Marija Jelušić

Clinical Features, Treatment, and Outcome of Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A Multinational, Multicenter Study of 362 Patients

To describe the clinical, laboratory, and histopathologic features, current treatment, and outcome of patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA).

Elicitation of Expert Prior Opinion: Application to the MYPAN Trial in Childhood Polyarteritis Nodosa

Objectives 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). Methods 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. Results 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. Conclusions We suggest that the methodological template we propose could be applied to trial design for other rare diseases.

Epidemiology of cardiomyopathies in children and adolescents: a retrospective study over the last 10 years

We conducted a retrospective study at the Department of Paediatric Cardiology of the University Hospital Centre Rebro, Zagreb, over the period from 1988 to 1998, so as to assess the epidemiology of childhood cardiomyopathies. The patients were categorized according to the guidelines of the Task Force on Cardiomyopathies of the World Health Organization and the International Society and Federation of Cardiology. We identified 121 infants, children and adolescents as having cardiomyopathy, giving an average occurrence for all cardiomyopathies of 38.81 for each 10,000 patients examined in our outpatient clinics for paediatric cardiology. Of the patients, 50 were female (41.3%) and 71 were male (58.7%). The cardiomyopathy was of the dilated variant in 52 patients (42.9%), with 43 patients (35.5%) having hypertrophic cardiomyopathy, and 6 patients (4.8%) identified with restrictive cardiomyopathy. We encountered no patients with arrhythmogenic right ventricular cardiomyopathy. In nine patients (7.4%), it proved impossible to classify the cardiomyopathy. We placed 11 patients (9.0%) in the group of specific cardiomyopathies. Most of those with dilated cardiomyopathy had been diagnosed prior to the age of 3 years (RR 1.9, 95% CI 1.4-2.47). There were no statistically significant differences in the incidences of dilated as compared to hypertrophic cardiomyopathy (Z 0.923, p = 0.1779), but we encountered a significantly lower occurrence of restrictive cardiomyopathy (Z 6.044, p < 0.001). Of those with hypertrophic cardiomyopathy, 15 patients (34.8%) had the asymmetric variant, while 28 patients (65.2%) exhibited the concentric form. During the period of follow-up, 10 patients died, 4 with dilated cardiomyopathy, 4 with hypertrophic cardiomyopathy, 1 with restrictive cardiomyopathy, and 1 with a specific cardiomyopathy. We encountered 12 (9.9%) patients who, besides cardiomyopathies, also suffered from neuromuscular disorders. Most of these had dilated cardiomyopathy. Mitochondrial disorders, in contrast, were more frequently found in patients with hypertrophic cardiomyopathy.

The presence of high mobility group box-1 and soluble receptor for advanced glycation end-products in juvenile idiopathic arthritis and juvenile systemic lupus erythematosus

BackgroundThe involvement of high mobility group box-1 (HMGB1) in various inflammatory and autoimmune diseases has been documented but clinical trials on the contribution of this pro-inflammatory alarmin in children with juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE) are basically absent. To address the presence of HMGB1 and a soluble receptor for advanced glycation end products (sRAGE) in different subtypes of JIA and additionally in children with SLE, we enrolled a consecutive sample of children harvested peripheral blood as well as synovial fluids (SF) at diagnosis and correlated it with ordinary acute-phase reactants and clinical markers.MethodsSerum and synovial fluids levels of HMGB1 and sRAGE in total of 144 children (97 with JIA, 19 with SLE and 27 healthy controls) were determined by ELISA.ResultsThe children with JIA and those with SLE were characterised by significantly higher serum levels of HMGB1 and significantly lower sRAGE levels compared to the healthy controls. A positive correlation between serum HMGB1 and ESR, CRP, α2 globulin was found while serum sRAGE levels were inversely correlated with the same inflammatory markers in children with JIA. Additionally, high level of serum HMGB1 was related to hepatosplenomegaly or serositis in systemic onset JIA.ConclusionThe inverse relationship of the HMGB1 and its soluble receptor RAGE in the blood and SF indicates that inflammation triggered by alarmins may play a role in pathogenesis of JIA as well as SLE. HMGB1 may serve as an inflammatory marker and a potential target of biological therapy in these patients. Further studies need to show whether the determination of HMGB1 levels in patients with JIA can be a useful guideline for detecting disease activity.

