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Objective: The aim of this study was to quantify costs of hospital-associated care for juvenile idiopathic arthritis (JIA), provide insights in patient-level variation in costs, and investigate costs over time from the moment of JIA diagnosis. Results were reported for all JIA patients in general and by subtype. Methods: This study was a single-center, retrospective analysis of prospective data from electronic medical records of children with JIA, ages 0–18 years, between April 1, 2011 and March 31, 2019. Patient characteristics (age, sex, JIA subtype) and hospital-based resource use (consultations, medication, radiology procedures, laboratory testing, surgeries, emergency department [ED] visits, hospital stays) were extracted and analyzed. Unit prices were obtained from Dutch reimbursement lists and pharmaceutical and hospital list prices. Results: The analysis included 691 patients. The mean total cost of hospital care was €3,784/patient/year, of which €2,103 (55.6%) was attributable to medication. Other costs involved pediatric rheumatologist visits (€633/patient/year [16.7%]), hospital stays (€439/patient/year [11.6%]), other within-hospital specialist visits (€324/patient/year [8.6%]), radiology procedures (€119/patient/year [3.1%]), laboratory tests (€114/patient/year [3.0%]), surgeries (€46/patient/year [1.2%]), and ED visits (€6/patient/year [0.2%]). Mean annual total costs varied between JIA subtypes and between individuals and were the highest for systemic JIA (€7,772/patient/year). Over the treatment course, costs were the highest in the first month after JIA diagnosis. Conclusion: Hospital care costs of JIA vary substantially between individuals, between subtypes, and over the treatment course. The highest annual costs were for systemic JIA, primarily attributable to medication (i.e., biologics). Costs of other hospital-associated care were comparable regardless of subtype.

Objective To investigate medication prescription patterns among children with JIA, including duration, sequence and reasons for medication discontinuation. Methods This study is a single-centre, retrospective analysis of prospective data from the electronic medical records of JIA patients receiving systemic therapy aged 0–18 years between 1 April 2011 and 31 March 2019. Patient characteristics (age, gender, JIA subtype) and medication prescriptions were extracted and analysed using descriptive statistics, Sankey diagrams and Kaplan–Meier survival methods. Results Over a median of 4.2 years follow-up, the 20 different medicines analysed were prescribed as monotherapy (n = 15) or combination therapy (n = 48 unique combinations) among 236 patients. In non-systemic JIA, synthetic DMARDs were prescribed to almost all patients (99.5%), and always included MTX. In contrast, 43.9% of non-systemic JIA patients received a biologic DMARD (mostly adalimumab or etanercept), ranging from 30.9% for oligoarticular persistent ANA-positive JIA, to 90.9% for polyarticular RF-positive JIA. Among systemic JIA, 91.7% received a biologic DMARD (always including anakinra). When analysing medication prescriptions according to their class, 32.6% involved combination therapy. In 56.8% of patients, subsequent treatment lines were initiated after unsuccessful first-line treatment, resulting in 68 unique sequences. Remission was the most common reason for DMARD discontinuation (44.7%), followed by adverse events (28.9%) and ineffectiveness (22.1%). Conclusion This paper reveals the complexity of pharmacological treatment in JIA, as indicated by: the variety of mono- and combination therapies prescribed, substantial variation in medication prescriptions between subtypes, most patients receiving two or more treatment lines, and the large number of unique treatment sequences.

OBJECTIVE To identify serum protein biomarkers that might distinguish patients with early inflammatory arthritis (IA) with psoriatic arthritis (PsA) from those with rheumatoid arthritis (RA) and may be used to support appropriate early intervention. METHODS The serum proteome of patients with PsA and patients with RA was interrogated using nano-liquid chromatography mass spectrometry (nano-LC-MS/MS) (n = 64 patients), an aptamer-based assay (SomaScan) targeting 1,129 proteins (n = 36 patients), and a multiplexed antibody assay (Luminex) for 48 proteins (n = 64 patients). Multiple reaction monitoring (MRM) assays were developed to evaluate the performance of putative markers using the discovery cohort (n = 60 patients) and subsequently an independent cohort of PsA and RA patients (n = 167). RESULTS Multivariate machine learning analysis of the protein discovery data from the 3 platforms revealed that it was possible to differentiate PsA patients from RA patients with an area under the curve (AUC) of 0.94 for nano-LC-MS/MS, 0.69 for bead-based immunoassay measurements, and 0.73 for aptamer-based analysis. Subsequently, in the separate verification and evaluation studies, random forest models revealed that a subset of proteins measured by MRM could differentiate PsA and RA patients with AUCs of 0.79 and 0.85, respectively. CONCLUSION We present a serum protein biomarker panel that can separate patients with early-onset IA with PsA from those with RA. With continued evaluation and refinement using additional and larger patient cohorts, including those with other arthropathies, we suggest that the panel identified here could contribute to improved clinical decision making.

Objectives Burden of comorbidities are largely unknown in JIA. From 2000, national and international patient registries were established to monitor biologic treatment, disease activity and adverse events in patients with JIA. The aim of this analysis was to investigate in parallel, for the first time, three of the largest JIA registries in Europe/internationally—UK JIA Biologic Registers (BCRD/BSPAR-ETN), German biologic registers (BiKeR/JuMBO), multinational Pharmachild—to quantify the occurrence of selected comorbidities in patients with JIA. Methods Information on which data the registers collect were compared. Patient characteristics and levels of comorbidity were presented, focussing on four key conditions: uveitis, MAS, varicella, and history of tuberculosis. Incidence rates of these on MTX/biologic therapy were determined. Results 8066 patients were registered into the three JIA registers with similar history of the four comorbidities across the studies; however, varicella vaccination coverage was higher in Germany (56%) vs UK/Pharmachild (16%/13%). At final follow-up, prevalence of varicella infection was lower in Germany (15%) vs UK/Pharmachild (37%/50%). Prevalence of TB (0.1–1.8%) and uveitis (15–19%) was similar across all registers. The proportion of systemic-JIA patients who ever had MAS was lower in Germany (6%) vs UK (15%) and Pharmachild (17%). Conclusion This analysis is the first and largest to investigate the occurrence of four important comorbidities in three JIA registries in Europe and the role of anti-rheumatic drugs. Combined, these three registries represent one of the biggest collection of cases of JIA worldwide and offer a unique setting for future JIA outcome studies.

Objectives The aim of this study was to identify factors associated with patients’ and parents’ reported satisfaction with JIA care, measured with the juvenile arthritis child and parent acceptable symptom state (JA-CASS and JA-PASS, respectively). Methods A prospective cohort of 239 JIA patients and 238 parents in a tertiary centre who completed the juvenile arthritis multidimensional assessment report (JAMAR) was analysed cross-sectionally. The primary outcomes were positive JA-CASS and JA-PASS, respectively. Items in the JAMAR, as well as JIA subtype, demographics, and disease activity parameters, were analysed in univariate analysis. A multivariable logistic regression analysis was used to build models explaining the variance of the primary outcome as a dependent variable. Results According to the JAMAR, 141 (59.0%) of 239 patients and 149 (62.6%) of 238 parents were satisfied with their or their child’s current condition. For patients, the determinants in the final model were a shorter duration of morning stiffness (P = 0.001), a lower age at disease onset (P = 0.044), a longer disease duration (P = 0.009) and a higher rating of the patient’s well-being measured on a visual analogue scale (VAS) (P = 0.004). For parents, the determinants were the current state of disease activity (current state of persistent activity P = 0.002, relapse P Conclusion Our data highlight the importance of patients’ and parents’ opinions in the evaluation of disease activity, and support their integration into the shared decision-making in daily clinical practice to improve the quality of medical care.

