Treatment Of Juvenile Idiopathic Arthritis Research Articles

Recommendations for the Management of Uveitis Associated With Juvenile Idiopathic Arthritis: The Czech and Slovak adaptation of SHARE Initiative.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and uveitis is its most important extra-articular manifestation. Evidence-based recommendations are available only to alimited extent and therefore JIA associated uveitis management is mostly based on physicians experience. Consequently, treatment practices differ widely, both nationally and internationally. Therefore, an effort to optimize and publish recommendations for the care of children and young adults with rheumatic diseases was launched in 2012 as part of the international project SHARE (Single Hub and Access Point for Pediatric Rheumatology in Europe) to facilitate clinical practice for paediatricians and (paediatric) rheumatologists. The aim of this work was to translate published international SHARE recommendations for the diagnosis and treatment of JIA associated uveitis and to adapt them for use in the Czech and Slovak Republics. International recommendations were developed according to the standard methodology of the European League against Rheumatism (EULAR) by agroup of nine experienced paediatric rheumatologists and three experts in ophthalmology. It was based on asystematic literature review and evaluated in the form of an online survey and subsequently discussed using anominal group technique. Recommendations were accepted if > 80% agreement was reached (including all three ophthalmologists). Atotal of 22 SHARE recommendations were accepted: 3 on diagnosis, 5 on disease activity assessment, 12 on treatment and 2 on future recommendations. Translation of the original text was updated and modified with data specific to the czech and slovak health care systems and supplemented with aproposal for aprotocol of ophthalmological dispensarization of paediatric JIA patients and atreatment algorithm for JIA associated uveitis. Conclusion: The aim of the SHARE initiative is to improve and standardize care for paediatric patients with rheumatic diseases across Europe. Therefore, recommendations for the diagnosis and treatment of JIA-associated uveitis have been formulated based on the evidence and agreement of leading European experts in this field.

Prefilled pen versus prefilled syringe: a pilot study evaluating two different methods of methotrexate subcutaneous injection in patients with JIA

BackgroundMethotrexate is the most commonly used disease-modifying antirheumatic drug recommended in the treatment of juvenile idiopathic arthritis. It can be administered orally or subcutaneously, the latter method is associated with fewer side effects and higher drug bioavailability. Nevertheless, the pain associated with injection is a considerable drawback of this treatment option in the pediatric population. Currently, there are two single-use subcutaneous injection devices available: the prefilled syringe and the prefilled pen. This prospective, two-sequence crossover study aimed to compare ease of use, frequency of therapy side effects, injection-site pain and parent/patient preference of those methotrexate parenteral delivery systems.MethodsTwenty-three patients with juvenile idiopathic arthritis, already treated with subcutaneous methotrexate in the form of prefilled syringe in the period October 2018 – April 2019 completed a questionnaire evaluating their experience with this device. Subsequently, children received a one-month supply of pen autoinjector and completed the same questionnaire, regarding their experience with the new methotrexate delivery system. If the patient was not performing the injections himself the questionnaires were completed by the caregiver administrating MTX. The results obtained in both questionnaires were compared using the Wilcoxon matched-pairs signed-rank test.Results82,6% patients and their caregivers voted for the prefilled pen as their preferred method of subcutaneous methotrexate administration. Moreover, the injection with the prefilled pen was reported as less painful in comparison to the prefilled syringe (p < 0.01). Side effects of methotrexate were less pronounced after the prefilled pen treatment, this difference was most prominent regarding gastrointestinal adverse events associated with the injection (p < 0.01).ConclusionAdministration of methotrexate using the pen device is a promising way of subcutaneous methotrexate delivery in children with juvenile idiopathic arthritis, as the injection is less painful and associated with fewer side effects.

Evaluation of impaired growth plate development of long bones in skeletally immature mice by antirheumatic agents.

