Polyarticular Juvenile Idiopathic Arthritis Patients 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.

Comparison of Biopsychosocial Characteristics of Children with Juvenile Idiopathic Arthritis According to Common Disease Subtypes.

In this study, we assessed the functional and biopsychosocial characteristics of juvenile idiopathic arthritis (JIA) patients according to disease subtypes. Child Health Assessment Questionnaire (CHAQ), Juvenile Arthritis Disease Activity Score-71 (JADAS-71), and Juvenile Arthritis Biopsychosocial Questionnaire (JAB-Q) scales were administered to 304 JIA patients, and the subscale of JAB-Q was administered to their families. The median age of JIA patients at diagnosis was 7.9 (5.5-13) years (female/male = 1.3). Most patients were under treatment (68.7%) and had inactive disease (69.3%). While there was no significant difference between JADAS-71 scores according to the JIA subtypes, total CHAQ scores in polyarticular JIA patients were higher than in systemic JIA patients (P = .005). Enthesitis-related arthritis (ERA) patients had higher JAB-Q fatigue total scores compared to systemic JJIA patients (P = .001). Juvenile Arthritis Biopsychosocial Questionnaire-child psychosocial status scores were higher in polyarticular JIA patients than oligoarticular and systemic JIA patients (P = .004 and P = .003, respectively), and they had higher JAB-Q child form total scores than systemic JIA patients (P = .006). In addition, systemic JIA patients' parents had higher JAB-Q family total scores compared to oligoarticular JIA patients' parents (P = .03). Our results suggest that polyarticular JIA patients had higher CHAQ, JAB-Q psychosocial status, and child form total scores, and the JAB-Q fatigue score was higher in ERA patients. Also, JAB-Q-parent scores were higher in systemic JIA patients' parents. Biopsychosocial characteristics should be evaluated in both JIA patients and their parents.

Oral or Parenteral Methotrexate for the Treatment of Polyarticular Juvenile Idiopathic Arthritis.

Subcutaneous methotrexate injections are considered to be more effective or work faster than oral methotrexate. Therefore, the extent and the kinetics of response were analyzed in juvenile idiopathic arthritis patients treated with oral versus subcutaneous methotrexate. The BIKER databank was searched for biologics-naive juvenile idiopathic arthritis patients treated with methotrexate as initial treatment. The Juvenile Arthritis Disease Activity Score-10 defini- tion of remission and the pediatric American College of Rheumatology's response parameters were utilized as outcome criteria. A total of 410 polyarticular juvenile idiopathic arthritis patients receiving oral methotrexate were compared to 384 patients receiving subcutaneous methotrexate. Rheumatoid factor-negative polyarthritis was the most common juvenile idiopathic arthritis category (50%/51%) in this cohort followed by extended oligoarthritis (27%/26%), polyarticular psoriatic arthritis (18%/16%), and few had rheumatoid factor-positive polyarthritis (5%/8%). The oral cohort's disease duration (2.3 ± 3.0 vs. 1.9 ± 2.7) was significantly longer (P=.04), although their age at onset and baseline were similar. Furthermore, at baseline, disease activity (Juvenile Arthritis Disease Activity Score-10 16.5 ± 7.2 vs. 14.7 ± 8.2; P = .001 due to a higher active joint count 9.0 ± 10.1 vs. 7.4 ± 7.7; P = .011) was higher in the subcutaneous cohort. The weekly methotrexate doses were comparable with 13.6 ± 5.4 mg/m2 and 13.3 ± 4.5 mg/m2, respectively. With oral/subcutaneous methotrexate, a pediatric American College of Rheumatology's 90 was achieved in 98(38.3%)/128(40.4%), while 96(38.1 %)/75(40.1%) attained Juvenile Arthritis Disease Activity Score remission after 12 months of therapy. There was no difference in the early kinetics of response according to Kaplan-Meyer analysis. Adverse events including nausea, vomiting, and increased transaminases were considerably more common after methotrexate subcutaneous administration than after oral treatment. In terms of effectiveness, but not safety, our retrospective analysis found some advan- tages of subcutaneous methotrexate. Adverse effects limit treatment continuance and thus must be considered a disadvantage. Furthermore, oral methotrexate eliminates the need for injections, which is especially essential for younger children. Controlled, randomized prospective trials in children and juvenile patients are necessary for definitive recommendations for the subcutaneous route of admin- istration of methotrexate therapy.