Treg cells are critical regulators of immune homeostasis, and environment-driven Treg cell differentiation into effector (e)Treg cells is crucial for optimal functioning. However, human Treg cell programming in inflammation is unclear. Here, we combine transcriptional and epigenetic profiling to identify a human eTreg cell signature. Inflammation-derived functional Treg cells have a transcriptional profile characterized by upregulation of both a core Treg cell (FOXP3, CTLA4, TIGIT) and effector program (GITR, BLIMP-1, BATF). We identify a specific human eTreg cell signature that includes the vitamin D receptor (VDR) as a predicted regulator in eTreg cell differentiation. H3K27ac/H3K4me1 occupancy indicates an altered (super-)enhancer landscape, including enrichment of the VDR and BATF binding motifs. The Treg cell profile has striking overlap with tumor-infiltrating Treg cells. Our data demonstrate that human inflammation-derived Treg cells acquire a conserved and specific eTreg cell profile guided by epigenetic changes, and fine-tuned by environment-specific adaptations.

ObjectivesGut and joint inflammation commonly co-occur in spondyloarthritis (SpA) which strongly restricts therapeutic modalities. The immunobiology underlying differences between gut and joint immune regulation, however, is poorly understood. We therefore assessed the immunoregulatory role of CD4+FOXP3+regulatory T (Treg) cells in a model of Crohn’s-like ileitis and concomitant arthritis.MethodsRNA-sequencing and flow cytometry was performed on inflamed gut and joint samples and tissue-derived Tregs from tumour necrosis factor (TNF)∆AREmice. In situ hybridisation of TNF and its receptors (TNFR) was applied to human SpA gut biopsies. Soluble TNFR (sTNFR) levels were measured in serum of mice and patients with SpA and controls. Treg function was explored by in vitro cocultures and in vivo by conditional Treg depletion.ResultsChronic TNF exposure induced several TNF superfamily (TNFSF) members (4-1BBL, TWEAK and TRAIL) in synovium and ileum in a site-specific manner. Elevated TNFR2 messenger RNA levels were noted in TNF∆ARE/+mice leading to increased sTNFR2 release. Likewise, sTNFR2 levels were higher in patients with SpA with gut inflammation and distinct from inflammatory and healthy controls. Tregs accumulated at both gut and joints of TNF∆AREmice, yet their TNFR2 expression and suppressive function was significantly lower in synovium versus ileum. In line herewith, synovial and intestinal Tregs displayed a distinct transcriptional profile with tissue-restricted TNFSF receptor and p38MAPK gene expression.ConclusionsThese data point to profound differences in immune-regulation between Crohn’s ileitis and peripheral arthritis. Whereas Tregs control ileitis they fail to dampen joint inflammation. Synovial resident Tregs are particularly maladapted to chronic TNF exposure.

ObjectiveTo study the effect of methotrexate (MTX) therapy on new-onset uveitis in patients with biological-naïve juvenile idiopathic arthritis (JIA).MethodsIn this matched case–control study, we compared MTX exposure between cases with JIA-associated chronic uveitis (JIA-U) and patients with JIA and without JIA-U at the time of matching (controls). Data were collected from electronic health records of the University Medical Centre Utrecht, the Netherlands. Cases with JIA-U were matched 1:1 to JIA control patients based on JIA diagnosis date, age at JIA diagnosis, JIA subtype, antinuclear antibodies status and disease duration. The effect of MTX on JIA-U onset was analysed using a multivariable time-varying Cox regression analysis.ResultsNinety-two patients with JIA were included and characteristics were similar between cases with JIA-U (n=46) and controls (n=46). Both ever-use of MTX and exposure years were lower in cases with JIA-U than in controls. Cases with JIA-U significantly more often discontinued MTX treatment (p=0.03) and out of those who did, 50% afterwards developed uveitis within 1 year. On adjusted analysis, MTX was associated with a significantly reduced new-onset uveitis rate (HR: 0.35; 95% CI: 0.17 to 0.75). No different effect was observed between a low (2/week) and standard MTX dose (≥10 mg/m2/week).ConclusionThis study demonstrates an independent protective effect of MTX on new-onset uveitis in patients with biological-naïve JIA. Clinicians might consider early initiation of MTX in patients at high uveitis risk. We advocate more frequent ophthalmologic screening in the first 6–12 months after MTX discontinuation.

Background: This study aims to quantify medication costs in juvenile idiopathic arthritis (JIA), based on subtype. Research design and methods: This study is a single-center, retrospective analysis of prospective data from electronic medical records of JIA patients, aged 0–18 years between 1 April 2011 and 31 March 2019. Patient characteristics (age, gender, subtype) and medication use were extracted. Medication use and costs were reported as: 1) mean total annual costs; 2) between-patient heterogeneity in these costs; 3) duration of medication use; and, 4) costs over the treatment course. Results: The analysis included 691 patients. Mean total medication costs were €2,103/patient/year, including €1,930/patient/year (91.8%) spent on biologicals. Costs varied considerably between subtypes, with polyarticular rheumatoid-factor positive and systemic JIA patients having the highest mean costs (€5,020/patient/year and €4,790/patient/year, respectively). Mean annual medication costs over the patient’s treatment course ranged from €11,000/year (2.5% of patients). Etanercept and adalimumab were the most commonly used biologicals. Cost fluctuations over the treatment course were primarily attributable to biological use. Conclusions: Polyarticular rheumatoid-factor positive and systemic JIA patients had the highest mean total annual medication costs, primarily attributable to biologicals. Costs varied considerably between subtypes, individuals, and over the treatment course.