Restriction of physical growth and development is a known problem in patients with juvenile idiopathic arthritis (JIA). However, the effect of medical treatment for JIA on skeletal growth in affected children has not been properly investigated. We, therefore, hypothesize that naproxen and methotrexate (MTX) affect endochondral ossification and will lead to reduced skeletal development. Treatment of ATDC5 cells, an in vitro model for endochondral ossification, with naproxen or MTX resulted in increased chondrogenic but decreased hypertrophic differentiation. In vivo, healthy growing C57BL/6 mice were treated with naproxen, MTX, or placebo for 10 weeks. At 15 weeks postnatal, both the length of the tibia and the length of the femur were significantly reduced in the naproxen‐ and MTX‐treated mice compared to their controls. Growth plate analysis revealed a significantly thicker proliferative zone, while the hypertrophic zone was significantly thinner in both experimental groups compared to their controls, comparable to the in vitro results. Micro‐computed tomography analysis of the subchondral bone region directly below the growth disc showed significantly altered bone microarchitecture in naproxen and MTX groups. In addition, the involvement of the PTHrP‐Ihh loop in naproxen‐ and MTX‐treated cells was shown. Overall, these results demonstrate that naproxen and MTX have a profound effect on endochondral ossification during growth plate development, abnormal subchondral bone morphology, and reduced bone length. A better understanding of how medication influences the development of the growth plate will improve understanding of endochondral ossification and reveal possibilities to improve the treatment of pediatric patients.

Early Prediction of Clinical Response to Etanercept Treatment in Juvenile Idiopathic Arthritis Using Machine Learning.

Background and AimsAt present, there is a lack of simple and reliable model for early prediction of the efficacy of etanercept in the treatment of juvenile idiopathic arthritis (JIA). This study aimed to generate and validate prediction models of etanercept efficacy in patients with JIA before administration using machine learning algorithms based on electronic medical record (EMR).Materials and MethodsEMR data of 87 JIA patients treated with etanercept between January 2011 and December 2018 were collected retrospectively. The response of etanercept was evaluated by using DAS44/ESR-3 simplified standard. The stepwise forward and backward method based on information gain was applied to select features. Five machine learning algorithms, including Extreme Gradient Boosting (XGBoost), Random Forest (RF), Gradient Boosting Decision Tree (GBDT), Extremely Random Trees (ET) and Logistic Regression (LR) were used for model generation and validation with fifty-fold stratified cross-validation. EMR data of additional 14 patients were collected for external validation of the model.ResultsTender joint count (TJC), Time interval, Lymphocyte percentage (LYM), and Weight were screened out and included in the final model. The model generated by the XGBoost algorithm based on the above 4 features had the best predictive performance: sensitivity 75%, specificity 66.67%, accuracy 72.22%, AUC 79.17%, respectively.ConclusionA pre-administration model with good prediction performance for etanercept response in JIA was developed using advanced machine learning algorithms. Clinicians and pharmacists can use this simple and accurate model to predict etanercept response of JIA early and avoid treatment failure or adverse effects.

A controversial topic in juvenile idiopathic arthritis: Association between biologic agents and malignancy

Over the last 2 decades, the usage of biological agents in the treatment of juvenile idiopathic arthritis (JIA) has been a successful and promising approach in controlling disease activity and preventing chronic sequelae. However, there are ongoing concerns about the long-term safety data and side-effect profile. We aimed to present preliminary data on the incidence of malignancy in patients with JIA treated with biological agents versus the general population rates in Turkey. A single-center hospital-based cohort study was performed to analyze cancer occurrence among JIA patients treated with biologic agents during the observation period between January 2004 and May 2019. As reference data for direct standardization, age, gender, and calendar year-specific incidence rates from the Turkish cancer registry were used. The standardized incidence ratio (SIR, ratio of cancers observed to expected) was generated with 95% confidence intervals. The study sample consisted of 1023 JIA patients who had been treated with biologic or non-biologic agents. In the biologic-experienced group (n=656), the mean age (at the study) was 16.7±5.6years. The mean length of follow-up was 9.9±5.0years. One cancer was detected within the observation period (SIR: 1.3, 95% CI: 0.06-6.3). The patient was an 18-year-old male who had previously received etanercept and tocilizumab until the diagnosis of the hematologic malignancy (SIR: 2.5, 95% CI: 0.1-12.6). Patients treated with biologic agents appeared to have an increased rate of incident hematologic malignancy versus the general population in Turkey. However, before mentioning a clear causal relationship, other potential contributing factors should be taken into consideration.