Intracardiac Juvenile Xanthogranuloma in a Newborn

Abstract. Juvenile xanthogranuloma (JXG) presents a normolipemic non-Langerhans cells histiocytosis. JXG usually presents with cutaneous lesions. Visceral involvement is rare but may affect various organs. Deep JXG differs histologically from the cutaneous form by its tendency to consist solely of homogeneous proliferation of histiocytes without any xanthomatous or Touton giant cells. Awareness of the possibility of this atypical presentation of JXG helps in making the correct histologic diagnosis, which is supported by proving adequate immunomarkers on histiocytes (mainly PG-M1, an antibody against the CD68 antigen). JXG may present with intramuscular lesions only; however, rarely JXG has been reported to affect the heart but not without the typical cutaneous manifestations. We present an unusual case of deep JXG without systemic disease or metabolic abnormalities. To our knowledge, this is a first reported case of intracavitar JXG without skin lesions.

Mutation in the type II collagen gene (COL2AI) as a cause of primary osteoarthritis associated with mild spondyloepiphyseal involvement

OBJECTIVE To define the clinical, radiologic and molecular characteristics of a patient with early progressive osteoarthritis and mild spondyloepiphyseal dysplasia. METHODS We describe an 18-year-old girl with early progressive osteoarthritis and mild spondyloepiphyseal dysplasia. The index case underwent a physical examination, anthropometric measurements and radiologic and laboratory studies. DNA of the patient and her only living parent (mother) was sequenced for the type II collagen gene (COL2A1). RESULTS Mild scoliosis was noticed in the proband at the age of 13 years. At the same age, she began to have arthralgia in almost all the joints and osteoarthritis progressed fast, necessitating a hip, knee and ankle prosthesis at the age of 18 years. She was eumorphic with no ocular or hearing abnormalities. Molecular testing of the COL2A1 gene revealed a p.Gly204Val mutation. The mutation was absent in the healthy mother. CONCLUSION This patient provides further proof that an early osteoarthritic phenotype can be caused by a mutation in the COL2A1 gene.

Osteoblastogenesis from synovial fluid-derived cells is related to the type and severity of juvenile idiopathic arthritis

IntroductionJuvenile idiopathic arthritis (JIA) is characterized by synovial inflammation, followed by hyperplastic changes of the synovium, and destruction of articular cartilage along with underlying bone. This hyperplastic process is the result of inflammation-induced activation of NF-κB, which may be accompanied by decreased osteogenic differentiation of synovial mesenchymal progenitors and contribute to bone resorption. We aimed to explore osteoblast differentiation of synovial fluid (SF)-derived mesenchymal progenitors and correlate it with intensity of inflammation in patients with JIA.MethodsPeripheral blood from 18 patients with oligoarticular (o)JIA, 22 patients with polyarticular (p)JIA and 18 controls was collected along with SF from 18 patients with oJIA and 9 patients with pJIA. SF-derived cells were cultured to assess osteoblastogenesis, using alkaline phosphatase histochemical staining and colorimetric activity assay. The expression of osteoblast-related genes, Runt-related transcription factor 2 (Runx2), Osteoprotegerin (OPG), Receptor activator of nuclear factor κB ligand (RANKL) and arthritis-related cytokine/chemokine genes, Tumor necrosis factor alpha (TNF-α, Fas, Fas ligand (FasL), Interleukin (IL)-1β, IL-4, IL-6, IL-17, IL-18, CC chemokine ligand (CCL)-2, CCL3, CCL4 was evaluated. Osteoblastogenesis was correlated with systemic and local inflammatory indicators. Expression of osteoblast genes was also analyzed in peripheral blood mononuclear cells (PBMC) and total SF-derived cells from patients with JIA. Additionally, we assessed the inhibitory effect of SF from patients with JIA on differentiation of human bone marrow (hBM)-derived osteoblasts.ResultsOsteoblastogenesis from SF-derived progenitors was decreased in patients with pJIA compared to those with oJIA. Osteoblastogenesis from primary SF-derived cells negatively correlated with erythrocyte sedimentation rate (ρ = -0.391, P = 0.05), C-reactive protein concentration (ρ = -0.527, P<0.01) and synovial concentration of IL-17 (ρ = -0.552, P = 0.01). SF-derived osteoblasts from pJIA patients expressed more CCL2 and CCL3 genes than in oJIA (P = 0.04 and P = 0.03, respectively; Mann-Whitney test). Expression of Fas was significantly higher in osteoblasts from patients with pJIA than those with oJIA (P = 0.03, Mann-Whitney test). SF-derived cells from patients with pJIA expressed higher levels of RANKL than in oJIA (P = 0.05, Mann-Whitney test). PBMCs from patients with JIA expressed less OPG than healthy control patients (P = 0.05, Kruskal-Wallis test). SF from all tested JIA patients inhibited differentiation of hBM-derived osteoblasts (P = 0.04, Kruskal-Wallis test).ConclusionsOsteoblast differentiation was decreased in patients with severe forms of JIA and accompanied by altered cytokine/chemokine expression pattern. Development of therapeutic interventions targeting synovial mesenchymal or osteoblast lineage cells in JIA would contribute to alleviating both bone destruction and inflammation in severe forms of the disease.