Objective To describe risk factors for IBD development in a cohort of children with JIA. Methods JIA patients who developed IBD were identified from the international Pharmachild register. Characteristics were compared between IBD and non-IBD patients and predictors of IBD were determined using multivariable logistic regression analysis. Incidence rates of IBD events on different DMARDs were calculated, and differences between therapies were expressed as relative risks (RR). Results Out of 8942 patients, 48 (0.54% ) developed IBD. These were more often male (47.9% vs 32.0%) and HLA-B27 positive (38.2% vs 21.0%) and older at JIA onset (median 8.94 vs 5.33 years) than patients without IBD development. They also had more often a family history of autoimmune disease (42.6% vs 24.4%) and enthesitis-related arthritis (39.6% vs 10.8%). The strongest predictors of IBD on multivariable analysis were enthesitis-related arthritis [odds ratio (OR): 3.68, 95% CI: 1.41, 9.40] and a family history of autoimmune disease (OR: 2.27, 95% CI: 1.12, 4.54). Compared with methotrexate monotherapy, the incidence of IBD on etanercept monotherapy (RR: 7.69, 95% CI: 1.99, 29.74), etanercept with methotrexate (RR: 5.70, 95% CI: 1.42, 22.77) and infliximab (RR: 7.61, 95% CI: 1.27, 45.57) therapy was significantly higher. Incidence on adalimumab was not significantly different (RR: 1.45, 95% CI: 0.15, 13.89). Conclusion IBD in JIA was associated with enthesitis-related arthritis and a family history of autoimmune disease. An increased IBD incidence was observed for etanercept therapy regardless of concomitant methotrexate use.

Objective The objective of this study was to assess the relationship between adalimumab trough concentrations and treatment response in paediatric patients with JIA. Methods This was a monocentric cohort study of JIA patients treated with adalimumab. Clinical data and samples were collected during routine follow-up. Adalimumab trough concentrations were quantified by a novel liquid chromatography–tandem mass spectrometry assay. Anti-adalimumab antibodies were measured in samples with trough concentrations of ≤5mg/l. Disease activity was evaluated using the clinical Juvenile Arthritis DAS with 71-joint count (cJADAS71). Response to adalimumab was defined according to recent international treat-to-target guidelines. Results A total of 35 adalimumab trough samples were available from 34 paediatric patients with JIA. Although there was no significant difference in adalimumab dose, trough concentrations were significantly lower in patients with secondary failure [median 1.0 mg/l; interquartile range (IQR) 1.0–5.3] compared with patients with primary failure (median 13.97 mg/l; IQR 11.81–16.67) or an adequate response (median 14.94 mg/l; IQR 10.31–16.19) to adalimumab. Conclusion Adalimumab trough concentrations were significantly lower in JIA patients with secondary failure compared with patients with primary failure or an adequate response to adalimumab. Our results suggest that trough concentration measurements could identify JIA patients who require increased adalimumab doses to achieve or maintain therapeutic drug concentrations.

Background Pediatric patients with juvenile idiopathic arthritis (JIA) are at risk for a lower health-related quality of life compared to their healthy peers. Remote monitoring of health-related quality of life using electronic patient-reported outcomes could provide important information to treating physicians. The aim of this study was to investigate if self-assessment with the EuroQol five-dimensional ‘youth’ questionnaire with five levels (EQ-5D-Y-5 L) inside a mobile E-health application could identify JIA patients in need of possible treatment adjustments. Methods The EQ-5D-Y-5 L was completed via a mobile application (Reuma2Go) between October 2017 and January 2019. The clinical juvenile arthritis disease activity score with 71 joint count (cJADAS-71) was reported at every corresponding visit as reference for disease activity. Previously described cJADAS-71 thresholds were used to identify patients in possible need of treatment adjustments. Discriminatory power of the EQ-5D-Y-5 L was assessed by ROC-curves and diagnostic characteristics. Results Sixty-eight JIA patients completed the EQ-5D-Y-5 L questionnaire. Median cJADAS-71 indicated low disease activity overall in the studied population. ROC curves and diagnostic characteristics demonstrated that self-assessment with the EQ-5D-Y-5 L could distinguish between patients with inactive disease (or minimal disease activity) and moderate to high disease activity with good accuracy (87%), sensitivity (85%), specificity (89%) and negative predictive value (86%). Conclusions Results demonstrate that the EQ-5D-Y-5 L was able to identify JIA patients in need of possible treatment adjustments in our studied population. Remote monitoring of health-related quality of life and patient-reported outcomes via E-health applications could provide important additional information to determine the frequency of clinical visits, assess therapeutic efficacy and guide treat-to-target strategies in pediatric patients with JIA.

Objective To build a prediction model for uveitis in children with JIA for use in current clinical practice. Methods Data from the international observational Pharmachild registry were used. Adjusted risk factors as well as predictors for JIA-associated uveitis (JIA-U) were determined using multivariable logistic regression models. The prediction model was selected based on the Akaike information criterion. Bootstrap resampling was used to adjust the final prediction model for optimism. Results JIA-U occurred in 1102 of 5529 JIA patients (19.9%). The majority of patients that developed JIA-U were female (74.1%), ANA positive (66.0%) and had oligoarthritis (59.9%). JIA-U was rarely seen in patients with systemic arthritis (0.5%) and RF positive polyarthritis (0.2%). Independent risk factors for JIA-U were ANA positivity [odds ratio (OR): 1.88 (95% CI: 1.54, 2.30)] and HLA-B27 positivity [OR: 1.48 (95% CI: 1.12, 1.95)] while older age at JIA onset was an independent protective factor [OR: 0.84 (9%% CI: 0.81, 0.87)]. On multivariable analysis, the combination of age at JIA onset [OR: 0.84 (95% CI: 0.82, 0.86)], JIA category and ANA positivity [OR: 2.02 (95% CI: 1.73, 2.36)] had the highest discriminative power among the prediction models considered (optimism-adjusted area under the receiver operating characteristic curve = 0.75). Conclusion We developed an easy to read model for individual patients with JIA to inform patients/parents on the probability of developing uveitis.

Treg are critical regulators of immune homeostasis, and increasing evidence demonstrates that environment-driven Treg differentiation into effector (e)Treg is crucial for optimal functioning. However, human Treg programming under inflammatory conditions remains poorly understood. Here, we combine transcriptional and epigenetic profiling to identify the human eTreg core signature. Functional autoimmune inflammation-derived Treg display a unique transcriptional profile characterized by upregulation of both a core Treg (FOXP3, CTLA-4, TIGIT) and effector program (GITR, BLIMP-1, BATF). We identified a specific human eTreg signature that includes the vitamin D receptor (VDR) as predicted key-regulator in eTreg differentiation. H3K27ac/H3K4me1 occupancy revealed pronounced changes in the (super-)enhancer landscape, including enrichment of the binding motif for VDR and BATF. The observed Treg profile showed striking overlap with tumor-infiltrating Treg. Our data demonstrate that human inflammation-derived Treg acquire a specific eTreg profile guided by epigenetic changes. The core eTreg profile is conserved, and fine-tuned by environment-specific adaptations.