Update on the treatment of nonsystemic juvenile idiopathic arthritis including treatment-to-target: is (drug-free) inactive disease already possible?

This review concerns the outcome for nonsystemic juvenile idiopathic arthritis (JIA) with emphasis on treatment-to-target (T2T) and treatment strategies aiming at inactive disease by giving an overview of recent articles. More efficacious therapies and treatment strategies/T2T with inactive disease as target, have improved the outcome for JIA significantly. Recent studies regarding treatment strategies have shown 47-68% inactive disease after 1 year. Moreover, probability of attaining inactive disease at least once in the first year seems even higher in recent cohort-studies, reaching 80%, although these studies included relatively high numbers of oligoarticular JIA patients. However, 26-76% of patients flare upon therapy withdrawal and prediction of flares is still difficult. Remission can be achieved and sustained in (some) JIA patients, regardless of initial treatment. Cornerstone principles in the management of nonsystemic JIA treatment are early start of DMARD therapy, striving for inactive disease and T2T by close and repeated monitoring of disease activity. T2T and tight control appear to be more important than a specific drug in JIA. Next to inactive disease, it is important that patients/parents are involved in personal targets, like reduction of pain and fatigue. Future studies should focus on predictors (based on imaging-methods or biomarkers) for sustained drug-free remission and flare.

Biologics in juvenile idiopathic arthritis-main advantages and major challenges: A narrative review.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. The disease is divided in different subtypes based on main clinical features and disease course. Emergence of biological agents targeting specific pro-inflammatory cytokines responsible for the disease pathogenesis represents the revolution in the JIA treatment. Discovery and widespread usage of biological agents have led to significant improvement in JIA patients’ treatment, with evidently increased functionality and decreased disease sequel. Increased risk of infections remains the main discussion topic for years. Despite the slightly increased frequency of upper respiratory tract infections reported in some studies, the general safety of drugs is acceptable with rare reports of severe adverse effects (SAEs). Tuberculosis (TBC) represents the important threat in regions with increased TBC prevalence. Therefore, routine screening for TBC should not be neglected when prescribing and during the follow-up of biological treatment. Malignancy represents a hypothetical complication that sometimes causes hesitations for physicians and patients in its prescription and usage. On the other hand, current reports from the literature do not support the increased risk for malignancy among JIA patients treated with biological agents. A multidisciplinary approach including a pediatric rheumatologist and an infectious disease specialist is mandatory in the follow- up of JIA patients. Although the efficacy and safety of biological agents have been proven in different studies, there is still a need for long-term, multicentric evaluation providing relevant data.

Rheumatic diseases in childhood and adolescence: importance of early multi-professional care

Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory rheumatic disease in children. Both the disease, which is accompanied by pain and movement restrictions, and its usually complex, long-term therapy, are associated with burdens for those affected until adulthood. Impairments can affect many areas of life. Holistic care that considers the preferences and expressed needs of patients and their families is crucial in order to achieve the desired therapeutic goals of remission and the best possible quality of life. Since JIA begins in avery early phase of life, long-term consequences due to illness and therapy are of considerable importance.The approval of new substances that specifically intervene in the inflammatory process has fundamentally changed the treatment of JIA in recent years. Above all, early effective therapy makes adecisive contribution to an improved prognosis of JIA patients. Meanwhile, JIA patients enter adulthood with good everyday function and quality of life as well as less secondary damage and concomitant diseases, although only about half achieve stable therapy-free remission. In order to support the necessary transition into adult medicine, transition programmes have been developed to prepare young rheumatics for the new form of care and to prevent gaps in care and unfavourable outcomes. Last but not least, the recording of psychological factors is important in order to support the chronically ill in dealing with their illness and the resulting challenges, if necessary.

