Interleukin-33 as a marker of disease activity in rheumatoid factor positive polyarticular juvenile idiopathic arthritis.

OBJECTIVE: To investigate clinical usefulness of serum interleukin (IL)-33 levels as an indicator of disease activity in juvenile idiopathic arthritis (JIA). METHODS: We measured serum levels of IL-33 in 39 patients with JIA, including 7 patients with rheumatoid factor positive poly-JIA (RF + poly-JIA), 8 patients with RF negative poly-JIA (RF-poly-JIA), 20 patients with oligoarticular JIA (Oligo-JIA), 4 patients with enthesitis-related arthritis (ERA) and 30 age-matched healthy controls. Furthermore, we determined their correlation with measures of disease activity. RESULTS: Serum IL-33 levels in patients with RF + poly-JIA were significantly elevated compared to those in patients with RF-poly-JIA, oligo-JIA and HC. Serum IL-33 levels in patients with RF-poly-JIA, oligo-JIA and ERA were not elevated compared to those in HC. Serum IL-33 levels in RF + poly-JIA patients normalized in remission phase. Serum IL-33 levels correlated positively with RF in patients with RF + poly-JIA. CONCLUSIONS: These results indicate that serum IL-33 levels in RF + poly-JIA patients correlated with disease activity, suggesting a potential role of IL-33 as a promising indicator of disease activity.

Transcriptomic signatures of classical monocytes reveal pro-inflammatory modules and heterogeneity in polyarticular juvenile idiopathic arthritis.

Introduction: Polyarticular juvenile idiopathic arthritis (pJIA) is a childhood-onset autoimmune disease. Immune cells contribute to persistent inflammation observed in pJIA. Despite the crucial role of monocytes in arthritis, the precise involvement of classical monocytes in the pathogenesis of pJIA remains uncertain. Here, we aimed to uncover the transcriptomic patterns of classical monocytes in pJIA, focusing on their involvement in disease mechanism and heterogeneity. Methods: A total of 17 healthy subjects and 18 premenopausal women with pJIA according to ILAR criteria were included. Classical monocytes were isolated, and RNA sequencing was performed. Differential expression analysis was used to compare pJIA patients and healthy control group. Differentially expressed genes (DEGs) were identified, and gene set enrichment analysis (GSEA) was performed. Using unsupervised learning approach, patients were clustered in two groups based on their similarities at transcriptomic level. Subsequently, these clusters underwent a comparative analysis to reveal differences at the transcriptomic level. Results: We identified 440 DEGs in pJIA patients of which 360 were upregulated and 80 downregulated. GSEA highlighted TNF-α and IFN-γ response. Importantly, this analysis not only detected genes targeted by pJIA therapy but also identified new modulators of immuno-inflammation. PLAUR, IL1B, IL6, CDKN1A, PIM1, and ICAM1 were pointed as drivers of chronic hyperinflammation. Unsupervised learning approach revealed two clusters within pJIA, each exhibiting varying inflammation levels. Conclusion: These findings indicate the pivotal role of immuno-inflammation driven by classical monocytes in pJIA and reveals the existence of two subclusters within pJIA, regardless the positivity of rheumatoid factor and anti-CCP, paving the way to precision medicine.

Th17/1 and ex-Th17 cells are detected in patients with polyarticular juvenile arthritis and increase following treatment.

