Intravenous immunoglobulin for corticosteroid-resistant intestinal Henoch-Schönlein purpura: worth a controlled trial against corticosteroids?

OBJECTIVES: Henoch-Schönlein purpura (HScP) may present in children with severe, occasionally refractory, gastrointestinal (GI) involvement. The use of corticosteroids (CSs) is commonplace in the management of the disease, but to date no standardized protocol is available and, although rare, resistance to CS therapy may be challenging to clinicians. IVIG has been proposed as an effective alternative to CSs, but to date no controlled trial has been conducted to ascertain their real efficacy. We share our personal experience of successful IVIG treatment in two cases of GI HScP, comparing it with similar experiences reported in literature. METHODS: Retrospective clinical data collection, comparison with available literature. RESULTS: We describe two children with severe HScP GI vasculitis refractory to high-dose intravenous CSs that responded rapidly to IVIG administration, with complete recovery within a few days. Patient characteristics and response to IVIG administration were comparable to those of other previously reported cases. CONCLUSION: Our observation confirms that IVIG may be useful in the treatment of CS-resistant HScP-related GI vasculitis in children, and highlights the need for more structured research, including a randomized trial against CSs, in order to ascertain their real effectiveness.

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.

Defining criteria for high disease activity in juvenile idiopathic arthritis based on the juvenile arthritis disease activity score.

OBJECTIVE: To determine cutoff values for defining the state of high disease activity (HDA) in juvenile idiopathic arthritis (JIA) using the Juvenile Arthritis Disease Activity Score (JADAS). METHODS: For the selection of cutoff values, data from a clinical database including 609 patients were used. Optimal cutoff values were determined against external criteria by calculating the 25th and 10th centile of cumulative score distribution and through receiver operating characteristic curve analysis. External criteria were based on the therapeutic decision made by the attending doctor. Cross-validation was performed using five patient samples that included 1421 patients. RESULTS: The optimal cutoff values were those obtained through the 90% fixed sensitivity method. The selected JADAS cutoff values were the following: 4.2 and 8.5 for JADAS27 in oligoarthritis and polyarthritis, respectively; 4.2 and 10.5 for both JADAS10 and JADAS71 in oligoarthritis and polyarthritis, respectively. In cross-validation analyses, the cutoff values showed strong ability to discriminate between different levels of American College of Rheumatology paediatric response in two clinical trials and could predict worse functional and radiographic outcome. CONCLUSIONS: Cutoff values for classifying HDA in JIA using the JADAS were developed. In cross-validation analyses, they proved to have good construct and discriminant validity and ability to predict disease outcome.

Safety and Efficacy of Using Advanced Hybrid Closed Loop Off-Label in an Infant Diagnosed with Permanent Neonatal Diabetes Mellitus: A Case Report and a Look to the Future.

The case report shows the safety and efficacy of insulin treatment with Advanced Hybrid Closed Loop (AHCL) system in a young patient affected by permanent neonatal diabetes mellitus (PNDM) due to chromosome 8 deletion syndrome involving the GATA4 gene. In the first days of life, he presented hyperglycaemia and started an intravenous insulin infusion therapy, replaced by a continuous subcutaneous insulin infusion (CSII) with Medtronic Minimed 780G® insulin pump (Medtronic, Northridge, CA, USA). At the age of 2 years, the off-label activation of SmartGuard® automated insulin delivery mode led to a great improvement in glycaemic control, reaching all recommended targets. At the 1-month follow-up visit, Time in Range (TIR) increased from 66% to 79%, with a Time in Tight Range (TTIR) of 55% and a reduction of 11% in time in hyperglycaemia and of 2% in time in hypoglycaemia. During the entire follow-up, no episodes of ketoacidosis or severe hypoglycaemia were observed and the patient maintained the glycaemic recommended targets reached at 1 month. Maintaining optimal glycaemic control and reducing hyperglycaemia are essential for brain growth and neurocognitive development in young patients. AHCL use should be considered to ensure good glycaemic control in patients affected by neonatal diabetes.

Glucometrics and device satisfaction in children and adolescents with type 1 diabetes using different treatment modalities: A multicenter real-world observational study.

