Repression of CTSG, ELANE and PRTN3-mediated histone H3 proteolytic cleavage promotes monocyte-to-macrophage differentiation.

Chromatin undergoes extensive reprogramming during immune cell differentiation. Here we report the repression of controlled histone H3 amino terminus proteolytic cleavage (H3ΔN) during monocyte-to-macrophage development. This abundant histone mark in human peripheral blood monocytes is catalyzed by neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase and proteinase 3. NSPs are repressed as monocytes mature into macrophages. Integrative epigenomic analysis reveals widespread H3ΔN distribution across the genome in a monocytic cell line and primary monocytes, which becomes largely undetectable in fully differentiated macrophages. H3ΔN is enriched at permissive chromatin and actively transcribed genes. Simultaneous NSP depletion in monocytic cells results in H3ΔN loss and further increase in chromatin accessibility, which likely primes the chromatin for gene expression reprogramming. Importantly, H3ΔN is reduced in monocytes from patients with systemic juvenile idiopathic arthritis, an autoinflammatory disease with prominent macrophage involvement. Overall, we uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development.

LACC1 deficiency leading to juvenile arthritis and anemia.

OBJECTIVE: Juvenile arthritis caused by loss-of-function LACC1 mutations is characterized by early onset of symmetric and chronic arthritis, associated with an elevation of inflammatory markers. We aimed to describe serum cytokine levels, explore the type I interferon pathway, and evaluate the efficacy of treatment in a patient presenting with polyarthritis and anemia caused by novel compound heterozygous variations in LACC1. METHODS: Clinical data of a patient with compound heterozygous variations in LACC1 was collected. Serum cytokine levels and IFN-stimulated cytokine genes were analyzed at diagnosis, at disease flare, and after treatment. Full-length cDNA of LACC1 was checked by RNA analysis. Single-cell RNA sequencing was performed in PBMCs. RESULTS: Two novel variants in the LACC1 gene were identified in a patient presenting with polyarthritis and anemia. LACC1-cDNA was normally expressed in the healthy control, the target production at 1384 bp was not observed in the patient. Compared to nine patient controls with non-systemic juvenile idiopathic arthritis, serum interleukin(IL)-6 level was significantly elevated in the affected patient. The median IFN score for the patient, her mother, and controls were 118, 8, and 4.9, respectively. The combined treatment of JAK inhibitors with prednisone or tocilizumab led to a complete response, including remission of joint symptoms, resolution of anemia, reduced expression of IFN-stimulated cytokine genes, and normalized levels of inflammatory markers, including CRP, ESR, SAA, and serum IL-6. CONCLUSION: LACC1 may play a crucial role in multiple inflammatory signaling pathways. The combination therapy of JAK inhibitors and tocilizumab may be effective for a subset of refractory patients.

Detection of inflammation by whole-body MRI in young people with juvenile idiopathic arthritis.

OBJECTIVES: To assess the frequency of joint inflammation detected by whole-body MRI (WBMRI) in young people (YP) with JIA and controls, and to determine the relationship between WBMRI-detected inflammation and clinical findings. METHODS: YP aged 14-24 years, with JIA (patients) or arthralgia without JIA (controls), recruited from one centre, underwent a WBMRI scan after formal clinical assessment. Consensus between at least two of the three independent radiologists was required to define inflammation and damage on WBMRI, according to predefined criteria. YP with JIA were deemed clinically active as per accepted definitions. The proportions of YP with positive WBMRI scans for joint inflammation (one or more inflamed joint) as well as serum biomarkers were compared between active vs inactive JIA patients and controls. RESULTS: Forty-seven YP with JIA (25 active and 22 inactive patients) and 13 controls were included. WBMRI detected joint inflammation in 60% (28/47) of patients with JIA vs 15% (2/13) of controls (difference: 44%, 95% CI 20%, 68%). More active than inactive JIA patients had WBMRI-detected inflammation [76% (19/25) vs 41% (9/22), difference: 35% (95% CI 9%, 62%)], and this was associated with a specific biomarker signature. WBMRI identified inflammation in one or more clinically inactive joint in 23/47 (49%) patients (14/25 active vs 9/22 inactive JIA patients). CONCLUSIONS: WBMRI's validity in joint assessment was demonstrated by the higher frequency of inflammation in JIA patients vs controls, and in active vs inactive JIA patients. WBMRI found unsuspected joint inflammation in 49% YP with JIA, which needs further investigation of potential clinical implications.