ObjectivesTo identify serum protein biomarkers which might separate early inflammatory arthritis (EIA) patients with psoriatic arthritis (PsA) from those with rheumatoid arthritis (RA) to provide an accurate diagnosis and support appropriate early intervention.MethodsIn an initial protein discovery phase, the serum proteome of a cohort of patients with PsA and RA was interrogated using unbiased liquid chromatography mass spectrometry (LC-MS/MS) (n=64 patients), a multiplexed antibody assay (Luminex) for 48 proteins (n=64 patients) and an aptamer-based assay (SOMAscan) targeting 1,129 proteins (n=36 patients). Subsequently, analytically validated targeted multiple reaction monitoring (MRM) assays were developed to further evaluate those proteins identified as discriminatory during the discovery. During an initial verification phase, MRM assays were developed to a panel of 150 proteins (by measuring a total of 233 peptides) and used to re-evaluate the discovery cohort (n=60). During a second verification phase, the panel of proteins was expanded to include an additional 23 proteins identified in other proteomic discovery analyses of arthritis patients. The expanded panel was evaluated using a second, independent cohort of PsA and RA patients (n=167).ResultsMultivariate analysis of the protein discovery data revealed that it was possible to discriminate PsA from RA patients with an area under the curve (AUC) of 0.94 for nLC-MS/MS, 0.69 for Luminex based measurements; 0.73 for SOMAscan analysis. During the initial verification phase, random forest models confirmed that proteins measured by MRM could differentiate PsA and RA patients with an AUC of 0.79 and during the second phase of verification the expanded panel could segregate the two disease groups with an AUC of 0.85.ConclusionWe report a serum protein biomarker panel which can separate EIA patients with PsA from those with RA. We suggest that the routine use of such a panel in EIA patients will improve clinical decision making and with continued evaluation and refinement using additional patient cohorts will support the development of a diagnostic test for patients with PsA.

Made available in DSpace on 2020-12-10T20:01:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-06-05 Objective This study aimed to assess the safety and immunogenicity of the quadrivalent human papillomavirus (qHPV) vaccination in childhood-onset systemic lupus erythematosus (cSLE) patients. Methods Volunteer cSLE patients aged 9-20 years and healthy controls (HC) were enrolled to receive a two- or three-dose qHPV vaccination schedule from March 2014 to March 2016. Study visits were performed before the first dose, one month after the second and third doses and one year after the first dose. In each study visit, disease activity and adverse events following vaccination were analyzed, and a serum sample was collected for testing antibody concentrations. Participant recruitment was conducted in 15 Brazilian paediatric rheumatology units. Of the 256 cSLE patients included, 210 completed the two- or three-dose schedules; 15 had previously received one dose, and 18 had received two doses of the vaccine. The analysis was based on intention-to-treat so that participants who did not complete the entire study protocol were also included. Results No severe adverse events were related to the vaccination. Disease activity was generally low and remained stable or even improved. The HC presented 100% seropositivity to HPV16 and HPV18, whereas the two- and three-dose cSLE groups presented 93% and 83% versus 97% and 91%, respectively. One year after the first dose, seropositivity of the three-dose cSLE group was 91% to HPV16 and 84% to HPV18. Conclusions HPV vaccination in cSLE patients is safe and immunogenic. Since the seropositivity to HPV16 and HPV18 was higher for the three-dose schedule group, this regimen should be recommended for cSLE patients. Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Paediat Immunol & Rheumatol, Utrecht, Netherlands Univ Fed Parana, Hosp Clin, Dept Paediat, Curitiba, Parana, Brazil Univ Sao Paulo, Dept Paediat, Fac Med Ribeirao Preto, Sao Paulo, Brazil Univ Estado Rio De Janeiro, Dept Paediat Rheumatol, Rio De Janeiro, Brazil Univ Sao Paulo, Hosp Clin, Inst Crianca, Dept Paediat Rheumatol,Fac Med, Sao Paulo, Brazil Hosp Infantil Albert Sabin, Dept Paediat Rheumatol, Fortaleza, Ceara, Brazil Univ Florida, Coll Med, Dept Paediat Immunol & Rheumatol, Gainesville, FL USA Univ Estadual Campinas, Dept Paediat Rheumatol, Sao Paulo, Brazil Hosp Crianca Brasilia Jose Alencar, Dept Paediat Rheumatol, Brasilia, DF, Brazil Univ Estadual Paulista, Dept Paediat Rheumatol, Botucatu, SP, Brazil Univ Fed Rio de Janeiro, Inst Puericultura & Pediat Martagao Gesteira IPPM, Dept Paediat Rheumatol, Rio De Janeiro, Brazil Univ Fed Rio de Janeiro, Dept Paediat Rheumatol, Rio De Janeiro, Brazil Hosp Infantil Darcy Vargas, Dept Paediat Rheumatol, Sao Paulo, Brazil Hosp Estadual Infantil Nossa Senhora da Gloria, Dept Paediat Rheumatol, Vitoria, ES, Brazil Santa Casa Sao Paulo, Dept Paediat Rheumatol, Sao Paulo, Brazil Univ Fed Bahia, Dept Paediat Rheumatol, Fac Med, Salvador, BA, Brazil Univ Fed Sao Paulo, Dept Paediat Rheumatol, Sao Paulo, Brazil Hosp Pequeno Principe, Dept Paediat Rheumatol, Curitiba, Parana, Brazil Natl Inst Publ Hlth & Environm RIVM, Ctr Infect Dis Control, Bilthoven, Netherlands Fac Med Barretos FACISB, Dept Paediat Rheumatol, Barretos, Brazil Univ Estadual Paulista, Dept Paediat Rheumatol, Botucatu, SP, Brazil

Background: Concerns about the safety and efficacy of vaccinations in patients with pediatric rheumatic diseases, such as juvenile dermatomyositis, have led to contradictions and low vaccination coverage in this group, who are at a higher risk of infections, including by human papillomavirus (HPV). Although HPV vaccine should be recommended for all juvenile dermatomyositis patients, there is a lack of data to support the safety of this vaccine. The aim of this study was to assess the safety and immunogenicity of the quadrivalent HPV vaccination in juvenile dermatomyositis patients.Methods: Juvenile dermatomyositis patients aged from 9-20 years and healthy controls were enrolled to receive a 3-dose schedule of quadrivalent HPV vaccination from March/2014 until March/2016. Study visits were performed before the first dose, one month after the second and third doses and one year after the first dose. Participants completed a diary of possible adverse events following each dose, and disease activity was measured. At each visit, serum samples was collected for testing antibody concentrations. Participants recruitment was conducted in ten Brazilian centers. From 48 eligible patients, 42 completed the 3 doses schedule of the vaccine (5 patients had received doses previously). The McNemar test and the Kappa concordance coefficient were applied to compare the disease activity scores used for juvenile dermatomyositis patients between quadrivalent HPV vaccine doses and before the vaccination. The software used was SAS 9.4.Results: No severe adverse events were related to the vaccination. The disease activity scores were usually low, and remained stable, or even improved during the follow-up. After three vaccine doses the juvenile dermatomyositis group presented seropositivity of 100% for HPV16 and 97% for HPV18, similarly to the control group who presented 100% for both. One year after the first dose the seropositivity for the patients group was 94% for both HPV types.Conclusions: The HPV vaccination in juvenile dermatomyositis patients is safe and immunogenic. Since the seropositivity against HPV16 and HPV18 was very high after the 3-dose schedule, this regimen should be recommended for juvenile dermatomyositis patients.

