Remission In Juvenile Idiopathic Arthritis Research Articles

The immune landscape of the inflamed joint defined by spectral flow cytometry.

Cellular phenotype and function are altered in different microenvironments. For targeted therapies it is important to understand site-specific cellular adaptations. Juvenile Idiopathic Arthritis (JIA) is characterised by autoimmune joint inflammation, with frequent inadequate treatment responses. To comprehensively assess the inflammatory immune landscape, we designed a 37-parameter spectral flow cytometry panel delineating mononuclear cells from JIA synovial fluid (SF) of autoimmune inflamed joints, compared to JIA and healthy control blood. Synovial monocytes and NK cells (CD56bright) lack Fc-receptor CD16, suggesting antibody-mediated targeting may be ineffective. B cells and DCs, both in small frequencies in SF, undergo maturation with high 4-1BB, CD71, CD39 expression, supporting T cell activation. SF effector and regulatory T cells were highly active with newly described co-receptor combinations that may alter function, and suggestion of metabolic reprogramming via CD71, TNFR2 and PD-1. Most SF effector phenotypes, as well as an identified CD4-Foxp3+ T cell population, were restricted to the inflamed joint, yet specific SF-predominant CD4+Foxp3+ Treg subpopulations were increased in blood of active but not inactive JIA, suggesting possible recirculation and loss of immunoregulation at distal sites. This first comprehensive dataset of the site-specific inflammatory landscape at protein level will inform functional studies and the development of targeted therapeutics to restore immunoregulatory balance and achieve remission in JIA.

Assessment of quality of life and physical activity in patients with oligoarticular juvenile idiopathic arthritis in remission.

The purpose of this study was to evaluate physical activity (PA) and health-related quality of life (HRQOL) in children with oligoarticular juvenile idiopathic arthritis (JIA) in remission in comparison with healthy peers and to determine the disease-related factors affecting PA levels. This study was conducted with 50 oligoarticular JIA patients in remission and 50 healthy peers between 9 and 14years. Demographic and clinical characteristics, laboratory parameters, and treatments were noted from electronic medical records. HRQOL was assessed with the Pediatric Quality of Life Inventory (PedsQL). PA was evaluated with the Physical Activity Questionnaire for Children (PAQ-C). Oligoarticular JIA patients had significantly lower self-reported median PedsQL scores in the domains of school functioning and social functioning compared to the control group (67.5 (10) vs. 75 (25), p = 0.001 and 70 (15) vs. 85 (26.3), p < 0.001, respectively). The median PAQ-C score was 2.6 (1.1) in patients with JIA and 3 (0.9) in their healthy peers (p = 0.02). The PAQ-C score was 2.8 (1.2) in patients < 8years at the disease onset and 2.3 (1) in those aged ≥ 8years (p = 0.022). There was no significant difference in the number of affected joints, type of affected joint, MTX and biologic agent treatment, and remission with or without drugs with the total score of the PedsQL and PAQ-C. All PedsQL domains were positively correlated with the PAQ-C. Conclusion: Oligoarticular JIA patients demonstrated lower PA and HRQOL scores compared to healthy controls despite favorable disease control. What is Known: • Oligoarticular JIA has fewer functional limitations and disabilities compared to other JIA subtypes. • As JIA can affect all aspects of a child's life, there is a need to improve the quality of life related to the disease. What is New: • It should be considered that patients with oligoarticular JIA may show lower PA and HRQOL scores compared to healthy controls despite favorable disease control. • Since there may be a relationship between PA and HRQOL, factors that may affect PA should be investigated to provide a holistic approach to JIA treatment.

Can Whole-Body Magnetic Resonance Imaging Predict Relapse in Juvenile Idiopathic Arthritis? A Longitudinal Pilot Study.