Serum interleukin-18 levels can improve the diagnostic performance of the PRINTO and ILAR criteria for systemic juvenile idiopathic arthritis.

OBJECTIVE: Recently, the Pediatric Rheumatology International Trials Organization (PRINTO) has proposed revisions to the current International League of Associations for Rheumatology (ILAR) criteria for systemic juvenile idiopathic arthritis (s-JIA). Interleukin (IL)-18 overproduction plays a significant role in the pathogenesis of s-JIA. This study aimed to evaluate the performance of the PRINTO criteria compared with the ILAR criteria and determine whether serum IL-18 levels improve their diagnostic performances. METHODS: Overall, 90 patients with s-JIA and 27 patients with other febrile disease controls presenting with a prolonged fever of > 14 days and arthritis and/or erythematous rash were enrolled. The ILAR and PRINTO classification criteria were applied to all patients and examined with expert diagnoses. Enzyme-linked immunosorbent assay was used for measuring serum IL-18 levels. RESULTS: The PRINTO criteria had higher sensitivity but lower specificity than the ILAR criteria (sensitivity: PRINTO 0.856, ILAR 0.533; specificity: PRINTO 0.259, ILAR 0.851). With the addition of serum IL-18 levels ≥ 4,800 pg/mL, the sensitivity of the ILAR criteria and specificity of the PRINTO criteria were improved to 1.000 and 1.000, respectively. PRINTO plus serum IL-18 levels ≥ 4,800 pg/mL showed the highest value in Youden's index (sensitivity - [1 - specificity]). CONCLUSION: Serum IL-18 levels could improve the diagnostic performance of the PRINTO and ILAR criteria for s-JIA. The PRINTO criteria plus serum IL-18 levels ≥ 4,800 pg/mL could be the best diagnostic performance for s-JIA.

Parotid saliva and blood biomarkers in juvenile idiopathic arthritis in relation to temporomandibular joint magnetic resonance imaging findings.

BACKGROUND: Juvenile idiopathic arthritis (JIA) often affects the temporomandibular joint (TMJ) caused by an abnormal immune system that includes overactive inflammatory processes. Salivary biomarkers may be a powerful tool that can help establishing diagnosis, prognosis and monitor disease progress. OBJECTIVE: The objective was to investigate biomarkers in parotid saliva and blood plasma in relation to temporomandibular joint (TMJ) magnetic resonance imaging (MRI) findings in patients with JIA and healthy individuals. METHODS: Forty-five children aged 6 to 16 years with JIA and 16 healthy age- and sex-matched controls were included. Unstimulated parotid saliva samples and venous blood were collected. Biochemical analyses were performed for the cytokine biomarkers. The participants underwent MR imaging of the TMJs, where changes in the inflammatory and the damage domains were assessed. RESULTS: In the JIA patients, lower concentrations of IL-6R and gp130 were found in parotid saliva than in plasma. Higher concentrations of IL-6 were found in parotid saliva than in plasma. IL-6, IL-6R and gp130 in parotid saliva explained the presence of bone marrow oedema and effusion in the JIA patients. CONCLUSIONS: This study suggests that the IL-6 family in parotid saliva is associated with TMJ bone marrow oedema and effusion in patients with JIA, suggesting that IL-6 has promising properties as a parotid saliva biomarker for TMJ inflammatory activity.

Association of IL-17A and IL-10 Polymorphisms with Juvenile Idiopathic Arthritis in Finnish Children.