Efficacy and safety of tofacitinib in the treatment of refractory cases of polyarticular course juvenile idiopathic arthritis: Astudy from Bangladesh.

Biological disease-modifying antirheumatic drugs (bDMARDs) are treatment options for refractory juvenile idiopathic arthritis (JIA) cases which cannot be afforded by the majority. Tofacitinib is a novel Janus kinase inhibitor, which is reported to be a cost-effective oral alternative to biologics. This prospective observational study was carried out to observe the efficacy and safety of tofacitinib in refractory polyarticular course JIA patients. The study was conducted in the Department of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka. Twenty-seven refractory polyarticular course JIA patients were included in this study. Patients received tofacitinib at recommended doses. Disease activity level was assessed by Juvenile Arthritis Disease Activity Score (JADAS) 27. Cases were evaluated at baseline and at the 6th, 12th and 24th weeks. Safety was monitored from history, examination findings and laboratory reports. Data were analyzed using appropriate statistical tests. Enthesitis-related arthritis was the commonest type (37%) followed by polyarticular (rheumatoid factor+) and systemic JIA. There was significant improvement in JADAS 27 in all the subtypes of JIA except oligoarticular extended type. Among 100% high disease activity state cases at baseline, 70.4% were inactive at 24weeks. It was also possible to significantly reduce the dose of steroid. Few side effects like headache and vomiting, elevation of alanine aminotransferase and anemia were observed at 6weeks. These side effects subsequently improved. Significant reduction of disease activity score was observed from baseline to follow up in this study. Tofacitinib was well tolerated with minimum side effects.

P010 Clinico-epidemiological characteristics and outcomes of Juvenile Idiopathic Arthritis (JIA) patients in Kenya: data from the KAPRI registry

Abstract Background Pediatric rheumatic diseases pose a significant disease burden upon children and their families (1–3). They lead to physical disability and diminished quality of life (1–3). Determination of the burden and clinical characteristics of these diseases is a critical first step to improving access to care and optimizing use of existing health systems for the well-being of these patients (4). This is in line with the goal of the Bone and Joint decade (2000–2010) aimed at increasing recognition and understanding of the impact of musculoskeletal diseases (5,6). The Kenya Pediatric Rheumatology Registry (KAPRI) offers a unique opportunity to pioneer and spearhead a systematic and organized format to inform policy and better healthcare provision. Our objective was to determine the patient characteristics, clinical features and outcomes of Juvenile Idiopathic Arthritis (JIA) patients assessed at the Aga Khan University Medical College East Africa from March 2019 to December 2020. Methods Data of JIA patients on age, gender, laboratory and clinical features at diagnosis and treatment options offered were extracted from the database. A further detailed chart review was undertaken to determine the proportion of patients who achieved remission or minimally active diseases. Results Among the 207 patients enrolled thus far, 16 (7.7%) were diagnosed to have JIA. Majority of the patients were females (75%; n = 12) with a mean age of 7 years and 3 months (Range : 1 year—13 years 7 months). All patients had joint pain and swelling as the initial presenting complaints. Majority of the patients had polyarticular JIA (75%, n = 12). The other 4 patients were oligoarticular (n = 2) and systemic JIA (n = 2). Among the polyarticular JIA patients (n = 12), only 3 (25%) were rheumatoid factor (RF) positive and 1 was antinuclear antibody (ANA) positive. The oligoarticular and systemic JIA patients were all negative for antinuclear antibody, rheumatoid factor and cyclic citrullinated peptide antibodies (anti-ccp). Seven patients (43.8%) required biological therapies; tocilizumab (n = 2: systemic JIA), adalimumab (n = 2: polyarticular JIA), etanercept (n = 2: polyarticular JIA) andtofacitnib (n = 1: polyarticular JIA). One patient with systemic JIA on tocilizumab developed herpes simplex which was successfully managed with oral acyclovir. All the other patients did not develop any infections, allergic reactions or any other untoward events as adverse outcomes following the use of biological therapies. Five patients have attained remission as illustrated in the table below. Two patients have been lost to follow up. Conclusion Seronegative polyarticular JIA was the predominant form of JIA observed with a predilection to affect more girls and boys. Over a period of 2 years, remission has been attained among 31.25% of the patients (5 of 16) with use of synthetic disease modifying anti-rheumatic drugs and biological therapies.

