-screen devices will revolutionise information collection from parents and children, foster the regular collection of PCROs in routine care, and ultimately improve the quality of self-reported health data, and patient outcomes.

Heading toward a modern imaging approach in juvenile idiopathic arthritis.

MR imaging and musculoskeletal ultrasound are expanding their utility in the assessment of patients with chronic inflammatory arthritis. These imaging techniques, by providing additional and more sensitive information over clinical examination and conventional radiographs, are promising tools for the diagnosis, prognosis and assessment of treatment efficacy in patients with juvenile idiopathic arthritis (JIA). Owing to the peculiarities of the growing skeleton, knowledge of imaging in healthy children is of high priority. A sound understanding of growth-related changes is of foremost value in establishing whether the apparent changes on joint surface reflect real damage or are actually part of normal development. This review explores current evidence and suggests a new workflow for imaging in JIA, in which conventional and modern imaging modalities can be integrated for optimal management.

Ultrasound-detected synovial abnormalities are frequent in clinically inactive juvenile idiopathic arthritis, but do not predict a flare of synovitis.

OBJECTIVES: To investigate whether children with juvenile idiopathic arthritis (JIA) in clinical remission have subclinical synovial disease on ultrasound, and whether ultrasound abnormalities predict an early flare of synovitis. METHODS: Thirty-nine consecutive children who had clinically defined inactive disease (ID) for a minimum of 3 months underwent ultrasound assessment of 52 joints. All joints were scanned for synovial hyperplasia, joint effusion, power Doppler (PD) signal and tenosynovitis. Patients were then followed clinically for up to 2 years until a flare of synovitis occurred in one or more joints, or until the 2-year visit if the disease remained in clinical remission. RESULTS: Synovial hyperplasia, joint effusion, PD signal and tenosynovitis in at least one joint were detected in 76.9%, 66.7%, 33.3% and 15.4% of patients, respectively. During the 2-year follow-up, 24 patients (61.5%) experienced sustained ID, whereas 15 patients (38.5%) had a flare of synovitis in a total of 45 joints after a median of 10.6 months (range 6.3-13.7 months). At study entry, the rate of synovial hyperplasia, joint effusion and tenosynovitis was comparable between patients with persistent ID and patients with synovitis flare, whereas patients with persistent ID had a greater frequency of PD signal than patients with synovitis flare. Only 17 of the 45 flared joints had ultrasound abnormalities at study entry. CONCLUSION: The authors found that ultrasound-detected synovial abnormalities are common in children with JIA in clinical remission. However, the presence of ultrasound pathology did not predict an early flare of synovitis in the affected joints.

Towards a role of ultrasound in children with juvenile idiopathic arthritis.

US is a powerful tool for the assessment of joint synovitis in children with JIA and has been shown to be more accurate than clinical examination in detecting synovial disease. Recent studies have documented the presence of US-detected synovial pathology in children with JIA in clinical remission. US assessment enables the differentiation of joint synovitis from tenosynovitis, may help detect enthesitis and is valuable for capturing cartilage damage and early bone erosions. Guidance to local injection therapy represents an important application of US in routine care. Although US has a great potential for diffusion among paediatric rheumatologists, several issues need to be addressed. In particular, a thorough knowledge of US anatomy of joints in growing children is necessary to interpret US findings in JIA patients. The present review examines the potential role of US in the assessment of joint disease in children with JIA.

Can early-onset acquired demyelinating syndrome (ADS) hide pediatric Behcet's disease? A case report.

Behcet's disease (BD) is a rare vasculitis characterized by multisystemic inflammation. Central nervous system (CNS) involvement is rare and heterogeneous, particularly in the pediatric population. A diagnosis of neuro-Behcet could be highly challenging, especially if neurological manifestations precede other systemic features; however, its timely definition is crucial to prevent long-term sequelae. In this study, we describe the case of a girl who, at 13 months of age, presented with a first episode of encephalopathy compatible with acute disseminated encephalomyelitis, followed, after 6 months, by a neurological relapse characterized by ophthalmoparesis and gait ataxia, in association with new inflammatory lesions in the brain and spinal cord, suggesting a neuromyelitis optica spectrum disorder. The neurological manifestations were successfully treated with high-dose steroids and intravenous immunoglobulins. In the following months, the patient developed a multisystemic involvement suggestive of Behcet's disease, characterized by polyarthritis and uveitis, associated with HLA-B51 positivity. The challenge presented by this unique case required a multidisciplinary approach involving pediatric neurologists, neuro-radiologists, and pediatric rheumatologists, with all of these specialists creating awareness about early-onset acquired demyelinating syndromes (ADSs). Given the rarity of this presentation, we performed a review of the literature focusing on neurological manifestations in BD and differential diagnosis of patients with early-onset ADS.

