To develop and validate a diagnostic score that aids in identifying macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (sJIA). The clinical and laboratory features of 362 patients with sJIA-associated MAS and 404 patients with active sJIA without evidence of MAS were collected in a multinational collaborative project. Eighty percent of the study population was used to develop the score and the remaining 20% constituted the validation sample. A Bayesian Model Averaging approach was used to assess the role of each clinical and laboratory variables in the diagnosis of MAS and to obtain the coefficients of selected variables. The final score, named MAS/sJIA (MS) score, resulted from the linear combination of these coefficients multiplied by the values of each variable. The cut-off that best discriminated MAS from active sJIA was calculated by means of receiver operating characteristic (ROC) curve analysis. Score performance was evaluated in both developmental and validation samples. The MS score ranges from -8.4 to 41.8 and comprises seven variables: central nervous system dysfunction, haemorrhagic manifestations, active arthritis, platelet count, fibrinogen, lactate dehydrogenase and ferritin. A cut-off value ≥-2.1 revealed the best performance in discriminating MAS from active sJIA, with a sensitivity of 0.85, a specificity of 0.95 and a kappa value of 0.80. The good performance of the MS score was confirmed in the validation sample. The MS score is a powerful and feasible tool that may assist practitioners in making a timely diagnosis of MAS in patients with sJIA.

Objectives To describe the clinical characteristics, treatment response and genetic findings in a large cohort of patients with undefined systemic autoinflammatory diseases (SAIDs). Methods Clinical and genetic data from patients with undefined SAIDs were extracted from the Eurofever registry, an international web-based registry that retrospectively collects clinical information on patients with autoinflammatory diseases. Results This study included 187 patients. Seven patients had a chronic disease course, 180 patients had a recurrent disease course. The median age at disease onset was 4.3 years. Patients had a median of 12 episodes per year, with a median duration of 4 days. Most commonly reported symptoms were arthralgia (n=113), myalgia (n=86), abdominal pain (n=89), fatigue (n=111), malaise (n=104) and mucocutaneous manifestations (n=128). In 24 patients, relatives were affected as well. In 15 patients, genetic variants were found in autoinflammatory genes. Patients with genetic variants more often had affected relatives compared with patients without genetic variants (p=0.005). Most patients responded well to non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine and anakinra. Complete remission was rarely achieved with NSAIDs alone. Notable patterns were found in patients with distinctive symptoms. Patients with pericarditis (n=11) were older at disease onset (33.8 years) and had fewer episodes per year (3.0/year) compared with other patients. Patients with an intellectual impairment (n=8) were younger at disease onset (2.2 years) and often had relatives affected (28.6%). Conclusion This study describes the clinical characteristics of a large cohort of patients with undefined SAIDs. Among these, patients with pericarditis and intellectual impairment appear to comprise distinct subsets.

Nephritis is the most important chronic complication of IgA Vasculitis (IgAV)/Henoch-Schönlein purpura (IGAV/HSP) and thus the main prognostic factor of this most common childhood vasculitis. Since the prognosis and treatment selection depends on the mode of interpretation of biopsy material, in this manuscript we have presented several issues related to the uneven application of different histological classifications in IgAV/Henoch-Schönlein purpura nephritis (HSPN). The nephritis of IgAV/IGAV/HSP will be abbreviated as HSPN for this paper. In clinical practice we use different histological classifications for HSPN. It is not known which of these classifications best correlates with severity of renal disease and renal outcome in IgAV/IGAV/HSP. One of the major problem with existing histological classifications is that there is no consensus on the implementation of biopsy in the treatment of HSPN. There is a histologic classification system conventionally used in HSPN, of the International Study of Kidney Disease in Children (ISKDC). On the other hand there is the new classification system suggested for IgA nephropathy, the Oxford classification. The latter has been validated only in IgA nephropathy. There are also two further histologic classifications of Haas and Koskela that have been developed. Current treatment strategies in HSPN are not standardised nor predominantly based on histological classification. One of the possible solutions to problems related to the application of different histological classification in HSPN is the implementation of multicenter multinational prospective studies with joint collaboration between pediatric rheumatologists, nephrologists and nephropathologists to correlate the clinical features and outcome with the classification systems as well among the classifications. This classification should be the basis for the construction of guidelines for the treatment of patients with HSPN.

IgA vasculitis (IgAV) or Henoch-Schönlein purpura (HSP) is the most common vasculitis in children, and nephritis (IgAVN or HSPN) is the most important and only chronic manifestation of the disease. Despite this, there are no diagnostic criteria and we rely on the European League Against Rheumatism/Paediatric Rheumatology International Trials Organization/Paediatric Rheumatology European Society-endorsed Ankara 2008 classification criteria in our daily practice. Basic investigations that should be done in every patient with IgAVN include blood pressure measurement, estimated glomerular filtration rate and urinalysis. Kidney biopsy is still the gold standard for the diagnosis of IgAVN since noninvasive confirmation of nephritis is still pending. According to the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) recommendations, the first-line treatment for with mild forms of IgAVN is oral glucocorticoids, for patients with moderate IgAVN parenterally administrated glucocorticoids in pulsed doses, while initial treatment for patients with the most severe forms of IgAVN include pulsed doses of glucocorticoids in combination with intravenous cyclophosphamide pulses. New therapeutic options are currently being tested, aiming to reduce the production of galactose-deficient IgA₁ and autoantibodies or suppress the alternative or lectin complement pathway and blocking mesangial cell activation.

The 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. Serum 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. The 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. The 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.

What are the challenges ahead and how have we responded so far when it comes to the non-granulomatous systemic vasculitis, characterized mainly by deposits of IgA immune complexes in the endothelium of small blood vessels—IgA vasculitis (IgAV)? That is the question to which we tried to answer. We summarized existing knowledge about epidemiology, pathogenesis, genetics, diagnostic tests and therapy in this somewhat neglected entity in pediatric rheumatology. Since etiopathogenesis of IgA vasculitis is complex, with factors other than galactose-deficient IgA₁-containing immune complexes also being important, and may involve numerous interactions between environmental and genetic factors, genomics alone cannot explain the entirety of the risk for the disease. The incidence of IgAV and nephritis varies worldwide and may be a consequence of overlapping genetic and environmental factors. In addition to the role of the HLA class II genes, some studies have pointed to the importance of non-HLA genes, and modern geostatistical research has also indicated a geospatial risk distribution, which may suggest the strong influence of different environmental factors such as climate, pathogen load, and dietary factors. The application of modern geostatistical methods until recently was completely unknown in the study of this disease, but thanks to the latest results it has been shown that they can help us a lot in understanding epidemiology and serve as a guide in generating new hypotheses considering possible environmental risk factors and identification of potential genetic or epigenetic diversity. There is increasing evidence that an integrative approach should be included in the understanding of IgA vasculitis, in terms of the integration of genomics, proteomics, transcriptomics, and epigenetics. This approach could result in the discovery of new pathways important for finding biomarkers that could stratify patients according to the risk of complications, without an invasive kidney biopsy which is still the gold standard to confirm a diagnosis of nephritis, even if biopsy findings interpretation is not uniform in clinical practice. Ultimately, this will allow the development of new therapeutic approaches, especially important in the treatment of nephritis, for which there is still no standardized treatment.