Features and Clinical Course of Infantile Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of 7 chronic arthritides categories that affects children younger than 16 years. This case series elucidates the characteristics of patients from a single center diagnosed with JIA at younger than 12 months. We included patients who presented to the rheumatology clinic for JIA with symptom onset at younger than 1 year. Chart review was conducted to complete case report forms that included demographics, historical features, examination features, laboratory results, imaging results, and treatment courses. We identified 12 patients who met our inclusion criteria. Eight of our patients were diagnosed with oligoarticular JIA, 3 had polyarticular JIA, and 1 was diagnosed with systemic JIA. Overall, 58% (7/12) of patients had joint contractures at their initial visit. Of the patients with oligoarticular JIA, 50% (4/8) required a disease-modifying antirheumatic drug to achieve disease remission; 12.5% (1/8) required biologic therapy. All of the polyarticular JIA patients had highly positive antinuclear antibodies, as well as elevated inflammatory markers. Children with infantile JIA are overall similar to the larger population of patients with JIA. Disease severity may not be different compared with that of older children with JIA; however, there is likely a larger delay in diagnosis and the presence of contractures, which occurred in more than half of our patients.

14-3-3η Protein as a Potential Biomarker in Juvenile Idiopathic Arthritis.

The 14-3-3η (eta) protein was evaluated as a biomarker in a cohort of patients with juvenile idiopathic arthritis (JIA), as well as disease- and healthy-controls, to determine its potential clinical utility. In this case-control study, levels of 14-3-3η protein were evaluated in archival specimens from patients with JIA, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), as well as healthy pediatric controls. Just over 200 patients were evaluated, using specimens banked between 1990 and 2011. Comparisons were made to complete blood cell count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, and anti-nuclear antibody (ANA) positivity. 14-3-3η at levels 0.2 ng/mL or higher was considered positive. Fisher’s exact tests, odds ratios, 95% confidence intervals, and p-values were reported. 14-3-3η positivity was seen in all included JIA subtypes. The rate of positivity was the highest in RF-positive (pos) polyarticular JIA. In the disease and healthy controls, lower rates of positivity were observed. The frequency of 14-3-3η positivity among RF-positive and RF-negative (neg) polyarticular JIA patients, especially at values ≥0.5 ng/mL (associated with poor outcomes in adults), was also highest. Several JIA patients with 14-3-3η positivity developed RF and anti-CCP positivity later in their disease. Significant levels of 14-3-3η can be found in approximately 30% of RF-pos and RF-neg patients with polyarticular JIA. This protein may represent a new biomarker for polyarticular JIA, particularly RF-neg polyarticular JIA.

Early combination therapy with etanercept and methotrexate in JIA patients shortens the time to reach an inactive disease state and remission: results of a double-blind placebo-controlled trial

BackgroundRemission is the primary objective of treating juvenile idiopathic arthritis (JIA). It is still debatable whether early intensive treatment is superior in terms of earlier achievement of remission. The aim of this study was to evaluate the effectiveness of early etanercept+methotrexate (ETA+MTX) combination therapy versus step-up MTX monotherapy with ETA added in refractory disease.MethodsA multi-centre, double-blind, randomized study in active polyarticular JIA patients treated with either ETA+MTX (n = 35) or placebo+MTX (n = 33) for up to 24 weeks, followed by a 24-week open-label phase. The efficacy endpoints included pedACR30 criteria improvement at week 12, inactive disease at week 24, and remission at week 48. Patients who failed to achieve the endpoints at week 12 or at week 24 escaped to open-label ETA+MTX. Safety was assessed at each visit.ResultsBy intention-to-treat analysis, more patients in the ETA+MTX group reached the pedACR30 response at week 12 (33 (94.3%)) than in the placebo+MTX group (20 (60.6%); p = 0.001). At week 24, comparable percentages of patients reached inactive disease (11 (31.4%) vs 11 (33.3%)). At week 48, 11 (31.4%) and eight (24.2%) patients achieved remission. The median (+/−IQR) times to achieve an inactive disease state in the ETA+MTX and placebo+MTX groups were 24 (14–32) and 32 (24–40) weeks, respectively. Forty-four (74/100 patient-years) adverse events (AEs) were reported, leading to treatment discontinuation in 6 patients.ConclusionsEarly combination therapy with ETA+MTX proved to be highly effective compared to the standard step-up regimen. Compared to those treated with the standard regimen, more patients treated with a combination of ETA+MTX reached the pedACR30 response and achieved inactive disease and remission more rapidly.

