Juvenile Idiopathic Arthritis Subgroups Research Articles

Polyarticular juvenile idiopathic arthritis has a distinct co-inhibitor receptor profile.

Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic disease of childhood; the pathogenesis is associated with T cell activation. T cell activation can be counter-balanced by signals generated by inhibitory receptors (IRs) such as CTLA-4, PD-1, LAG-3, and TIM-3. Here, we identify the role of IRs in the pathogenesis of different JIA subtypes. In total, we included 67 oligoarticular JIA, 12 IgM-RF negative polyarticular JIA, 17 enthesitis related arthritis, 11 systemic JIA patients and 10 healthy controls. We collected plasma (and synovial fluid) samples from the patients either at the onset or during a flare of their disease. We measured the soluble levels of co-IRs (IL-2Rα, 4-1BB, CD86, TGF-β1, CTLA-4, PD-L1, PD-1, TIM-3, LAG- 3, Galectin-9) by cytometric bead array kits and their cellular expression (PD-1, CTLA-4, TIM-3, LAG-3) by flow cytometry. We compared the plasma levels and cellular expressions of different co-IRs within different JIA subgroups. The polyarticular-JIA group was different from the three other examined JIA subgroups, having higher levels of plasma sCTLA-4(p< 0.001), sPD-1(p< 0.05), and s4-1BB(p< 0.05) when compared with the other JIA subgroups and healthy controls. We analyzed the cellular surface expression of different co-IRs on the PBMCs of different JIA subtypes. Similar to plasma levels, both the percentage(p< 0.05) and the MFI (mean fluorescence intensity) (p< 0.01) of CTLA4 expression were higher in the poly-JIA subgroup. This is the first report studying the expression profile of different co-IRs in different subtypes of JIA. Polyarticular JIA patients had a different co-IR profile, having more CTLA-4, PD-1 and 4-1BB in their plasma than the other subtypes of JIA.

Ovarian dysfunction in adolescent girls with autoimmune rheumatic diseases

ObjectiveTo explore the different menstrual and pubertal abnormalities in adolescent females with systemic autoimmune rheumatic diseases (ARD).MethodsThe study included adolescent girls aged 13–18 years with juvenile idiopathic arthritis (JIA), juvenile systemic lupus erythematosus (JSLE), and juvenile dermatomyositis (JDM) classified according to their international classification criteria. Data were collected from our patients’ files and interpreted with respect to the demographic, clinical, disease assessment parameters, medications used, and the hormonal profile. The aspects of puberty and menstruation were assessed by a gynaecologist with ultrasound evaluation as well. The girls were classified according to their menstrual pattern into those with regular cycles versus abnormal ones. The subgroups were compared and significant variables entered into a logistic regression model to detect the independent predictors.ResultsTwenty-one girls with JSLE were included, besides 23 JIA and 8 JDM cases. Ten patients with JSLE (47.6%) had menstrual abnormalities, whereas only four JIA (17.4%) and 1 JDM girls had these alterations without significant difference between the three groups. The median of the SLICC/ACR damage index was statistically higher in JSLE with abnormal menstrual cycles, similarly were the cumulative steroid dose and puberty onset. No difference was observed between JIA or JDM subgroups concerning the disease parameters, hormonal profile, ultrasound assessment or the treatment lines. The most significant predictor for menstrual abnormalities in JSLE was the SLICC/ACR damage index.ConclusionMenstrual abnormalities is a common disturbance among adolescent girls with ARDs. The SLICC/ACR damage index is the main determinant for menstrual abnormalities rather than the cumulative steroid use or disease duration in JSLE.

Patients with Systemic Juvenile Idiopathic Arthritis (SJIA) Show Differences in Autoantibody Signatures Based on Disease Activity.

Systemic juvenile idiopathic arthritis (SJIA) is a severe rheumatic disease in children. It is a subgroup of juvenile idiopathic arthritis (JIA; MIM #604302), which is the most common rheumatic disease in children. The diagnosis of SJIA often comes with a significant delay, and the classification between autoinflammatory and autoimmune disease is still discussed. In this study, we analyzed the immunological responses of patients with SJIA, using human proteome arrays presenting immobilized recombinantly expressed human proteins, to analyze the involvement of autoantibodies in SJIA. Results from group comparisons show several differentially reactive antigens involved in inflammatory processes. Intriguingly, many of the identified antigens had a high reactivity against proteins involved in the NF-κB pathway, and it is also notable that many of the detected DIRAGs are described as dysregulated in rheumatoid arthritis. Our data highlight novel proteins and pathways potentially dysregulated in SJIA and offer a unique approach to unraveling the underlying disease pathogenesis in this chronic arthropathy.

