Sj Vastert

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

BackgroundMacrophage 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.MethodsA 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.Results27 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.ConclusionMAS 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.

Effectiveness of first line use of recombinant IL-1RA treatment in steroid naïve systemic juvenile idiopathic arthritis: Results of a prospective cohort study

To conduct a prospective cohort study using anakinra, a recombinant IL‐1 receptor antagonist (IL‐1Ra), as first‐line therapy in patients with new‐onset systemic juvenile idiopathic arthritis (JIA).

Self‐Sustained Resistance to Suppression of CD8+ Teff Cells at the Site of Autoimmune Inflammation Can Be Reversed by Tumor Necrosis Factor and Interferon‐γ Blockade

Resistance of Teff cells to Treg cell–mediated suppression contributes to the breakdown of peripheral tolerance in the inflamed joints of patients with juvenile idiopathic arthritis (JIA). However, unanswered questions are whether this resistant phenotype is self‐sustained and whether CD8+ and CD4+ Teff cells share the same mechanism of resistance to suppression. We undertook this study to investigate intrinsic resistance of CD8+ Teff cells to suppression and to determine how this can be targeted therapeutically.

Consensus-based recommendations for the management of uveitis associated with juvenile idiopathic arthritis: the SHARE initiative

Background In 2012, a European initiative called Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and uveitis is possibly its most devastating extra-articular manifestation. Evidence-based guidelines are sparse and management is mostly based on physicians’ experience. Consequently, treatment practices differ widely, within and between nations. Objectives To provide recommendations for the diagnosis and treatment of JIA-associated uveitis. Methods Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was constituted, consisting of nine experienced paediatric rheumatologists and three experts in ophthalmology from Europe. Recommendations derived from a validated systematic literature review were evaluated by an Expert Committee and subsequently discussed at two consensus meetings using nominal group techniques. Recommendations were accepted if >80% agreement was reached (including all three ophthalmologists). Results In total, 22 recommendations were accepted (with >80% agreement among experts): 3 on diagnosis, 5 on disease activity measurements, 12 on treatment and 2 on future recommendations. Conclusions The SHARE initiative aims to identify best practices for treatment of patients suffering from JIA-associated uveitis. Within this remit, recommendations for the diagnosis and treatment of JIA-associated uveitis have been formulated by an evidence-informed consensus process to suggest a standard of care for JIA-associated uveitis patients throughout Europe.

Akinra restores the defective IL-18 NK cell axis in steroid naïve systemic onset JIA patients

Systemic Onset Juvenile Idiopathic Arthritis (SoJIA) is characterized by systemic inflammation and chronic arthritis. Intriguingly, the IL-18-NK cell axis seems to be disturbed in the majority of SoJIA patients. The observed NK cell dysfunction in SoJIA patients contributes to important features of the disease including the susceptibility for macrophage activation syndrome. Here we describe the effects of Anakinra mono treatment on the IL-18-NK cel axis in steroid naive SoJIA patients. In this study sixteen consecutive patients diagnosed with systemic onset JIA were included. Clinical response to Anakinra was evaluated using the validated core set parameters for JIA as well as several biochemical parameters of disease activity. In this cohort we show a good clinical response to Anakinra in 14/16 patients SoJIA patients prior to standard steroid treatment. After 3 weeks of treatment 75% of patients achieved a pACR90 score. Clinical improvement was accompanied by normalization of IL-1, IL-6 and IL-18 levels in plasma. Interestingly, the use of Anakinra in patients with short disease duration induces restoration of the IL-18 - NK cell axis resulting in improved lytic NK cell function and regaining of the NK cell responsiveness to IL-18 stimulation. Moreover, Anakinra seems to down regulate inflammasome activation. These data suggest that the mechanisms of inflammatory control induced by Anakinra in SoJIA patients involves more than blocking IL-1R signaling, since it seems to restore the IL-18-NK cell route as well.