AIMS: To analyze metabolic outcomes, diabetes impact and device satisfaction in children and adolescents with type 1 diabetes in Italy who used different treatment modalities for diabetes care in a real-life context. METHODS: In this multicenter, nationwide, cross-sectional study, 1464 participants were enrolled at a routine visit. The following treatment modalities were considered MDI + SMBG; MDI + CGM; Sensor Augmented Pump Therapy; predictive management of low glucose; Hybrid Closed Loop (HCL); Advanced Hybrid Closed Loop (AHCL). Health related quality of life was evaluated by the Italian version of the Diabetes Impact and Device Satisfaction Scale (DIDS) questionnaire. RESULTS: Patients treated with AID systems were more likely to have HbA1c ≤ 6.5 %, higher percentage of time with glucose levels between 70 and 180 mg/dL, lower percentage of time with glucose levels above 180 mg/dL, higher device satisfaction, and reduced impact of diabetes. All the therapeutic modalities with respect to MDI + CGM, except for MDI + SMBG, contributed to increase the device satisfaction. HCL and AHCL respect to MDI + CGM were associated with lower diabetes impact. CONCLUSION: Real-life use of automated insulin delivery systems is associated with reduced type 1 diabetes impact, increased device satisfaction, and achievement of glycemic goals.

Remission, minimal disease activity, and acceptable symptom state in juvenile idiopathic arthritis: defining criteria based on the juvenile arthritis disease activity score.

OBJECTIVE: To determine cutoff values for defining remission, minimal disease activity, and parent and child acceptable symptom state in juvenile idiopathic arthritis (JIA) using the Juvenile Arthritis Disease Activity Score (JADAS). METHODS: For the selection of cutoff values, data from a clinical database including 609 children with JIA were used. Optimal cutoff values were determined against external criteria by calculating the 75th percentile of cumulative score distribution and through receiver operating characteristic curve analysis. External criteria included formal definitions of inactive disease and minimal disease activity, subjective rating of remission by physicians, parents, and children, and rating of acceptable symptom state by parents and children. The choice of cutoffs was made based on clinical and statistical grounds. Cross-validation was performed using 4 JIA patient samples that included a total of 1,323 patients, and was based on assessment of construct, discriminant, and predictive validity. RESULTS: With all versions of the JADAS, the cutoff score for classifying a patient as having inactive disease was 1, whereas the cutoff for classification of minimal disease activity was 2 for oligoarticular JIA and 3.8 for polyarticular JIA. Cutoffs for physicians', parents', and children's subjective rating of remission ranged from 2 to 2.3. Cutoffs for acceptable symptom state ranged from 3.2 to 5.4 for parents and from 3 to 4.5 for children. Results of cross-validation analyses strongly supported the selected cutoff values. CONCLUSION: Cutoff values for classifying various disease states in JIA using the JADAS were developed. In cross-validation analyses, they proved to have good construct and discriminant validity and ability to predict disease outcome.

Corrigendum: The silent epidemic of diabetic ketoacidosis at diagnosis of type 1 diabetes in children and adolescents in italy during the covid-19 pandemic in 2020.

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The Silent Epidemic of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Children and Adolescents in Italy During the COVID-19 Pandemic in 2020.

Aim/Hypothesis: To compare the frequency of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes in Italy during the COVID-19 pandemic in 2020 with the frequency of DKA during 2017-2019. Methods: Forty-seven pediatric diabetes centers caring for >90% of young people with diabetes in Italy recruited 4,237 newly diagnosed children with type 1 diabetes between 2017 and 2020 in a longitudinal study. Four subperiods in 2020 were defined based on government-imposed containment measures for COVID-19, and the frequencies of DKA and severe DKA compared with the same periods in 2017-2019. Results: Overall, the frequency of DKA increased from 35.7% (95%CI, 33.5-36.9) in 2017-2019 to 39.6% (95%CI, 36.7-42.4) in 2020 (p=0.008), while the frequency of severe DKA increased from 10.4% in 2017-2019 (95%CI, 9.4-11.5) to 14.2% in 2020 (95%CI, 12.3-16.4, p<0.001). DKA and severe DKA increased during the early pandemic period by 10.4% (p=0.004) and 8% (p=0.002), respectively, and the increase continued throughout 2020. Immigrant background increased and high household income decreased the probability of presenting with DKA (OR: 1.55; 95%CI, 1.24-1.94; p<0.001 and OR: 0.60; 95 CI, 0.41-0.88; p=0.010, respectively). Conclusions/Interpretation: There was an increase in the frequency of DKA and severe DKA in children newly diagnosed with type 1 diabetes during the COVID-19 pandemic in 2020, with no apparent association with the severity of COVID-19 infection severity or containment measures. There has been a silent outbreak of DKA in children during the pandemic, and preventive action is required to prevent this phenomenon in the event of further generalized lockdowns or future outbreaks.