E06 Does GGT level correlate with activity parameters in enthesitis-related arthritis?

Abstract Introduction Enthesitis-related arthritis (ERA) is one of the main subgroups of juvenile idiopathic arthritis. As in the adult population, monitoring of patients with ERA is based on clinical and laboratory evaluation. Some studies showed a correlation between Gamma-glutamyl transferase (GGT) levels and rheumatoid arthritis disease activity markers. Thus, we aimed to evaluate the correlation between GGT levels and ERA activity parameters. Methods This is a cross-sectional monocentric study including patients meeting the International League of Associations for Rheumatology (ILAR) 2001 criteria for ERA. We collected the demographic and clinical data. We assessed the ERA activity using clinical parameters including Patient Global Assessment (PGA), Visual Analogue Scale (VAS), Morning stiffness (MS), tender joint count (TJC), swollen joint count (SJC), active enthesitis count (AEC), clinical sacroiliitis, back mobility, and ocular involvement. We collected biological parameters such as the C-reactive protein (CRP) and the Erythrocyte sedimentation rate (ESR). We calculated the Juvenile spondyloarthritis disease activity (JSpADA). GGT level was measured on the same day. The correlation was evaluated using Spearman’s rho coefficient (r). r-value &amp;lt;0.3 was considered poor; between 0.3 and 0.39, moderate; between 0.4 and 0.69, strong; and &amp;gt;0.7 very strong. Results Thirty patients with a mean age of 15.1 ± 4.1 years, and a ratio-sex of 2.75 were included. The mean disease duration was 4.3 ± 3.2 years. The mean PGA and the mean VAS were 6.2 ± 7.1 and 8.9 ± 2.9 respectively. Mean TJC, mean SJC, and mean AEC were 1.53 ± 2.8, 0.18 ± 0.47, and 1.2 ± 1.6 respectively. Clinical sacroiliitis was found in eight patients, limited back mobility in six, and uveitis in three patients. The mean CRP and ESR were 15.1 ± 22.7 mg/l and 23.8 ± 21.2 mm, respectively. The mean JSpADA was 2.6 ± 1.7. Mean GGT was 14.3 ± 6.6 mg/l. A strong correlation was noted between the GGT level and both CRP (r = 0.504, P = 0.05) and ESR (r = 0.601, P = 0.01). However, no correlation was noted between GGT level and PGA (r = 0.107, P = 0.6), VAS (r = 0.03, P = 0.9), SJC (r = -0.17, P = 0.368), nor JSpADA (r = 0.323, P = 0.87). Conclusion Our results suggest a strong correlation between GGT level and biological ERA activity parameters, unlike clinical parameters and disease activity scores. More studies are needed to confirm these findings. Ethics The authors have no conflicts of interest to declare.

Associations between power Doppler ultrasound findings and B-mode synovitis and clinical arthritis in juvenile idiopathic arthritis using a standardised scanning approach and scoring system

ObjectivesTo describe power Doppler (PD) ultrasound findings in joint regions with B-mode (BM) synovitis using a standardised scanning protocol and scoring system in patients with juvenile idiopathic arthritis (JIA). Further,...

Juvenile idiopathic arthritis of the knee: is contrast needed to score disease activity when using an augmented MRI protocol comprising PD-weighted sequences?