PD-1+CD8+ T cells are clonally expanding effectors in human chronic inflammation

Chronic inflammatory diseases are characterized by recurrent inflammatory attacks in the tissues mediated by autoreactive T cells. Identity and functional programming of CD8+ T cells at the target site of inflammation still remain elusive. One key question is whether, in these antigen-rich environments, chronic stimulation leads to CD8+ T cell exhaustion comparable to what is observed in infectious disease contexts. In the synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients, a model of chronic inflammation, an overrepresentation of PD-1+CD8+ T cells was found. Gene expression profiling, gene set enrichment analysis, functional studies, and extracellular flux analysis identified PD-1+CD8+ T cells as metabolically active effectors, with no sign of exhaustion. Furthermore, PD-1+CD8+ T cells were enriched for a tissue-resident memory (Trm) cell transcriptional profile and demonstrated increased clonal expansion compared with the PD-1– counterpart, suggesting antigen-driven expansion of locally adapted cells. Interestingly, this subset was also found increased in target tissues in other human chronic inflammatory diseases. These data indicate that local chronic inflammation drives the induction and expansion of CD8+ T cells endowed with potential detrimental properties. Together, these findings lay the basis for investigation of PD-1–expressing CD8+ T cell targeting strategies in human chronic inflammatory diseases.

A1.06 Phagocyte involvement in systemic onset juvenile idiopathic arthritis

Background Systemic onset Juvenile Idiopathic Artritis (sJIA) is a systemic autoinflammatory disease, characterised by arthritis, spiking fever and rash and elevation of serum S100-proteins and interleukin (IL)-18. The role of monocytes and neutrophils in the inflammatory cascade of sJIA is still unclear. Objective To study the role of monocytes and neutrophils in the inflammatory cascade of sJIA. Methods We determined neutrophil activation ex vivo (phenotype and cell membrane markers) and after stimulation (ROS-production and degranulation) of cells derived from sJIA with disease onset or in remission, compared to healthy donors (HDs). To investigate the role of monocytes, we assessed cytokine production of PBMCs from sJIA patients and HDs after stimulation with TLR-4 activating S100-proteins (+/- ATP) or other TLR-ligands. In a cohort of sJIA patients at onset and during inactive disease, we evaluated cell counts and serum levels of cytokines, chemokines and other analytes. Cytokine concentrations in supernatant and serum were determined by multiplex immunoassay. Results Twenty-one of 23 patients with onset sJIA had elevated neutrophil counts, while monocyte counts were elevated in only 5/23 patients. Many inflammatory markers were significantly elevated in serum of onset sJIA patients, among which several neutrophil specific proteins indicating the importance of this cell type. Neutrophils from onset sJIA patients showed an activated phenotype, reflected by higher ex vivo cell membraneexpression of FC-gamma receptors (CD32 and CD64), markers of secretory vesicles (CD35) and specific granules (CD66b). ROS production and degranulation were also enhanced in onset sJIA. Neutrophil phenotypenormalized when patients were in remission. In contrast to the hyperactivated status of neutrophils in active sJIA, PBMCs from these patients produced less Il-1b, IL-18, IL-6 and TNF-a upon TLR-stimulation compared to PBMCs from remission patients or HDs, suggesting tolerance after exposure to high TLR4 stimulating S100-levels in vivo. Conclusions We show here that monocytes from onset sJIA patients produce less cytokines upon stimulation, while the neutrophils are hyperactivated, reflected by increased cell membrane activation markers, ROS production and degranulation. The exact role of each cell type and activity and their interaction in sJIA pathology is currently under investigation.

S100A12 as diagnostic tool in the differential diagnosis of sJIA associated MAS vs. hereditary or acquired HLH

8th International Congress of Familial Mediterranean Fever and Systemic Autoinflammatory Diseases

PReS-FINAL-2181: Recombinant il-1ra restores the il-18-nk cell axis in steroid naive systemic juvenile idiopathic arthritis

Systemic onset juvenile idiopathic arthritis (sJIA) is an acquired auto-inflammatory disease characterized by systemic inflammation and innate immune activation reflected in uncontrolled production of cytokines such as IL-1, IL-6 and IL-18. In sJIA, NK cell function is severely hampered despite high levels of IL-18. We recently found that defective phosphorylation of the IL-18 receptor beta is responsible for the deficient IL-18-NK cell axis in sJIA.

PReS-FINAL-1019: Inflammatory monocytes induce resistance of effector t cells to suppression

Ever since their discovery research has focused on whether deficiencies in FOXP3+ regulatory T cells (Treg) underlie human autoimmune pathology. Very recently however, the topic of Treg extrinsic factors as the cause of regulatory defects in chronic autoimmune inflammation has become more prominent in the discussion. It has become clear that resistance of effector cells (Teff) to suppression contributes to disturbed immune regulation in autoimmune inflammation, especially at the site of inflammation. Therefore, targeting this unresponsiveness to suppression could be a promising treatment option for patients with autoimmune disease. It remains unknown how resistance of T cells to suppression is induced.