The clinical and experimental treatment of Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and comprises of multiple subtypes. The most relevant disease subtypes, grouped upon current insight in disease mechanisms, are nonsystemic (oligo- and polyarticular) JIA and systemic JIA (sJIA). In this review, we summarize some of the main proposed mechanisms of disease in both nonsystemic and sJIA and discuss how current therapeutic modalities target some of the pathogenic immune pathways. Chronic inflammation in nonsystemic JIA is the result of a complex interplay between effector and regulatory immune cell subsets, with adaptive immune cells, specifically T-cell subsets and antigen-presenting cells, in a central role. There is, however, also innate immune cell contribution. SJIA is nowadays recognized as an acquired chronic inflammatory disorder with striking autoinflammatory features in the first phase of the disease. Some sJIA patients develop a refractory disease course, with indications for involvement of adaptive immune pathways as well. Currently, therapeutic strategies are directed at suppressing effector mechanisms in both non-systemic and sJIA. These strategies are often not yet optimally tuned nor timed to the known active mechanisms of disease in individual patients in both non-systemic and sJIA. We discuss current treatment strategies in JIA, specifically the 'Step-up' and 'Treat to Target approach' and explore how increased insight into the biology of disease may translate into future more targeted strategies for this chronic inflammatory disease at relevant time points: preclinical disease, active disease, and clinically inactive disease.

How autoinflammation may turn into autoimmune inflammation: Insights from monogenetic and complex IL-1 mediated auto-inflammatory diseases.

IL-1 mediated auto-inflammatory diseases are characterised by episodes of unexplained fever, generalized and localized inflammation. The characteristic symptoms predominantly result from exaggerated activation of innate immune pathways. However, in some patients with typical IL-1 mediated diseases, chronic disease manifestations develop in the absence of acute inflammation, suggesting the involvement of adaptive immune pathways. We discuss clinical observations as well as novel insights in how chronic activation of innate immune pathways can lead to auto-immune disease features in patients with auto-inflammatory diseases and how we need to better understand these sequelae in order to improve treatment strategies.

Trends in prescription of biological agents and outcomes of juvenile idiopathic arthritis: results of the Dutch national Arthritis and Biologics in Children Register.

BACKGROUND: Treatment of juvenile idiopathic arthritis (JIA) has changed dramatically since the introduction of biological agents in 1999. OBJECTIVE: To evaluate trends in prescription patterns of biological agents and the subsequent outcome of JIA. METHODS: The Arthritis and Biologics in Children register (multicentre prospective observational study) aimed to include all consecutive patients with JIA in the Netherlands who had started biological agents since 1999. Patients were divided according to year of introduction of first biological agent. Patient characteristics at introduction of the first biological agent and its effectiveness were analysed over 12 years. RESULTS: 335 patients with non-systemic JIA and 86 patients with systemic JIA started a biological agent between 1999 and 2010. Etanercept remained the most often prescribed biological agent for non-systemic JIA; anakinra became first choice for systemic JIA. The use of systemic glucocorticoids and synthetic disease-modifying antirheumatic drugs before biological agents decreased. During these 12 years of observation, biological agents were prescribed earlier in the disease course and to patients with lower baseline JADAS (Juvenile Arthritis Disease Activity Score) disease activity. All baseline disease activity parameters were lowered in patients with non-systemic JIA. In systemic JIA, prescription patterns changed towards very early introduction of biological agents (median 0.4 years of disease duration) in patients with a low number of joints with active arthritis and high erythrocyte sedimentation rates. These changes for both systemic and non-systemic JIA resulted in more patients with inactive disease after 3 and 15 months of treatment. CONCLUSIONS: Biological agents are increasingly prescribed, earlier in the disease and in patients with JIA with lower disease activity. These changes are accompanied by better short-term disease outcomes.

Systemic Juvenile Idiopathic Arthritis in two children; case report on clinical course, challenges in diagnosis and the role of FDG-PET/CT-scan.

Systemic juvenile idiopathic arthritis (sJIA, also called Still's disease) is a rare childhood auto-inflammatory disease with significant morbidity. This case report illustrates the clinical course and highlights diagnostic challenges. FDG-PET/CT imaging may be beneficial in the diagnostic process for some cases, in order to achieve rapid diagnosis and early treatment.

Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy.