To determine the utility of whole-body magnetic resonance imaging (WB MRI) to predict relapse in children with juvenile idiopathic arthritis (JIA) in clinical remission. Consecutive patients with JIA who fulfilled the Wallace criteria for remission were recruited into this longitudinal pilot study and underwent WB MRI. A radiological score was devised, incorporating synovitis, bone marrow edema, sacroiliitis, enthesitis, and bone erosions. Two readers independently scored the MR data sets. The same score was calculated for both knee joints individually and correlated with outcome for that joint. Score-based models incorporating clinical and laboratory variables were generated. Logistic regression analysis was done to determine predictors for relapse. Receiver operating characteristic curve was drawn for significant variables. Twenty-two children (median age, 12 years; interquartile range, 9.5-14.25 years) were included in the final analysis. At 24 months' follow-up, 15 joints in 5 children relapsed; knee was the most common site. Seven knee joints had disease relapse. On univariate analysis, synovitis and total score on WB MRI were significant predictors of relapse at follow-up, with odds ratios of 9.46 (bias-corrected 95% confidence interval, 3.07-29.13) and 2.8 (bias-corrected 95% confidence interval, 1.23-6.39) respectively. Two models, which included a higher number of joints involved at presentation and abrupt drug withdrawal strategy as predictor variables, were also statistically significant (odds ratio, approximately 1.9). On multivariate analysis of the predictors variables in models where p < 0.6, it was found that only synovitis score and total score were near statistical significance ( p = 0.06); no clinical or laboratory variables were significant. The areas under the receiver operating characteristic curve for relapse prediction were approximately 0.82, 0.87, 0.79, and 0.81 for synovitis score, total MRI score, and both models, respectively. Synovitis on WB MRI is the strongest independent predictor for disease relapse in children with JIA in remission.

The role of ultrasonography in assessing remission in juvenile idiopathic arthritis: a systematic review.

Musculoskeletal ultrasound (MSUS) is an important measurement tool in pediatric rheumatology as it detects subclinical disease activity and enables clinicians to treat patients during "the window of opportunity". However, the role of MSUS in assessing remission in JIA patients is not well-defined. This systematic review aimed to provide the most up-to-date published literature regarding the added value of MSUS in JIA patients in remission. This systematic review followed the preferred reporting items for systematic reviews guidelines. Original articles from PubMed and Scopus, published until February 7th 2022, and tackling the role of MSUS in JIA patients in remission were included. Eight studies met the inclusion criteria. They were published between 2011 and 2019 and included 356 children with JIA. Remission criteria were unanimous and relied on the Wallace criteria. Subclinical synovitis and Power Doppler signal (PD) were found in up to 84% and 33% of patients in remission, respectively. In most of the studies, predictors of future flares were abnormal MSUS findings at baseline particularly the presence of PD signal and patients without medication. Conclusion: Published data indicate that JIA children in remission may have abnormal MSUS findings including PD signal. The application of a specific scoring system for the pediatric joint may be helpful in homogenizing outcomes in future trials. Further studies on this matter are needed to ascertain the specific implication for each subset for a better holistic approach. What is Known: • In these recent years, significant progress has been made on building the evidence base for MSUS in pediatric rheumatology, particularly in juvenile idiopathic arthritis (JIA). • In the frame of the OMERACT ultrasound pediatric subtask force, standardized musculoskeletal US examination for the pediatric population was established. What is New: • Published data indicate that JIA children in remission may have abnormal MSUS findings including PD signal. The role of MSUS in assessing remission in JIA is still not well-defined. • The application of a specific scoring system for the pediatric joint may be helpful in homogenizing outcomes and comparing results.

Prevalence of Subclinical Activity by Ultrasound Examination in Mexican Children with Juvenile Idiopathic Arthritis in Remission

Background: Juvenile Idiopathic Arthritis (JIA) is a chronic disease that affects 0.6 - 1.9 /1,000 children. Persistent joint inflammation conditions cartilage damage and erosions. Recent studies have shown that clinical examination significantly underestimates joint inflammation, with ultrasound having a higher sensitivity. The aim of this study was determined the prevalence of subclinical synovitis by musculoskeletal ultrasound in Mexican children with JIA in remission. Methods: Cross-sectional study, patients with JIA in clinical remission based on the Wallace criteria were included, with and without pharmacological treatment, we also included a control group of healthy children. The evaluation was performed by a certified Rheumatologist in Pediatric Musculoskeletal Ultrasound by EULAR. Joints clinically examined were also evaluated following the standard guidelines. Results: A total of 37 JIA patients with clinical remission and 33 healthy children were evaluated (1260 joints scanned), subclinical activity was detected in 15/37 (40.5%) patients and none of healthy children; 14 patients were still on treatment (93.3%). The subclinical activity was detected by gray scale in 22/1260 (1.7%) or by power Doppler (PD) in 15/1260 (1.1%) joints, the knee was involved in 13/22 (59%) joints. The subtype mainly affected was the rheumatoid factor-positive (FR) polyarticular (33.3%), erosions were detected in three patients (8%). In the knee, we observed slight distention of the supra patellar recess, evidenced in 19/33 healthy children (57.5%), predominantly among children aged 4 to 8 years. When comparing the groups with or without subclinical synovitis, no statistically significant differences were found with regard to age, evolution time or acute phase reactants. Conclusions: Subclinical synovitis was detected in 40.5% of the patients in clinical remission using gray scale or by power Doppler, mainly on those who were still on treatment. The most affected subtype was the rheumatoid factor-positive polyarticular, the knees were the most frequent involved. In the healthy children, a slight distention of the supra patellar recess was observed in almost half of cases.