To analyze the role of interleukin IL-17A and IL-10 polymorphisms in susceptibility to juvenile idiopathic arthritis (JIA), 98 Finnish children and adolescents with JIA were studied. Data from the 1000 Genomes Project, consisting of 99 healthy Finns, served as the controls. The patients were analyzed for four IL-17A and three IL-10 gene-promoter polymorphisms, and the serum IL-17A, IL-17F, IL-10, and IL-6 levels were determined. The IL-17A rs8193036 variant genotypes (CT/CC) were more common among the patients than controls, especially in those with polyarthritis (OR 1.93, 95% CI 1.11-3.36; p = 0.020). IL-17A rs2275913 minor allele A was more common in patients (OR 1.45, 95% Cl 1.08-1.94; p = 0.014) and especially among patients with oligoarthritis and polyarthritis than the controls (OR 1.61, 95%CI 1.06-2.43; p = 0.024). Carriers of the IL-17A rs4711998 variant genotype (AG/AA) had higher serum IL-17A levels than those with genotype GG. However, carriers of the variant genotypes of IL-17A rs9395767 and rs4711998 appeared to have higher IL-17F levels than those carrying wildtype. IL-10 rs1800896 variant genotypes (TC/CC) were more abundant in patients than in the controls (OR 1.97, 95%CI 1.06-3.70; p = 0.042). Carriers of the IL-10 rs1800896 variant genotypes had lower serum levels of IL-17F than those with wildtype. These data provide preliminary evidence of the roles of IL-17 and IL-10 in the pathogenesis of JIA and its subtypes in the Finnish population. However, the results should be interpreted with caution, as the number of subjects included in this study was limited.

The Role of Serum Calprotectin in Defining Disease Outcomes in Non-Systemic Juvenile Idiopathic Arthritis: A Pilot Study.

Serum calprotectin (MRP8/14) is currently being studied as a promising biomarker of disease activity and outcome in patients with juvenile idiopathic arthritis (JIA) but the data in the literature are conflicting. The aim of our study was to investigate the potential role of serum calprotectin as biomarker of disease activity and flare/remission in a group of nsJIA patients during a follow-up period of 18 months. In this prospective longitudinal study, two groups of patients with ns-JIA (55 active patients and 56 patients in remission according to Wallace's criteria) and a control group (50 children) were recruited at baseline from January 2020 to September 2021. JIA patients were followed for up to 18 months at four timepoints: 3 months (T1), 6 months (T2), 12 months (T3) and 18 months (T4). At each timepoint, the following were recorded: JADAS27, blood counts, ESR, CRP, albumin, ferritin and serum calprotectin. To illustrate the performance of calprotectin, Kaplan-Meier curves were constructed from baseline to relapse/remission, dichotomizing patients at baseline in positive/negative on the basis progressive calprotectin cut-offs. Associations between baseline factors and relapse were determined using Cox regression models. Multivariate models were constructed to analyze the effect of covariates. Comparing baseline clinical and laboratory data of the three groups (active vs. inactive JIA vs. controls), only serum calprotectin reached statistical significance (active patients vs. inactive (p = 0.0016) and vs. controls (p = 0.0012)). In the inactive group, during the 18 months of follow up, 31 patients (55.3%) had a relapse. Comparing the baseline data of relapsers vs. non-relapsers, serum calprotectin showed higher levels (p = 0.001) in relapsers. In survival analysis, a log rank test showed significant differences of up to 12 ng/mL (p = 0.045). Multivariate Cox regression confirmed that only baseline calprotectin levels were independently associated with disease recurrence. In the active group, in the 12 months of follow-up, 19 patients (38%) entered remission of the disease. In addition, in this group, the only statistical difference at the baseline was the value of MPR8/14 (p = 0.0001). Log rank test showed significant differences up to 10 ng/mL (p = 0.003). In the multivariate Cox regression, serum calprotectin levels at baseline were independently associated with remission. In conclusion, our study would suggest a dual role for calprotectin in predicting future relapse and treatment response in patients with nsJIA, thus influencing therapeutic decisions and management of these patients during follow up.

Serum protein signatures differentiate paediatric autoimmune/inflammatory disorders.