ObjectivesTo assess if the Juvenile Arthritis Disease Activity Score (JADAS71) could be used to correctly identify patients with juvenile idiopathic arthritis (JIA) in need of antitumour necrosis factor therapy (anti-TNF) therapy 3 and 6 months after start of methotrexate (MTX).MethodsMonocentric retrospective cohort study from 2011 to 2015 analysing all patients with oligoarticular JIA (OJIA) (n=39) and polyarticular course JIA (PJIA) (n=74) first starting MTX. Three and 6 months after MTX start, clinical and laboratory features and the 2011 American College of Rheumatology (ACR) JIA treatment recommendations (ACR clinical practice guideline (ACR-CPG)) were compared between groups starting and not starting anti-TNF therapy. The sensitivity and specificity of the ACR-CPG, JADAS71 and the clinical JADAS to identify non-responders after 12 months were calculated.ResultsPhysicians escalated patients with significantly higher physician global assessment, clinical JADAS (cJADAS) and patient Visual Analogue Scale (VAS). The decision not to escalate was correct in 70%–75% as shown by MTX response. The implementation of the ACR-CPG would increase the current anti-TNF use from 12% to 65%. The use of (c)JADAS in identifying patients in need of anti-TNF therapy outperformed the ACR-CPG with a much higher sensitivity, specificity and accuracy. The cJADAS threshold for treatment escalation at month 3 and 6 was >5 and >3 for OJIA and >7 and >4 for PJIA, respectively. The performance of the cJADAS decreased when the patient VAS contribution to the total score was restricted and overall did not improve by adding the erythrocyte sedimentation rate.ConclusionsThe cJADAS identifies patients in need of anti-TNF and is a user-friendly tool ready to be used for treat to target in JIA. The patient VAS is a critical item in the cJADAS for the decision to escalate to anti-TNF.

ObjectivesThe International League of Associations for Rheumatology classification criteria define systemic juvenile idiopathic arthritis (SJIA) by the presence of fever, rash and chronic arthritis. Recent initiatives to revise current criteria recognise that a lack of arthritis complicates making the diagnosis early, while later a subgroup of patients develops aggressive joint disease. The proposed biphasic model of SJIA also implies a ‘window of opportunity’ to abrogate the development of chronic arthritis. We aimed to identify novel SJIA biomarkers during different disease phases.MethodsChildren with active SJIA were subgrouped clinically as systemic autoinflammatory disease with fever (SJIAsyst) or polyarticular disease (SJIApoly). A discovery cohort of n=10 patients per SJIA group, plus n=10 with infection, was subjected to unbiased label-free liquid chromatography mass spectrometry (LC-MS/MS) and immunoassay screens. In a separate verification cohort (SJIAsyst, n=45; SJIApoly, n=29; infection, n=32), candidate biomarkers were measured by multiple reaction monitoring MS (MRM-MS) and targeted immunoassays.ResultsSignatures differentiating the two phenotypes of SJIA could be identified. LC-MS/MS in the discovery cohort differentiated SJIAsyst from SJIApoly well, but less effectively from infection. Targeted MRM verified the discovery data and, combined with targeted immunoassays, correctly identified 91% (SJIAsyst vs SJIApoly) and 77% (SJIAsyst vs infection) of all cases.ConclusionsMolecular signatures differentiating two phenotypes of SJIA were identified suggesting shifts in underlying immunological processes in this biphasic disease. Biomarker signatures separating SJIA in its initial autoinflammatory phase from the main differential diagnosis (ie, infection) could aid early-stage diagnostic decisions, while markers of a phenotype switch could inform treat-to-target strategies.

Objective: Systemic juvenile idiopathic arthritis (JIA) is a multifactorial autoinflammatory disease with a historically poor prognosis. With current treatment regimens, approximately half of patients still experience active disease after 1 year of therapy. This study was undertaken to evaluate a treat-to-target approach using recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) as first-line monotherapy to achieve early inactive disease and prevent damage. Methods: In this single-center, prospective study, patients with new-onset systemic JIA with an unsatisfactory response to nonsteroidal antiinflammatory drugs received rIL-1Ra monotherapy according to a treat-to-target strategy. Patients with an incomplete response to 2 mg/kg rIL-1Ra subsequently received 4 mg/kg rIL-1Ra or additional prednisolone, or switched to alternative therapy. For patients in whom inactive disease was achieved, rIL-1Ra was tapered after 3 months and subsequently stopped. Results: Forty-two patients, including 12 who had no arthritis at disease onset, were followed up for a median of 5.8 years. The median time to achieve inactive disease was 33 days. At 1 year, 76% had inactive disease, and 52% had inactive disease while not receiving medication. High neutrophil counts at baseline and a complete response after 1 month of rIL-1Ra were highly associated with inactive disease at 1 year. After 5 years of follow-up, 96% of the patients included had inactive disease, and 75% had inactive disease while not receiving medication. Articular or extraarticular damage was reported in

Background: Heterogeneity in response to biological medication is a major challenge in the management of Juvenile Idiopathic Arthritis (JIA) (1). Biomarkers such as cytokines or whole blood RNA expression profiles that predict therapy efficacy prior to treatment pose a solution and could enable precision medicine. It was previously demonstrated that whole blood gene expression profiles can predict response to anti-TNF-α therapy in patients with JIA (2). These findings currently await validation in a multicenter prospective cohort study. Harmonization of data from different cohorts, however, is often hampered by site-dependent differences in biological sample collection and processing (3). For instance, the biological material that is retrospectively available from biobanks depends on what is stored exactly, e.g. whole blood versus peripheral blood mononuclear cells (PBMC). Furthermore, different blood collection tubes containing different additives can affect sample quality at an early stage and make interchangeability or comparability of data impossible. Objectives: We evaluated the comparability of gene expression profiles when whole blood from patients with JIA is collected in different RNA collection tubes and processed accordingly. Next, we will investigate the predictive capacity for therapy response of RNA expression profiles from frozen PBMC of 63 JIA patients. Methods: Peripheral blood from 11 children with non-systemic JIA with active disease was collected in PAXgene (PreAnalytiX) and Tempus (Applied Biosystems) tubes. All tubes were subsequently stored in the freezer at -80 °C. After thawing, RNA from the PAXgene tubes was extracted with use of the PAXgene Blood RNA Kit and RNA from the Tempus tubes was isolated by using the Tempus Preserved Blood RNA Purification Kit I. Gene expression of CSNK1D, C1D, ASAP2, SRRD, PPP1R3B, HLA-DQA1, PDZK1IP1 and MZB1 was determined with qPCR. For our next experiment, frozen PBMC derived from patients with non-systemic JIA who are included in our longitudinal Pharmachild registry biobank will be used. Of the 63 patients, 28 (44.4%) children were diagnosed with oligo articular JIA, 19 (30.2%) with poly articular JIA, 9 (14.3%) with enthesitis-related JIA, 4 (6.3%) with psoriatic JIA and 3 (4.8%) with undifferentiated JIA. The average age at sampling was 11.5 years ± 4.0 and 65% of the patients was female. These samples will be run on a 96-analyte NanoString panel and associated with clinical response at time points 3 and 6 months after start of TNF-α blockade. Results: Both RNA blood collection systems yielded high-quality RNA, with overall higher RNA concentrations for blood collected in Tempus tubes in comparison to PAXgene tubes. qPCR data showed that gene expression of all measured genes is affected by the method of blood collection and processing. However, the inter-individual variation was similar between both collection tubes, indicating that similar RNA profiles were observed. Conclusion: Gene expression profiles derived from whole blood collected in PAXgene or Tempus tubes are comparable, but are not interchangeable. References: [1] Swart JF, de Roock S, & Prakken BJ. Understanding inflammation in juvenile idiopathic arthritis: How immune biomarkers guide clinical strategies in the systemic onset subtype. Eur J Immunol 2016;46(9):2068-2077. [2] Cui A, Quon G, Rosenberg AM et al. Gene Expression Deconvolution for Uncovering Molecular Signatures in Response to Therapy in Juvenile Idiopathic Arthritis. PloS one 2016;11(5):1-17. [3] Yeung RS, Albani S, Feldman BM et al. Enhancing translational research in paediatric rheumatology through standardization. Nature Reviews Rheumatology 2016;12(11):684. Disclosure of Interests: None declared