Peripheral Blood Lymphocyte Analysis in Oligo- and Polyarticular Juvenile Idiopathic Arthritis Patients Receiving Methotrexate or Adalimumab Therapy: A Cross-Sectional Study.

Juvenile idiopathic arthritis (JIA) is an umbrella term for seven distinct chronic immune-mediated diseases. Disease-modifying anti-rheumatic drugs (DMARD) are used to treat the underlying joint inflammation as well as extra-articular manifestations. Immunosuppression is a considerable side effect of the drugs. The main goal of this study was to investigate the effect of different JIA therapies on leukocyte subpopulations, which play a role in immune-defense. Three study groups were established. The first group consisted of JIA patients treated with methotrexate solely, the second one received a combination of methotrexate (MTX) and adalimumab (ADA). The control group was made up of the patients' healthy siblings. A total of 63 children were recruited. Fourty-one children with JIA and 22 healthy controls were included in the study. The absolute number of CD3+ T-cells was significantly elevated in patients treated with biological therapy compared to healthy controls (p2 = 0.017). In contrast, the number of CD56+ natural killer cells was significantly lower in children receiving biological therapy in comparison with healthy donors (p2 = 0.039). A significant alteration was also demonstrated between patients treated with MTX and MTX/ADA group concerning CD 19+ B-cells (p3 = 0.042). This is the first study that demonstrates significant alterations in the number of B-cells and T-cells with a relative decrease of NK-cell ratios in JIA patients receiving different DMARD therapy.Clinical Trial Registration: NCT03833271. 21.01.2019.

Patient satisfaction and clinical effectiveness of switching from intravenous tocilizumab to subcutaneous tocilizumab in patients with juvenile idiopathic arthritis: an observational study.

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of idiopathic inflammatory arthritis affecting children younger than 16years of age. Tocilizumab (TCZ) is a humanized anti-interleukin 6 (IL-6) receptor antibody that was approved for systemic and polyarticular JIA patients. However, the studies regarding patients' satisfaction while receiving TCZ therapy is scarce. Herein, we aimed to evaluate the effect of subcutaneous (SC) TCZ administration on patient satisfaction and disease control of JIA patients. All JIA patients receiving TCZ were included in the study. Clinical features, laboratory findings and JADAS71 scores were recorded at baseline and every 3 months during follow-up. Nine of the patients on intravenous (IV) TCZ treatment were switched to SC form. All patients receiving TCZ-SC were questioned by a clinical nurse specialist (CNS) to assess patient satisfaction. A total of 39 patients receiving TCZ were included in the study. Among them, treatment of nine patients (five female, four male) was switched to SC form with a median of 11.5 (8-69) months after initiation of TCZ. Patients were stable both clinically and in laboratory means at the 3rd month of TCZ-SC treatment. There was no deterioration in terms of active joint counts, physician's VAS, patient's VAS and JADAS71. According to patient satisfaction questionnaire, eight of the patients felt satisfied with SC administrations in terms of life quality, school success and reduced school absenteeism. However, one patient did not agree that the SC form is as effective as IV form and wanted to continue with IV form. TCZ is an effective treatment option in JIA and switching from IV to SC route when necessary is found to be an effective and acceptable alternative by the patients as well.

TP2 INITIAL PRESCRIBING PATTERNS TRENDS IN NEWLY DIAGNOSED CHILDREN WITH NON-SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS IN US: ANALYSIS OF ELECTRONIC MEDICAL RECORDS FROM 2009 TO 2018