Because of their rarity, limited awareness among non-specialists, and significant overlaps in their clinical presentation, childhood autoimmune/inflammatory conditions represent a diagnostic and therapeutic challenge. Juvenile idiopathic arthritis (JIA), with its 7 sub-forms, is the most common paediatric "rheumatic" disease. Juvenile-onset systemic lupus erythematosus (jSLE) is a severe autoimmune/inflammatory disease that can affect any organ system and shares clinical features with JIA. To overcome issues around diagnostic approaches in the context of clinical overlap, we aimed at the definition of disease sub-form specific cytokine and chemokine profiles. Serum samples from patients with JIA (n = 77) and jSLE (n = 48), as well as healthy controls (n = 30), were collected. Samples were analysed using the Meso Scale Discovery (MSD) U-PLEX Biomarker Group 1 (hu) panel. Distinct serum protein signatures associate with JIA vs jSLE disease groups. Proteins with high discriminatory ability include IL-23, MIP-1ß, MCP-1, M-CSF and MDC. Furthermore, serum IL-18, MIF, MIP-5 and YKL-40 discriminate between systemic JIA and other JIA subtypes. Thus, simultaneous quantification of serum proteins in a panel format may provide an avenue for the diagnosis and monitoring of childhood autoimmune/inflammatory conditions.

Unbalanced expression of membrane-bound and soluble programmed cell death 1 and programmed cell death ligand 1 in systemic juvenile idiopathic arthritis.

The study aimed to investigate the soluble programmed death-1 (sPD-1) and its ligand (sPD-L1) levels in systemic juvenile idiopathic arthritis (sJIA) patients and elucidate its underlying immunomodulatory mechanisms. Plasma levels of sPD-1, sPD-L1 and related cytokines and proteins were detected using an enzyme-linked immunosorbent assay (ELISA) and Luminex. The effects of PD-1/PD-L1 signal on mDC (myeloid dendritic cell) and IL-6 secretion were measured using flow cytometry. The results revealed decreased levels of sPD-1 in sJIA patients negatively correlated with JADAS-27, PGA, PtGA and CRP. sJIA patients had lower CD86 and MHC-II expression on mDC. When blocking PD-1/PD-L1 signal, IL-6 secretion of DC were increased. Our finding displayed downregulated sPD-1 was related with clinical indicators and could be a new biomarker for sJIA diagnosis. The reduced membrane and soluble forms of PD-1/PD-L1 might take part in sJIA pathogenesis by enhancing mDC proliferation and IL-6 secretion.

Monocyte and bone marrow macrophage transcriptional phenotypes in systemic juvenile idiopathic arthritis reveal TRIM8 as a mediator of IFN-γ hyper-responsiveness and risk for macrophage activation syndrome.

OBJECTIVES: Systemic juvenile idiopathic arthritis (SJIA) confers high risk for macrophage activation syndrome (MAS), a life-threatening cytokine storm driven by interferon (IFN)-γ. SJIA monocytes display IFN-γ hyper-responsiveness, but the molecular basis of this remains unclear. The objective of this study is to identify circulating monocyte and bone marrow macrophage (BMM) polarisation phenotypes in SJIA including molecular features contributing to IFN response. METHODS: Bulk RNA-seq was performed on peripheral blood monocytes (n=26 SJIA patients) and single cell (sc) RNA-seq was performed on BMM (n=1). Cultured macrophages were used to define consequences of tripartite motif containing 8 (TRIM8) knockdown on IFN-γ signalling. RESULTS: Bulk RNA-seq of SJIA monocytes revealed marked transcriptional changes in patients with elevated ferritin levels. We identified substantial overlap with multiple polarisation states but little evidence of IFN-induced signature. Interestingly, among the most highly upregulated genes was TRIM8, a positive regulator of IFN-γ signalling. In contrast to PBMC from SJIA patients without MAS, scRNA-seq of BMM from a patient with SJIA and MAS identified distinct subpopulations of BMM with altered transcriptomes, including upregulated IFN-γ response pathways. These BMM also showed significantly increased expression of TRIM8. In vitro knockdown of TRIM8 in macrophages significantly reduced IFN-γ responsiveness. CONCLUSIONS: Macrophages with an 'IFN-γ response' phenotype and TRIM8 overexpression were expanded in the bone marrow from an MAS patient. TRIM8 is also upregulated in SJIA monocytes, and augments macrophage IFN-γ response in vitro, providing both a candidate molecular mechanism and potential therapeutic target for monocyte hyper-responsiveness to IFNγ in cytokine storms including MAS.