Background Last year the International League of Associations for Rheumatology (ILAR) classification criteria for juvenile idiopathic arthritis (JIA), [1] were challenged by the provisional Paediatric Rheumatology International Trials Organisation (PRINTO) classification criteria.[2] Four disorders were proposed: (a) systemic JIA; (b) rheumatoid factor (RF)-positive JIA; (c) enthesitis/spondylitis-related JIA; and (d) early-onset antinuclear antibody (ANA)-positive JIA. Early-onset ANA-positive JIA is defined by: arthritis for ≥ 6 weeks, and early-onset (≤ 6 yrs), and presence of 2 positive ANA tests with a titer ≥ 1/160 at least 3 months apart with the exclusions of having systemic JIA, RF-positive arthritis, or enthesitis/spondylitis-related JIA. Objectives To evaluate the shifts from the original subtypes of JIA in the new disorder of early-onset ANA–positive JIA. Methods This study used data from the international PRINTO based registry regarding pharmacovigilance in JIA called Pharmachild.[3] For this analysis we used the data of 4,165 patients completely categorized following the ILAR ‘oligoarthritis’, ‘RF-negative polyarthritis’, ‘psoriatic arthritis’ and ‘undifferentiated JIA’ (UJIA) subtypes and with complete determination of ANA status. These patients were if possible reclassified in the early-onset ANA–positive JIA according to the provisional PRINTO classification criteria. Results Table 1 shows the characteristics of all 4,165 patients according to the ILAR criteria. Of this final set of 4165 patients, 1279 (30.7%) were ANA-positive and 957 (74.8%) classified into the PRINTO ‘early onset ANA-positive JIA’ category. Of these 957, 2 patients were RF-positive, which is an exclusion criterion for the ‘early onset ANA-positive JIA’ category and therefore were not categorized as early onset ANA-positive JIA. The female proportion was higher than in any ILAR subtype being 83.0% (793/955). The origin (ILAR categories) of the 955 patients in the ‘early onset ANA-positive JIA’ category consisted of 33.7% patients with persistent oligoarthritis (322/955), 24.7% (236/955) with extended oligoarthritis, 28.0% with RF-negative polyarthritis (267/955), 4.2% with psoriatic arthritis (40/955) and 9.4% with UJIA (90/955). Conclusion This study shows that of all ANA-positive JIA patients belonging to the ‘oligoarthritis’, ‘RF-negative polyarthritis’, ‘psoriatic arthritis’ and ‘UJIA’ ILAR subtypes, 74.8% met the criteria for the PRINTO ‘early onset ANA-positive’ category. The female proportion was higher than in any ILAR subtype being 83.0%. This new category consists largely of 3 ILAR subtypes: persistent oligoarthritis (34%), extended oligoarthritis (25%) and RF negative polyarthritis (28%). Further studies on these provisional criteria are ongoing. References [1] Petty RE, Southwood TR, Manners P et al. International League of Associations for Rheumatology Classification of Juvenile Idiopathic Arthritis: Second Revision, Edmonton, 2001. J Rheumatol. 2014 [2] Martini A, Ravelli A, Avcin T et al. Toward New Classification Criteria for Juvenile Idiopathic Arthritis: First Steps, PRINTO International Consensus. J Rheumatol. 2018 Oct 1 [3] Swart J, Giancane G, Horneff G et al. Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries. Arthritis Res Ther. 2018 Dec 27 Disclosure of Interests Vera Mars: None declared, Joost F. Swart: None declared, Gabriella Giancane: None declared, Sytze De Roock: None declared, Anne Estmann: None declared, Marija Jelusic: None declared, Estefania Moreno Ruzafa: None declared, Jaime de Inocencio: None declared, Jelena Vojinovic: None declared, Agustin Remesal: None declared, M Laday: None declared, Rolando Cimaz: None declared, A V Cochino: None declared, Inmaculada Calvo Grant/research support from: received research grants from Pfizer, Roche, Novartis, Clementia, Sanofi, MSD, BMS and GSK, Consultant for: Advisory boards: Novartis, AbbVie, Speakers bureau: AbbVie, Roche, Novartis, SOBI, M Harjacek: None declared, Nico Wulffraat: None declared, Nicolino Ruperto Grant/research support from: The Gaslini Hospital, where NR works as full-time public employee, has received contributions (> 10.000 USD each) from the following industries in the last 3 years: BMS, Eli-Lilly, GlaxoSmithKline, F Hoffmann-La Roche, Janssen, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties., Consultant for: Received honoraria for consultancies or speaker bureaus (