The study describes patterns of initial medication prescriptions among children newly diagnosed with non-systemic forms of juvenile idiopathic arthritis (JIA), and its association with the disease activity outcomes from 2009- 2018. Using a pediatric hospital’s electronic medical record (EMR) between 2009 to 2018, we identified all patients with newly diagnosed JIA. Five subtypes of JIA were considered: oligoarticular JIA, polyarticular JIA, juvenile psoriatic arthritis, enthesitis-related arthritis, and undifferentiated arthritis. We examined patient baseline characteristics and initial prescribing patterns. The disease outcomes of initial prescribing patterns were described. A total of 821 patients were included in the analysis. Most patients were female (66.3%) and white race (88.9%). The median age was 11 years (IQR: 5–14). The proportion of patients who had an initial disease-modifying antirheumatic drugs (DMARD) prescription increased substantially from 2009 to 2018. The most common initial prescriptions were conventional synthetic (cs)DMARD and non-steroidal anti-inflammatory drugs (NSAIDs). For patients who were prescribed DMARD as initial therapy, csDMARDs monotherapy (57.3%) was most frequently used, followed by biologic agents and csDMARDs combination therapy (28.3%), and biologic (b)DMARDs monotherapy (14.4%). Methotrexate was the most commonly prescribed csDMARD throughout the study period, comprising more than 90% of monotherapy or combination therapy. Etanercept (56.3%) was the most prescribed bDMARDs, followed by adalimumab (36.6%). Nearly half (43.3%) of polyarticular JIA patients received a bDMARD prescription as initial therapy. The proportion of intra-articular glucocorticoid users increased considerably from 1.1% in 2009 to 25.6% in 2018. csDMARDs and NSAIDs appear to be the mainstay of first-line treatment initiated among non-systemic JIA patients over the past decade. However, biologic DMARDs are increasing in use, especially for treating children with polyarticular JIA.

ASSESSMENT OF 14-3-3 PROTEIN ETA AND ANTI-CYCLIC CITRULLINATED PEPTIDE (ANTI-CCP) IN JUVENILE IDIOPATHIC ARTHRITIS VERSUS ADULT ONSET RHEUMATOID ARTHRITIS

Background: 14-3-3(eta) protein, is an intracellular chaperone (cellular adapter) protein, which released to the extra cellular space during the early stages of the rheumatoid arthritis (RA), and acts as an inducer of innate immune system. Many inflammatory mediators and pathways that involved in the pathogenesis and progression of RA have been upregulated through 14-3-3 eta protein. So, this marker in addition to existing biomarkers can augment the lab efficacy in the early identification and progression assessment of the RA. Objective: Investigating the existence of anti-CCP antibodies and 14-3-3 protein eta in juvenile idiopathic arthritis (JIA) and RA patients, comparing that with healthy controls and correlated their levels with Disease Activity Score (DAS 28). Patients and Methods: Serum levels of 14-3-3 eta protein and anti-CCP were measured using enzyme-linked immunosorbent assay (ELISA) in 40 patients including 20 JIA cases (group I), 20 RA cases (group II), and 40 apparently healthy controls. Results: There were highly significant statistical increases in RF, and anti-CCP antibodies in JIA patients as compared with their controls, while there was insignificant statistical difference between both groups regarding 14-3-3 protein eta. There were significant statistical increases in14-3-3 protein eta and anti-CCP antibodies in adult RA patients as compared with their controls. In JIA patients, there was significant increase in disease activity score 28 (DAS 28) among patients with +ve RF and +ve anti-CPP, meanwhile there were non-significant relation between DAS 28 and CRP results. Among cases with RA, there was non-significant relation between DAS 28 and the 3 markers (CRP, RF, and anti-CCP antibodies). At cutoff point of 0.19 ng/ml (which was used in many previous studies as the best for 14-3-3 eta protein), our results showed sensitivity and specificity for this marker in JIA (15% and 100%) . In RA, we found 90% sensitivity and 90% specificity for this marker at the same cutoff point. Our study revealed that serum 14-3-3 eta protein level was significantly correlated to disease severity score 28 (DAS 28) for JIA (r = 0.49 / P = 0.0288), while for RA (r = 0.8502 / P= 0.0001). Conclusion: anti-CCP antibodies were prevalent among polyarticular onset JIA patients compared to other subtypes of the disease. 14-3-3 protein had +ve correlation with disease severity in both groups and needs further evaluation on larger samples.

Identification of enhanced IFN-γ signaling in polyarticular juvenile idiopathic arthritis with mass cytometry.

