Objective
We explored damage occurrence in patients with childhood-onset SLE (cSLE) and aimed to predict the risk of organ damage occurrence in time.
Methods
The retrospective study included patients ...treated for cSLE at the Centre of Reference for Pediatric and Adolescent Rheumatology of the Republic Croatia over a 29-year period.
Results
The disease development of 97 patients (77 females) with cSLE was examined. The median (Q1, Q3) follow-up time was 6.5 (2.3, 12.0) years. SDI was determined at 5 time points (6, 12, 24, 36 months, and last follow-up). Thirty-eight patients (48%) had organ damage at the last follow-up. Prepubertal group of patients showed higher SLEDAI scores at the disease onset, while post-pubertal group had significantly lower proportion of patients with relapses. We estimated the time from the first symptom to the moment of damage and our findings suggest that it is unlikely that organ damage will occur in 50% of patients in the first 6 years since the diagnosis. The number of 2019 ACR/EULAR classification criteria at the time of diagnosis associated with SDI determined after 1 year of the follow-up period. The patients who received higher doses of glucocorticoids accumulated damage faster and mycophenolate mofetil was found to be a more frequent therapy in patients with SDI ≥3.
Conclusion
Knowing that damage will most likely happen after the first 6 years after diagnosis in 50% of patients enables physicians to better predict damage occurrence. High number of 2019 ACR/EULAR criteria and treatment with glucocorticoids in childhood-onset SLE are associated with damage accrual and these findings could enable us to detect patients which should be closely monitored for higher risk of damage development.
Abstract
Objective
To describe risk factors for IBD development in a cohort of children with JIA.
Methods
JIA patients who developed IBD were identified from the international Pharmachild register. ...Characteristics were compared between IBD and non-IBD patients and predictors of IBD were determined using multivariable logistic regression analysis. Incidence rates of IBD events on different DMARDs were calculated, and differences between therapies were expressed as relative risks (RR).
Results
Out of 8942 patients, 48 (0.54% ) developed IBD. These were more often male (47.9% vs 32.0%) and HLA-B27 positive (38.2% vs 21.0%) and older at JIA onset (median 8.94 vs 5.33 years) than patients without IBD development. They also had more often a family history of autoimmune disease (42.6% vs 24.4%) and enthesitis-related arthritis (39.6% vs 10.8%). The strongest predictors of IBD on multivariable analysis were enthesitis-related arthritis odds ratio (OR): 3.68, 95% CI: 1.41, 9.40 and a family history of autoimmune disease (OR: 2.27, 95% CI: 1.12, 4.54). Compared with methotrexate monotherapy, the incidence of IBD on etanercept monotherapy (RR: 7.69, 95% CI: 1.99, 29.74), etanercept with methotrexate (RR: 5.70, 95% CI: 1.42, 22.77) and infliximab (RR: 7.61, 95% CI: 1.27, 45.57) therapy was significantly higher. Incidence on adalimumab was not significantly different (RR: 1.45, 95% CI: 0.15, 13.89).
Conclusion
IBD in JIA was associated with enthesitis-related arthritis and a family history of autoimmune disease. An increased IBD incidence was observed for etanercept therapy regardless of concomitant methotrexate use.
Uveitis (JIA-U), the most common extra-articular manifestation in juvenile idiopathic arthritis (JIA), may cause severe impairment of vision in children and affect their quality of life (QoL). ...Considering the lack of uveitis-related QoL assessment questionnaire, and multidimensional nature of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR), commonly used for monitoring and assessing the health status of children with JIA, we performed a cross-sectional study to investigate the potential of the JAMAR in estimation of QoL in children suffering from JIA-U. The study included 42 children with JIA, 21 of whom had JIA-U. Both children and their parents completed the JAMAR. We compared two groups of children (JIA-U and JIA without uveitis) and their parents against five extracted questionnaires items (QoL, functional ability, pain level, disease activity estimation, and current emotional state of the child) using the independent-samples
t
test to verify the differences and the Pearson correlation coefficient to measure the strength of a linear association between variables. No significant statistical difference in any of the examined variables was found between the two groups of children. In the groups of parents, current emotional state of children with JIA-U was assessed to be significantly worse (
t
= 2.05,
p
< 0.05) and the overall level of functioning significantly lower (
t
= 2.03,
p
< 0.05) than children without uveitis. Our results suggest the need for adding the uveitis-specific questionnaires items to JAMAR to improve its sensitivity and specificity in the assessment of QoL in children suffering from JIA-U, as well as designing a second assessment tool such as uveitis-specific questionnaires.
Background:
We analysed clinical and biochemical parameters in predicting severe gastrointestinal (GI) manifestations in childhood IgA vasculitis (IgAV) and the risk of developing renal ...complications.