BACKGROUND: A better understanding of the pathogenesis of polyarticular juvenile idiopathic arthritis (polyJIA) is needed to aide in the development of data-driven approaches to guide selection between therapeutic options. One inflammatory pathway of interest is JAK-STAT signaling. STAT3 is a transcription factor critical to the differentiation of inflammatory T helper 17 cells (Th17s). Previous studies have demonstrated increased STAT3 activation in adult patients with rheumatoid arthritis, but less is known about STAT3 activation in polyJIA. We hypothesized that Th17 cells and STAT3 activation would be increased in treatment-naïve polyJIA patients compared to pediatric controls. METHODS: Blood from 17 patients with polyJIA was collected at initial diagnosis and again if remission was achieved (post-treatment). Pediatric healthy controls were also collected. Peripheral blood mononuclear cells were isolated and CD4 + T cell subsets and STAT activation (phosphorylation) were evaluated using flow cytometry. Data were analyzed using Mann-Whitney U and Wilcoxon matched-pairs signed rank tests. RESULTS: Treatment-naïve polyJIA patients had increased Th17 cells (CD3 + CD4 + interleukin(IL)-17 +) compared to controls (0.15% v 0.44%, p < 0.05), but Tregs (CD3 + CD4 + CD25 + FOXP3 +) from patients did not differ from controls. Changes in STAT3 phosphorylation in CD4 + T cells following ex vivo stimulation were not significantly different in patients compared to controls. We identified dual IL-17 + and interferon (IFN)γ + expressing CD4 + T cells in patients, but not controls. Further, both Th17/1 s (CCR6 + CD161 + IFNγ + IL-17 +) and ex-Th17s (CCR6 + CD161 + IFNγ + IL-17neg) were increased in patients' post-treatment (Th17/1: 0.3% v 0.07%, p < 0.05 and ex-Th17s: 2.3% v 1.4%, p < 0.05). The patients with the highest IL-17 expressing cells post-treatment remained therapy-bound. CONCLUSIONS: Patients with polyJIA have increased baseline Th17 cells, potentially reflecting higher tonic STAT3 activation in vivo. These quantifiable immune markers may identify patients that would benefit upfront from pathway-focused biologic therapies. Our data also suggest that inflammatory CD4 + T cell subsets not detected in controls but increased in post-treatment samples should be further evaluated as a tool to stratify patients in remission on medication. Future work will explore these proposed diagnostic and prognostic biomarkers.

Microscopic Polyangiitis with Pulmonary-renal Involvement in a Patient with Polyarticular Juvenile Idiopathic Arthritis: A Case Report.

The association of polyarticular juvenile idiopathic arthritis (p-JIA) and microscopic polyangiitis (MPA) is extremely rare. Very few case reports described the coexistence of these two diseases to date. Here we report a 26-year-old female, a diagnosed patient of rheumatoid factor positive p-JIA for 15 years who developed MPA with renal and pulmonary involvement at the age of 26 years. She was successfully treated with intravenous corticosteroid and injection rituximab. This case report is unique as an association between MPA and p-JIA is very rare.

Identification of key biomarkers in RF-negative polyarticular and oligoarticular juvenile idiopathic arthritis by bioinformatic analysis.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a broad term used to describe arthritis of unknown origin. JIA commonly persists into adulthood, often causing substantial morbidity such as restricted joint function, which can lead to challenges in employment and independence. This study aims to identify diagnostic biomarkers and investigate the role of immune cells in the pathogenesis of rheumatoid factor-negative polyarticular juvenile idiopathic arthritis (RF-negative pJIA) and oligoarticular juvenile idiopathic arthritis (oJIA). METHODS: We retrieved a JIA dataset from the GEO database and conducted an analysis of differentially expressed genes (DEGs). Subsequently, functional enrichment analysis was performed on the DEGs. Weighted gene co-expression network analysis (WGCNA) was utilized to identify key modules. Additionally, we constructed a protein‒protein interaction network to identify hub genes that serve as signature genes. Furthermore, we employed CIBERSORT to classify immune cell infiltration. RESULTS: From the GSE20307 dataset, we identified a total of 1438 DEGs in RF-negative pJIA and 688 DEGs in oJIA. WGCNA clustered the data into 6 modules in pJIA and 4 modules in oJIA. Notably, the ME5 and ME2 modules exhibited significant associations with pJIA and oJIA, respectively. In both pJIA and oJIA, we identified six hub genes, four of which demonstrated high diagnostic sensitivity and specificity in pJIA, while five showed high diagnostic sensitivity and specificity in oJIA. CIBERSORT analysis suggested the potential involvement of these signature genes in immune cell infiltration. CONCLUSION: In this study, we identified JUN, CXCL8, SOCS3, and KRAS as biomarkers for RF-negative pJIA and JUN, CXCL8, SOCS3, PTGS2, and NFKBIA as biomarkers for oJIA. Furthermore, our findings suggest that Tfh cells may play a role in the early onset of both RF-negative pJIA and oJIA.