Intra-articular venous malformations of the knee: a diagnostic challenge.

BACKGROUND: Intra-articular venous malformations (IAVM) are rare benign vascular anomalies that usually affect young patients and most common locate in the knee. The terminology of these lesions is still ill-defined, as they are often termed in the literature as synovial hemangiomas. Early diagnosis can be difficult, because they usually present with nonspecific clinical manifestations that are similar those of other rheumatic diseases, especially juvenile idiopathic arthritis (JIA). CASE SERIES: We conducted a retrospective analysis of five pediatric patients admitted to our units for recurrent swelling of the knee, and compared their characteristics with those of literature reports. The average age at first symptom and time from onset to diagnosis was 3.9 years (range 18 months-7 years) and 3.5 years (range 1-7 years), respectively. In our patients, an initial misdiagnosis of JIA, bleeding disorder or traumatic arthropathy was made. On MRI imaging, the features of the lesion were similar in all patients, and were marked by isointense-to-hypointense signal in T1-weighted images, and hyperintense signal in T2-weighted images. When performed, arthrocentesis led to aspiration of bloody fluid. The diagnosis was confirmed with a biopsy and histopathologic assessment in all patients. Open surgery enabled complete excision of the mass and was followed by stable remission over time in all cases. CONCLUSIONS: Our report highlights the challenges that may be posed by the detection of knee IAVM and the frequent long delay between onset of symptoms and diagnosis. The key elements for early recognition include careful assessment of patient history, demonstration of bloody fluid on arthrocentesis, and proper interpretation of MRI scanning.

A prediction rule for lack of achievement of inactive disease with methotrexate as the sole disease-modifying antirheumatic therapy in juvenile idiopathic arthritis.

BACKGROUND: To investigate the frequency of achievement of inactive disease (ID) in children with juvenile idiopathic arthritis (JIA) treated with methotrexate (MTX) as the sole disease-modifyng antirheumatic (DMARD) therapy and to develop a prediction model for lack of attainment of ID. METHODS: The clinical charts of consecutive patients started with MTX as the sole DMARD between 2000 and 2013 were reviewed. Patient follow-up was censored at first episode of ID or, in case ID was not reached, at last follow-up visit or when a biologic DMARD was prescribed. The characteristic at MTX start of patients who achieved or did not achieve ID were compared with univariate 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 lack of achievement of ID. RESULTS: A total of 375 patients were included in the study. During MTX administration, 8.8% were given systemic corticosteroids and 44.1% intra-articular corticosteroids. After MTX start, 229 (61%) patients achieved ID after a median of 1.7 years, whereas 146 patients (39%) did not reach ID after a median of 1.2 years. On multivariable analysis, independent correlations with lack of achievement of ID were identified for the disease categories of systemic arthritis, enthesitis-related arthritis (ERA) and polyarthritis and C-reactive protein (CRP) >  1.4 mg/dl. The prediction score ranged from 0 to 3 and its cutoff that discriminated best between patients who achieved or did not achieve ID was > 0.5. The categories of systemic arthritis or ERA, both of which had a score greater than 0.5, were sufficient alone to predict a lower likelihood to reach ID. Polyarthritis and increased CRP, whose score was 0.5, assumed a predictive value only when present in association. CONCLUSION: A conventional treatment regimen based on MTX as the sole DMARD led to achievement of ID in a sizeable proportion of children with JIA. Our findings help to outline the characteristics of patients who may deserve a synthetic DMARD other than MTX or the introduction of a biologic DMARD from disease outset.

IL-1 Inhibition in Systemic Juvenile Idiopathic Arthritis.