ObjectiveTo compare unenhanced versus enhanced knee joint magnetic resonance imaging (MRI) to assess disease activity of juvenile idiopathic arthritis (JIA).MethodsFifty-three knee joint MRI examinations were performed on a 3-Tesla system in 27 patients (age: 11.40 ± 3.61 years; 21 females, 6 males). MRI protocols comprised PD-weighted sequences in addition to the widely used standard protocol. JIA subgroups comprised oligoarticular arthritis (n = 16), extended oligoarthritis (n = 6), rheumatoid factor-negative polyarticular arthritis (n = 3), enthesitis-related arthritis (n = 1), and psoriatic arthritis (n = 1). MR images were retrospectively analyzed by 3 experienced radiologists in two readings, using JAMRIS (juvenile arthritis MRI scoring) system and a modified IPSG (international prophylaxis study group) classification. In the first reading session, only unenhanced MR images were evaluated. In a second reading session, all images before and after contrast medium application were included. In order to avoid bias, an interval of at least 2 weeks was set between the two readings. The clinical JADAS10 (juvenile arthritis disease activity score) was calculated including clinical assessment and laboratory workup and correlated with MRI scores. Statistical analysis comprised Pearson’s correlation for correlating two scoring results of unenhanced and the enhanced MRI, intra-class correlation coefficient (ICC) for inter- and intra-reader agreement. Diagnostic accuracy was calculated using ROC (receiver operating characteristics) curve analysis.ResultsInter-reader agreement determined by ICC for unenhanced and enhanced MRI scores for IPSG was moderate (0.65, 95% CI 0.51–0.76, and 0.62, 95% CI 0.48–0.75) and high for JAMRIS (0.83, 95% CI 0.75–0.89, and 0.82, 95% CI 0.74–0.89). Intra-reader agreement was good to very good for JAMRIS (0.85 95% CI 0.81–0.88, 0.87 95% CI 0.83–0.89 and 0.96 95% CI 0.92–0.98) and IPSG (0.76 95% CI 0.62–0.86, 0.86 95% CI 0.77–0.92 and 0.92 95% CI 0.86–0.96). Scores of unenhanced MRI correlated with contrast-enhanced MRI: JAMRIS (r = 0.97, R2 = 0.93, p < 0.01), modified IPSG (r = 0.95, R2 = 0.91, p < 0.01). When using JADAS10 as a reference standard, moderate accuracy for both unenhanced and enhanced MRI scores was noted: JAMRIS (AUC = 0.68, 95% CI 0.51–0.85, and AUC = 0.66, 95% 0.49–0.82), IPSG score (AUC = 0.68, 95% 0.50–0.86, and AUC = 0.61, 95% 0.41–0.81).ConclusionsOur results suggest that contrast agent application could be omitted in JIA patients with an augmented knee MRI protocol comprising PD-weighted sequence.Key Points• Unenhanced MRI can detect disease activity of the knee joint in patients with JIA with equally high accuracy compared to contrast-enhanced MRI.• The intra- and inter-reader agreement was high for unenhanced and enhanced MRI JAMRIS scores, which indicate relatively good applicability of the scoring system, even for less experienced readers.• When using the clinical JADAS10 as a reference standard for the detection of disease activity, moderate accuracy for both unenhanced and enhanced MRI scores, both JAMRIS and IPSG, was noted, which might be caused by the fact that the majority of patients had either no or minimal clinical disease activity.

An overview of the relationship between juvenile idiopathic arthritis and potential environmental risk factors: Do early childhood habits or habitat play a role in the affair?

The current study was undertaken to evaluate the influence of breastfeeding on the development and outcome measures of juvenile idiopathic arthritis (JIA). The second aim was to determine the consequences of particular sociodemographic and sociocultural characteristics and nutritional behavior of early childhood on JIA. The study includes the patients diagnosed with JIA and regularly followed up at the Department of Pediatric Rheumatology in Istanbul University-Cerrahpasa. The comparison group consisted of healthy subjects and patients with juvenile systemic lupus erythematosus (jSLE). A face-to-face survey method was conducted with the parents of the participants between February 1, 2021, and September 1, 2021. The mean age of the JIA cohort (n=324) was 12.2 ± 4.7 years, with a female ratio of 64.8%. The breastfeeding rate differed from the control groups (253 healthy subjects and 88 patients with jSLE) but was higher with a value of 94.8%. There was no difference between the groups (P=.097, P=.064) or within the subgroups of JIA (P=.12) regarding breastfeeding duration. Cow's milk introduction time (P=.02, P=.0001), household pet-keeping (P=.001), income level (P=.0001), maternal literacy (P=0.013) made a statistical difference vs the control groups. No relationship was established between the rate or duration of breastfeeding and the development or severity of JIA. The early introduction of cow's milk was found to be higher in the patient cohorts. The income level and maternal literacy appeared to be relevant with the high disability and damage scores, and frequent relapse rates. Secondhand smoking, higher in JIA, may prompt the basis of primary preventable strategies in JIA.