Risk stratification using anti-citrullinated peptide antibodies (ACPA) in polyarticular subtypes of juvenile idiopathic arthritis in adulthood.

OBJECTIVES: Polyarticular juvenile idiopathic arthritis (pJIA) is a subset of juvenile idiopathic arthritis (JIA), divided into two subtypes according to the presence of rheumatoid factor: pJIA without rheumatoid factor (pJIA RF-) and pJIA with positive rheumatoid factor (pJIA RF+), this latter is characterised with more structural damage. Anti-citrullinated peptide antibodies (ACPA) are often associated with RF. The respective performance of ACPA versus RF in structural outcome in pJIA, and in particular in adulthood pJIA remains unknown. Therefore, the aim of this study was to determine whether ACPA could be of value to assess structural damage in pJIA persisting in adulthood. METHODS: Patients with pJIA and available data for ACPA, RF and X-ray were included retrospectively. Structural damage was assessed by two independent blinded investigators using Sharp Van Der Heijde scores. RESULTS: 56 pJIA adult patients were included: 62% (35/56) had pJIA RF+ and 38% (21/56) pJIA RF-. ACPA positivity in pJIA was significantly associated with presence of RF (96% vs 26%, P<0.001). RF positivity was significantly associated with higher Sharp van Der Heijde erosion and total scores (respectively P<0.01 and P<0.05). There were higher Sharp Van Der Heijde erosion, joint space narrowing and total scores in the pJIA ACPA+ subgroup than in the pJIA ACPA- subgroup, although there was no statistical significance. However, when adjusted on disease duration, pJIA ACPA+ patients had significantly higher erosion and total scores than pJIA ACPA- patients (P<0.05), and pJIA ACPA+ patients required more bDMARDs than pJIA ACPA- patients (P<0.05). Moreover, pJIA patients with high Sharp van Der Heijde joint space narrowing and total scores had significantly higher ACPA levels (P<0.01). A correlation was identified between ACPA levels and Sharp van Der Heijde total score (r=0.54, P<0.05). In the pJIA RF+ subgroup the presence of ACPA was associated with additional structural damage compared to no ACPA: sharp Van Der Heijde erosion, joint space narrowing and total scores were higher in the pJIA RF+ ACPA+ subgroup than in the pJIA RF+ ACPA- subgroup although these results did not reach significance. CONCLUSION: Our results suggest that pJIA RF+ ACPA+ adult patients may have a more severe articular phenotype than pJIA RF+ ACPA- patients. ACPA could bring an additional value to RF for pJIA patients regarding structural damage. Altogether our results show that RF and ACPA are associated with structural damage measured by Sharp Van Der Heijde score in pJIA persisting in adulthood.

Factors associated with medication adherence among children with rheumatic diseases.

Introduction: Failure to take medications regularly leads to poorer health outcomes. The Pediatric Rheumatology Adherence Questionnaire (PRAQ) is an effective tool for assessing medication adherence in rheumatic patients. Therefore, we aimed to determine the factors associated with poor medication adherence among children with rheumatic diseases. Methods: This was a cross-sectional study. Patients with rheumatic diseases who had taken at least one medication and had been followed up at our pediatric rheumatology clinic were included in the study, together with their caregivers. Patients with poor medication adherence were characterized as those who had taken less than 80% of their prescribed drugs, as determined using the pill count method. The original PRAQ was translated and validated in Thai language and was completed by caregivers and literate patients over age 13 years. Interviewing for additional problems with taking medications was conducted. We performed descriptive and logistic regression analyses. Results: From 210 patients, 52.86% had juvenile idiopathic arthritis (JIA), and 46.19% had connective tissue diseases. The mean patient age was 14.10 ± 4.74 years, with a median (interquartile range) disease duration of 4.33 (2.08-6.98) years. PRAQ scores in the group with poor adherence were significantly higher than scores in the group with good adherence (11.00 ± 3.47 vs. 9.51 ± 3.16, p = 0.004). Enthesitis-related arthritis (ERA) (odds ratio [OR] 9.09, 95% confidence interval [CI] 1.25-66.18; p = 0.029) and polyarticular JIA (OR 6.43, 95% CI 1.30-31.75; p = 0.022) were associated with poor treatment adherence. Disease duration ≥5 years (OR 3.88, 95% CI 1.17-12.87; p = 0.027), active disease (OR 6.49, 95% CI 1.76-23.99; p = 0.005), PRAQ scores ≥12 (OR 6.48, 95% CI 1.76-23.82; p = 0.005), forgetting to take medications (OR 14.18, 95% CI 4.21-47.73; p < 0.001), and unawareness about the importance of the medicines (OR 44.18, 95% CI 11.30-172.73; p < 0.001) were predictors of poor drug adherence. Conclusion: In the present study, poor medication adherence was found in one-fourth of children with rheumatic illnesses, particularly those with ERA, polyarticular JIA, longer disease duration, active disease, and high PRAQ scores. The most frequent reasons for inadequate medication adherence were forgetfulness and unawareness about the importance of disease control and consistency with treatment.