Methods:
A national multicentric retrospective study included children with IgAV reviewed in five Croatian University Centres for paediatric rheumatology in the period 2009–2019.
Results:
Out of 611 children, 281 (45.99%) had at least one GI manifestation, while 42 of 281 (14.95%) had the most severe GI manifestations. Using logistic regression several clinical risk factors for the severe GI manifestations were identified: generalized rash odds ratio (OR) 2.09 (95% confidence interval (CI) 1.09–4.01), rash extended on upper extremities (OR 2.77 (95% CI 1.43–5.34) or face OR 3.69 (95% CI 1.42–9.43) and nephritis (IgAVN) OR 4.35 (95% CI 2.23–8.50), as well as lower values of prothrombin time (OR 0.05 (95% CI 0.01–0.62), fibrinogen OR 0.45 (95% CI 0.29–0.70) and IgM OR 0.10 (95% I 0.03–0.35) among the laboratory parameters. Patients with severe GI involvement more frequently had relapse of the disease OR 2.14 (CI 1.04–4.39) and recurrent rash OR 2.61 (CI 1.27–5.38). Multivariate logistic regression found that the combination of age, GI symptoms at the beginning of IgAV and severity of GI symptoms were statistically significant predictors of IgAVN. Patients in whom IgAV has started with GI symptoms OR 6.60 (95% CI 1.67–26.06), older children OR 1.22 (95% CI 1.02–1.46) with severe GI form of IgAV (OR 5.90 (95% CI 1.12–31.15) were particularly high-risk for developing IgAVN.
Conclusion:
We detected a group of older children with the onset of GI symptoms before other IgAV symptoms and severe GI form of the IgAV, with significantly higher risk for acute and chronic complications of IgAV.
S100A8/A9 protein is a well-known marker of disease activity or severity in many autoimmune and autoinflammatory diseases, but there have not been many studies about the role of S100A8/A9 in IgA ...vasculitis (IgAV). The aim of our study was to evaluate S100A8/A9 as a possible biomarker of activity in IgAV. We measured the serum levels of S100A8/A9 in pediatric patients with IgA vasculitis at the onset of the disease, after three months, and after six months. We compared these levels between patients with active disease, remission, and a control group, and assessed their correlation with disease activity and other markers of inflammation. Patients with active disease had significantly higher levels of serum S100A8/A9 (median ± SD) than those in the control group at the beginning of the disease (5740 ± 3157 ng/mL vs. 1447 ± 858.3 ng/mL;
< 0.0001), but also three months and six months after disease onset (
< 0.001). There was a positive correlation between S100A8/A9 serum levels and disease activity (
= 0.0003). Patients with active disease had significantly higher levels of S100A8/A9 than those in remission three months after disease onset (
= 0.0260). There was a correlation between S100A8/A9 and C-reactive protein, the C3 component of complement, ferritin, and fibrinogen. Serum levels of S100A8/A9 were also higher in patients with greater skin areas covered with rash. We demonstrated that serum levels of S100A8/A9 correlated well with disease activity and other biomarkers of inflammation in children with IgAV. According to our results, serum S100A8/A9 may be a good indicator of active disease in IgAV.
Definitive sample sizes for clinical trials in rare diseases are usually infeasible. Bayesian methodology can be used to maximise what is learnt from clinical trials in these circumstances. We ...elicited expert prior opinion for a future Bayesian randomised controlled trial for a rare inflammatory paediatric disease, polyarteritis nodosa (MYPAN, Mycophenolate mofetil for polyarteritis nodosa).
A Bayesian prior elicitation meeting was convened. Opinion was sought on the probability that a patient in the MYPAN trial treated with cyclophosphamide would achieve disease remission within 6-months, and on the relative efficacies of mycophenolate mofetil and cyclophosphamide. Expert opinion was combined with previously unseen data from a recently completed randomised controlled trial in ANCA associated vasculitis.
A pan-European group of fifteen experts participated in the elicitation meeting. Consensus expert prior opinion was that the most likely rates of disease remission within 6 months on cyclophosphamide or mycophenolate mofetil were 74% and 71%, respectively. This prior opinion will now be taken forward and will be modified to formulate a Bayesian posterior opinion once the MYPAN trial data from 40 patients randomised 1:1 to either CYC or MMF become available.
We suggest that the methodological template we propose could be applied to trial design for other rare diseases.