Complement Activation Profiles in Patients with Juvenile Idiopathic Arthritis

Objectives: Besides T- and B-cells also the innate immunity is playing an effective role in the pathogenesis of Juvenile idiopathic arthritis (JIA) reported in literature. The complement system (CS) is activated by the three different ways classical pathway (CP), lectin pathway (LP) and alternative pathway (AP). This is a controlled prospective observational single center study focused on the three pathways of CS and its effector, the terminal complement complex (TCC), associated with disease activity in all clinical JIA subgroups. Methods: Peripheral blood (PB) samples (n=159) of 60 JIA patients (partially also longitudinal visits) were analyzed for specific complement pathway activation (COMPL300 ELISA), complement factor H (CFH)-autoantibodies (CFHAb ELISA), and the soluble TCC (sC5b-9 ELISA) in serum (S) and EDTA plasma (P). TCC was also analyzed in synovial fluid (SF) of JIA patients (n=9) controlled with samples of healthy adults (n=12) obtained by arthroscopy (primarily gonarthrosis). As healthy controls (HC) adults (n=100) and children (n=18) without inflammatory diseases were tested. The JADAS10 defined the acute phase of the disease. Results: We compared the elevated serum TCC levels of JIA patients in the acute phase of the disease (13.32 IQR 8.09-19.48; p&lt;0,001) with the controls' levels (7.78 IQR 4.93-10.31). Subgroup analyses showed statistically significant (s.s.) elevation in PArf+, OAper, and OAext. COMPL300 analyses revealed that JIA patients with acute disease had lower CP (82% IQR 37-97% vs 105% IQR 98-115%; p&lt;0.001), LP (31% IQR 2-86% vs 80% IQR 20-101%; p&lt;0.001), and AP (25% IQR 2-88% vs 85% IQR 70-98%; p&lt;0.001) capacity compared to the HC average due to chronic activation in all three pathways. Both TCC and COMPL300 analyses during acute phase and remission showed a clear tendency, especially in PArf+ but only s.s. in the individual course. Remarkable sJIA patients neither in TCC nor in COMPL300 analyses showed complement activation. No evidence of CFH-autoantibodies was found in our study group. The TCC levels in SF showed a median of 2.48 IQR 1.71-2.76 AU/ml in JIA patients and surprisingly high levels in HC with 6.7 IQR 3.9-9.24 AU/ml. Conclusion: Specific subgroups of JIA patients (extOA, PARf+, ERA) showed increased CS activation in TCC in PB in the acute course of the disease. Furthermore, the decreased CS capacity, especially in the CP and AP, confirms the consumption of complement components as an additional contributor to the disease pathogenesis and acute course. Due to the CS activation throughout all disease activity states, we could not determine s.s. between the acute and remission phases in our cohort. However, COMPL300 in combination with TCC seems to be a helpful acute disease biomarker in the individual course. The pharmacological modulation of CS components might be a valid alternative approach in treatmentresistant patients, although further investigations are needed.

P018 Functional impairment in enthesitis related arthritis patients

Abstract Background Enthesitis related arthritis (ERA) is a subgroup of juvenile idiopathic arthritis. It is characterized by the presence of enthesitis and predominately lower limb arthritis and can affect sacroiliac joint and spine. Recent studies showed that ERA is associated with worse physical status and poorer quality of life (1). The main objective of this study was to compare the aspects of functional status in patients (ERA) and patients with spondyloarthritis (SpA). Methods A retrospective monocentric study was carried out on patients with ERA (ILAR criteria) or SpA (ASAS Criteria). Demographic data and clinical characteristics were obtained from medical records. Disease activity was evaluated by: erythrocyte sedimentation rate (ESR), C-reactive protein rate (CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Functional impairment was evaluated by Bath Ankylosing Spondylitis Functional Index (BASFI) and Ankylosing Spondylitis Quality of life Questionnaire (ASQoL). Global well-being was assessed by Bath Ankylosing Spondylitis Global Index (BASGI). Population was divided into two groups: group 1 (G1) stands for ERA patients and group 2 (G2) stands for SpA patients. P &amp;lt; 0.05 was considered statistically significant. Results A total of 174 patients (40 ERA and 134 SpA) were enrolled. Mean age at disease onset was 12.4 ± 3 years in G1 and 27.8 ± 8 years in G2. Male to female sex ratio was 5.6 in G1 and 3.7 in G2. Morning stiffness (&amp;gt;60 min) was reported by 37.5% of G1 and 49.3%. G1 patients had longer morning stiffness than G2 (61 [0–90] min vs 30 [0–240] min; P = 0.58). Multiple nocturnal awakenings were reported by 45% of G1 patients and 58.2% of G2 patients. Median BASDAI score was 4.9 [1–44] in G1 and 4.5 in G2 [0–10] (P = 0.48). Median BASGI score was 6 [1.5–9.5] in G1 and 6 [0–10] in G2 (P = 0.58). Median ESR was 35 mm/h [8–90] in G1 and 35 mm/h [2–125] in G2. Median CRP was 18.2 mg/l [1–70] in G1 and 13 mg/l [3–180] in G2. The assessment of functional status revealed that G1 patients had higher BASFI scores than G2 patients (5.2 vs 4.5). The association between G1 and BASFI was statistically significant (P = 0.05). Median ASQoL was 12 [2–17] in G1 and 9 [0–18] in G2. No link was noted between G1 and ASQoL score (P = 0.152). Conclusion Our study showed that ERA was associated with higher BASFI scores in comparison with SpA. Treat-to target strategies are mandatory in order to optimize the functional status of children with ERA.

