A systematic strategy for identifying causal single nucleotide polymorphisms and their target genes on Juvenile arthritis risk haplotypes.

BACKGROUND: Although genome-wide association studies (GWAS) have identified multiple regions conferring genetic risk for juvenile idiopathic arthritis (JIA), we are still faced with the task of identifying the single nucleotide polymorphisms (SNPs) on the disease haplotypes that exert the biological effects that confer risk. Until we identify the risk-driving variants, identifying the genes influenced by these variants, and therefore translating genetic information to improved clinical care, will remain an insurmountable task. We used a function-based approach for identifying causal variant candidates and the target genes on JIA risk haplotypes. METHODS: We used a massively parallel reporter assay (MPRA) in myeloid K562 cells to query the effects of 5,226 SNPs in non-coding regions on JIA risk haplotypes for their ability to alter gene expression when compared to the common allele. The assay relies on 180 bp oligonucleotide reporters ("oligos") in which the allele of interest is flanked by its cognate genomic sequence. Barcodes were added randomly by PCR to each oligo to achieve > 20 barcodes per oligo to provide a quantitative read-out of gene expression for each allele. Assays were performed in both unstimulated K562 cells and cells stimulated overnight with interferon gamma (IFNg). As proof of concept, we then used CRISPRi to demonstrate the feasibility of identifying the genes regulated by enhancers harboring expression-altering SNPs. RESULTS: We identified 553 expression-altering SNPs in unstimulated K562 cells and an additional 490 in cells stimulated with IFNg. We further filtered the SNPs to identify those plausibly situated within functional chromatin, using open chromatin and H3K27ac ChIPseq peaks in unstimulated cells and open chromatin plus H3K4me1 in stimulated cells. These procedures yielded 42 unique SNPs (total = 84) for each set. Using CRISPRi, we demonstrated that enhancers harboring MPRA-screened variants in the TRAF1 and LNPEP/ERAP2 loci regulated multiple genes, suggesting complex influences of disease-driving variants. CONCLUSION: Using MPRA and CRISPRi, JIA risk haplotypes can be queried to identify plausible candidates for disease-driving variants. Once these candidate variants are identified, target genes can be identified using CRISPRi informed by the 3D chromatin structures that encompass the risk haplotypes.

Ready to leave? - Adolescents' and parents' perceptions of transition from paediatric to adult rheumatology care.

BACKGROUND: In Sweden, approximately 2000 children live with Juvenile Idiopathic Arthritis (JIA). About half of them continue to have an active disease and need to transfer to adult rheumatology care. This study aimed to investigate Swedish adolescents' and parents´ perceptions of readiness for transition from pediatric to adult rheumatology care. METHODS: The study was a cross-sectional quantitative study. Patients at the pediatric rheumatology clinic at a university hospital in Sweden and members of The Swedish National Organization for Young Rheumatics aged 14-18 and their parents were invited to participate in the study. Data was collected with the Readiness for Transition Questionnaire (RTQ) focusing on adolescents' transition readiness, adolescents' healthcare behaviors and responsibility, and parental involvement. Data were analyzed with descriptive statistics. Comparative analyses were made using non-parametric tests with significance levels of 0.05 as well as factor analyses and logistic regression. RESULTS: There were 106 adolescents (85 girls, 20 boys) and 96 parents answering the RTQ. The analysis revealed that many adolescents and parents experienced that the adolescents were ill-prepared to take over responsibility for several healthcare behaviors, such as booking specialty care appointments, calling to renew prescriptions and communicating with medical staff on phone and to transfer to adult care. Parents and adolescents alike stated that it was especially difficult for the adolescents to take responsibility for healthcare behaviors meaning that the adolescents had to have direct interaction with the healthcare professionals (HCPs) at the paediatric rheumatology clinic, for example to renew prescriptions. It was evident that the adolescents who perceived they were ready to take responsibility for the aspects related to direct interaction with HCPs were more overall ready to be transferred to adult care. CONCLUSION: Adolescents need more support to feel prepared to transfer to adult care. With the results from this study, we can develop, customize, and optimize transitional care programs in Sweden for adolescents.