Clinical significance of interleukin-18 for the diagnosis and prediction of disease course in systemic juvenile idiopathic arthritis.

OBJECTIVE: To investigate the clinical significance of serum IL-18 levels for the diagnosis of systemic JIA (s-JIA) and to predict the disease course of s-JIA. METHODS: Overall, 116 patients with s-JIA, 151 with other diseases and 20 healthy controls were analysed. Serum IL-18 levels were measured longitudinally in 41 patients with s-JIA from active phase through remission phase. Serum IL-18 levels were quantified via enzyme-linked immunosorbent assay and the results were compared with clinical features and the disease course of s-JIA. RESULTS: The serum IL-18 level cut-off value for differentiation of s-JIA from other diseases was 4800 pg/ml. In patients with a monocyclic course, serum IL-18 levels steadily decreased during the inactive phase and low levels were sustained during remission. In contrast, in patients with a chronic course, elevated serum IL-18 levels were sustained even during the inactive phase. In patients with a polycyclic course, serum IL-18 levels were elevated during disease flares and normalized during the inactive phase. The serum IL-18 level cut-off value for diagnosis of remission in s-JIA was 595 pg/ml. CONCLUSION: Serum IL-18 levels of >4800 pg/ml may be useful for differentiating between s-JIA and other diseases. Monitoring of serum IL-18 levels might be useful for predicting the disease course and assessing remission in s-JIA.

A dysregulated interleukin-18-interferon-γ-CXCL9 axis impacts treatment response to canakinumab in systemic juvenile idiopathic arthritis.

OBJECTIVES: The monoclonal IL-1ß antibody canakinumab is approved for the treatment of systemic juvenile idiopathic arthritis (SJIA). Its efficacy has been proven in several trials, but not all patients show a complete and sustained response to therapy. We aimed to analyse the association of baseline serum biomarkers with treatment outcome in patients with SJIA treated with canakinumab. METHODS: Serum samples from 54 patients with active SJIA without recent macrophage activation syndrome (MAS) treated with canakinumab in an open-label response characterization study were subjected to a multiplexed bead array assay. Interesting targets from these analyses were validated by ELISA. Clinical treatment outcomes included modified paediatric ACR (pACR) 30 and 90 responses, clinically inactive disease (CID) within 15 days of treatment and sustained complete response, defined as pACR100 or CID within 15 days of treatment plus no future flare or MAS. RESULTS: In canakinumab-naïve patients most biomarkers were elevated when compared with healthy controls at baseline and some rapidly decreased by day 15 [IL-1 receptor antagonist (IL-1RA), IL-6, IL-18 and S100A12]. Responders had higher IL-18 and IFN-γ levels and lower chemokine (C-X-C motif) ligand 9 (CXCL9) levels at baseline, emphasized by the IL-18: CXCL9 and IFN-γ: CXCL9 ratios. These ratios had significant accuracy in predicting treatment responses. CONCLUSION: Differential regulation of the IL-18-IFN-γ-CXCL9 axis is observed in patients with SJIA. Higher IL-18: CXCL9 and IFN-γ: CXCL9 ratios at baseline are associated with a better clinical response to canakinumab treatment in SJIA. Future studies are needed to validate these findings and determine their generalizability to patients with recent MAS.

Comparison of serum cytokine profiles in macrophage activation syndrome complicating different background rheumatic diseases in children.