Functional Ability and Health-Related Quality of Life in Randomized Controlled Trials of Tocilizumab in Patients With Juvenile Idiopathic Arthritis.

To evaluate changes in health-related quality of life (HRQoL) and disability in children with systemic juvenile idiopathic arthritis (JIA) or polyarticular JIA treated with tocilizumab. Secondary analyses of two double-blind, placebo-controlled trials of intravenous tocilizumab in children with active systemic JIA or polyarticular JIA were conducted. Patient-reported outcomes of disability (Childhood Health Assessment Questionnaire [C-HAQ]), HRQoL (Child Health Questionnaire Parent Form 50 [CHQ-P50], health concepts, physical summary score [CHQ-P50-PhS], psychosocial summary score [CHQ-P50-PsS]), pain, and well-being (100-mm visual analog scale [VAS]) were measured at weeks 0 and 12 for systemic JIA, weeks 16 and 40 for polyarticular JIA, and week 104 for both JIA subgroups. The trial included 112 patients with systemic JIA and 188 patients with polyarticular JIA. In patients with polyarticular JIA, the mean ± SD C-HAQ score decreased from 1.39 ± 0.74 at baseline to 0.67 ± 0.65 at week 16 (P < 0.001). In patients with systemic JIA, the mean ± SD CHQ-P50-PhS improved more with tocilizumab therapy than with placebo at week 12 (7.3 ± 10.2 versus 2.4 ± 10.6) (P < 0.05). Almost all mean CHQ-P50 health concept scores, CHQ-P50-PsS, and CHQ-P50-PhS improved (P ≤ 0.002) by week 104 for patients with systemic JIA. Patients with polyarticular JIA and patients with systemic JIA showed significant reductions in disability (mean ± SD C-HAQ scores of -1.09 ± 0.71 and -1.17 ± 0.80, respectively), improvements in well-being (mean ± SD well-being VAS scores of -43.76 ± 26.61 and -51.53 ± 23.57, respectively), and decreases in pain (mean ± SD pain VAS scores of -41.56 ± 31.06 and -51.26 ± 26.79, respectively) (P < 0.001); in patients with polyarticular JIA and patients with systemic JIA who were treated with tocilizumab, 92.9% of polyarticular JIA patients and 96.8% of systemic JIA patients reported no more than minimal pain (a score of ≤35 mm on the VAS) at week 104. Tocilizumab treatment was associated with significantly reduced disability and pain and improved HRQoL in patients with systemic JIA and polyarticular JIA.

Serum calprotectin (S100A8/A9): a promising biomarker in diagnosis and follow-up in different subgroups of juvenile idiopathic arthritis

IntroductionIn the management of juvenile idiopathic arthritis (JIA), there is a lack of diagnostic and prognostic biomarkers. This study assesses the use of serum calprotectin (sCal) as a marker to...

Acute monoarthritis in young children: comparing the characteristics of patients with juvenile idiopathic arthritis versus septic and undifferentiated arthritis

Acute arthritis is a common cause of consultation in pediatric emergency wards. Arthritis can be caused by juvenile idiopathic arthritis (JIA), septic (SA) or remain undetermined (UA). In young children, SA is mainly caused by Kingella kingae (KK), a hard to grow bacteria leading generally to a mild clinical and biological form of SA. An early accurate diagnosis between KK-SA and early-onset JIA is essential to provide appropriate treatment and follow-up. The aim of this work was to compare clinical and biological characteristics, length of hospital stays, duration of intravenous (IV) antibiotics exposure and use of invasive surgical management of patients under 6 years of age hospitalized for acute monoarthritis with a final diagnosis of JIA, SA or UA. We retrospectively analyzed data from < 6-year-old children, hospitalized at a French tertiary center for acute mono-arthritis, who underwent a joint aspiration. Non-parametric tests were performed to compare children with JIA, SA or UA. Bonferroni correction for multiple comparisons was applied with threshold for significance at 0.025. Among the 196 included patients, 110 (56.1%) had SA, 20 (10.2%) had JIA and 66 (33.7%) had UA. Patients with JIA were older when compared to SA (2.7 years [1.8–3.6] versus 1.4 [1.1–2.1], p < 0.001). Presence of fever was not different between JIA and SA or UA. White blood cells in serum were lower in JIA (11.2 × 109/L [10–13.6]) when compared to SA (13.2 × 109/L [11–16.6]), p = 0.01. In synovial fluid leucocytes were higher in SA 105.5 × 103 cells/mm3 [46–211] compared to JIA and UA (42 × 103 cells/mm3 [6.4–59.2] and 7.29 × 103 cells/mm3 [2.1–72] respectively), p < 0.001. Intravenous antibiotics were administered to 95% of children with JIA, 100% of patients with SA, and 95.4% of UA. Arthrotomy-lavage was performed in 66.7% of patients with JIA, 79.6% of patients with SA, and 71.1% of patients with UA. In children less than 6 years of age with acute mono-arthritis, the clinical and biological parameters currently used do not reliably differentiate between JIA, AS and UA. JIA subgroups that present a diagnostic problem at the onset of monoarthritis before the age of 6 years, are oligoarticular JIA and systemic JIA with hip arthritis. The development of new biomarkers will be required to distinguish JIA and AS caused by Kingellakingae in these patients.