OMERACT International Consensus for Ultrasound Definitions of Tenosynovitis in Juvenile Idiopathic Arthritis: Systematic Literature Review and Delphi Process.

OBJECTIVE: Synovitis and tenosynovitis are present in juvenile idiopathic arthritis (JIA), both as joint pain and/or inflammation, making them difficult to detect on physical examination. Although ultrasonography (US) allows for discrimination of the 2 entities, only definitions and scoring of synovitis in children have been established. This study was undertaken to produce consensus-based US definitions of tenosynovitis in JIA. METHODS: A systematic literature search was performed. Selection criteria included studies focused on US definition and scoring systems for tenosynovitis in children, as well as US metric properties. Through a 2-step Delphi process, a panel of international US experts developed definitions for tenosynovitis components (step 1) and validated them by testing their applicability on US images of tenosynovitis in several age groups (step 2). A 5-point Likert scale was used to rate the level of agreement. RESULTS: A total of 14 studies were identified. Most used the US definitions developed for adults to define tenosynovitis in children. Construct validity was reported in 86% of articles using physical examination as a comparator. Few studies reported US reliability and responsiveness in JIA. In step 1, experts reached a strong group agreement (>86%) by applying adult definitions in children after one round. After 4 rounds of step 2, the final definitions were validated on all tendons and at all locations, except for biceps tenosynovitis in children <4 years old. CONCLUSION: The study shows that the definition of tenosynovitis used in adults is applicable to children with minimal modifications agreed upon through a Delphi process. Further studies are required to confirm our results.

Toward a treat-to-target approach in the management of juvenile idiopathic arthritis.

Recent advances in the management of juvenile idiopathic arthritis (JIA) render disease remission an attainable goal in many, if not most, patients. This has led to suggestions that future treatment guidelines include an overriding goal to achieve clinical remission or, at least, minimal disease activity. Furthermore, implementation of treatment strategies aimed at achieving and maintaining tight disease control in standard paediatric rheumatology practice has been proposed. A compelling argument is available at this time to suggest that the incorporation of treat-to-target approach in the management of children with JIA may improve disease outcome. Recently, descriptions of disease states that represent suitable therapeutic targets, such as inactive disease, minimal disease activity, or parent- or child-acceptable symptom states, have been developed. In addition, criteria for these states based on the Juvenile Arthritis Disease Activity Score (JADAS) have been identified. Future studies will clarify whether the addition of an imaging assessment to the management of children with JIA will improve the prediction of clinical outcomes.

Infection-Triggered Hyperinflammatory Syndromes in Children.

An association between infectious diseases and macrophage activation syndrome (MAS) has been reported, yet the exact role of infection in MAS development is still unclear. Here, a retrospective analysis of the clinical records of patients with rheumatic diseases complicated with MAS who were treated in a pediatric tertiary care center between 2011 and 2020 was performed. Any infection documented within the 30 days preceding the onset of MAS was reported. Out of 125 children in follow-up for systemic rheumatic diseases, 12 developed MAS, with a total of 14 episodes. One patient experienced three episodes of MAS. Clinical and/or laboratory evidence of infection preceded the onset of MAS in 12 events. Clinical features, therapeutic strategies, and patient outcomes were described. The aim of this study was to evaluate the possible role of infection as a relevant trigger for MAS development in children with rheumatic conditions. The pathogenetic pathways involved in the cross-talk between uncontrolled inflammatory activity and the immune response to infection deserve further investigation.

Outcome and predicting factors of single and multiple intra-articular corticosteroid injections in children with juvenile idiopathic arthritis.