Prevalence of Subclinical Activity by Ultrasound Examination in Mexican Children with Juvenile Idiopathic Arthritis in Remission

Background: Juvenile Idiopathic Arthritis (JIA) is a chronic disease that affects 0.6 - 1.9 /1,000 children. Persistent joint inflammation conditions cartilage damage and erosions. Recent studies have shown that clinical examination significantly underestimates joint inflammation, with ultrasound having a higher sensitivity. The aim of this study was determined the prevalence of subclinical synovitis by musculoskeletal ultrasound in Mexican children with JIA in remission. Methods: Cross-sectional study, patients with JIA in clinical remission based on the Wallace criteria were included, with and without pharmacological treatment, we also included a control group of healthy children. The evaluation was performed by a certified Rheumatologist in Pediatric Musculoskeletal Ultrasound by EULAR. Joints clinically examined were also evaluated following the standard guidelines. Results: A total of 37 JIA patients with clinical remission and 33 healthy children were evaluated (1260 joints scanned), subclinical activity was detected in 15/37 (40.5%) patients and none of healthy children; 14 patients were still on treatment (93.3%). The subclinical activity was detected by gray scale in 22/1260 (1.7%) or by power Doppler (PD) in 15/1260 (1.1%) joints, the knee was involved in 13/22 (59%) joints. The subtype mainly affected was the rheumatoid factor-positive (FR) polyarticular (33.3%), erosions were detected in three patients (8%). In the knee, we observed slight distention of the supra patellar recess, evidenced in 19/33 healthy children (57.5%), predominantly among children aged 4 to 8 years. When comparing the groups with or without subclinical synovitis, no statistically significant differences were found with regard to age, evolution time or acute phase reactants. Conclusions: Subclinical synovitis was detected in 40.5% of the patients in clinical remission using gray scale or by power Doppler, mainly on those who were still on treatment. The most affected subtype was the rheumatoid factor-positive polyarticular, the knees were the most frequent involved. In the healthy children, a slight distention of the supra patellar recess was observed in almost half of cases.

Сироватковий цистатин С як маркер ниркової дисфункції в дітей з ювенільним ідіопатичним артритом

An accurate assessment of the estimated glomerular filtration rate (eGFR) is important for early detection of chronic kidney disease, control of nephrotoxicity, and dose adjustment of drugs. To date, there has been only one cohort retrospective study of the prevalence of chronic kidney disease in children with juvenile idiopathic arthritis (JIA). Purpose - to determine the level of serum cystatin C and, on its basis, the state of eGFR depending on the form of the clinical course, degree of activity, methods of treatment of JIA in children. Materials and methods. 80 children with JIA were examined. The content of serum cystatin C was determined by enzyme-linked immunosorbent assay. The Hoek formula was used to calculate eGFR based on the level of cystatin C in blood serum. Results. A decrease in eGFR below 90 ml/min/1.73m2 to 63.08 ml/min/1.73m2 based on serum cystatin C was found in 41.3% of children with JIA. The variant of the clinical course of JIA does not affect the concentration of serum cystatin С and the level of eGFR. Meanwhile, a high degree of risk of developing a decrease in eGFR in children with polyarthritis was established - 72.7% versus 48.9% (OR=2.78; CI: 1.07-7.24; p&lt;0.04). Elevated serum cystatin С levels and decreased eGFR are associated with the degree of JIA activity and its duration. A decrease in eGFR is observed in all children with high activity of JIA, 71.4% - with low activity, 28.3% - in remission. A low risk of developing a decrease in eGFR in children in remission of JIA was established - 51.5% versus 91.5% (OR=0.10; CI: 0.03-0.34; p&lt;0.001). The duration of the active stage of JIA ≥4 years negatively affects the level of eGFR, which leads to a high risk of developing a decrease in eGFR - 39.4% versus 17% (OR=3.17; CI: 1.13-8.9; p&lt;0.04). A high risk of developing a decrease in eGFR was established in children with JIA who received non-steroidal anti-inflammatory drugs (NSAIDs) at the time of the examination - 54.5% versus 8.5% (OR=12.9; CI: 3.76-44.25; p&lt;0.001). The use of immunobiological therapy is associated with a low risk of developing a decrease in eGFR - 9.1% versus 46.8% (OR=0.11; CI: 0.03-0.42; p&lt;0.001). Conclusions. Renal dysfunction was found in 41.3% of children with JIA. Its development is affected by high activity of JIA, duration of the active stage of JIA ≥4 years, and treatment with NSAIDs. The study was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the institution specified in the work. Informed consent was obtained from the parents of the children for the research. No conflict of interests was declared by the authors. Key words: juvenile idiopathic arthritis, renal dysfunction.