Social determinants of health influence disease activity and functional disability in Polyarticular Juvenile Idiopathic Arthritis.

BACKGROUND: Social determinants of health (SDH) greatly influence outcomes during the first year of treatment in rheumatoid arthritis, a disease similar to polyarticular juvenile idiopathic arthritis (pJIA). We investigated the correlation of community poverty level and other SDH with the persistence of moderate to severe disease activity and functional disability over the first year of treatment in pJIA patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance Registry. METHODS: In this cohort study, unadjusted and adjusted generalized linear mixed effects models analyzed the effect of community poverty and other SDH on disease activity, using the clinical Juvenile Arthritis Disease Activity Score-10, and disability, using the Child Health Assessment Questionnaire, measured at baseline, 6, and 12 months. RESULTS: One thousand six hundred eighty-four patients were identified. High community poverty (≥20% living below the federal poverty level) was associated with increased odds of functional disability (OR 1.82, 95% CI 1.28-2.60) but was not statistically significant after adjustment (aOR 1.23, 95% CI 0.81-1.86) and was not associated with increased disease activity. Non-white race/ethnicity was associated with higher disease activity (aOR 2.48, 95% CI: 1.41-4.36). Lower self-reported household income was associated with higher disease activity and persistent functional disability. Public insurance (aOR 1.56, 95% CI 1.06-2.29) and low family education (aOR 1.89, 95% CI 1.14-3.12) was associated with persistent functional disability. CONCLUSION: High community poverty level was associated with persistent functional disability in unadjusted analysis but not with persistent moderate to high disease activity. Race/ethnicity and other SDH were associated with persistent disease activity and functional disability.

Infliximab therapy and outcomes in patients with polyarticular juvenile idiopathic arthritis: a single-center study in China.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease that includes seven heterogeneous subgroups with different prognoses. In particular, polyarticular JIA (pJIA) has a longer period of active disease and a poorer prognosis. Tumor necrosis factor (TNF)-alpha inhibitors are effective in patients with pJIA, but the therapeutic regimen remains controversial. Here, we performed a single-center study to determine the potential correlation between TNF-alpha inhibitor (infliximab) therapy and outcomes in these patients. METHODS: Clinical data of 40 pJIA patients were collected at our center from January 1, 2010 to January 1, 2018, and patients were grouped according to the timing of infliximab therapy. The erythrocyte sedimentation rate (ESR), the number of joints with active disease, and the 27-point juvenile arthritis disease activity score (JADAS-27) were analyzed. RESULTS: The ESR, the active joint count, and the JADAS-27 decreased significantly in all groups after 3 months (P = 0.041/0.415/0.008, 0.022/0.030/ < 0.001, and 0.05/0.012/ < 0.001, respectively) and 6 months (P = 0.036/0.045/0.041, 0.076/0.037/ < 0.001, and 0.096/0.006/ < 0.001, respectively) of infliximab treatment, although the rates of change of these parameters were similar. However, after 12 months, only patients treated with infliximab within 3 months of disease onset had a stable ESR, active joint count, and JADAS-27, while these parameters increased sharply when infliximab was administered 3 months and especially 1 year after disease onset. CONCLUSIONS: TNF-alpha is a pleiotropic pro-inflammatory cytokine of crucial importance in the pathogenesis of JIA. Infliximab can improve the outcomes of patients with pJIA significantly, and should be introduced early during the clinical course.