Background Juvenile idiopathic arthritis (JIA) has a reported prevalence varying from 16 to 150 per 100,000 patients and it thereby is the most frequent chronic rheumatologic disease presenting in childhood. Inflammatory bowel disease (IBD) is an auto-inflammatory disease that can develop in patients with JIA. Results from multiple studies suggest an association between therapy with Etanercept (ETN) and occurrence of IBD in patients with JIA, which may or may not be counteracted by methotrexate. Objectives The aim of this study was to describe characteristics of JIA patients who developed IBD and to evaluate a possible relationship between IBD onset and medication use at IBD onset. Methods Pharmachild, the largest international JIA registry, was used for this study. Patients were enrolled via members of the Paediatric Rheumatology INternational Trials Organisation (PRINTO). The registry contains both retrospective and prospective data. Results A total of 8,309 patients were included in this study. 290 gastrointestinal disorders were reported in 260 patients. 50 cases in 47 patients were classified as IBD or suspected IBD. Age at JIA onset was significantly higher in patients who developed IBD (9.1 vs 7.1 years p=0.002), and female predominance was lower (48.9% versus 67.6% p=0.011). Enthesitis related arthritis (ERA) was the JIA subtype in 40.4% of the patients who developed IBD. In 14 out of 47 patients more detailed information about IBD disease onset was available, such as date of disease onset and medication used at that time. 71.4% of all 14 patients used etanercept and 50.0% used MTX 3 months prior or at IBD onset. Etanercept exposure prior to IBD onset varied from no exposure to 6.39 years with a median of 1.3 years. Methotrexate exposure prior to disease onset varied from no exposure to 8.10 years with a median of 2.9 years. Information regarding quality of life was available for 2,752 patients of which 17 IBD patients. Quality of life, both physical and psychosocial, was significantly lower in patients who developed IBD patients (p=0.018 and p=0.046 respectively). Conclusion In this study ERA patients were more at risk of developing IBD and 71.4% used etanercept while developing IBD. We did not find a protective role of MTX since 50.0% of patients with available data developed IBD while using MTX. Lastly, IBD has an important physical and psychosocial impact on quality of life. Reference [1] Swart JF; Giancane G; Horneff G; Magnusson B; Hofer M; Alexeeva E; Panaviene V; Bader-Meunier B; Anton J; Nielsen S; De Benedetti F; Kamphuis S; Stanevicha V; Trachana M; Ailioaie LM; Tsitsami E; Klein A; Minden K; Foeldvari I; Haas JP; Klotsche J; Horne. Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from pharmachild and national registries. Arthritis Res Ther. 2018; Disclosure of Interests Roline Krol: None declared, Joost F. Swart: None declared, Gabriella Giancane: None declared, Sytze De Roock: None declared, Troels Herlin: None declared, Pavla Dolezalova: None declared, Helga Sanner: None declared, Gordana Susic: None declared, Flavio R. Sztajnbok: None declared, D Maritsi: None declared, Tamas Constantin: None declared, V Vargova: None declared, Sujata Sawhney: None declared, Marite Rygg: None declared, SHEILA KNUPP DE OLIVEIRA: None declared, Marco Cattalini: None declared, Ellen Nordal: None declared, Claudia Magalhaes: None declared, Alberto Martini Consultant for: I do not have any conflict of interest to declare since starting from 1 March 2016 I became the Scientific Director of the G. Gaslini Hospital; therefore, my role does not allow me to render private consultancies resulting in personal income. I perform consultancy activities on behalf of the Gaslini Institute for the companies listed below: AbbVie, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono, Janssen, Novartis, Pfizer, R-Pharm. The money received for these activities are directly transferred to the Gaslini Institute’s bank account. Before March 2016, I was the head of the Pediatric Rheumatology Department at the G. Gaslini Hospital, where the PRINTO Coordinating Centre is located. For the coordination activity of the PRINTO network, the Gaslini Hospital received contributions from the industries listed in this section. This money has been reinvested for the research activities of the hospital in fully independent manners besides any commitment with third parties., Nico Wulffraat: None declared, Nicolino Ruperto Grant/research support from: The Gaslini Hospital, where NR works as full-time public employee, has received contributions (> 10.000 USD each) from the following industries in the last 3 years: BMS, Eli-Lilly, GlaxoSmithKline, F Hoffmann-La Roche, Janssen, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties., Consultant for: Received honoraria for consultancies or speaker bureaus (

Background: In recent years, juvenile idiopathic arthritis (JIA) research has shifted towards treat-to-target therapy based on clinical assessments and patient-reported outcomes (1). A well-known measurement of quality of life is the EQ-5D-5L (2). Herewith, we report preliminary results of a retrospective study using the child-friendly ‘EQ-5D-5L-Y’ with an E-health application (Reuma2GO) to monitor children with JIA in an outpatient setting. Objectives: To assess the relationship between dimensions of the health-related quality of life ‘EQ-5D-5L-Y’ questionnaire and conventional assessments for children with JIA, including the Juvenile Arthritis Multidimensional Assessment Report (JAMAR) and active joint count (AJC), and to investigate the potential of the EQ-5D-5L-Y as instrument for outpatient management. Methods: The study was designed as monocentric retrospective cohort study. Data from October 2017 to January 2019 were available for 70 patients with JIA. The relationships between individual dimensions of the EQ-5D-5L-Y, JAMAR and several clinical assessments were investigated. Furthermore, dimensions of the EQ-5D-5L-Y were investigated as possible predictors for binary disease activity using AJC > 0 as reference standard for active disease. Results: Seventy patients with JIA completed 115 EQ-5D-5L-Y and JAMAR questionnaires within two weeks before a clinical visit. Moderate to high correlations were found between the EQ-5D-5L-Y and JAMAR. Moreover, the best possible EQ-5D-5L-Y score, with and without health-related visual analogue scale (EQ-VAS), demonstrated high sensitivity (81.1%) and negative predictive value (84.8%) for active disease (Table 1). The few patients who were incorrectly classified as having inactive disease (false-negatives) did not have their medication changed at the clinical visit and experienced little to no impact of disease activity on their quality of life, as indicated by the JAMAR questionnaire. PPV: positive predictive value; NPV: negative predictive value. Conclusion: These results demonstrate the discriminatory value of the EQ-5D-5L-Y between active and inactive disease in our cohort of patients with JIA. High negative predictive value was found for the total EQ-5D-5L-Y score, with and without EQ-VAS. In conclusion, the EQ-5D-5L-Y could be a valuable instrument for monitoring children with JIA in an outpatient setting which could aid physicians with deciding whether a clinical visit is necessary or not. References [1] Filocamo G, et al. A new approach to clinical care of juvenile idiopathic arthritis: The juvenile arthritis multidimensional assessment report. J Rheumatol2011;38:938–953. [2] Janssen MF, et al. Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual Life Res2013;22:1717–1727. Disclosure of Interests: Martijn J.H. Doeleman: None declared, Sytze De Roock: None declared, Nathan Buijsse: None declared, Mark Klein: None declared, Gouke J. Bonsel: None declared, V. Seyfert Shareholder of: VS is CEO and founder at MyOwnMed, Inc., Employee of: VS is CEO and founder at MyOwnMed, Inc., Nico Wulffraat: None declared, Joost F. Swart: None declared

PURPOSE: To identify candidate biomarkers that have the potential to distinguish between patients with psoriatic arthritis (PsA) or rheumatoid arthritis (RA) and explore the value of combining different protein discovery platforms for the development of a multiplexed protein biomarker panel. EXPERIMENTAL DESIGN: Serum samples from 32 patients (PsA; n = 16 and RA; n = 16) defined as active, early onset, and treatment naïve were analyzed using unbiased label-free LC-MS/MS, a microsphere bead-based immunoassay (Luminex xMAP) and an aptamer-based assay (SOMAscan). RESULTS: LC-MS/MS was used to quantify 324 proteins, while the Luminex xMAP targeted 48 proteins and SOMAscan supported the measurement of 1129 proteins. The combined data from these techniques gave reproducible quantification of 1501 proteins in total. Of these, 42 (LC-MS/MS), 3 (Luminex xMAP), and 127 (SOMAscan) proteins were found to be differentially expressed between PsA and RA (p < 0.05). CONCLUSION AND CLINICAL RELEVANCE: Using three different and potentially complementary proteomic platforms we identified a total of 172 proteins that are differentially expressed in patients with PsA compared to RA. These proteins collectively represent candidates for inclusion in a protein signature that could be developed as a diagnostic test to discriminate patients with PsA from RA and therefore be of clinical utility.