Prevention of disease flares by risk-adapted stratification of therapy withdrawal in juvenile idiopathic arthritis: results from the PREVENT-JIA trial

ObjectivesTo investigate the ability of high-sensitivity C-reactive protein (hsCRP) and S100A12 to serve as predictive biomarkers of successful drug withdrawal in children with clinical remission of juvenile idiopathic arthritis (JIA).MethodsThis...

Эффективность и безопасность отмены ингибиторов фактора некроза опухоли альфа при длительной ремиссии ювенильного идиопатического артрита без системных проявлений: когортное исследование

The biological agents when long-term clinical remission of juvenile idiopathic arthritis (JIA) is achieved is necessary to reduce the risk of side effects and costs and to minimize the non-economic burden of therapy on patients and their families. Objective. To evaluate the efficacy and safety of discontinuing inhibitors of tumor necrosis factor alpha (TNF-α) in patients with JIA without systemic manifestations due to long-term clinical remission. Patients and methods. A total of 137 patients with JIA (27.0% male, mean age: 10 years) were enrolled in this study, of whom 95 (69.3%) received etanercept (0.8 mg/kg/week) and the rest – adalimumab (24 mg/m2 once every two weeks). The retrospective study included patients with JIA without systemic manifestations and disease remission of ≥24 months, during which the patients received TNF-α inhibitors. The latter were discontinued as directed by a physician or due to unavailability of the drug. The primary outcome measure of the study was maintenance of clinically inactive disease status (according to American College of Rheumatology criteria) for 6 months (&lt;210 days including 30 days’ tolerance for deviation from the recommended rehospitalization time) after discontinuation of therapy with TNF-α inhibitors. Results. At the time of TNF-α withdrawal, the median duration of JIA was about 6 years, the duration of TNF-α therapy was 3.5 years, and remission lasted for 3 years. After TNF-α withdrawal, 60 (43.8%) patients continued therapy with traditional disease-modifying antirheumatic drugs (DMARs). In the first 210 days after TNF-α discontinuation, 92 (67.2%) patients with JIA maintained the inactive disease status. The median time for the development of JIA exacerbations in 45 patients was 123 (95; 150) days. Biological agents therapy was resumed in 42 of 45 patients, and the inactive disease status was achieved in 41 cases. DMARs were received by 23 (55%) of 42 patients on therapy with biological agents. Conclusion. In two thirds of patients with JIA, the discontinuation of TNF-α inhibitors due to long-term clinical remission did not lead to disease exacerbations in the next six months. The resumption of biological agents therapy in case of JIA worsening allows most patients to reach the status of clinically inactive disease. Key words: genetically engineered biopharmaceutical drugs, tumor necrosis factor inhibitors, juvenile idiopathic arthritis, therapy withdrawal, long-term remission, clinically inactive disease

Отмена ингибиторов фактора некроза опухоли-α при достижении лекарственной ремиссии ювенильного идиопатического артрита без системных проявлений

Juvenile idiopathic arthritis (JIA) is one of the most common and disabling rheumatic diseases in children. Pharmaceutical therapy for JIA can prevent the progression of the disease, achieve long-term remission, and significantly improve the quality of life in most patients. In cases where the initial therapy for JIA is not effective enough, it is recommended to escalate it, and vice versa, when remission is achieved, the de-escalation of therapy may be discussed. The latter is necessary due to the high risk of developing infectious complications and certain oncological diseases against the background of continuous biological treatment of JIA, as well as the negative impact of regular injections and/or infusions of medications on the quality of life, the interruption of educational process, the psychological burden of “lifelong” treatment with medications, and the economic burden on families and healthcare system. Currently, optimal regimens for the discontinuation of biopharmaceuticals, including TNFalpha inhibitors, remain a matter of debate. In this regard, the search for potential predictors of JIA exacerbation after withdrawal of biopharmaceuticals is relevant. Key words: juvenile idiopathic arthritis, biologic-free remission of JIA, tumor necrosis factor, inhibitors, etanercept, adalimumab, withdrawal, exacerbation, predictors

Infection with SARS-CoV-2 causes flares in patients with juvenile idiopathic arthritis in remission or inactive disease on medication