Macroautophagy (hereafter autophagy) is a lysosomal degradation pathway critical for maintaining cellular homeostasis and viability, and is predominantly regarded as a rapid and dynamic cytoplasmic process. To increase our understanding of the transcriptional and epigenetic events associated with autophagy, we performed extensive genome-wide transcriptomic and epigenomic profiling after nutrient deprivation in human autophagy-proficient and autophagy-deficient cells. We observed that nutrient deprivation leads to the transcriptional induction of numerous autophagy-associated genes. These transcriptional changes are reflected at the epigenetic level (H3K4me3, H3K27ac, and H3K56ac) and are independent of autophagic flux. As a proof of principle that this resource can be used to identify novel autophagy regulators, we followed up on one identified target: EGR1 (early growth response 1), which indeed appears to be a central transcriptional regulator of autophagy by affecting autophagy-associated gene expression and autophagic flux. Taken together, these data stress the relevance of transcriptional and epigenetic regulation of autophagy and can be used as a resource to identify (novel) factors involved in autophagy regulation.

[Two children with severe complications following incomplete removal of a percutaneous endoscopic gastrostomy (PEG) catheter]. / Twee kinderen met ernstige complicaties na onvolledige verwijdering van een percutane-endoscopischegastrostomie(PEG)-katheter.

A 6-year-old boy with multiple severe disabilities was admitted with acute and progressive dyspnoea. A new percutaneous endoscopic gastrostomy (PEG) catheter had been placed 2 weeks earlier, during which the old catheter was cut and left in the stomach. Radiological assessment revealed pneumonia and a traumatic fistula between the oesophagus and the left main bronchus. Respiratory support was required. The patient recovered after oesophagoscopic removal of the remaining portion of the PEG catheter. A 7-year-old boy with multiple severe disabilities presented with an acutely reduced level of consciousness, vomiting and progressive dyspnoea. Chest x-ray revealed signs of aspiration pneumonia and, after respiratory problems worsened, a foreign object in the oesophagus. The foreign object was likely the remaining portion of a PEG catheter that was removed 12 months earlier. The patient was discharged in good condition a few days after oesophagoscopic removal of the remaining catheter. PEG is a commonly used method for enteral feeding in children. The Dutch guideline on enteral feeding in children indicates that endoscopic removal of the PEG catheter is often necessary. In daily practice, however, endoscopic removal is not always performed. To avoid serious complications, authors recommend endoscopic removal ofthe silicon disk when replacing or removing a PEG catheter in children aged less than 6 years and all children with mental retardation, prior laparotomy or constipation. Endoscopic removal of the disk should be considered in all other children if the disk is not passed in stool within 2 weeks and an x-ray shows that the disk is in the oesophagus, stomach or proximal intestine.

Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

BACKGROUND: Macrophage activation syndrome (MAS) is a severe and potentially lethal complication of several inflammatory diseases but seems particularly linked to systemic juvenile idiopathic arthritis (sJIA). Standardized diagnostic and treatment guidelines for MAS in sJIA are currently lacking. The aim of this systematic literature review was to evaluate currently available literature on diagnostic criteria for MAS in sJIA and provide an overview of possible biomarkers for diagnosis, disease activity and treatment response and recent advances in treatment. METHODS: A systematic literature search was performed in MEDLINE, EMBASE and Cochrane. 495 papers were identified. Potentially relevant papers were selected by 3 authors after which full text screening was performed. All selected papers were evaluated by at least two independent experts for validity and level of evidence according to EULAR guidelines. RESULTS: 27 papers were included: 7 on diagnosis, 9 on biomarkers and 11 on treatment. Systematic review of the literature confirmed that there are no validated diagnostic criteria for MAS in sJIA. The preliminary Ravelli criteria, with the addition of ferritin, performed well in a large retrospective case-control study. Recently, an international consortium lead by PRINTO proposed a new set of diagnostic criteria able to distinguish MAS from active sJIA and/or infection with superior performance. Other promising diagnostic biomarkers potentially distinguish MAS complicating sJIA from primary and virus-associated hemophagocytic lymphohistiocytosis. The highest level of evidence for treatment comes from case-series. High dose corticosteroids with or without cyclosporine A were frequently reported as first-line therapy. From the newer treatment modalities, promising responses have been reported with anakinra. CONCLUSION: MAS in sJIA seems to be diagnosed best by the recently proposed PRINTO criteria, although prospective validation is needed. Novel promising biomarkers for sJIA related MAS are in need of prospective validation as well, and are not widely available yet. Currently, treatment of MAS in sJIA relies more on experience than evidence based medicine. Taking into account the severity of MAS and the scarcity of evidence, early expert consultation is recommended as soon as MAS is suspected.