Faekah Gohar

Proinflammatory S100A12 Can Activate Human Monocytes via Toll-like Receptor 4

RATIONALE S100A12 is overexpressed during inflammation and is a marker of inflammatory disease. Furthermore, it has been ascribed to the group of damage-associated molecular pattern molecules that promote inflammation. However, the exact role of human S100A12 during early steps of immune activation and sepsis is only partially described thus far. OBJECTIVES We analyzed the activation of human monocytes by granulocyte-derived S100A12 as a key function of early inflammatory processes and the development of sepsis. METHODS Circulating S100A12 was determined in patients with sepsis and in healthy subjects with experimental endotoxemia. The release of human S100A12 from granulocytes as well as the promotion of inflammation by activation of human monocytes after specific receptor interaction was investigated by a series of in vitro experiments. MEASUREMENTS AND MAIN RESULTS S100A12 rises during sepsis, and its expression and release from granulocytes is rapidly induced in vitro and in vivo by inflammatory challenge. A global gene expression analysis of S100A12-activated monocytes revealed that human S100A12 induces inflammatory gene expression. These effects are triggered by an interaction of S100A12 with Toll-like receptor 4 (TLR4). Blocking S100A12 binding to TLR4 on monocytes or TLR4 expressing cell lines (HEK-TCM) abrogates the respective inflammatory signal. On the contrary, blocking S100A12 binding to its second proposed receptor (receptor for advanced glycation end products [RAGE]) has no significant effect on inflammatory signaling in monocytes and RAGE-expressing HEK293 cells. CONCLUSIONS Human S100A12 is an endogenous TLR4 ligand that induces monocyte activation, thereby acting as an amplifier of innate immunity during early inflammation and the development of sepsis.

Management of juvenile idiopathic arthritis: hitting the target

The treatment of juvenile idiopathic arthritis (JIA) is evolving. The growing number of effective drugs has led to successful treatment and prevention of long-term sequelae in most patients. Although patients with JIA frequently achieve lasting clinical remission, sustained remission off medication is still elusive for most. Treatment approaches vary substantially among paediatric rheumatologists owing to the inherent heterogeneity of JIA and, until recently, to the lack of accepted and well-evidenced guidelines. Furthermore, many pertinent questions related to patient management remain unanswered, in particular regarding treatment targets, and selection, intensity and sequence of initiation or withdrawal of therapy. Existing JIA guidelines and recommendations do not specify treat-to-target or tight control strategies, in contrast to adult rheumatology in which these approaches have been successful. The concepts of window of opportunity (early treatment to improve long-term outcomes) and immunological remission (abrogation of subclinical disease activity) are also fundamental when defining treatment methodologies. This Review explores the application of these concepts to JIA and their possible contribution to the development of future clinical guidelines or consensus treatment protocols. The article also discusses how diverse forms of standardized, guideline-led care and personalized treatment can be combined into a targeted, patient-centred approach to optimize management strategies for patients with JIA.

Validation of Relapse Risk Biomarkers for Routine Use in Patients With Juvenile Idiopathic Arthritis

The myeloid‐related proteins 8 and 14 (MRP‐8/MRP‐14) and neutrophil‐derived S100A12 are biomarkers of inflammation. They can be used to determine the relapse risk in patients with juvenile idiopathic arthritis (JIA) after stopping antiinflammatory treatment. In this study, we tested the performance of different enzyme‐linked immunosorbent assays (ELISAs) in order to validate systems available for routine use.

Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin‐encoding MEFV mutations. Patients present with recurrent but self‐limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil‐derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF.

Secretory Activity of Neutrophils Correlates With Genotype in Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin‐encoding MEFV mutations. Patients present with recurrent but self‐limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil‐derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF.