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.

Disease activity assessment for juvenile idiopathic arthritis in transitional care.

OBJECTIVE: The indices to measure disease activity of chronic arthritis in adulthood and childhood are different. Therefore, assessing the status of the disease in young patients with juvenile idiopathic arthritis (JIA) can be tricky, especially when the transition to adult care is ongoing. The aim of our study was to assess the level of correlation between adult and juvenile scores in the measurement of disease activity in JIA patients during transitional care. METHODS: We estimated the disease activity by using the Juvenile Arthritis Disease Activity Score 71 (JADAS71), clinical JADAS, adult Disease Activity Score (DAS28), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) in JIA patients in transitional care. We enrolled patients older than 16 years at the time of the first transition visit, and disease activity was assessed at baseline and 12 months. Regression analyses were carried out to estimate the level of agreement among the different indices. RESULTS: We recruited 26 patients with JIA; 11 patients were polyarticular (42.3%) and 15 patients were oligoarticular (53.1%). The mean age at diagnosis was 7.7±3.9 years and the age at the first evaluation was 20.9±3.7 years. The correlation between JADAS71 and DAS28 was r2=0.69, r2=0.86 between JADAS71 and SDAI, and r2=0.81 between JADAS71 and CDAI. CONCLUSIONS: SDAI and JADAS71 showed the best correlation, but a few patients were not captured at the same level of disease activity. New prospective studies with a larger number of patients will be needed in this field.

Outcomes after anti-tumour necrosis factor originator to biosimilar switching in children and young people with juvenile idiopathic arthritis in the UK: a national cohort study.

BACKGROUND: For cost-saving purposes, children and young people with juvenile idiopathic arthritis (JIA) are being switched (for non-medical reasons) from biological originators to biosimilars. Here, we aimed to investigate those who switched from an anti-tumour necrosis factor (TNF) originator to a biosimilar, regarding drug survival and disease activity, compared with a matched cohort who continued the originator. METHODS: This analysis included all patients in the UK JIA Biologics Register switching directly from an anti-TNF originator to a biosimilar of the same product. All patients were matched (age, sex, disease duration, calendar year of when patients started originator therapy, line of therapy, and International League of Associations for Rheumatology [ILAR] category) to patients continuing the originator. For those matched successfully, a Cox proportional hazard model assessed whether drug persistence differed between those who switched compared with those who continued the originator. Overall change in the 71-joint juvenile arthritis disease activity score and the proportion of patients with a clinically important worsening score (by ≥1·7 units) after 6 months was compared between cohorts. This analysis was designed to address a priority research area set by our patient partners. FINDINGS: There were 224 children and young people with non-systemic JIA (139 [62%] were female, and 85 [38%] were male) identified as switching from a biological originator to a biosimilar of the same product from Jan 1, 2017, to July 7, 2023. 143 (64%) patients were originally on adalimumab, 56 (25%) on etanercept, and 25 (11%) on infliximab. Of these, 164 patients were matched successfully to those continuing the originator. There was no evidence that patients switching were more likely to stop treatment compared with those continuing the originator, with a hazard ratio of 1·46 (95% CI 0·93-2·30). Of the 51 patients in the biosimilar group who stopped treatment, 18 (35%) switched back to the originator (14 in the first year), 28 (55%) started a different biological drug, and five (10%) discontinued all treatment by the last follow-up. Of the 87 matched patients with available disease activity, there was no evidence that JADAS-71 worsened more after 6 months, with an odds ratio of 0·71 (95% CI 0·34-1·51; p=0·38). INTERPRETATION: In this matched comparative effectiveness analysis, children and young people with JIA switched from originators to biosimilars. Disease activity was similar between patients switching compared with those continuing the originator. Three quarters of patients were still receiving their biosimilar after 1 year, with switching back to originator uncommon, at only 9% after 1 year, suggesting good tolerability of non-medical switching in this patient population. This information is reassuring to clinicians and patients regarding the effect of non-medical biological switching. FUNDING: British Society for Rheumatology, Versus Arthritis, and National Institutes for Health Research Manchester Biomedical Research Centre.