Mutations in STAT3 have recently been shown to cause autoimmune diseases through increased lymphoproliferation. We describe a novel Pro471Arg STAT3 mutation in a patient with multiple autoimmune diseases, causing hyperactivation of the Th17 pathway. We show that IL-17 production by primary T cells was enhanced and could not be further increased by IL-6, while IL-10 reduced Th17 cell numbers. Moreover, specific inhibition of STAT3 activation resulted in diminished IL-17 production. We show that the Pro471Arg STAT3 mutation yields both increased levels of IgA and IgG, probably due to high IL-21 levels. When remission was reached through medical intervention, IL-17 levels normalized and the clinical symptoms improved, supporting the idea that STAT3 gain-of-function mutations can cause hyperactivation of the Th17 pathway and thereby contribute to autoimmunity.

Objective Neutrophils are the most abundant innate immune cells in the blood, but little is known about their role in (acquired) chronic autoinflammatory diseases. This study was undertaken to investigate the role of neutrophils in systemic-onset juvenile idiopathic arthritis (JIA), a prototypical multifactorial autoinflammatory disease that is characterized by arthritis and severe systemic inflammation. Methods Fifty patients with systemic-onset JIA who were receiving treatment with recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) were analyzed at disease onset and during remission. RNA sequencing was performed on fluorescence-activated cell-sorted neutrophils from 3 patients with active systemic-onset JIA and 3 healthy controls. Expression of activation markers, apoptosis, production of reactive oxygen species (ROS), and degranulation of secretory vesicles from neutrophils were assessed by flow cytometry in serum samples from 17 patients with systemic-onset JIA and 15 healthy controls. Results Neutrophil counts were markedly increased at disease onset, and this correlated with the levels of inflammatory mediators. The neutrophil counts normalized within days after the initiation of rIL-1Ra therapy. RNA-sequencing analysis revealed a substantial up-regulation of inflammatory processes in neutrophils from patients with active systemic-onset JIA, significantly overlapping with the transcriptome of sepsis. Correspondingly, neutrophils from patients with active systemic-onset JIA displayed a primed phenotype that was characterized by increased ROS production, CD62L shedding, and secretory vesicle degranulation, which was reversed by rIL-1Ra treatment in patients who had achieved clinical remission. Patients with a short disease duration had high neutrophil counts, more immature neutrophils, and a complete response to rIL-1Ra, whereas patients with symptoms for >1 month had normal neutrophil counts and an unsatisfactory response to rIL-1Ra. In vitro, rIL-1Ra antagonized the priming effect of IL-1β on neutrophils from healthy subjects. Conclusion These results strongly support the notion that neutrophils play an important role in systemic-onset JIA, especially in the early inflammatory phase of the disease. The findings also demonstrate that neutrophil numbers and the inflammatory activity of systemic-onset JIA are both susceptible to IL-1 blockade.

Objectives To compare the total number of adverse events (AEs) before and after mesenchymal stromal cell (MSC) infusion in refractory JIA and to evaluate its effectiveness. Methods Single-centre Proof of Mechanism Phase Ib, open label intervention study in JIA patients previously failing all biologicals registered for their diagnosis. Six patients received 2 million/kg intravenous infusions of allogeneic bone-marrow derived MSC. In case of ACR-Ped30-response but subsequent loss of response one and maximal two repeated infusions are allowed. Results Six JIA patients with 9.2 years median disease duration, still active arthritis and damage were included. All had failed methotrexate, corticosteroids and median five different biologicals. MSC were administered twice in three patients. No acute infusion reactions were observed and a lower post-treatment than pre-treatment incidence in AEs was found. The one systemic onset JIA (sJIA) patient had again an evolving macrophage activation syndrome, 9 weeks after tocilizumab discontinuation and 7 weeks post-MSC infusion. Statistically significant decreases were found 8 weeks after one MSC infusion in VAS well-being (75–56), the JADAS-71 (24.5–11.0) and the cJADAS10 (18.0–10.6). Conclusion MSC infusions in six refractory JIA patients were safe, although in sJIA stopping the ‘failing’ biologic treatment carries a risk of a MAS flare, as the drug might still suppress the systemic features. Trial registration Trial register.nl, http://https://www.trialregister.nl, NTR4146.

Objective To assess humoral and cellular responses to live-attenuated varicella zoster virus (VZV) vaccination of patients with juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM) or juvenile scleroderma (JScle) compared to those of healthy controls (HC). Methods Before, 4–6 weeks and one year after VZV vaccination, blood samples of patients and HC were collected. VZV-specific antibody concentrations were measured by ELISA and multiplex immune-assay. IFN-γ ELISpot assays were performed to assess VZV-specific T-cell responses. Cytokine production upon VZV stimulation were measured with a Luminex-assay. Results 49 patients (39 JIA, 5 JDM, 5 JScle) and 18 HC were included. All patients used methotrexate (MTX), 16 also used corticosteroids, 3 patients used biologics. No disease flares were reported after vaccination. Antibody response to the vaccine was similar in patients and controls (p = 0.139). Use of immunosuppressive drugs did not affect the response (p = 0.203). A second vaccination (n = 21) increased VZV-specific antibody concentrations (p = 0.02). VZV-specific T-cells increased after vaccination (p = 0.043), with a cytokine profile suggesting a VZV-specific Th1 and cytotoxic T-cell response. Conclusion The humoral response to VZV vaccination in patients with pediatric rheumatic diseases (PRD) is similar to that of HC. Generally, patients are able to mount a VZV-specific cellular response. This study has been registered in the Brazilian Clinical Trials Registry under number U1111-1189-9837 .

Objectives JIA is an autoimmune disease involving disturbed T-cell homeostasis, marked by highly activated effector T cells. Autophagy, a lysosomal degradation pathway, is crucial for maintaining cellular homeostasis by regulating the survival, differentiation and function of a large variety of cells, including T cells. The aim of this study was to examine the rate of autophagy in JIA T cells and to investigate the effect of inhibition of autophagy on the inflammatory phenotype of JIA T cells. Methods Autophagy-related gene expression was analysed in CD4+ T cells from the SF of JIA patients and healthy controls using RNA sequencing. Autophagy was measured by flow cytometry and western blot. The effect of inhibition of autophagy, using HCQ, on the cellular activation status was analysed using flow cytometry and multiplex immunoassay. Results Autophagy was increased in T cells derived from the site of inflammation compared with cells from the peripheral blood of patients and healthy controls. This increase in autophagy was not induced by JIA SF, but is more likely to be the result of increased cellular activation. Inhibition of autophagy reduced proliferation, cytokine production and activation marker expression of JIA SF-derived CD4+ T cells. Conclusion These data indicate that autophagy is increased in JIA SF-derived T cells and that targeting autophagy could be a promising therapeutic strategy to restore the disrupted T-cell homeostasis in JIA.