IL-21+ CD4+ T helper cells co-expressing IFN-γ and TNF-α accumulate in the joints of antinuclear antibody positive patients with juvenile idiopathic arthritis

Juvenile Idiopathic Arthritis (JIA) is currently classified into seven subgroups. Recently, antinuclear antibody (ANA) positive JIA patients were suggested to encompass a clinically homogenous new subgroup. CD4+ T helper (Th) cells play an essential role in JIA pathogenesis. Herein, we analyzed cytokine expression in synovial fluid (SF) CD4+ Th cells of JIA patients by using flow cytometry and compared cytokine patterns between JIA subgroups. We could show increased frequencies of IL-21 expressing CD4+ Th cells in the joints of ANA+ Oligo-/Poly-JIA patients, which co-expressed the Th-1 cytokines IFN-γ/TNF-α. In contrast, frequencies of IL-17 expressing cells were lowest in the joints of ANA+ Oligo-/Poly-JIA but enriched in that of ERA-JIA patients. This is the first description of a diverse SF Th cell cytokine pattern in different JIA subgroups. Additionally, we could define IL-21 as an effector cytokine expressed in SF Th cell in a significant proportion of ANA+ JIA patients.

Enthesitis-related Arthritis: Prevalence and Complications of Associated Uveitis in Children and Adolescents From a Population-based Nationwide Study in Germany

Enthesitis-related arthritis (ERA) represents a subgroup of juvenile idiopathic arthritis (JIA) that is regularly accompanied by anterior uveitis. This study describes the prevalence and characteristics of ERA-related uveitis. Cross-sectional data from the National Pediatric Rheumatological Database (NPRD) were used to characterize ERA-related uveitis (ERA-U). In addition to sociodemographic variables, we documented the occurrence of uveitis and course of disease, including symptoms, visual acuity, and complications, as well as JIA characteristics such as disease activity (Juvenile Arthritis Disease Activity Score 10), functional ability (Childhood Health Assessment Questionnaire score), laboratory variables, and treatment. In the years from 2002 to 2014, there were 3778 (15.2%) of a total of 24,841 JIA patients recorded in the NPRD who had ERA, and 280 (7.4%) of them had developed uveitis. Detailed ophthalmological documentation by a uveitis add-on module was available for 22.9% of these patients. Uveitis onset was acutely symptomatic in 63% of patients. Patients with uveitis were more frequently male, HLA-B27-positive, younger at ERA onset, and they had higher erythrocyte sedimentation rate values at first uveitis documentation than those without uveitis. Uveitis was diagnosed at a mean age of 11.5 (± 3.9) years (50% within 2 years after ERA onset). Systemic treatment with corticosteroids and synthetic and biologic disease-modifying antirheumatic drugs was associated with a (not significantly) lower risk of developing uveitis. The course of disease in ERA-U patients is frequently similar to HLA-B27-associated uveitis in adults; however, a subgroup of patients presents with asymptomatic uveitis.

Physical activity in patients with oligo- and polyarticular juvenile idiopathic arthritis diagnosed in the era of biologics: a controlled cross-sectional study

BackgroundKnowledge about objectively measured levels of physical activity (PA) and PA participation (included facilitators and barriers for PA) in patients with juvenile idiopathic arthritis (JIA) diagnosed in the era of biologics is limited. We aimed to compare objectively measured PA in patients with oligo- and polyarticular JIA diagnosed in the biologic era with controls and to examine associations between PA and disease variables; furthermore, to explore participation in PA, physical education (PE) and facilitators and barriers for PA participation in patients and controls.MethodsThe study cohort included 60 patients (30 persistent oligo JIA/30 poly-articular disease) and 60 age- and sex-matched controls. Age range was 10–16 years and 83% were female. PA was measured with accelerometry for seven consecutive days. Disease activity, current treatment, disease duration, functional ability, pain and fatigue were assessed. Structured interviews were applied to explore participation in PA and PE, and PA facilitators and barriers.ResultsPatients spent less time in daily vigorous PA than controls, (mean(SE) 21(2) min vs. 26(2) min, p = 0.02), while counts per minute (cpm), steps daily, sedentary time and light and moderate PA did not differ. No differences were found between JIA subgroups. The use of biologic medication was associated with higher cpm and lower sedentary time. Most patients and controls participated in organized or unorganized PA and PE, and enjoyment was the most reported facilitator for PA participation. More patients than controls reported pain as a PA barrier.ConclusionThe PA levels and participation in patients with oligo- and polyarticular JIA are mostly comparable to controls, but patients still need to be encouraged to increase vigorous PA. Enjoyment is the most important facilitator for PA participation in patients with JIA.