S100 proteins as potential predictive biomarkers of abatacept response in polyarticular juvenile idiopathic arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA). METHODS: Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months. RESULTS: At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25-5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48-9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03-8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02-5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57-5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23-5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46-9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76-7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07-3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10-4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15-8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders. CONCLUSION: Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.

Orthodontic and orthopedic management of dentofacial deformity from juvenile idiopathic arthritis: a systematic literature review.

BACKGROUND: An update on the knowledge regarding the orthopedic/orthodontic role in treating JIA-related dentofacial deformities is relevant. OBJECTIVES: This systematic review aimed to assess the level of evidence regarding the management of dentofacial deformity from juvenile idiopathic arthritis (JIA) with orthodontics and/or dentofacial orthopedics. SEARCH METHODS: The following databases were searched without time or language restrictions up to 31 January 2024 (Medline, Embase, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and Latin American and Caribbean Health Sciences Literature). SELECTION CRITERIA: Inclusion criteria were studies dealing with JIA subjects receiving treatment with orthodontic and/or dentofacial orthopedic functional appliances. DATA COLLECTION AND ANALYSIS: After the removal of duplicate studies, data extraction, and risk of bias assessment according to ROBINS-I guidelines were conducted. Data extraction was conducted by two independent authors. RESULTS: The electronic database search identified 397 eligible articles after the removal of duplicates. Following the application of the pre-defined inclusion and exclusion criteria, 11 articles were left for inclusion. Two trials were associated with a severe risk of bias, four trials were at moderate risk of bias, and the other five presented a low risk of bias. Various research groups employed and documented the effects of different types of appliances and methodologies. The study heterogeneity did not allow for meta-analyses. In addition, a lack of uniformity in treatment objectives was observed across the included studies. After treatment with dentofacial orthopedics skeletal improvement was demonstrated in 10 studies, and a decrease in orofacial signs and symptoms was reported in 7 studies. CONCLUSIONS: Across the available literature, there is minor evidence to suggest that dentofacial orthopedics may be beneficial in the management of dentofacial deformities from JIA. There is little evidence to suggest that it can reduce orofacial signs and symptoms in patients with JIA. Based on current evidence, it is not possible to outline clinical recommendations for specific aspects of orthopedic management in growing subjects with JIA-related dentofacial deformity. REGISTRATION: PROSPERO (CRD42023390746).

Health Literacy Levels of Patients With Juvenile Idiopathic Arthritis and Their Parents.

BACKGROUND: The aim of this study was to reveal the relationship between the health literacy (HL) levels of children with juvenile idiopathic arthritis (JIA) and their parents, and the general health status and physical performance of the children. METHODS: This study included 79 children aged 9-18 years with a diagnosis of JIA and one of their parents. HL levels were evaluated with the Turkish version of the Health Literacy for School-Aged Children and Turkish Health Literacy-32 (THL-32) for children and Adult Health Literacy Scale (AHLS) for their parents. The Childhood Health Assessment Questionnaire (CHAQ), 6-minute walk test (6-MWT), 10-meter walking test (10-MWT) and 10-stair climbing test (10-SCT) was used to evaluate the children. Juvenile Arthritis Biopsychosocial Questionnaire (JAB-Q) was used to assess the children's and parents' psychosocial status and perception of health. RESULTS: HL levels of patients with JIA were 16.5% low HL, %55.7 moderate HL and 27.8% high HL. According to THL-32 scale score, HL level of parents were as follows: inadequate, 3.8%; problematic, 22.8%; sufficient, 34.2%; and excellent, 39.2%. Children's HL levels increase positively as they get older, and no significant relationship was found with other parameters. The AHLS, CHAQ and JAB-Q scores were better in the group with higher education levels of the parents. No statistically significant association was found between the HL of the children and that of the parents. CONCLUSION: In our study, it was found that the high education levels of the parents positively affected the quality of life and physical condition of their children and parental HL levels. In addition, it was shown that the HL levels of children with JIA were not statistically related to other parameters. PATIENT OR PUBLIC CONTRIBUTION: Children diagnosed with JIA and one of their parents actively participated in the study. Feedback from children and families provided important information about obtaining and using HL information before and during the study. The importance of therapy programs and information focusing on the patient and their family, as well as the inter-multidisciplinary approach, in combating a chronic disease at an early age was reinforced by the feedback received from patients and their families.