Systemic juvenile idiopathic arthritis (sJIA) is the form of childhood arthritis whose treatment is most challenging. The demonstration of the prominent involvement of interleukin (IL)-1 in disease pathogenesis has provided the rationale for the treatment with biologic medications that antagonize this cytokine. The three IL-1 blockers that have been tested so far (anakinra, canakinumab, and rilonacept) have all been proven effective and safe, although only canakinumab is currently approved for use in sJIA. The studies on IL-1 inhibition in sJIA published in the past few years suggest that children with fewer affected joints, higher neutrophil count, younger age at disease onset, shorter disease duration, or, possibly, higher ferritin level may respond better to anti-IL-1 treatment. In addition, it has been postulated that use of IL-1 blockade as first-line therapy may take advantage of a "window of opportunity," in which disease pathophysiology can be altered to prevent the occurrence of chronic arthritis. In this review, we analyze the published literature on IL-1 inhibitors in sJIA and discuss the rationale underlying the use of these medications, the results of therapeutic studies, and the controversial issues.

Defining criteria for disease activity states in nonsystemic juvenile idiopathic arthritis based on a three-variable juvenile arthritis disease activity score.

OBJECTIVE: To determine cutoff values for defining the states of inactive disease (ID), low disease activity (LDA; or minimal disease activity), moderate disease activity (MDA), and high disease activity (HDA) using the clinical (3-variable) Juvenile Arthritis Disease Activity Score (cJADAS). METHODS: For selection of cutoffs, data from a clinical database including 609 children with juvenile idiopathic arthritis (JIA) were used. Optimal cutoffs were determined against external criteria by calculating the 75th and 90th percentile (for ID and LDA) and 10th and 25th percentile (for HDA) of cumulative score distribution and through receiver operating characteristic curve analysis. External criteria included definitions for ID and LDA cutoffs and therapeutic decisions for HDA cutoffs. MDA cutoffs were set at the score interval in-between LDA and HDA cutoffs. Crossvalidation was performed using 2 JIA patient samples (n = 485) and was based on assessment of construct and discriminant validity. RESULTS: The selected cutoffs were as follows: ≤1 for ID in both oligoarthritis and polyarthritis; ≤1.5 and ≤2.5 for LDA in oligoarthritis and polyarthritis, respectively; 1.51-4 and 2.51-8.5 for MDA in oligoarthritis and polyarthritis, respectively; and >4 and >8.5 for HDA in oligoarthritis and polyarthritis, respectively. In crossvalidation analyses, the cutoffs showed a strong ability to discriminate between disease activity states defined subjectively by physicians and parents, levels of pain, and presence/absence of functional impairment and disease damage. CONCLUSION: Cutoff values for classifying various disease states in nonsystemic JIA using the cJADAS were developed. The cutoffs revealed good measurement characteristics in crossvalidation analyses and are suited for application in clinical practice and research.

Seeking insights into the EPidemiology, treatment and Outcome of Childhood Arthritis through a multinational collaborative effort: Introduction of the EPOCA study.

The epidemiology of juvenile idiopathic arthritis (JIA) is variable worldwide. In particular, a wide disparity exists in the prevalence of the diverse disease subtypes across different geographic areas. The therapeutic approach to JIA is not standardized and no established and widely accepted guidelines are available. In the past decade, there have been important progresses in the management of the disease, but the availability of the novel and costly biologic medications is not uniform throughout the world. This issue may have significant impact on disease prognosis, with children living in poorer countries being at greater risk of accumulating disease- and treatment-related damage than children followed in Western pediatric rheumatology centers. The multinational study of the EPidemiology, treatment and Outcome of Childhood Arthritis (EPOCA study) is aimed to obtain information on the frequency of JIA subtypes in different geographic areas, the therapeutic approaches adopted by pediatric rheumatologists practicing in diverse countries or continents, and the disease and health status of children with JIA currently followed worldwide. Parent- and child-reported outcomes are meant to be recorded through the administration of a new multidimensional questionnaire, the Juvenile Arthritis Multidimensional Assessment Report (JAMAR). The first step of the study is based on the translation and cross-cultural adaptation of the questionnaire in the national language of each participating country. Each center is, then, asked to enroll a sample of consecutive JIA patients, who should undergo a retrospective assessment and a cross-sectional evaluation, including completion of the JAMAR, a standardized joint examination, and the assessment of articular and extra-articular damage. At the end of May 2012, 124 centers in 55 countries have agreed to participate in the study. The JAMAR has been or is currently being translated in 38 national languages. The target patient sample is more than 10,000 JIA children worldwide.