OBJECTIVES: To compare the cytokines involved in the development of macrophage activation syndrome (MAS) in different background rheumatic diseases and to identify serum biomarkers for MAS diagnosis. METHODS: Serum neopterin, IL-6, IL-18 and soluble TNF receptor (sTNFR) type I (sTNFR-I) and type II (sTNFR-II) levels were determined using ELISA in 12 patients with SLE, including five with MAS; 12 patients with JDM, including four with MAS; 75 patients with Kawasaki disease (KD), including six with MAS; and 179 patients with systemic JIA (s-JIA), including 43 with MAS. These results were compared with the clinical features of MAS. RESULTS: Serum neopterin, IL-18 and sTNFR-II levels were significantly higher during the MAS phase than during the active phase in patients with all diseases. Furthermore, serum sTNFR-I levels were significantly higher during the MAS phase than during the active phase in patients with SLE, KD and s-JIA. Receiver operating characteristic (ROC) curve analysis revealed that serum sTNFR-I levels for SLE, serum IL-18 levels for JDM, and serum sTNFR-II levels for KD and s-JIA had the highest areas under the ROC curve. Serum levels of these cytokines were significantly and positively correlated with serum ferritin levels. CONCLUSIONS: Overproduction of IFN-γ, IL-18 and TNF-α might be closely related to the development of MAS. Serum levels of sTNFR-I for SLE, IL-18 for JDM, and sTNFR-II for KD and s-JIA might be useful diagnostic markers for the transition from active phase to MAS.

Cytokine profile in patients with chronic non-bacterial osteomyelitis, juvenile idiopathic arthritis, and insulin-dependent diabetes mellitus.

OBJECTIVES: Our study aimed to evaluate the cytokine levels in pediatric chronic non-bacterial osteomyelitis (CNO) patients and compare these with other immune-mediated diseases and healthy controls. METHODS: In this prospective study, we included 42 children with CNO, 28 patients with non-systemic juvenile idiopathic arthritis (JIA), 17 children with insulin-dependent diabetes mellitus (IDDM), and 30 healthy age-matched controls. In each of the CNO patients and comparison groups, the levels of 14-3-3-η protein, S100A8/A9 protein, interleukin-4 (IL-4), interleukin-17 (IL-17), interleukin-18 (IL-18), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) were measured by ELISA assay. RESULTS: All studied cytokines in the CNO patients were significantly higher than controls, and IDDM, 14-3-3-η protein, IL-18, IL-4, IL-17, IL-1ß, and TNF-α were less than in JIA patients. In the discriminant analysis, ESR, 14-3-3 protein, S100A8/A9, IL-18, IL-4, and TNF-α can discriminate CNO from JIA, and 14-3-3 protein, S100A8/A9, IL-18, IL-17, IL-4, and TNF-α can distinguish CNO from other diseases and HC. CONCLUSION: The increased level of pro-inflammatory cytokines confirms the role of monocyte-driven inflammation in CNO patients. Cytokines may prove valuable as biomarkers and potential therapeutic targets for CNO.

Antibodies against carbamylated proteins: prevalence and associated disease characteristics in Belgian patients with rheumatoid arthritis or other rheumatic diseases.

Objectives: Anti-carbamylated protein antibodies (anti-CarP) are reported to be associated with increased disease activity and with more severe joint damage in rheumatoid arthritis (RA) patients. The present study investigated the presence of anti-CarP in various rheumatic diseases, and their specific clinical significance in RA, in Belgian rheumatology patients.Method: We tested sera from 254 RA patients, 56 healthy controls, and 153 patients with different rheumatic conditions: juvenile idiopathic arthritis (JIA), axial spondyloarthritis, systemic sclerosis, and Sjögren's syndrome (SS). An in-house enzyme-linked immunosorbent assay was used to detect immunoglobulin G antibodies against carbamylated foetal calf serum.Results: Anti-CarP were detected in 88 RA patients (34.6%), of whom 82% were also positive for anti-citrullinated protein antibodies (ACPAs) and 81% were also rheumatoid factor (RF) positive. Of note, 11 anti-CarP single-positive patients were detected (4.3%). The previously reported association with joint erosions was not detected. However, in ACPA- and RF-negative RA patients, the presence of anti-CarP was associated with higher disease activity and disability. Fifteen per cent of JIA patients and 30% of SS patients also tested positive for anti-CarP and their antibody levels did not differ significantly from those of anti-CarP-positive RA patients. Anti-CarP levels were, however, significantly higher in ACPA- or RF-positive patients.Conclusion: Anti-CarP antibodies were detected in the sera of a cohort of Belgian RA patients. Moreover, they were also detected in primary SS patients and in JIA patients. In the seronegative subset of RA patients, anti-CarP antibodies showed prognostic value.