S100A12 Is Associated with Response to Therapy in Juvenile Idiopathic Arthritis

Objective. Around one-third of patients with juvenile idiopathic arthritis (JIA) fail to respond to first-line methotrexate (MTX) or anti-tumor necrosis factor (TNF) therapy, with even fewer achieving ≥ American College of Rheumatology Pediatric 70% criteria for response (ACRpedi70), though individual responses cannot yet be accurately predicted. Because change in serum S100-protein myeloid-related protein complex 8/14 (MRP8/14) is associated with therapeutic response, we tested granulocyte-specific S100-protein S100A12 as a potential biomarker for treatment response. Methods. S100A12 serum concentration was determined by ELISA in patients treated with MTX (n = 75) and anti-TNF (n = 88) at baseline and followup. Treatment response (≥ ACRpedi50 score), achievement of inactive disease, and improvement in Juvenile Arthritis Disease Activity Score (JADAS)-10 score were recorded. Results. Baseline S100A12 concentration was measured in patients treated with anti-TNF [etanercept n = 81, adalimumab n = 7; median 200, interquartile range (IQR) 133–440 ng/ml] and MTX (median 220, IQR 100–440 ng/ml). Of the patients in the anti-TNF therapy group, 74 (84%) were also receiving MTX. Responders to MTX (n = 57/75) and anti-TNF (n = 66/88) therapy had higher baseline S100A12 concentration compared to nonresponders: median 240 (IQR 125–615) ng/ml versus 150 (IQR 87–233) ng/ml, p = 0.021 for MTX, and median 308 (IQR 150–624) ng/ml versus 151 (IQR 83–201) ng/ml, p = 0.002, for anti-TNF therapy. Followup S100A12 could be measured in 44/75 MTX-treated patients (34/44 responders) and 39/88 anti-TNF-treated patients (26/39 responders). Responders had significantly reduced S100A12 concentration (MTX: p = 0.031, anti-TNF: p < 0.001) at followup versus baseline. Baseline serum S100A12 in both univariate and multivariate regression models for anti-TNF therapy and univariate analysis alone for MTX therapy was significantly associated with change in JADAS-10. Conclusion. Responders to MTX or anti-TNF treatment can be identified by higher pretreatment S100A12 serum concentration levels.

Sleep Fragmentation and Biomarkers in Juvenile Idiopathic Arthritis.

Objectives: (1) To compare sleep (nighttime sleep duration and sleep efficiency) and sleep fragmentation (movement and fragmentation index), as measured by actigraphy, and symptoms (pain and fatigue) in 8- to 14-year-old children with polyarticular and extended oligoarticular juvenile idiopathic arthritis (JIA) and (2) to examine the associations between sleep fragmentation (movement and fragmentation index) and the calcium-binding protein biomarkers S100A12 and myeloid-related protein (MRP8/14). Method: Participants included 40 children with extended oligoarticular (n = 15) or polyarticular (n = 25) JIA and their parents. Serum protein samples were obtained during routine rheumatology clinic visits. Children completed the PedsQL Multidimensional Fatigue Scale and daily pain and sleep diaries and wore actigraphy monitors for 9 consecutive days. Parents completed the Children’s Sleep Habits Questionnaire (CSHQ). Results: Of the 40 children, 68% scored above the CSHQ clinical cutoff score for sleep disturbances. Mean nighttime sleep duration was 7.5 hr, and mean sleep efficiency was 85.3%. Group differences were not found for nighttime sleep duration, sleep efficiency, movement and fragmentation index, or S100A12 and MRP8/14 protein concentrations. In a stepwise regression, medications, joint count, and movement and fragmentation index explained 21% of the variance in MRP8/14 concentration. Conclusion: Decreased nighttime sleep duration, poor sleep efficiency, and fragmented sleep were observed in our sample, regardless of JIA category. Sleep fragmentation was a significant predictor of MRP8/14 protein concentration. Additional research is needed to understand the interrelations among sleep fragmentation, effects of medication, and S100A12 and MRP8/14 protein biomarkers in JIA.

P wave dispersion and QT dispersion in adult Turkish migrants with familial mediterranean fever living in Germany.