Reliability of ultrasonography to detect inflammatory lesions and structural damage in juvenile idiopathic arthritis

BackgroundMusculoskeletal Ultrasonography (MSUS) is an important tool for the clinical assessment in Juvenile Idiopathic Arthritis (JIA). The objective of this study was to evaluate the reliability of MSUS to detect elementary lesions: synovitis, tenosynovitis, cartilage damage and bone erosions in the wrist and metacarpal (MCP) joints of patients with JIA.MethodsThirty children in various subgroups of JIA according to ILAR criteria, were included in this cross-sectional study. Clinical data including painful, swollen and limited joints were recorded. Five rheumatologist ultrasonographers, blinded to the clinical evaluation, evaluated the presence of elementary lesions in the wrist and MCP 2 and 3 joints bilaterally. The synovitis was graded in B-Mode and Power Doppler (PD). In addition to descriptive statistics intra- and inter-observer reliability was calculated using Cohen’s kappa according to Landis and Koch.ResultsUS detected more synovitis than the clinical examination (62% vs 28%, 30% vs 23% and 22% vs 17% in the wrist, second and third MCP joints respectively). The intra-observer concordance for synovitis in all joints was excellent in B-Mode (k 0.84 .63–1.0 p = 0.001), except for MCP 2, where it was good (0.61, IC 95% .34–89, p = 0.001). For both modalities (PD, B-Mode) tenosynovitis, cartilage damage and bone erosions it was also excellent. Regarding synovitis grading the concordance was excellent for all grades (0.83–1.0, IC 95% 0.51.1.0, p = 0.001), except for grade 1 where it was good (0.61, IC 95% 0.43–.83, p = 0.001). Reliability inter-observer for grayscale synovitis (0.67–0.95, IC 95% 0.67–1.0, p = 0.001), tenosynovitis grayscale (0.89, IC 95% 0.78–0.99, p.001), damage cartilage (0.89, IC 95% 0.78–0.99, p = 0.001), PD (0.66, IC 95% 0.39–1.0, p = 0.001). The concordance for grading synovitis was excellent, but for grayscale grade 1 and 2 (.66, IC 95% .53–.74, p = 0.007) and PD grade 1 and 2 (0.63, IC 95% .58–.91, p = 004) was good.ConclusionsThe intra- and inter-observer reliability of MSUS for inflammatory and structural lesions is good to excellent for the wrist and MCP in patients with JIA.

Changes in thiol/disulfide homeostasis in juvenile idiopathic arthritis.

The pathogenesis of juvenile idiopathic arthritis (JIA) remains unknown, but imbalance between the oxidant and antioxidant defense systems may play a role. Measuring thiols in plasma provides an indirect indication of antioxidative defense. The aim of the present study was to investigate the association between JIA and dynamic thiol/disulfide homeostatic status. This case-control study involved 34 JIA patients and 30 age- and gender-matched healthy controls. Thepatients were divided into subgroups according to Simplified Disease Activity Index (SDAI) score: active, SDAI > 3.3; remission, SDAI ≤ 3.3. Native thiol and total thiol were significantly lower in the JIA group than in the control group (P = 0.001). There was no significant difference in the disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios between the JIA and control groups (P > 0.05). Based on SDAI score, 22 JIA patients were in the remission subgroup, and 12 JIA patients were in the active subgroup. Native thiol and total thiol were significantly lower in the active JIA subgroup than in the remission subgroup (P = 0.001), but there were no significant differences in the other parameters. There was no significant difference in thiol and disulfide levels between systemic-onset JIA and other JIA (P > 0.05). Plasma thiol is lower in JIA patients, especially during periods of active disease, than in healthy controls, indicating that low thiol might be an important factor in the etiology of JIA and that antioxidant systems are negatively affected by inflammatory diseases, especially during periods of active disease.

Update on the pathogenesis and treatment of juvenile idiopathic arthritis.