Patients with juvenile idiopathic arthritis have decreased clonal diversity in the CD8+ T cell repertoire response to influenza vaccination.

Recurrent exposures to a pathogenic antigen remodel the CD8+ T cell compartment and generate a functional memory repertoire that is polyclonal and complex. At the clonotype level, the response to the conserved influenza antigen, M158-66 has been well characterized in healthy individuals, but not in patients receiving immunosuppressive therapy or with aberrant immunity, such as those with juvenile idiopathic arthritis (JIA). Here we show that patients with JIA have a reduced number of M158-66 specific RS/RA clonotypes, indicating decreased clonal richness and, as a result, have lower repertoire diversity. By using a rank-frequency approach to analyze the distribution of the repertoire, we found several characteristics of the JIA T cell repertoire to be akin to repertoires seen in healthy adults, including an amplified RS/RA-specific antigen response, representing greater clonal unevenness. Unlike mature repertoires, however, there is more fluctuation in clonotype distribution, less clonotype stability, and more variable IFNy response of the M158-66 specific RS/RA clonotypes in JIA. This indicates that functional clonal expansion is altered in patients with JIA on immunosuppressive therapies. We propose that the response to the influenza M158-66 epitope described here is a general phenomenon for JIA patients receiving immunosuppressive therapy, and that the changes in clonal richness and unevenness indicate a retarded and uneven generation of a mature immune response.

Optical coherence tomography for the screening of anterior chamber inflammation in paediatric patients diagnosed with juvenile idiopathic arthritis.

OBJECTIVES: To evaluate the effectiveness of the anterior segment optical coherence tomography (AS-OCT) for the screening of anterior uveitis in children diagnosed with juvenile idiopathic arthritis (JIA). METHODS: A cross-sectional, observational, non-randomised study was conducted in JIA patients younger than 18 years. All patients underwent anterior segment (AS-OCT) and macular OCT. RESULTS: A total of 300 eyes of 150 patients diagnosed with JIA were included; 74% were females, and mean age was 11.12 ± 3.51 years old (range 4.13-18.60). In the slit-lamp examination, anterior uveitis was diagnosed in 16 eyes. In the AS-OCT, anterior uveitis was suspected in 27 eyes; cells were detected in 27 eyes and retrokeratic precipitates in 5 eyes. Sensitivity was 0.94 and specificity was 0.96, positive predictive value was 0.59 and negative predictive value was 0.99, and Kappa-Cohen index was 0.71. CONCLUSIONS: AS-OCT could be considered for the screening of anterior segment uveitis in children diagnosed with JIA.

Dynamics of serum levels of TNF-α in a longitudinal follow-up study in 98 patients with juvenile idiopathic arthritis treated with anti-TNF-α biological drugs.