BackgroundFlares of juvenile idiopathic arthritis (JIA) have been described in the context of various infections. Flares of rheumatic diseases in adults have been described following infection with SARS-CoV-2 in several cohorts. So far, the effect of infection with SARS-CoV-2 on the course of JIA is unknown.MethodsThe database of the German Center for Pediatric and Adolescent Rheumatology was searched for patients with confirmed infection with SARS-CoV-2 and subsequent disease flare, admitted from July 2020 until June 2021. cJADAS-27, ESR and C-reactive protein, as well as uveitis activity, medication at the time of flare and treatment of flare was extracted. Patient cases were described individually.ResultsOut of 988 patients admitted, five patients with remission off medication (n = 2) or inactive disease on medication (n = 3) were identified, with flare symptoms up to four weeks after infection with SARS-CoV-2.ConclusionsFlares can occur after infection with SARS-CoV-2 in patients with JIA in remission or inactive disease on medication. Treating physicians need to be aware of this fact, especially when counseling patients with rheumatic diseases about the respective dangers of COVID-19 and vaccination against SARS-CoV-2.

Early intra-articular corticosteroid injection is predictors of remission of juvenile idiopathic arthritis.

The aim of this study was to assess predictors of remission in children with juvenile idiopathic arthritis (JIA), treated with intra-articular corticosteroid injection (IACI) as monotherapy or in combination with methotrexate (MTX). A retrospective study of 43 patients diagnosed with different JIA subtypes and followed-up at a tertiary center between 2000 and 2014. We included patients treated with IACI as monotherapy or in combination with MTX at onset or thereafter. We excluded patients treated with MTX as monotherapy or in combination with biologics. Patients were divided into two groups on the basis of assigned treatment. Primary outcomes were disease remission and duration. We performed descriptive analysis, bivariate analysis and cross-correlation analysis between variables. Statistically significant results (P value <0.05) were chosen as variables for multivariate analysis. Median age of onset was 4.56 years (SD±3.85). Median time between disease onset and first IACI was 16.9 months (SD±34.7). We evaluated between time to remission in relation to age, time interval between onset and first IACI, time between onset and start of treatment with MTX, and time between first and second IACI. All of these were statistically significant (P value <0.05) in bivariate analysis, but time between onset and first IACI was the only statistically significant result, using multiple linear regression analysis. Therefore, in our study, 37 patients (86%) of patients went into remission on medication after a median disease duration of 48.8 months. We found that remission was related to time between onset and first IACI. Our predictive model showed that early IACI can be considered as a strong predictor of remission.

Changes in Treatments and Outcomes After Implementation of a National Universal Access Program for Juvenile Idiopathic Arthritis.

To evaluate the clinical and demographic characteristics of patients with juvenile idiopathic arthritis (JIA) in Chile and compare treatments and outcomes before and after the introduction in 2010 of the Explicit Health Guarantees (GES) for JIA, a national universal access program for diagnosis and treatment of this condition. The clinical records of 280 patients with JIA followed at a private tertiary academic health network between 2007 and 2018 were reviewed. Seventy percent of patients with JIA were female, mean age at diagnosis was 8.5 ± 4.8 years and mean follow-up was 4.0 ± 3.7 years. After GES implementation (post-GES), time to evaluation by pediatric rheumatologist and diagnostic delay were significantly reduced (15.0 ± 4.5 vs 9.0 ± 4.2 months, P = 0.004). In addition, use of magnetic resonance imaging significantly increased post-GES (P < 0.001). In terms of JIA treatments, before GES implementation, no patients received biologics. Of the 67 patients diagnosed before 2010 with continued follow-up at our center, 34% began biologic treatment after GES implementation. Of 196 patients diagnosed post-GES, 46% were treated with biologics. JIA remission rates were significantly higher in patients diagnosed post-GES compared to pre-GES (43% vs 29%, P = 0.02). Post-GES, we observed a significant decrease in uveitis complications among JIA patients (45% vs 13%, P = 0.04). The implementation of a national government-mandated universal access program for guaranteed JIA diagnosis and treatment led to earlier access to a pediatric rheumatologist and JIA diagnosis, increased rates of treatment with biologic drugs, higher rates of clinical remission, and lower rates of uveitis complications in Chilean children with JIA.

Biomarkers of Response to Biologic Therapy in Juvenile Idiopathic Arthritis.