OBJECTIVES: To investigate the efficacy of IA CS (IAC) therapy in single and multiple joints in children with JIA and to seek for predictors of synovitis flare. METHODS: The clinical charts of patients who received their first IAC injection between January 2002 and December 2008 were reviewed. The CS used was triamcinolone hexacetonide for large joints and methylprednisolone acetate for small or difficult to access joints. Patients were stratified as follows: one joint injected; two joints injected; and three or more joints injected. Predictors included sex, age at disease onset, JIA category, age and disease duration, ANA status, iridocyclitis, general anaesthesia, number and type of injected joints, acute-phase reactants and concomitant MTX therapy. RESULTS: The cumulative probability of survival without synovitis flare for patients injected in one, two, or three or more joints was 70, 45 and 44%, respectively, at 1 year; 61, 32 and 30%, respectively, at 2 years; and 37, 22 and 19%, respectively, at 3 years. On Cox regression analysis, positive CRP, negative ANA and injection in the ankle were the strongest predictors for synovitis flare. The only significant side effect was skin hypopigmentation or s.c. atrophy, which occurred in <2% of patients. CONCLUSION: IAC therapy-induced sustained remission of synovitis in a substantial proportion of patients injected either in single or multiple joints, with a good safety profile. The risk of synovitis flare was higher in patients who had positive CRP, negative ANA and were injected in the ankle.

Comparison Between Clinical and Ultrasound Assessment of the Ankle Region in Children With Juvenile Idiopathic Arthritis.

OBJECTIVE: To compare the frequency of joint and tendon disease on ultrasound (US) and clinical examination, and to investigate agreement between US and clinical evaluation in ankles with clinically active juvenile idiopathic arthritis (JIA). METHODS: US and clinical evaluation were performed independently in the joint and tendon compartments of 105 ankles. Gray-scale (GS) US and power Doppler (PD) US joint abnormalities were scored on a 4-point semiquantitative scale. A joint with a GS score ≥2 and/or a PD score ≥1 was defined as active on US. Agreement was tested using kappa statistics. RESULTS: A total of 163 joints in 89 ankles had active synovitis on US. The tibiotalar (TT) joint was the most commonly affected joint on US and on clinical evaluation. The intertarsal (IT) joint and the subtalar (ST) joint were the second in frequency on US and on clinical evaluation, respectively. Tenosynovitis was found more commonly on US than on clinical evaluation (70.5% and 32.4%, respectively), and was more frequent in the medial and lateral than in the anterior tendon compartment. Isolated tenosynovitis was detected on US in 12 of 105 ankles. Agreement between US and clinical evaluation for detection of active synovitis and tenosynovitis was less than acceptable (κ <0.4). No correlation was found between any feature of active disease recorded on clinical evaluation (joint swelling, tenderness/pain on motion, and restricted motion) and active synovitis on US in the TT joint, ST joint, and IT joint. CONCLUSION: Coupling clinical evaluation with US aids in correctly localizing pathology. US training of practitioners is recommended to manage ankle disease in JIA.

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.

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.

A new short and simple health-related quality of life measurement for paediatric rheumatic diseases: initial validation in juvenile idiopathic arthritis.

OBJECTIVE: To develop and validate a new short and simple measure of health-related quality of life (HRQL) in children with juvenile idiopathic arthritis (JIA). METHODS: The Paediatric Rheumatology Quality of Life Scale (PRQL) is a 10-item questionnaire that explores HRQL in two domains: physical health (PhH) and psychosocial health (PsH). Validation of the parent proxy report and child self-report versions of the instrument was accomplished by evaluating 472 JIA patients and approximately 800 healthy children. Validation analyses included assessment of feasibility, face and content validity; construct and discriminative ability; internal structure and consistency; test-retest reliability; responsiveness to clinical change; and minimal clinically important difference. RESULTS: The PRQL was found to be feasible and to possess both face and content validity. The PRQL score correlated in the predicted range with most of the other JIA outcome measures, thereby demonstrating good construct validity, and discriminated well between different levels of disease severity. Assessment of internal structure (factor analysis) revealed that the PhH and PsH subscales identify two unambiguously separated domains. The internal consistency (Cronbach's alpha) was 0.86. The intraclass correlation coefficient for test-retest reliability was 0.91. The PRQL revealed fair responsiveness, with a standardized response mean of 0.67 in improved patients. Overall, the PRQL appeared to be more able to capture physical HRQL than psychosocial HRQL. CONCLUSION: The PRQL was found to possess good measurement properties and is, therefore, a valid instrument for the assessment of HRQL in children with JIA. This tool is primarily proposed for use in standard clinical care.