Polyarticular juvenile idiopathic arthritis (JIA) is among the most challenging of the JIA subtypes to treat. Even with current biologic therapies, the disease remains difficult to control in a substantial subset of patients, highlighting the need for new therapies. The aim of this study was to use the high dimensionality afforded by mass cytometry with phospho-specific antibodies to delineate signaling abnormalities in immune cells from treatment-naive polyarticular JIA patients. Peripheral blood mononuclear cells were isolated from 17 treatment-naive polyarticular JIA patients, 10 of the patients after achieving clinical remission, and 19 healthy controls. Samples were stimulated for 15 minutes with IL-6 or IFN-γ and analyzed by mass cytometry. Following IFN-γ stimulation, increased STAT1 and/or STAT3 phosphorylation was observed in subsets of CD4 T cells and classical monocytes from treatment-naive patients. The enhanced IFN-γ signaling was associated with increased expression of JAK1 and SOCS1 in CD4 T cells. Furthermore, substantial heterogeneity in surface marker expression was observed among the subsets of CD4 T cells and classical monocytes with increased IFN-γ responsiveness. The identification of enhanced IFN-γ signaling in CD4 T cells and classical monocytes from treatment-naive polyarticular JIA patients provides mechanistic support for investigations into therapies that attenuate IFN-γ signaling in this disease.

Fluorescence optical imaging and musculoskeletal ultrasonography in juvenile idiopathic polyarticular disease before and during antirheumatic treatment\xa0- a multicenter non-interventional diagnostic evaluation

BackgroundValid detection of inflamed joints is essential for correct classification, therapeutic decisions, prognosis and assessment of treatment efficacy in juvenile idiopathic arthritis (JIA). Fluorescence optical imaging (FOI) enables visualization of inflammation in arthritis of finger and hand joints and might be used for monitoring.MethodsA 24-week observational study in polyarticular JIA patients newly starting treatment with methotrexate or an approved biologic was performed in three centers. Patients were evaluated clinically, by gray-scale ultrasonography (GSUS), power-Doppler ultrasonography (PDUS) and FOI at baseline, week 12 and week 24.ResultsOf 37 patients enrolled, 24 patients started methotrexate and 13 patients a biologic for the first time (etanercept n = 11, adalimumab and tocilizumab n = 1 each). Mean JADAS 10 decreased significantly from 17.7 at baseline to 12.2 and 7.2 at week 12 and 24 respectively. PedACR 30/50/70/100 response rates at week 24 were 85%/73%/50%/27%. The total number of clinically active joints in hand and fingers at baseline/week 12/week 24 was 262 (23.6%)/162 (16.4%)/162 (9.0%). By GSUS, at baseline/week 12/week 24, 192 (19.4%)/135 (16.1%)/83 (11.5%) joints showed effusions and 186 (18.8%)/107 (12.7%)/69 (9.6%) showed synovial thickening, and by PDUS 68 (6.9%)/15 (1.8%)/36 (5%) joints showed hyperperfusion. Any sign of arthritis was detected by US in a total of 243 joints (24.5%) at baseline, 161 joints (19.2%) at week 12 and 123 joints (17%) at week 24. By FOI at baseline/week 12/week 24, 430 (38.7%)/280 (29.2%)/215 (27.6%) showed a signal enhancement in at least one phase.Summarizing all three points of time, the highest numbers of signals were detected by FOI with 32% of joints, especially in phase 2, while by US 20.7% and by clinical examination 17.5% of joints were active. A high number of joints (21.1%) had FOI signals but were inactive by clinical examination. A total 20.1% of joints with signals in FOI did not show effusion, synovial thickening or hyperperfusion by US.Because of the high number of negative results, specificity of FOI compared with clinical examination/US/PD was high (84–95%), and sensitivity was only moderate.ConclusionFOI and US could detect clinical but also subclinical inflammation. FOI detected subclinical inflammation to a higher extent than US. Improvement upon treatment with either methotrexate or a biologic can be visualized by FOI and US.Trial registrationDeutsches Register Klinischer Studien DRKS00011579. Registered 10 January 2017.

Retraction: Early Prediction for Over Two Years Efficacy of The First Biologic Agent for Polyarticular Juvenile Idiopathic Arthritis: A Multi-Institutional Study In Japan