Background: Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory arthritis of childhood, characterized by various clinical phenotypes associated with variable prognosis. Significant progress has been achieved with the use of biologic treatments, which specifically block pro-inflammatory molecules involved in the disease pathogenesis. The most commonly used biologics in JIA are monoclonal antibodies and recombinant proteins targeting interleukins 1 (IL-1) and 6 (IL-6), and tumor necrosis factor α (TNF-α). Several biomarkers have been investigated in JIA. Aims: To assess the level of evidence available regarding the role of biomarkers in JIA related to guiding clinical and therapeutic decisions, providing disease prognostic information, facilitating disease activity monitoring and assessing biologic treatment response in JIA, as well as propose new strategies for biologic therapy-related biomarker use in JIA. Methods: We searched PubMed for relevant literature using predefined key words corresponding to several categories of biomarkers to assess their role in predicting and assessing biologic treatment response and clinical remission in JIA. Results: We reviewed serological, cellular, genetic, transcriptomic and imaging biomarkers, to identify candidates that are both well-established and widely used, as well as newly investigated in JIA on biologic therapy. We evaluated their role in management of JIA as well as identified the unmet needs for new biomarker discovery and better clinical applications. Conclusion: Although there are no ideal biomarkers in JIA, we identified serological biomarkers with potential clinical utility. We propose strategies of combining biomarkers of response to biologics in JIA, as well as routine implementation of clinically acceptable imaging biomarkers for improved disease assessment performance.

Novel biomarkers for early targeted and individualized treatment in Juvenile Idiopathic Arthritis.

Background:The programmed cell death protein-1 (PD-1) and its ligands (PD-L 1 and 2) suppress immune responses, thus promoting self-tolerance. Among the immunomodulatory cells, acting through the PD-1 pathway, are the B-regulatory cells (Bregs). The role of the PD-1 pathway in Juvenile Idiopathic Arthritis (JIA) has not been adequately studied.Aims of the study:To investigate the immunophenotypic profile of T- and B-cells and the activity of the PD-1 pathway in JIA patients. More specifically, we will examine the levels of: a) the soluble form of PD-1 (sPD-1), b) Bregs; and the expression levels of: c) PD-1 on CD4+ and CD8+ T-cells, d) PD-L1 on Bregs and CD19+ B-cells, in blood and synovial fluid samples, at various stages of the disease (onset, relapse, remission, on or off treatment). The above biomarkers will be investigated for correlation with JIA activity.Methods:A case-control study of JIA patients (expected number: 60) and healthy controls (n: 20). Total expected number of samples: 100 of peripheral blood, 120 of serum (solely for soluble markers) and 60 of synovial fluid. The patients’ demographic data and treatment will be recorded. JIA will be classified according to the ILAR and the recently proposed PReS/PRINTO criteria. JIA activity will be assessed using the JADAS-10 tool. The biomarkers will be determined using multiparametric-polychromatic flow cytometry (quintuple fluorescence protocol) and immunoenzymatic assay ELISA.Anticipated benefits:Further elucidation of the immunophenotypic expression and variation of the abovementioned molecules and cells during active inflammation and remission in JIA. Thereby, the present study is expected to contribute to: a) the modern research and understanding of the confirmed immune dysfunction at the cellular level, which leads to the development of serious autoimmune diseases in childhood, such as JIA, and b) the search for biomarkers that could be targets of early “intelligent” treatment and thereby could support the implementation of precision-medicine. The early diagnosis and targeted treatment of JIA are crucial for the maintenance of normal physical functioning and the psychosocial balance of the still growing adolescent/child.

Validation of prediction models of severe disease course and non-achievement of remission in juvenile idiopathic arthritis: part 1\u2014results of the Canadian model in the Nordic cohort

BackgroundModels to predict disease course and long-term outcome based on clinical characteristics at disease onset may guide early treatment strategies in juvenile idiopathic arthritis (JIA). Before a prediction model can be recommended for use in clinical practice, it needs to be validated in a different cohort than the one used for building the model. The aim of the current study was to validate the predictive performance of the Canadian prediction model developed by Guzman et al. and the Nordic model derived from Rypdal et al. to predict severe disease course and non-achievement of remission in Nordic patients with JIA.MethodsThe Canadian and Nordic multivariable logistic regression models were evaluated in the Nordic JIA cohort for prediction of non-achievement of remission, and the data-driven outcome denoted severe disease course. A total of 440 patients in the Nordic cohort with a baseline visit and an 8-year visit were included. The Canadian prediction model was first externally validated exactly as published. Both the Nordic and Canadian models were subsequently evaluated with repeated fine-tuning of model coefficients in training sets and testing in disjoint validation sets. The predictive performances of the models were assessed with receiver operating characteristic curves and C-indices. A model with a C-index above 0.7 was considered useful for clinical prediction.ResultsThe Canadian prediction model had excellent predictive ability and was comparable in performance to the Nordic model in predicting severe disease course in the Nordic JIA cohort. The Canadian model yielded a C-index of 0.85 (IQR 0.83–0.87) for prediction of severe disease course and a C-index of 0.66 (0.63–0.68) for prediction of non-achievement of remission when applied directly. The median C-indices after fine-tuning were 0.85 (0.80–0.89) and 0.69 (0.65–0.73), respectively. Internal validation of the Nordic model for prediction of severe disease course resulted in a median C-index of 0.90 (0.86–0.92).ConclusionsExternal validation of the Canadian model and internal validation of the Nordic model with severe disease course as outcome confirm their predictive abilities. Our findings suggest that predicting long-term remission is more challenging than predicting severe disease course.