Comparative risk of infections among real-world users of biologics for juvenile idiopathic arthritis: data from the German BIKER registry.

To examine whether treatment with interleukin (IL)-1-, IL-6-, tumour necrosis factor α (TNFα)-inhibitors or Abatacept is associated with an increased risk of common infections, infections requiring hospitalization (SAE) or opportunistic infections among real-world juvenile idiopathic arthritis (JIA) patients. Furthermore, the influence of other patient-related covariates on the occurrence of infections was investigated. Patients diagnosed with JIA and treated with biologics were selected from the German BIKER registry. Incidence rates (IR) of infections per 100 person years were calculated and compared between the different cohorts. Using multivariate logistic regression, odds ratios with 95% confidence intervals (CI) were determined for the influence of patient-related covariates (age, diagnosis, laboratory data, concomitant medication, JIA activity, comorbidities, and premedication) on the occurrence of infections. 3258 patients entered the analysis. A total of 3654 treatment episodes were distributed among TNFα- (Etanercept, Adalimumab, Golimumab, Infliximab, n = 3044), IL-1- (Anakinra, Canakinumab, n = 105), IL-6- (Tocilizumab, n = 400) and T-cell activation inhibitors (Abatacept, n = 105). 813 (22.2%) patients had at least one infection, 103 (2.8%) patients suffered from an SAE infection. Both common and SAE infections were significantly more frequent in IL-1 (IR 17.3, 95% CI 12.5/24 and IR 4.3, 95% CI 2.3/8.3) and IL-6 cohort (IR 16.7, 95% CI 13.9/20 and IR 2.8, 95% CI 1.8/4.4) compared to TNFα-inhibitor cohort (IR 8.7, 95% CI 8.1/9.4 and IR 1, 95% CI 0.8/1.3). When comparing the influencing factors for various infectious diseases, the use of corticosteroids, younger age, cardiac comorbidities and higher JIA-activity are the most striking risk factors. Relative to TNFα inhibitors and Abatacept, IL-1 and IL-6 inhibitors were associated with an increased risk of common and SAE infections. The influencing covariates identified may be helpful for the choice of a suitable biologic to treat JIA.

JNK Pathway-Associated Phosphatase as a Serum Marker for Disease Activity and Treatment Outcome of Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is a heterogeneous autoimmune disease characterized by arthritis of unknown etiology. JNK pathway-associated phosphatase (JKAP) is reported to be a negative regulator of T-cell activation, but its clinical role in JIA is unknown. This study aimed to investigate the correlation of JKAP with disease activity and treatment response to a tumor necrosis factor (TNF) inhibitor, etanercept (ETN), in JIA patients. Totally, 104 JIA patients (6.9 ± 2.7 years old) and 100 age- and sex-matched healthy controls (HCs) (7.2 ± 2.4 years old) were enrolled, and their serum samples were collected for measuring JKAP by enzyme-linked immunoassay. In JIA patients, after 24-week ETN treatment, clinical response was assessed based on the American College of Rheumatology pediatric criteria (ACRpedi) 50 criteria. Results showed that JKAP levels were significantly lower in JIA patients compared with HCs, and of good value in differentiating JIA patients from HCs. Among JIA patients, higher JKAP levels were associated with lower disease activity indexes, including C-reactive protein, number of joints with active arthritis, physician's global assessment of disease activity, and the present history of disease-modifying antirheumatic drugs; higher baseline JKAP levels were correlated with worse ACRpedi 50 response to ETN at week 24, and was also an independent predictive factor for worse ACRpedi 50 response to ETN. Thus, it may be inappropriate to use ETN for JIA patients with higher JKAP levels. In conclusion, serum JKAP is a potential biomarker for JIA activity and treatment response to a TNF inhibitor.

Safety and effectiveness of adalimumab in Japanese patients with juvenile idiopathic arthritis: Results from a real-world postmarketing study.