Background Etanercept (ETN) and adalimumab (ADA) are considered equally effective biologicals in the treatment of arthritis in juvenile idiopathic arthritis (JIA) but no studies have compared their ...impact on patient-reported well-being. The objective of this study was to determine whether ETN and ADA have a differential effect on patient-reported well-being in non-systemic JIA using real-world data. Methods Biological-naive patients without a history of uveitis were selected from the international Pharmachild registry. Patients starting ETN were matched to patients starting ADA based on propensity score and outcomes were collected at time of therapy initiation and 3-12 months afterwards. Primary outcome at follow-up was the improvement in Juvenile Arthritis Multidimensional Assessment Report (JAMAR) visual analogue scale (VAS) well-being score from baseline. Secondary outcomes at follow-up were decrease in active joint count, adverse events and uveitis events. Outcomes were analyzed using linear and logistic mixed effects models. Results Out of 158 eligible patients, 45 ETN starters and 45 ADA starters could be propensity score matched resulting in similar VAS well-being scores at baseline. At follow-up, the median improvement in VAS well-being was 2 (interquartile range (IQR): 0.0 - 4.0) and scores were significantly better (P = 0.01) for ETN starters (median 0.0, IQR: 0.0 - 1.0) compared to ADA starters (median 1.0, IQR: 0.0 - 3.5). The estimated mean difference in VAS well-being improvement from baseline for ETN versus ADA was 0.89 (95% CI: -0.01 - 1.78; P = 0.06). The estimated mean difference in active joint count decrease was -0.36 (95% CI: -1.02 - 0.30; P = 0.28) and odds ratio for adverse events was 0.48 (95% CI: 0.16 -1.44; P = 0.19). One uveitis event was observed in the ETN group. Conclusions Both ETN and ADA improve well-being in non-systemic JIA. Our data might indicate a trend towards a slightly stronger effect for ETN, but larger studies are needed to confirm this given the lack of statistical significance. Keywords: Juvenile idiopathic arthritis, Etanercept, Adalimumab, Patient-reported outcomes, Epidemiology, Real-world data, Propensity score analysis
Childhood obesity is the public health issue with alarming rates recorded throughout developed world and an important modifiable health risk for developing various chronic diseases, with ...childhood-onset autoimmune rheumatic diseases among them also. The aim of this article was to summarize epidemiological, pathophysiological and clinical implication of obesity on juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), juvenile dermatomyositis (JDM), IgA vasculitis (IgAV) and Kawasaki disease (KD). We reviewed PubMed database and selected 74 relevant articles. Epidemiological data of obesity among children with autoimmune rheumatic diseases indicate an increased prevalence of it. Pathophysiological link between obesity, humoral adipokines and cytokines released from fat tissue and childhood-onset autoimmune rheumatic diseases is complex and still not entirely clear. From the clinical point of view, obesity was not associated with disease activity in JIA and cSLE, but proved to contribute on functional impairment in both diseases and affect poor treatment response in JIA patients. Early atherosclerosis and cardiovascular disease (CVD) development in obese children and adolescents with JIA, cSLE and JDM are certainly important obesity-related complications. Understanding how obesity affects children and adolescents with autoimmune rheumatic diseases may encourage clinicians to consider taking better preventive strategies in this population to improve their long-term outcome.
Pediatric vasculitides sometimes involve central nervous system (CNS). The manifestations are diverse, ranging from headache, seizures, vertigo, ataxia, behavioral changes, neuropsychiatric symptoms, ...consciousness disorders, and even cerebrovascular (CV) accidents that may lead to irreversible impairment and even death. Stroke, on the other hand despite the great progress in prevention and treatment, is still one of the leading causes of morbidity and mortality in the general population. The aim of this article was to summarize CNS manifestations and CV issues observed in primary pediatric vasculitides and the current knowledge of etiology and CV risk factors, preventive strategies, and therapeutic options in this target patient population. Pathophysiological links reveal similar immunological mechanisms involved in both pediatric vasculitides and CV events with endothelial injury and damage being the central point. From the clinical point of view, CV events in pediatric vasculitides were associated with increased morbidity and poor prognosis. If damage has already occurred, the therapeutic approach consists of good management of the vasculitis itself, antiplatelet and anticoagulation therapy, and early rehabilitation. Risk factors for acquiring cerebrovascular disease (CVD) and stroke, particularly hypertension and early atherosclerotic changes, already begin in childhood, with vessel wall inflammation contributing itself, once more emphasizing that appropriate preventive measures are certainly necessary in pediatric vasculitis population to improve their long-term outcome.
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about ...their contribution to disease pathogenesis. Amongst them, SH2B3-a negative regulator of cytokine and growth factor receptor signaling-harbors rare coding variants in over 5% of SLE patients. Here, we show that unlike the variant found exclusively in healthy controls, SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles, failing to suppress IFNGR signaling via JAK2-STAT1. The generation of two mouse lines carrying patients' variants revealed that SH2B3 is important in limiting the number of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair the negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk.
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