Treatment Withdrawal Following Remission in Juvenile Idiopathic Arthritis: A Systematic Review of the Literature.

Early diagnosis and treatment of juvenile idiopathic arthritis (JIA) with conventional and biologic disease-modifying anti-rheumatic drugs have vastly improved outcomes for children with these diseases. Currently, a large proportion of children with JIA are able to achieve clinical inactive disease and remission. With this success, important questions have arisen about when medications can be stopped and how to balance the risks and benefits of continuing medications versus the potential for flare after stopping. The aim was to conduct a systematic review of the available literature to summarize current evidence about medication withdrawal for JIA in remission. We conducted a systematic literature search in PubMed and Embase from 1990 to 2019. References were first screened by title and then independently screened by title and abstract by two authors. A total of 77 original papers were selected for full-text review. Data were extracted from 30 papers on JIA and JIA-associated uveitis, and the quality of the evidence was evaluated using National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) tools. Studies on biochemical and radiologic biomarkers were also reviewed and summarized. Most studies investigating treatment withdrawal in JIA have been observational and of poor or fair quality; interpretations of these studies have been limited by differences in study populations, disease and remission durations, the medications withdrawn, approaches to withdrawal, and definitions of disease outcomes. Overall the data suggest that flares are common after stopping JIA medications, particularly biologic medications. Clinical characteristics associated with increased risks of flare have not been consistently identified. Biochemical biomarkers and ultrasound findings have been shown to predict outcomes after stopping medications, but to date, no such predictor has been consistently validated across JIA populations. Studies have also not identified optimal strategies for withdrawing medication for well-controlled JIA. Promising withdrawal strategies include discontinuing methotrexate before biologic medications in children receiving combination therapy, dose reduction for children on biologics, and treat-to-target approaches to withdrawal. These and other strategies require further investigation in larger, high-quality studies. The published literature on treatment withdrawal in JIA has varied in design and quality, yielding little conclusive evidence thus far on the management of JIA in remission. Given the importance of this question, international collaborative efforts are underway to study clinical and biologic predictors of successful medication withdrawal in JIA. These efforts may ultimately support the development of personalized approaches to withdrawing medication in children with JIA in remission.

Predicting disease severity and remission in juvenile idiopathic arthritis: are we getting closer?

To summarize current research on the prediction of severe disease or remission in children with juvenile arthritis, and define further steps needed towards developing prediction tools with sufficient accuracy for clinical use. High disease activity, poor patient-reported outcomes, ankle or wrist involvement, and a longer time from onset to the start of treatment herald a severe disease course and a low chance of remission. Other studies confirmed that age less than 7 years and positive ANA are the strongest predictors of uveitis development. Preliminary evidence suggests ultrasound findings may predict flare in patients with clinically inactive disease, and several new biomarkers show promise. A few prediction tools that combine predictors to estimate the chance of remission or a severe disease course in the medium-term to long-term have shown good accuracy when internally validated in the population in which they were developed. Promising candidate tools for predicting disease severity and long-term remission in juvenile arthritis are now available. These tools need external validation in other populations, and ideally formal trials to assess whether their use in practice improves patient outcomes. We are definitively getting closer, but we are not there yet.

Switching to a Second TNF-_ Inhibitor in a Patient with Severe Juvenile Polyarthritis: A Clinical Case

Background. Insufficient efficacy or intolerance of the first TNF-_ inhibitor in patients with juvenile idiopathic arthritis (JIA) is an indication for the appointment of a second inhibitor. Golimumab is a new TNF-_ inhibitor registered for treating JIA under pediatric indications. Clinical Case Description. At an early age, the patient had an onset of polyarticular JIA. Due to the aggressive and rapidly progressive course, failure of therapy with nonsteroidal anti-inflammatory drugs, methotrexate and glucocorticosteroids for intra-articular administration, infliximab was prescribed to the patient, with a positive effect. Subsequently, the patient developed a secondary resistance to infliximab, inflammatory changes in the joints relapsed; thus, a second TNF-_ inhibitor (golimumab) was prescribed. In the course of therapy, pain and signs of arthritis in the patient were reversed, and the range of motion in the affected joints increased. After one year of therapy, JIA remission was ascertained. At the same time, the child was not administered oral glucocorticosteroids. The duration of remission of the joint syndrome was 5 years. Adverse events were not serious and did not constitute a basis for drug discontinuation. Conclusion. Switching to a second TNF-_ inhibitor (golimumab) was effective in a patient with a secondary resistance to the first TNF-_ inhibitor.