OBJECTIVE: To determine the dynamics of serum levels of TNF-α in patients with juvenile idiopathic arthritis (JIA) treated with anti-TNF-α biological drugs and investigate their association with the disease activity. METHODS: We conducted a single-centre, observational cohort study in 98 patients with JIA (30 boys, 68 girls, mean age 11.3 years) treated with anti-TNF-α biological drugs. Clinical examinations and laboratory assessments of serum levels of TNF-α were performed before starting therapy with biological drug and at 6-month intervals afterwards up to 2.5 years. RESULTS: The analysis of serum levels of TNF-α in relation to the disease activity states showed the highest mean serum levels of TNF-α in patients on etanercept who had low disease activity states and in patients on adalimumab who had inactive disease. The correlation analysis in patients with JIA treated with etanercept or adalimumab showed a weak negative correlation between the serum levels of TNF-α and JADAS10 scores (p = 0.007), (r = - 0.177). CONCLUSION: The assessment of serum levels of TNF-α in children with JIA during treatment with etanercept or adalimumab is not a reliable biomarker of disease activity or immunological remission. Longitudinal measurement of TNF-α has no added clinical value in patients with JIA treated with anti-TNF-α biological drugs. Key Points • There is limited evidence regarding the effect of anti-TNF therapy on serum concentrations of TNF-α in patients with juvenile idiopathic arthritis • Our study showed an increase in the serum level of TNF-α after the initiation of therapy with either etanercept or adalimumab, which was more significant in patients with inactive or low disease activity • Serum TNF-α is most likely not biologically active during therapy with TNF-α inhibitors and therefore not a reliable biomarker of disease activity or immunological remission in patients with juvenile idiopathic arthritis.

Single center clinical analysis of macrophage activation syndrome complicating juvenile rheumatic diseases.

BACKGROUND: Macrophage activation syndrome (MAS), an example of secondary hemophagocytic lymphohistiocytosis, is a potentially fatal complication of rheumatic diseases. We aimed to study the clinical and laboratory characteristics, treatment schemes, and outcomes of different rheumatic disorders associated with MAS in children. Early warning indicators of MAS have also been investigated to enable clinicians to make a prompt and accurate diagnosis. METHODS: Fifty-five patients with rheumatic diseases complicated by MAS were enrolled between January 2017 and December 2022. Clinical and laboratory data were collected before disease onset, at diagnosis, and after treatment with MAS, and data were compared between patients with systemic juvenile idiopathic arthritis (sJIA), Kawasaki disease (KD), and systemic lupus erythematosus (SLE). A random forest model was established to show the importance score of each variable with a significant difference. RESULTS: Most (81.8%) instances of MAS occurred during the initial diagnosis of the underlying disease. Compared to the active stage of sJIA, the platelet count, erythrocyte sedimentation rate, and fibrinogen level in sJIA-MAS were significantly decreased, whereas ferritin, ferritin/erythrocyte sedimentation rate, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and D-dimer levels were significantly increased. Ferritin level, ferritin/erythrocyte sedimentation rate, and platelet count had the greatest predictive value for sJIA-MAS. The level of IL-18 in the sJIA-MAS group was significantly higher than in the active sJIA group, whereas IL-6 levels were significantly lower. Most patients with MAS were treated with methylprednisolone pulse combined with cyclosporine, and no deaths occurred. CONCLUSIONS: Thrombocytopenia, ferritin levels, the ferritin/erythrocyte sedimentation rate, and elevated aspartate aminotransferase levels can predict the occurrence of MAS in patients with sJIA. Additionally, our analysis indicates that IL-18 plays an important role in the pathogenesis of MAS in sJIA-MAS.

Comparative efficacy and safety of different drugs in patients with systemic juvenile idiopathic arthritis: A systematic review and network meta-analysis.