Real-World Effectiveness of Common Treatment Strategies for Juvenile Idiopathic Arthritis: Results From a Canadian Cohort.

Undervaluing the effectiveness of conventional treatments may lead to overtreatment with biologic medications in children with juvenile idiopathic arthritis (JIA). Using data from a nationwide inception cohort and strict methods to control bias, the aim of our study was to estimate the real-world effectiveness of simple JIA treatment strategies recommended in current guidelines. Children with JIA who were recruited at 16 Canadian centers from 2005 to 2010 were followed for up to 5 years. For each child, all observed treatment changes over time were assessed by independent physicians using prospectively collected data and published response criteria. Success was defined as attainment of inactive disease or maintenance of this state when stepping down treatment; minimally active disease was deemed acceptable for children with polyarticular JIA. Success rates were calculated for treatments tried ≥25 times, and logistic regression analysis identified features associated with success. A total of 4,429 treatment episodes were observed in 1,352 children. Nonsteroidal antiinflammatory drug (NSAID) monotherapy was attempted 697 times, mostly as initial treatment when <5 joints were involved, with a 54.4% success rate (95% confidence interval [95% CI] 50.3-58.6). NSAIDs plus joint injections had a 64.7% success rate (95% CI 59.8-69.7). Adding methotrexate to NSAIDs and/or joint injections (attempted 566 times) had a 60.5% success rate (95% CI 55.7-65.3). In adjusted analyses, each additional active joint reduced chances of success for treatment with NSAIDs (odds ratio [OR] 0.90 [95% CI 0.85-0.94]) and for methotrexate combinations (OR 0.96 [95% CI 0.94-0.99]). Each additional year after disease onset reduced chances of success for treatment with methotrexate combinations (OR 0.83 [95% CI 0.72-0.95]). These real-world effectiveness estimates show that conventional nonbiologic treatment strategies that are recommended in current guidelines are effective in achieving treatment targets in many children with JIA.

Long non‑coding RNA RP11‑340F14.6 promotes a shift in the Th17/Treg ratio by binding with P2X7R in juvenile idiopathic arthritis.

Long non‑coding RNA (lncRNAs) have been identified to play important roles in multiple human diseases via the regulation of cell proliferation, cell invasion, or cell death. However, little is known about the role of lncRNAs in the process of shifts in the Th17/Treg ratio during the progression of juvenile idiopathic arthritis (JIA). The aim of the present study was to determine the role of lncRNA RP11‑340F14.6 in the shifting of the Th17/Treg ratio in JIA. The distribution of the T cell subgroup was detected by flow cytometry in peripheral blood mononuclear cells from patients with JIA and healthy controls. It was found that the expression of lncRNA RP11‑340F14.6 was upregulated, and to positively correlate with that of retinoic acid‑related orphan receptor gammat (RORγt), and to negatively correlate with Foxp3 expression in patients with JIA. RP11‑340F14.6 induced the expression of its neighbor, P2X7R. Through a P2X7R‑independent approach, this lncRNA was also found to play a pivotal role in stimulating Th17 differentiation and simultaneously suppressing Treg distribution. Taken together, the findings of the present study demonstrate that RP11‑340F14.6 specifically binds to P2X7R, which results in the continuous activation of P2X7R. Thus, RP11‑340F14.6 may serve as a promising therapeutic target for the treatment of JIA.

MTX intolerance in children and adolescents with juvenile idiopathic arthritis.

MTX is the medication most commonly used for antirheumatic treatment in juvenile idiopathic arthritis. It has high efficacy, is usually well tolerated and has an excellent safety profile. However, frequently intolerance symptoms develop that manifest as nausea, feelings of disgust or abdominal complaints prior to or directly after administration of the medication. No obvious toxicity is causing these intolerance symptoms, but symptoms are strictly limited to MTX and not transferred to other medications. MTX intolerance causes a significant reduction of quality of life in affected patients, frequently puts the treating physician in difficult situations regarding treatment choice, and may lead to uncomfortable decisions whether or not to stop an otherwise effective drug. Conventional countermeasures such as antiemetics, change of route from subcutaneous to oral or vice versa, or taste masking usually have only a limited effect. In this review, we present the current knowledge on MTX intolerance, its clinical picture and commonly employed strategies. We also consider newer behavioural treatment strategies that may offer a more effective symptom control.