Remission and Active Disease in Young Adult Patients with Juvenile Idiopathic Arthritis During the Transition Period from Paediatric to Adult Healthcare

The objective of the research was to study the frequency of remission in young adults with juvenile idiopathic arthritis during the transition period from paediatric to adult healthcare and factors contributing to its development. Materials and methods. In our study, there were included 165 adult patients from different regions of Ukraine diagnosed with juvenile idiopathic arthritis according to the classification criteria of the International League of Associations for Rheumatology. All the patients were examined in the Oleksandrivska City Clinical Hospital, Kyiv during 2015-2018. There were assessed the presence of rheumatoid factor, anti-cyclic citrullinated peptide, antinuclear antibodies, human leukocyte antigen B27, disease duration, disease activity (the Juvenile Arthritis Disease Activity Score-10 and the Disease Activity Score-28), C-reactive protein, past medical history, quality of life (the 36-Item Short Form Health Survey), the degree of depression (the Patient Health Questionnaire-9) and alexithymia (the 20-item Toronto Alexithymia Scale). In all the patients, bone mineral density was studied using dual-energy x-ray absorptiometry with the evaluation of T- and Z-scores in different regions of the skeleton. The disease was considered inactive at the Disease Activity Score-28 &lt;2.6 and the Juvenile Arthritis Disease Activity Score-10 &lt;1 and &lt;2 for oligoarticular and polyarticular variants of juvenile idiopathic arthritis, respectively. Results and discussion. All the patients were divided into 2 groups: Group I included 136 (82.4%) patients with active disease at the time of examination; Group II comprised 29 (17.6%) patients who achieved remission according to the Disease Activity Score-28 or the Juvenile Arthritis Disease Activity Score-10. In Group I, females prevailed accounting for 58.1% of patients as compared to Group II (31.0%). Disease duration was longer in patients of Group I (p&lt;0.01); however, they did not differ from patients of Group II in age at disease onset and the International League of Associations for Rheumatology variants of juvenile idiopathic arthritis. In Group II, lesions involving more than 3 joints (p&lt;0.01), hand arthritis (p&lt;0.01), symmetric arthritis (p&lt;0.01), enthesitis (p&lt;0.01), spinal pain (p&lt;0.01) were observed less frequently. Fewer patients required joint replacement (p&lt;0.01); the number of deformed and painful joints (p&lt;0.05, p&lt;0.001, respectively) was smaller. However, there was no difference in the level of rheumatoid factor, anti-cyclic citrullinated peptide, antinuclear antibodies, and the presence of human leukocyte antigen B27. The achievement of remission improved physical well-being of patients (the physical component score, p&lt;0.001), although overall mental well-being (the mental component score) did not change according to the 36-Item Short Form Health Survey. In patients with remission, the indicators of physical functioning (p&lt;0.001), role functioning (p&lt;0.001), social functioning (p&lt;0.001), bodily pain (p&lt;0.001), general health (p&lt;0.001), mental health (p&lt;0.001) improved. There was observed a reduction in the level of depression to the normal one according to the Patient Health Questionnaire-9 (p&lt;0.05); however, in both groups, there were observed elevated levels of alexithymia. Both groups did not differ in the frequency of immunobiological therapy prescription; however, the results should be intepreted with caution, since only 5 (17.1%) patients in Group II received immunobiological therapy earlier or at the time of examination. In Group II, patients did not receive glucocorticoids at the time of examination (p&lt;0.001) and earlier more often (p&lt;0.001). Both groups did not differ in both the duration of treatment with disease-modifying antirheumatic drugs and the doses of methotrexate and sulfasalazine. Conclusions. Remission of juvenile idiopathic arthritis was detected in 17.6% of the surveyed young adult patients from different regions of Ukraine during the transition period from paediatric to adult healthcare, that indicated that in most cases the goal of treat-to-target strategy was not achieved. Patients with active disease often developed joint deformities and required their replacement; they had worse physical well-being according to the 36-Item Short Form Health Survey, although mental well-being was affected in both patients with active disease and those with remission, which may be due to high levels of alexithymia in both groups. Patients with active disease had higher levels of depression according to the Patient Health Questionnaire-9, whereas patients in remission showed no depression.