Objective: To determine early predictors of long-term efficacy of the first biologic agent used to treat polyarticular Juvenile Idiopathic Arthritis (JIA). Methods: Data from patients treated at six medical institutions in Japan were analyzed. Patients were divided into two groups: those maintaining clinical remission with the first biologic agent >2 years (continuous treatment group) and those eventually switching to other biologic agents within 2 years (switching group). Three markers were examined: matrix metalloproteinase-3, Erythrocyte Sedimentation Rate (ESR), and Disease Activity Score (DAS) 28- ESR. Their associations with the continuity of the first biologic agent were assessed by multiple linear regression analysis. Cut-off points were calculated to distinguish these groups. Results: Thirty-two polyarticular JIA patients (8 boys, 24 girls) with median disease duration of 12 months were included. Agents used were adalimumab in 9 (28%) patients, etanercept in 8 (25%), infliximab in 2 (6%), and tocilizumab in 13 (41%). Twenty-four patients (75%) maintained clinical remission with the first biologic agent for a median 40 months (range, 24–119); 8 patients (25%) switched to a second biologic agent at a median 9.5 months (range, 6–18). Markers [odds ratio (95% confidence interval)] at 3 months were matrix metalloproteinase-3 [1.02 (0.99-1.05), p=0.219], ESR [1.00 (0.78-1.30), p=0.998], and DAS28-ESR [13.9 (2.08-409.82), p=0.035]. The cut-off point for DAS28-ESR at 3 months to distinguish the two groups was 2.49 (sensitivity, 87.5%; specificity, 87.5%). Conclusion: DAS28-ESR <2.49 at 3 months after initiating the first biologic agent may predict sustained clinical remission in polyarticular JIA patients.

Predictors of methotrexate response in Turkish children with oligoarticular and polyarticular juvenile idiopathic arthritis.

Batu ED, Sönmez HE, Gülhan B, Arıcı ZS, Topaloğlu R, Bilginer Y. Predictors of methotrexate response in Turkish children with oligoarticular and polyarticular juvenile idiopathic arthritis. Turk J Pediatr 2017; 59: 6-12. Methotrexate (MTX) is the most commonly used disease modifying anti-rheumatic drug in juvenile idiopathic arthritis (JIA). We aimed to define predictor factors for response to MTX in Turkish children with oligo- and polyarticular JIA. We reviewed the medical files of 59 oligo- and 57 polyarticular JIA patients seen in the clinic between May 2008 and May 2013 and who received MTX for ≥6 months. MTX responders were defined as having no/low disease activity according to juvenile arthritis disease activity score 71 (JADAS71) at 6 months after MTX initiation. Median age at JIA diagnosis/MTX initiation was 70/78 months. Involvement of the small or upper extremity joints at disease diagnosis and MTX initiation was more frequent; antinuclear antibody (ANA) positivity was less frequent; acute phase reactants, JADAS71 at MTX initiation, and the frequency of polyarticular subtype were higher in MTX non-responders. In multiple logistic regression, oligoarticular JIA subtype and ANA positivity were independent predictors of MTX response.

Epipolymorphisms associated with the clinical outcome of autoimmune arthritis affect CD4+ T cell activation pathways

Multifactorial diseases, including autoimmune juvenile idiopathic arthritis (JIA), result from a complex interplay between genetics and environment. Epigenetic mechanisms are believed to integrate such gene-environment interactions, fine-tuning gene expression, and possibly contributing to immune system dysregulation. Although anti-TNF therapy has strongly increased JIA remission rates, it is not curative and up to 80% of patients flare upon treatment withdrawal. Thus, a crucial unmet medical and scientific need is to understand the immunological mechanisms associated with remission or flare to inform clinical decisions. Here, we explored the CD4+ T-cell DNA methylome of 68 poly-articular and extended oligo-articular JIA patients, before and after anti-TNF therapy withdrawal, to identify features associated with maintenance of inactive disease. Individual CpG sites were clustered in coherent modules without a priori knowledge of their function through network analysis. The methylation level of several CpG modules, specifically those enriched in CpG sites belonging to genes that mediate T-cell activation, uniquely correlated with clinical activity. Differences in DNA methylation were already detectable at the time of therapy discontinuation, suggesting epigenetic predisposition. RNA profiling also detected differences in T-cell activation markers (including HLA-DR) but, overall, its sensitivity was lower than epigenetic profiling. Changes to the T-cell activation signature at the protein level were detectable by flow cytometry, confirming the biological relevance of the observed alterations in methylation. Our work proposes epigenetic discrimination between clinical activity states, and reveals T-cell-related biological functions tied to, and possibly predicting or causing, clinical outcome.

Diagnostic performance of anti-citrullinated protein/peptide antibodies in juvenile idiopathic arthritis.