BACKGROUND: The goal of this study was to estimate the relative efficacy and safety of different biological agents (infliximab, canakinumab, baricitinib, anakinra, adalimumab, tofacitinib, tocilizumab, and rilonacept) compared with placebo for systemic juvenile idiopathic arthritis (JIA) patients, through a network meta-analysis. METHODS: Pubmed, Embase, and Cochrane Library were searched from database inception to July 2023 for randomized controlled trials comparing different biological agents (infliximab, canakinumab, baricitinib, anakinra, adalimumab, tofacitinib, tocilizumab, and rilonacept) or placebo directly or indirectly in JIA. Bayesian network meta-analyses were conducted. Data was extracted and analyzed by R with gemtc package. The treatment options were ranked using the surface under the cumulative ranking curve (SUCRA) value. RESULTS: We identified 10 randomized controlled trials and analyzed 898 participants. Canakinumab (odds ratio 55.0, 95% credible intervals 2.4-67.0) was more effective than the placebo, and the difference was statistically significant. However, there was no statistical significance between other drugs versus placebo in terms of the modified ACRpedi30 (P > .05). The SUCRA shows that canakinumab ranked first (SUCRA, 86.9%), anakinra ranked second (SUCRA, 77.7%), adalimumab ranked third (SUCRA, 61.9%), and placebo ranked the last (SUCRA, 6.3%). Nevertheless, there were no notable discrepancies in the occurrence of adverse events, hepatic-related adverse events, infectious adverse event, serious adverse events, and serious infection following treatment with canakinumab, anakinra, tocilizumab, rilonacept, or the placebo. Based on the clustergram of modified ACRpedi30 and adverse events, canakinumab is suggested for JIA according to the surface under SUCRAs considering the symptom and adverse events simultaneously. CONCLUSIONS: Among patients with JIA, canakinumab exhibited the highest likelihood of being the optimal treatment for achieving the modified ACRpedi30 response rate, and neither of the tested biological agents carried a significant risk of serious adverse events.

Adherence to low-dose methotrexate in children with juvenile idiopathic arthritis using a sensitive methotrexate assay.

BACKGROUND: Low-dose weekly methotrexate (MTX) is the mainstay of treatment in juvenile idiopathic arthritis. Unfortunately, a substantial part of patients has insufficient efficacy of MTX. A potential cause of this inadequate response is suboptimal drug adherence. The aim of this study was to assess MTX adherence in juvenile idiopathic arthritis patients by quantification of MTX concentrations in plasma. Secondly, the association between MTX concentrations and either self-reported adherence issues, or concomitant use of biologics was examined. METHODS: This was a retrospective, observational study using plasma samples from juvenile idiopathic arthritis patients. An ultrasensitive liquid chromatography-tandem mass spectrometry method was developed for quantification of MTX and its metabolite 7-hydroxy-MTX in plasma. The determined MTX plasma concentrations in juvenile idiopathic arthritis patients were compared with corresponding adherence limits, categorising them as either adherent or possibly non-adherent to MTX therapy. RESULTS: Plasma samples of 43 patients with juvenile idiopathic arthritis were analysed. Adherence to MTX in this population was 88% shortly after initiation of MTX therapy and decreased to 77% after one year of treatment. Teenagers were more at risk for non-adherence (p = 0.002). We could not find an association between MTX adherence with either self-reported adherence issues, nor with the use of concomitant biological treatment (p = 1.00 and p = 0.27, respectively; Fisher's Exact). CONCLUSIONS: Quantification of MTX in plasma is a feasible and objective method to assess adherence in patients using low-dose weekly MTX. In clinical practice, the use of this method could be a helpful tool for physicians to refute or support suspicion of non-adherence to MTX therapy.

Association between inflammatory joint disease and severe or treatment-resistant depression: population-based cohort and case-control studies in Sweden.

OBJECTIVE: To investigate whether the association between depression and inflammatory joint disease (IJD; rheumatoid arthritis [RA], psoriatic arthritis [PsA], ankylosing spondylitis/spondyloarthropathies [AS], and juvenile idiopathic arthritis [JIA]) is affected by the severity or treatment-resistance of depression. METHOD: Parallel cohort studies and case-control studies among 600,404 patients with a depressive episode identified in Swedish nationwide administrative registers. Prospective and retrospective risk for IJD in patients with depression was compared to matched population comparators, and the same associations were investigated in severe or treatment-resistant depression. Analyses were adjusted for comorbidities and sociodemographic covariates. RESULTS: Patients with depression had an increased risk for later IJD compared to population comparators (adjusted hazard ratio (aHR) for any IJD 1.34 [95% CI 1.30-1.39]; for RA 1.27 [1.15-1.41]; PsA 1.45 [1.29-1.63]; AS 1.32 [1.15-1.52]). In case-control studies, patients with depression more frequently had a history of IJD compared to population controls (adjusted odds ratio (aOR) for any IJD 1.43 [1.37-1.50]; RA 1.39 [1.29-1.49]; PsA 1.59 [1.46-1.73]; AS 1.49 [1.36-1.64]; JIA 1.52 [1.35-1.71]). These associations were not significantly different for severe depression or TRD. CONCLUSION: IJD and depression are bidirectionally associated, but this association does not seem to be influenced by the severity or treatment resistance of depression.