Background: Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease associated with subclinical inflammation, which includes atherosclerosis arising from endothelial inflammation, which in turn increases the risk of atrial or ventricular arrhythmias. Conduction abnormalities can be detected using the electrocardiographic (ECG) indices P and QT dispersion (Pdisp and QTdisp). Currently, it is unknown whether patients with FMF are more likely to have abnormalities of these ECG indices. Moreover, existing studies were conducted in countries with higher FMF prevalence. We therefore perform the first prospective study assessing Pdisp and QTdisp in adult FMF patients in Germany, where prevalence of FMF is low. Method: Asymptomatic FMF patients (n=30) of Turkish ancestry living in Germany and age-matched healthy controls (n=37) were prospectively assessed using 12-lead ECG. Results: Patients and controls were comparable in gender and body mass index, and patients had higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum amyloid A (SAA) compared to controls (ESR: 23.7±14.3 vs. 16.1±13,3 mm/1sth, p=0.03, CRP: 0.73±0.9 vs. 0.26±0.4 g/dl, p=0.01, SAA: 3.14±4,8 vs. 0.37±0.3 mg/dl, p<0.01). No statistically significant difference between patients and controls respectively, for Pdisp (43.7±11.9 vs. 47.1±11.2ms, p=0.23), QTdisp (65.9±12.3 vs. 67.6±12.7 ms, p=0.58) or corrected QTdisp (cQTdisp: 73.9±15.0 vs. 76.0±13.3 ms, p=0.55) was found. No correlation could be found between Pdisp or QTdisp or cQTdisp and any of the biochemical markers of inflammation. Conclusion: FMF patients living in Germany show a Pdisp and QTdisp comparable to healthy controls, with no increased risk of atrial or ventricular arrhythmias indicated.

OR6-001 - S100A12 as pro-inflammatory TLR4 ligand

The granulocyte-specific Ca2+-binding protein S100A12 is overexpressed during autoinflammation as well as other inflammatory conditions in humans and has been ascribed to the group of pro-inflammatory Damage Associated Molecular Pattern molecules (DAMPs). S100A12-levels in human serum reveal excellent correlation with patients’ inflammation state, which renders S100A12 a powerful biomarker. In order to operate as DAMP S100A12 requires binding to cellular receptors. The protein was originally found to bind RAGE and was in turn entitled extracellular newly identified RAGE-binding protein (EN-RAGE). RAGE ligation by S100A12 is proposed to trigger a pro-inflammatory cascade in microvascular endothelial cells, macrophages and lymphocytes, culminating in NFκ-B activation. This amplifies the inflammatory response by triggering further RAGE expression and thus drives a feed-forward loop that can potentiate inflammation.

AB1017 Sleep Fragmentation and Biomarkers in Juvenile Idiopathic Arthritis

Background Children with JIA have been shown to have increased frequency of sleep fragmentation when compared to healthy peers. The relationship between this fragmentation and the underlying inflammatory process has not been established. The proteins S100A12 and myeloid-related protein 8/14 (MRP8/14) are associated with disease activity in JIA and have also been associated with sleep disordered breathing in children and adults without JIA. The associations between the S100A12 and MRP8/14 proteins and sleep fragmentation have not been evaluated in children with JIA and the contribution of inflammation to sleep disturbance is not known. Objectives To measure the associations between inflammatory S100A12 and MRP8/14 protein biomarkers and sleep fragmentation (wake after sleep onset) in 8-14 year-old children with polyarticular and extended oligoarticular juvenile idiopathic arthritis (JIA). Methods Forty children between 8-to-14 years of age, with extended oligoarticular (n=15) and polyarticular (n=25) JIA and their parents participated in this cross-sectional, observational study. The treating rheumatologist assessed disease activity and inactive disease was measured using modified provisional ACR criteria for clinically inactive disease. Serum samples were obtained during each childs routine rheumatology clinic visit. Children completed the PedsQL™ Multidimensional Fatigue scale, daily sleep diaries, and wore actigraphy monitors for 9 consecutive days. Parents completed the Childrens Sleep Habits Questionniare (CSHQ) regarding their childs sleep habits. Results Of the 40 children, 22 (55%) had inactive disease. 68% scored above the CSHQ clinical cut-off score for sleep disturbances. Average sleep duration was 7.5 hours. Mean S100A12 and MRP8/14 protein levels were not significantly different between JIA categories or between children with active versus inactive disease. After controlling for age and joint count, wake after sleep onset was a significant predictor for S100A12 but not MRP8/14 proteins. Conclusions Inadequate amounts of sleep, increased amounts of wake, and poor sleep quality were observed in our sample, regardless of whether children had active or inactive disease. Similarly, children with extended oligoarticular and polyarticular arthritis had similar levels of inflammatory proteins and sleep disruption. Additional prospective evaluation of these proteins in larger cohorts of children with more variation in disease activity is needed to better understand the associations between these biomarkers, inflammation, and sleep disturbances in JIA. Disclosure of Interest None declared