To provide an overview of recently published studies on pathogenesis and management of juvenile idiopathic arthritis (JIA). In the past year, the potential role of network analysis in the understanding of the molecular phenotype of individual JIA subgroups has been highlighted. In addition, potential new targets for pharmacologic interventions have been identified through the elucidation of mechanisms that modulate the function of cells involved in the inflammatory process. There is a growing interest for the role of the gut microbiome in disease pathogenesis, which may open the way to future therapeutic manipulations of fecal microbial population. Recent therapeutic studies have provided important information in large patient samples on the effectiveness and toxicity profile of biologic medications used in JIA. Concomitant administration of methotrexate was found to increase the effectiveness of intra-articular corticosteroid therapy in children with oligoarticular JIA. A great deal of work is being conducted to better define the molecular phenotype of the individual subsets of JIA and to identify potential new targets for therapeutic interventions. The results of the ongoing large-scale international data collections will help establish the long-term safety profiles of biologic medications, in particular the risk of malignancy.

Alteration of Fecal Microbiota Profiles in Juvenile Idiopathic Arthritis. Associations with HLA-B27 Allele and Disease Status.

Alteration of gut microbiota is involved in several chronic inflammatory and autoimmune diseases, including rheumatoid arthritis, and gut microbial “pro-arthritogenic” profiles have been hypothesized. Intestinal inflammation may be involved in spondyloarthropathies and in a subset of patients affected by Juvenile Idiopathic Arthritis (JIA), the most common chronic rheumatic disease of childhood. We compared the fecal microbiota composition of JIA patients with healthy subjects (HS), evaluating differences in microbial profiles between sub-categories of JIA, such as enthesitis-related arthritis (JIA-ERA), in which inflammation of entheses occurs, and polyarticular JIA, non-enthesitis related arthritis (JIA-nERA). Through taxon-level analysis, we discovered alteration of fecal microbiota components that could be involved in subclinical gut inflammation, and promotion of joint inflammation. We observed abundance in Ruminococcaceae in both JIA categories, reduction in Clostridiaceae and Peptostreptococcaceae in JIA-ERA, and increase in Veillonellaceae in JIA-nERA, respectively, compared with HS. Among the more relevant genera, we found an increase in Clostridium cluster XIVb, involved in colitis and arthritis, in JIA-ERA patients compared with HS, and a trend of decrease in Faecalibacterium, known for anti-inflammatory properties, in JIA-nERA compared with JIA-ERA and HS. Differential abundant taxa identified JIA patients for the HLA-B27 allele, including Bilophila, Clostridium cluster XIVb, Oscillibacter, and Parvimonas. Prediction analysis of metabolic functions showed that JIA-ERA metagenome was differentially enriched in bacterial functions related to cell motility and chemotaxis, suggesting selection of potential virulence traits. We also discovered differential microbial profiles and intra-group variability among active disease and remission, suggesting instability of microbial ecosystem in autoimmune diseases with respect to healthy status. Similarly to other chronic autoimmune and inflammatory diseases, different microbial profiles, as observed among different JIA subgroups compared to HS, and potential functional acquisition related to migration, could promote inflammation and contribute to the disease pathogenesis.

High mobility group box protein 1-A prognostic marker for structural joint damage in 10-year follow-up of patients with juvenile idiopathic arthritis.

High mobility group box protein 1 (HMGB1) is an important pro-inflammatory mediator in adult rheumatoid arthritis. The diagnostic utility of HMGB1 in Juvenile Idiopathic Arthritis (JIA) is still unclear. The aim was to examine whether serum HMGB1 levels are associated with inflammation, radiological disease progression, and long-term prognosis in JIA. We included 131 children with JIA from a population-based prevalence study; 38 of them were prospectively followed up for 10 years. Clinical and laboratory disease characteristics at study entry and after 10 years as well as radiological progression over 10 years were recorded. HMGB1 levels were analyzed by an ELISA. The HMGB1 levels were similar in children with different JIA subgroups and in children with established (53%) or newly diagnosed (47%) disease. HMGB1 levels did not differ between groups at entry into the study or at 10 years, by sex, or by the presence or absence of RF or ANA antibodies. HMGB1 levels at the study entry correlated with HMGB1 levels at 10 years and with blood neutrophil count. Most importantly, children with destructive arthritis at 10 years had a tendency toward higher HMGB1 levels at study entry (median 1.2 vs 0.6ng/ml, ns) and displayed 4-fold higher circulating HMGB1 levels (median 3.4 vs 0.8ng/ml, p = 0.0014) than children without radiological destructions. Our results suggest that HMGB1 is a marker of inflammatory activity in children with JIA. Higher serum HMGB1 levels are related to more destructive JIA and could be used as a negative prognostic marker at the disease start. Clinicaltrials.gov NCT01905319. Registered July 16, 2013.