Spectrum of paediatric rheumatic disorders at a tertiary hospital in Tanzania

BackgroundPaediatric rheumatic disorders are common in children and result in significant impairment in quality of life, morbidity and mortality. There is limited information on the burden of these disorders in lower income countries especially in sub-Saharan Africa. Few case reports have documented presence of paediatric rheumatic disorders in Tanzania. This study was conducted to determine the spectrum of rheumatic disorders among children at Muhimbili National Hospital (MNH).MethodsThis was a retrospective study conducted among children who were attended at MNH between January 2012 and August 2019. Paediatric patients seen in the out-patient clinics and those admitted in the wards were eligible. All patients with diagnosis of rheumatic disorders were identified from admission books and outpatient clinic logbooks, and later data were collected from their case notes and were recorded in clinical research forms. Collected information included age, sex, clinical features and laboratory tests results.ResultsA total of 52 children with mean age of 9.5 ± 4.3 years, 12 (40.4%) participants were aged above 10 years and 32 (61.5%) were females. Frequently reported clinical presentations were joint pain 44 (84.6%), joint swelling 34 (65.4%), fever 24 (46.2%) and skin rashes 21(40.4%). Juvenile idiopathic arthritis (JIA) was the predominant diagnosis reported in 28 (53.8%) participants followed by juvenile systemic lupus erythematosus 8 (15.4%), mixed connective tissue diseases 4 (7.7%) and juvenile dermatomyositis 4 (7.7%). Antinuclear antibody test was performed in 16 participants it was positive in 9 (56.2%). Nine participants were tested for anti-double stranded DNA test and 5 (55.6%) were positive for this test. C-reactive protein was tested in 46 participants out of which 32 (69.6%) had elevated levels. HIV was tested in 24 (46.2%) participants and results were negative. Thirty-five out of 52 (67.3%) participants had anaemia. Predominant drugs used for treatment of JIA include prednisolone and methotrexate.ConclusionsPaediatric rheumatic disorders are not uncommon in Tanzania-and were noted to affect more female children in this study. Predominant conditions included juvenile idiopathic arthritis (JIA), juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM).

Patient factors associated with waiting time to pediatric rheumatologist consultation for patients with juvenile idiopathic arthritis

BackgroundEarly diagnosis and treatment of Juvenile Idiopathic Arthritis (JIA) is essential to optimize outcomes. Wait times (WTs) to consultation with a pediatric rheumatologist consultation is a Canadian quality measure, with benchmarks set at 7 days for systemic JIA (sJIA) and 4 weeks for other JIA categories. In this study we assess WTs for JIA at a single academic center and describe factors associated with longer WTs.MethodsThis was a retrospective cohort study of 164 patients enrolled in a pharmacogenetic study in Alberta between 2002 and 2018. Limited chart reviews were conducted to evaluate dates of referral and first rheumatology visit to calculate WTs for receipt of pediatric rheumatology care. Cox proportional hazard models identified factors associated with WTs considering variables at the first pediatric rheumatology visit including: JIA category, age, sex, distance to the pediatric rheumatology clinic, number of active joints, pain and C-reactive protein.ResultsThe median age at diagnosis was 8.0 years (interquartile range, IQR 3.5, 12.0) and 46% of patients had oligoarticular JIA. Only 18 patients (11%) were from rural locations. The median WT for all patients met the national benchmark (22 days, IQR, 9, 44) with no statistically significant difference between WTs among JIA categories (p = 0.055). Importantly, the majority of sJIA cases met the 7-day benchmark (67%) with a median WT of 1.5 days. Older age was associated with longer WT (HR 0.94, 95% CI 0.89, 0.98, p = 0.005).ConclusionMedian benchmarks were met, however delays in older patients highlight the need for monitoring WTs.