The prevalence rates of anti-citrullinated protein/peptide antibodies (ACPAs) were investigated in a cohort of juvenile idiopathic arthritis (JIA) patients, and their diagnostic performances were compared. ACPAs, including anti-cyclic citrullinated peptide IgG (anti-CCP), anti-CCP IgG/IgA (anti-CCP3.1), citrullinated recombinant rat filaggrin antibodies (CPA), anti-mutated citrullinated vimentin (anti-MCV), and antibodies to citrullinated human IgG-derived peptides (RA/CP), were measured in the sera from 81 JIA patients. Serum samples from 55 children with other joint diseases or viral infections and 49 healthy donors were tested as controls. Of the 81 JIA patients, 7 (8.6%), 8 (9.9%), 17 (21.0%), 23 (28.4%), and 18 (22.2%) were found to be positive for anti-CCP, anti-CCP3.1, CPA, anti-MCV, and RA/CP, respectively, with specificities of 98.1, 95.1, 93.3, 84.6, and 86.5%. Analysis by subtype revealed that 7/7 (100%) of RF-positive polyarticular JIA patients tested positive at high serum levels for anti-MCV or RA/CP, and 5/7 (71.4%) were positive for anti-CCP, anti- CCP3.1, or CPA (P < 0.001, compared with controls). Eighteen of 81 JIA patients demonstrated joint erosions on radiographs and erosive arthritis occurred more often in ACPAs positive patients (P < 0.01). Our findings indicate that although ACPAs are not satisfactory screening biomarkers for JIA due to low sensitivity, ACPA measurement can aid in diagnosing RF-positive polyarticular JIA and identifying JIA patients with severe bone involvement. The diagnostic performance of each ACPA in JIA is different, and the careful selection of assays is necessary.

Differential plasma microRNAs expression in juvenile idiopathic arthritis

Objectives. To identify potential novel biomarkers for juvenile idiopathic arthritis (JIA), we evaluated the correlation between plasma expression levels of specific miRNAs and disease characteristics of JIA.Methods. Differentially expressed miRNAs in JIA plasma were identified by microarray analysis. Five candidate plasma miRNAs with differential expression were further evaluated by qRT-PCR. The correlation between the expression of candidate plasma miRNAs and clinical parameters of JIA patients was assessed.Results. The expression of miR-16, miR-146a, and miR-223 was higher, and miR-132 was lower, in the plasma of JIA patients as compared with healthy subjects and juvenile ankylosing spondylitis patients (p < 0.05). Plasma miR-16 concentrations were considerably higher for polyarticular JIA patients than oligoarticular JIA patients and correlated with the juvenile arthritis magnetic resonance imaging scores for the hip and plasma interleukin-6 or IL-6 levels. Additionally, miR-146a levels correlated directly with the Juvenile Arthritis Disease Activity Scores in 27 joints, the swollen joint count, the limited joint count, and the juvenile arthritis magnetic resonance imaging scores for the hip, but correlated inversely with plasma tumor necrosis factor-α or TNF-α levels.Conclusions. This study demonstrates that the expression of plasma miRNAs correlates with JIA disease and suggests that plasma miR-16 and miR-146a have potential novel value for JIA diagnosis.

Polyarticular juvenile idiopathic arthritis - epidemiology and management approaches.

Juvenile idiopathic arthritis (JIA) is a group of disorders characterized by arthritis persisting for at least 6 weeks with onset before the age of 16 years. Within this cluster of conditions, the polyarticular form (involving more than four joints within the first 6 months) is further divided based on the presence of rheumatoid factor. Children with polyarticular JIA pose unique diagnostic and therapeutic challenges compared to children with involvement of fewer joints. Polyarticular JIA patients tend to have a more refractory course and therefore are at increased risk for joint damage, resulting in poorer functional outcomes and decreased quality of life. Although the ability to treat this disorder continues to improve, especially with the advent of biologic agents, there is still much about the epidemiology and pathogenesis of polyarticular JIA that is unknown. The epidemiology of polyarticular JIA varies worldwide with a vast difference in reported cases between different global regions as well as within individual countries. Several genetic risk loci have been identified conferring increased susceptibility to JIA, many within the human leukocyte antigen region. Beyond the genome, environmental factors also seem to contribute to the etiology of polyarticular JIA. This review article will focus on the epidemiology and current treatments of polyarticular JIA and briefly discuss genetic and environmental influences on the pathogenesis of JIA as well as new and emerging therapies.