Protocols on classification, monitoring and therapy in children's rheumatology (PRO-KIND): results of the working group Polyarticular juvenile idiopathic arthritis.

OBJECTIVE: Several effective pharmacologic treatment options for polyarticual juvenile idiopathic arthritis (JIA) have emerged but initial treatment is heterogeneous in Germany. Therefore, the German Society of Pediatric Rheumatolgy has established a commission to develop consensus "Protocols on classification, monitoring and therapy in children's rheumatology (PRO-KIND)" to harmonize diagnostic and treatment approaches for new-onset JIA in Germany. METHODS: A set of definitions for in- and exclusion, diagnostic workup, parameters for the evaluation of disease activity criteria, therapeutic options, medication dosing, monitoring recommendations, targets, definitions of a therapy failure and four therapeutic algorithms developed by a working group were agreed by web based survey to which all members of the GKJR have been invited. A final protocol with 4 consensus treatment plans (CTP) was agreed in a face-to-face consensus conferences employing modified nominal group technique. RESULTS: The initial 17 definitions and recommendations for new-onset polyarticular JIA agreed by the working group reached >80% agreement in a web survey in 68 German paediatric rheumatologist. Four CTPs were developed based on treatment strategies for the first 12 months of therapy, as well as definitions for clinical and laboratory monitoring. The CTPs include a step-up plan (nonbiologic Disease-modifying antirheumatic drug [DMARD] followed by a biologic), a combination plan (combination of nonbiologic and biologic after failure of initial DMARD), an intensive pulse corticosteroid scheme in parallel with a DMARD followed by combination therapy and a multiple corticosteroids joint injections strategy in a treat to target approach. Step up will be guided by a treat to target strategy to reach a JADAS-improvement at month 3, acceptable disease at month 6 or 9 and JADAS remission or at least JADAS minimal disease activity at month 12. CONCLUSION: Standardized baseline work-up, disease activity evaluation and a definition of a treat to target approach will result in better health outcomes for polyarticular JIA patients. Four CTPs were developed for new-onset polyarticular JIA, which coupled with data collection at defined intervals will be evaluated and improved to optimize management of polyarticular JIA. Harmonization of treatment will be the basis for future comparative effectiveness research.

Pathway analysis based on Monte Carlo Cross-Validation in polyarticular juvenile idiopathic arthritis.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is a common chronic disease with onset before the 16 years old in a child. Polyarticular JIA has been reported as the main form of JIA in several locations. Until now, understanding of the genetic basis of JIA is incomplete. The purpose of this study was to identify pathway pairs of great potential functional relevance in the progression of polyarticular JIA. MATERIALS AND METHODS: Microarray data of 59 peripheral blood samples from healthy children and 61 samples from polyarticular JIA were transformed to gene expression data. Differential expressed genes (DEG) between patients and normal controls were identified using Linear Models for Microarray Analysis. After performed enrichment of DEG, differential pathways were identified with Fisher's test and false discovery rate. Differential pathway pairs were constructed with random two differential pathways, and were evaluated by Random Forest classification. Monte Carlo Cross-Validation was introduced to screen the best pathway pair. RESULTS: 42 DEG with P-values<0.01 were identified. 19 differential pathways with P-values<0.01 were identified. Area under the curve (AUC) of pathway pairs was generated with RF classification. After 50 bootstraps of Monte Carlo Cross-Validation, the best pathway pair with the highest AUC value was identified, and it was the pair of tumoricidal function of hepatic natural killer cells pathway and erythropoietin signaling pathway. CONCLUSION: These identified pathway pairs may play pivotal roles in the progress of polyarticular JIA and can be applied for diagnosis. Particular attention can be focused on them for further research.