Extraarticular manifestations of juvenile idiopathic arthritis and their impact on health-related quality of life.

OBJECTIVES: The objective of this study is to investigate extraarticular manifestations (EAMs) in patients with juvenile idiopathic arthritis (JIA) and assess their impact on health-related quality of life (HRQoL) among these patients. METHODS: This cross-sectional analytic study was carried out on 117 patients with JIA. EAMs were identified clinically by history and examination. Sicca symptoms, peripheral neuropathy, enthesitis, and skin lesions were picked up during clinical examination. Pulmonary involvement was evaluated by high-resolution CT chest. Patients were assessed by abdominal ultrasonography to assess the size of liver and spleen. Atlantoaxial subluxation was evaluated by cervical spine x-rays. Patients were evaluated by Pediatric Quality of Life Inventory-4 (PedsQL-4) and PedsQL-3 arthritis module. RESULTS: The median age of patients was 14 years with a median disease duration 4 years, 82.9% were females. Of the studied 117 JIA patients, 85 patients (72.6%) had at least one EAM. Persistent fatigue (51.3%) was the most prevalent EAM, followed by recurrent skin rash (16.2%), enthesitis (15.4%), recurrent fever (13.7%), and uveitis (12%). Patients with EAMs scored significantly lower in physical functioning (p = 0.001), emotional functioning (p < 0.001), social functioning (p = 0.005), and school functioning (p = 0.001). Regarding PedsQL arthritis module, patients with EAM had also significantly lower scores than did patients without EAM on the domains of pain and hurt (p < 0.001), daily activities (p = 0.008), and worry (p = 0.001). RESULTS: EAMs are prevalent among JIA patients and have a negative impact on their HRQoL. So, early identification and treatment are highly recommended. Key Points • A large percentage of JIA patients experienced at least one extraarticular manifestation (EAM). • Persistent fatigue and recurrent skin rash are the most prevalent EAMs in JIA patients. • JIA patients with EAMs have worse scores in almost all domains of HRQoL.

Identifying factors associated with substantially reduced adult height in patients with juvenile idiopathic arthritis: a retrospective cohort study.

BACKGROUND: Juvenile idiopathic arthritis (JIA), an autoimmune disease affecting children or adolescents and causing joint or systemic symptoms, reportedly has a negative effect on the patients' body height. This study aimed to identify factors attributable to substantially reduced adult height (SRAH) in JIA patients. METHODS: This single-center retrospective cohort study included patients from 2009 to 2019 in Taiwan. We collected JIA patients aged > 18 years at enrollment with a definite diagnosis and undergoing regular outpatient clinic follow-up or disease remission. Target height difference (THD), defined by adult height minus mid-parental height, was calculated for each patient. The calculation results yielded two groups, of which positive THD was defined as the optimal height (OH group) and those with THD below two standardized deviations as the SRAH group. Descriptive statistics and logistic regression analysis were used to analyze the data. RESULTS: Of 92 JIA patients, 57 and 12 were in the OH and the SRAH groups. Earlier disease onset, especially before the six-year-old, was noted in the SRAH group (p = 0.026). The distribution of JIA subtypes differed significantly between the two groups (p < 0.001); enthesis-related arthritis was the commonest subtype in the OH group, and systemic JIA was the commonest in the SRAH group. Half of the patients in the SRAH group had an active disease status at enrollment, which was higher than the OH group (50.0% vs. 21.1%, p = 0.066). More patients in the SRAH group had received orthopedic surgery due to JIA (25% vs. 3.5%, p = 0.034). Multiple logistic regression analysis showed that SRAH was independently related to systemic JIA (OR = 37.6, 95%CI 1.2-1210.5; p = 0.041). CONCLUSION: The subtype of systemic JIA, with its characteristics of early disease onset and active disease status, was the essential factor that significantly impacted adult height.