Association of Circulating COMP and YKL-40 as Markers of Metabolic Changes of Cartilage with Adipocytokines in Juvenile Idiopathic Arthritis.

The aim of this study was to evaluate the association of circulating cartilage oligomeric matrix protein (COMP) and human cartilage glycoprotein-39 (YKL-40) as markers of metabolic changes of cartilage, with leptin, adiponectin, and resistin in juvenile idiopathic arthritis (JIA) patients before and after treatment. A significant decrease of COMP and an increase of YKL-4 were found in blood of untreated patients. JIA treatment leading to clinical improvement resulted in normalization of COMP levels only. Concentrations of both markers in treated patients, while showing no clinical improvement, differed from those in controls and patients with remission. The leptin level decreased (p < 0.05) in untreated patients; however, concentrations of adiponectin and resistin increased (p < 0.05) as compared to controls. JIA treatment resulted in normalization of adipocytokine levels in remissive patients but not those with active JIA. Untreated patients showed a correlation between COMP and leptin, adiponectin, and body mass index (BMI) and between YKL-40 and leptin, adiponectin, BMI, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). In inactive JIA, a correlation between YKL-40 and leptin was shown. Treated patients with an active JIA demonstrated a correlation between COMP and adiponectin and between YKL-40 and leptin, adiponectin, BMI, CRP, and ESR. The results of this work indicate that leptin and adiponectin but not resistin may be involved in the development and progression of joint dysfunction in JIA. Additionally, we suggest that YKL-40 may be a useful biomarker of disease activity and may be used to assess treatment towards remission, as compared to COMP.

Pharmacological conditioning for juvenile idiopathic arthritis: a potential solution to reduce methotrexate intolerance

BackgroundMethotrexate (MTX) therapy has proven to be a successful and safe treatment for Juvenile Idiopathic Arthritis (JIA). Despite the high efficacy rates of MTX, treatment outcomes are often complicated by burdensome gastro-intestinal side effects. Intolerance rates for MTX in children are high (approximately 50%) and thus far no conclusive effective treatment strategies to control for side effects have been found. To address this need, this article proposes an innovative research approach based on pharmacological conditioning, to reduce MTX intolerance.Presentation of the hypothesisA collaboration between medical psychologists, pediatric rheumatologists, pharmacologists and patient groups was set up to develop an innovative research design that may be implemented to study potential improved control of side effects in JIA, by making use of the psychobiological principles of pharmacological conditioning. In pharmacological conditioning designs, learned positive associations from drug therapies (conditioning effects) are integrated in regular treatment regimens to maximize treatment outcomes. Medication regimens with immunosuppressant drugs that made use of pharmacological conditioning principles have been shown to lead to optimized therapeutic effects with reduced drug dosing, which might ultimately cause a reduction in side effects.Testing the hypothesisThis research design is tailored to serve the needs of the JIA patient group. We developed a research design in collaboration with an interdisciplinary research group consisting of patient representatives, pediatric rheumatologists, pharmacologists, and medical psychologists.Implications of the hypothesisBased on previous experimental and clinical findings of pharmacological conditioning with immune responses, we propose that the JIA patient group is particularly suited to benefit from a pharmacological conditioning design. Moreover, findings from this study may potentially also be promising for other patient groups that endure long-lasting drug therapies.

Biological disease-modifying antirheumatic drugs in juvenile idiopathic arthritis of polyarticular course, enthesitis-related arthritis, and psoriatic arthritis: a consensus statement.