Lupus nephritis in Croatian children: clinicopathologic findings and outcome

We report clinical and histopathological features, treatment and outcome of 37 Croatian children with biopsy-proven lupus nephritis seen over a 30-year period. The mean age at lupus nephritis presentation was 12.11 ± 2.59 years (range 4.66–17.0). The most frequent histopathological finding was class IV (37.8%), followed by class III (35.1%), class V (16.2 %) and class II (10.8 %) lupus nephritis. Compared with other classes there were more boys among patients with class IV lupus nephritis, and hypertension, nephrotic syndrome and decreased estimated glomerular filtration rate at presentation were more common. The median histopathological activity and total scores were highest in class IV lupus nephritis patients. The mean follow-up was 7.14 ± 4.71 years, ranging from 1.1 years to 21.0 years. Kaplan–Meier estimates of patient and kidney (without renal failure) survival rates were 90.5% and 87 % at five years. The renal survival rate of class IV lupus nephritis patients was found significantly lower compared with other histological classes combined. Decreased estimated glomerular filtration rate at the time of diagnosis, class IV lupus nephritis versus other lupus nephritis classes, and high total histological score were the parameters significantly associated with adverse outcome. The therapy with cyclophosphamide showed as superior to the therapy with azathioprine.

Development and testing of a hybrid measure of muscle strength in juvenile dermatomyositis for use in routine care

To develop and test a hybrid measure of muscle strength for juvenile dermatomyositis (JDM), which is based on the combination of the Manual Muscle Testing in 8 muscles (MMT‐8) and the Childhood Myositis Assessment Scale (CMAS) but is more comprehensive than the former and more feasible than the latter.

Systemic lupus erythematosus: A new autoimmune disorder in Kabuki syndrome

We report a case of a 17-year-old Caucasian girl with syndromic features of clinically unrecognized Kabuki syndrome (KS), who developed systemic lupus erythematosus (SLE). Diagnosis of KS was established after whole exome sequencing (WES) and detection of de novo frameshift 1bp deletion in histone-lysine N-methyltransferase 2D gene (KMT2D). The pathogenic variant in exon 34 (c.8626delC: 55 reads C, 56 reads delC), has not been described previously and is predicted to truncate the protein (p.Gln2876Serfs*34) resulting in KMT2D loss of function. Notwithstanding that patients with KS have a substantial susceptibility to various autoimmune diseases, to the best of our knowledge this is the first report of an SLE and KS association. The exact relationship between the two conditions in our patient is difficult to determine with certainty, as a number of clinical features, including positive antiphospholipid antibodies, persistent hypogammaglobulinemia and the episode of convulsions may occur in both conditions, suggesting potential overlap of KS and SLE. The combination of a high susceptibility towards infections and an autoimmune disorder present a great challenge when trying to achieve the optimum therapy which will enable the patient to stay on the thin line of remission. This case report emphasizes the value of WES as a powerful tool for the diagnosis of rare disorders and/or unusual disease presentations of possible genetic cause.