JAK inhibitors in refractory juvenile rheumatic diseases: Efficacy, tolerance and type-I interferon profiling, a single center retrospective study.

OBJECTIVES: - Janus Kinase inhibitors (JAKi) are a new class of drugs available for pediatric rheumatic diseases. This study aimed to describe the safety and effectiveness of JAKi in these diseases, with a focus on longitudinal interferon-stimulated genes (ISG) assessment. METHODS: - We present a single-center retrospective study of children with refractory pediatric rheumatic diseases including connective tissue diseases, monogenic type I interferonopathies or juvenile idiopathic arthritis, receiving JAKi. According to physicians' assessment, treatment effectiveness was classified at 12 months as a complete response in the total absence of disease activity, partial response in case of significant (>50%) but incomplete improvement or no response in the case of non-response or improvement of less than 50% of the clinical and biological parameters. ISG were monitored longitudinally using Nanostring technology. RESULTS: - 22 children were retrospectively included in this study, treated either by baricitinib or ruxolitinib. Complete response was achieved at 12 months in 9/22 (41%) patients. 6/22 (27%) patients were non-responders and treatment had been discontinued in five of them. Within the interferon (IFN)-related diseases group, ISG-score was significantly reduced 12 months after JAKi onset (p = 0.0068). At 12 months, daily glucocorticoid doses had been reduced with a median dose of 0.16 mg/kg/day (IQR 0.11; 0.33) (p = 0.0425). 7/22 (32%) patients had experienced side effects, infections being the most common. Increase of the body mass index was also recorded in children in the first 6 months of treatment. CONCLUSION: - JAKi represent a promising treatment of immune-mediated pediatric diseases, enabling to decrease type-I IFN transcriptomic signature in responding patients, especially in the context of juvenile dermatomyositis. JAKi represent steroid-sparing drugs but they induce metabolic changes linked to weight gain, posing a concern in the treatment of young patients and teenagers. More data are required to define the efficacy and safety of JAKi in the management of refractory pediatric rheumatic diseases.

Efficacy and safety of an early response-based tapering regimen of tocilizumab in children with systemic juvenile idiopathic arthritis.

INTRODUCTION: Systemic juvenile idiopathic arthritis (sJIA) is a distinct disease subset, with a poorer prognosis compared with other JIA subsets. Tocilizumab has an important role in the management of sJIA refractory to standard initial therapy. However, no specific guidelines exist for the tapering of tocilizumab therapy in sJIA, which could have implications on the overall cost and side effects of treatment. METHODS: This was an observational study which included 21 children with refractory sJIA, who were initially put on injection tocilizumab every 2 weekly, with subsequent dosing tapered to 4 weekly and 6 weekly intervals based on JIA ACR 70 responses at 12 and 24 weeks, respectively. The primary outcome at week 36 included JIA ACR 30, 50, 70, and 90 response rates with other efficacy and safety measures as secondary outcomes. RESULTS: At 36 weeks, JIA ACR 30, 50, 70, and 90 responses were observed in 90.5%, 90.5%, 71.4%, and 52.4% patients respectively along with significant improvement in hematological and inflammatory parameters. The mean prednisolone dose could be reduced from 0.54 to 0.13 mg/kg/day and around 29% patients were able to discontinue steroids altogether. No serious adverse events were recorded. With drug tapering, we could curtail on 26% of the total tocilizumab dose that would have been otherwise required on the continuous 2 weekly protocol. CONCLUSIONS: Tocilizumab, used in an early response-based tapering regimen, was both safe and efficacious in children with sJIA refractory to standard therapy. Larger and longer duration studies are required to further validate our observations.