Juvenile idiopathic arthritis (JIA) is the most common type of inflammatory arthritis in children. Treatment options have been expanded since the introduction of biologics, which are highly effective. The existing local JIA treatment guideline was published more than a decade ago, when use of biologics was not as common. In this article, we review the latest evidence on using biologics in three JIA subtypes: JIA of polyarticular course (pcJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA). Based on the latest information, an update on eligibility, response assessment, termination, and safety information for using biologics in these patients was performed. The JIA Work Group, which consisted of nine paediatricians experienced in managing JIA, was convened in 2016. Publications before July 2017 were screened. Eligible articles were clinical trials, extension studies, systemic reviews, and recommendations from international societies and regulatory agencies about the use of biologics in pcJIA, ERA, and PsA. Evidence extraction, appraisal, and drafting of propositions were performed by two reviewers. Extracted evidence and drafted propositions were presented and discussed at the first two meetings. Overwhelming consensus was obtained at the final meeting in May 2018. Seven practice consensus statements were formulated. Regular review should be performed to keep the practice evidence-based and up-to-date.

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.

Biologic Therapies in Polyarticular Juvenile Idiopathic Arthritis. Comparison of Long‐Term Safety Data from the German BIKER Registry

ObjectiveBiologics have an important role in the treatment of juvenile idiopathic arthritis (JIA). Long‐term safety data are limited. Direct comparison of different agents regarding occurrence of adverse events (AEs), especially of rare events, requires large quantities of patient years. In this analysis, long‐term safety with regard to AE of special interest (AESI) was compared between different biologics.MethodsPatients with nonsystemic JIA were selected from the German BIKER registry. Safety assessments were based on AE reports. Number of AEs, serious AEs, and 25 predefined AESIs, including medically important infection, uveitis, inflammatory bowel disease, cytopenia, hepatic events, anaphylaxis, depression, pregnancy, malignancy, and death, were analyzed. Event rates and relative risks were calculated using AEs reported after first dose through 70 days after last dose.ResultsA total of 3873 patients entered the analysis with 7467 years of exposure to biologics. The most common AESIs were uveitis (n = 231) and medically important infections (n = 101). Cytopenia and elevation of transaminases were more frequent with tocilizumab (risk ratio [RR] 8.0, 95% confidence interval [CI] 4.2‐15, and RR 4.7, 95% CI 1.8‐12.2, respectively). Anaphylactic events were associated with intravenous route of administration. In patients ever exposed to biologics, eight malignancies were reported. Six pregnancies have been documented in patients with tumor necrosis factor inhibitors. No death occurred in this patient cohort during observation.ConclusionSurveillance of pharmacotherapy as provided by the BIKER registry is an import approach, especially for long‐term treatment of children. Overall, tolerance was acceptable. Differences between biologics were noted and should be considered in daily patient care.

Proceedings From the Clinical and Scientific Innovations in Oral and Maxillofacial Surgery Conference 2019

Proceedings From the Clinical and Scientific Innovations in Oral and Maxillofacial Surgery Conference 2019

The feasibility of developing biomarkers from peripheral blood mononuclear cell RNAseq data in children with juvenile idiopathic arthritis using machine learning approaches

BackgroundThe response to treatment for juvenile idiopathic arthritis (JIA) can be staged using clinical features. However, objective laboratory biomarkers of remission are still lacking. In this study, we used machine learning to predict JIA activity from transcriptomes from peripheral blood mononuclear cells (PBMCs). We included samples from children with Native American ancestry to determine whether the model maintained validity in an ethnically heterogeneous population.MethodsOur dataset consisted of 50 samples, 23 from children in remission and 27 from children with an active disease on therapy. Nine of these samples were from children with mixed European/Native American ancestry. We used 4 different machine learning methods to create predictive models in 2 populations: the whole dataset and then the samples from children with exclusively European ancestry.ResultsIn both populations, models were able to predict JIA status well, with training accuracies > 74% and testing accuracies > 78%. Performance was better in the whole dataset model. We note a high degree of overlap between genes identified in both populations. Using ingenuity pathway analysis, genes from the whole dataset associated with cell-to-cell signaling and interactions, cell morphology, organismal injury and abnormalities, and protein synthesis.ConclusionsThis study demonstrates it is feasible to use machine learning in conjunction with RNA sequencing of PBMCs to predict JIA stage. Thus, developing objective biomarkers from easy to obtain clinical samples remains an achievable goal.