OBJECTIVES: This study was conducted to assess the real-world safety and effectiveness of adalimumab in patients with juvenile idiopathic arthritis (JIA). METHODS: In this all-case, postmarketing surveillance study (NCT01412021) conducted in Japan, patients receiving adalimumab for JIA affecting multiple joints were observed for 24 weeks. The safety (adverse drug reactions [ADRs]/serious ADRs) and effectiveness (4-variable Disease Activity Score in 28 joints using erythrocyte sedimentation rate [DAS28-4/ESR] remission rate) were assessed. RESULTS: In the safety population (n = 356), 90.3% (65/72; weight, ≥15-<30 kg) of patients received adalimumab 20 mg every 2 weeks (q2w) and 98.3% (236/240; weight ≥30 kg) received 40 mg q2w. Incidence of ADRs and serious ADRs was 29.8% (106/356) and 3.4% (12/356), respectively. Incidence of ADRs was significantly higher in patients aged <15 years vs. ≥15 years (34.6% vs. 21.1%, p = .0072), those with comorbidities vs. without (38.3% vs. 25.7%, p = .0155), and those receiving dose <40 mg q2w vs. ≥40 mg q2w (38.8% vs. 26.9%, p = .0418). DAS28-4/ESR remission rate improved from 21.7% (36/166) at baseline to 74.7% (112/150) at week 24. CONCLUSIONS: Adalimumab was well tolerated and had acceptable safety and effectiveness in patients with JIA in the real-world setting.

Identification of Prevotella Oralis as a possible target antigen in children with Enthesitis related arthritis.

OBJECTIVES: Patients with Crohn's disease often produce antibodies against flagellated intestinal bacteria. There are mixed data as to whether such antibodies are present in patients with spondyloarthritis. Our objectives were to evaluate for the presence of antibodies against intestinal organisms in children with enthesitis related arthritis (ERA). METHODS: Children with ERA and healthy controls were recruited at three sites. Sera were plated on a nitrocellulose array and incubated with labelled antibodies to human IgA and IgG. RESULTS: At UAB, patients and controls had similar antibody levels against the majority of the bacteria selected, with the exception of increased IgA antibodies among ERA patients against Prevotella oralis (1231 [IQR 750, 2566] versus 706 [IQR 428, 1106], p = .007.) These findings were partially validated at a second but not at a third site. CONCLUSIONS: ERA patients may produce increased IgA antibodies against P. oralis. The possible significance of this finding bears further exploration.

Adenosine deaminase 2 as a biomarker of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

OBJECTIVE: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterised by a vicious cycle of immune amplification that can culminate in overwhelming inflammation and multiorgan failure. The clinical features of MAS overlap with those of active sJIA, complicating early diagnosis and treatment. We evaluated adenosine deaminase 2 (ADA2), a protein of unknown function released principally by monocytes and macrophages, as a novel biomarker of MAS. METHODS: We established age-based normal ranges of peripheral blood ADA2 activity in 324 healthy children and adults. We compared these ranges with 173 children with inflammatory and immune-mediated diseases, including systemic and non-systemic JIA, Kawasaki disease, paediatric systemic lupus erythematosus and juvenile dermatomyositis. RESULTS: ADA2 elevation beyond the upper limit of normal in children was largely restricted to sJIA with concomitant MAS, a finding confirmed in a validation cohort of sJIA patients with inactive disease, active sJIA without MAS or sJIA with MAS. ADA2 activity strongly correlated with MAS biomarkers including ferritin, interleukin (IL)-18 and the interferon (IFN)-γ-inducible chemokine CXCL9 but displayed minimal association with the inflammatory markers C reactive protein and erythrocyte sedimentation rate. Correspondingly, ADA2 paralleled disease activity based on serial measurements in patients with recurrent MAS episodes. IL-18 and IFN-γ elicited ADA2 production by peripheral blood mononuclear cells, and ADA2 was abundant in MAS haemophagocytes. CONCLUSIONS: These findings collectively identify the utility of plasma ADA2 activity as a biomarker of MAS and lend further support to a pivotal role of macrophage activation in this condition.