Treatment Of Juvenile Idiopathic Arthritis Research Articles

New Diagnoses of Juvenile Idiopathic Arthritis Early in the COVID-19 Pandemic

Background/Objective Little is known about the rates of rheumatic disease diagnosis among children during the COVID-19 pandemic. We examined the impact of the pandemic on the diagnosis of juvenile idiopathic arthritis (JIA) in the United States. Methods We performed a historical cohort study using US commercial insurance data (2016–2021) to identify children aged <18 years without prior JIA diagnosis or treatment in the prior ≥12 months. New JIA diagnoses were identified using a combination of ICD-10-CM diagnosis codes, location, and timing of medical services. Crude rates with 95% confidence intervals (CIs) of JIA diagnosis per 100,000 enrolled children per quarter were estimated and stratified by age group, sex, region, JIA type, and uveitis. The incidence rate ratio (95% CI) for JIA diagnosis was estimated using Poisson regression, adjusted for various demographic variables. Results From 2018–2021, 643 children were diagnosed with JIA. Crude new JIA diagnoses per 100,000 children per quarter dropped from 2.62 (95% CI, 2.39–2.87) prepandemic to 1.94 (95% CI, 1.66–2.25) during the pandemic. Declines in JIA diagnosis were more apparent in the US Northeast and West regions and among children aged 6–11 years. After adjustment for covariates, JIA diagnoses fell by 30% during the pandemic compared with the prior 3 years (IRR, 0.70; 95% CI, 0.59–0.83). Conclusions Compared with the prepandemic period, JIA was diagnosed 30% less often during the early pandemic among commercially insured children in the United States. More research is needed to understand the underlying reasons for these changes in JIA diagnosis and more recent trends.

Transcriptional Profiling of Tofacitinib Treatment in Juvenile Idiopathic Arthritis: Implications for Treatment Response Prediction.

To assess changes in gene expression following tofacitinib treatment and investigate transcription patterns as potential predictors of treatment response in patients with active juvenile idiopathic arthritis (JIA). Whole blood samples were collected from JIA patients at baseline and after 18 weeks of open-label tofacitinib treatment (clinical trial NCT02592434). Patients who achieved a JIA-American College of Rheumatology (ACR) response of 70 or above at week 18 were classified as treatment-responders (TR) while those with at most a JIA-ACR30 response were classified as poor-responders (PR). Differential gene expression and gene ontology (GO) over-representation analyses were performed to compare RNA expression between week 18 and baseline samples, as well as between PR and TR samples at baseline. Samples from 67 patients at baseline and 60 at week 18 were analyzed. Following 18 weeks of tofacitinib treatment across all JIA subjects, 883 genes showed significant differential expression (week 18 - baseline). The most strongly downregulated genes were over-represented within IL-7, type I, and type II interferon pathways, while upregulated genes were enriched in ontologies related to neuronal cell processes and cell signaling. Comparing PR and TR at baseline, 663 genes showed differential expression. Upregulated genes were over-represented within ontologies including activation of MAPK activity (p=9.40x10-5), myeloid cell development (p=8.13 x10-5), activation of GTPase activity (p=0.00015), and organelle transport along microtubules (p=0.00021). Tofacitinib treatment in JIA downregulated genes in interferon and IL-7 signaling pathways regardless of effectiveness. Furthermore, baseline upregulation of MAPK signaling may predict poor response to tofacitinib treatment in JIA.

Extrapolation of Upadacitinib Efficacy in Juvenile Idiopathic Arthritis Leveraging Pharmacokinetics, Exposure-Response Models, and Real-World Patient Data.

Juvenile idiopathic arthritis (JIA) is the most prevalent pediatric rheumatic disease. While disease-modifying antirheumatic drugs (DMARDs), especially biologics, have greatly transformed the management of JIA, there remain some unmet medical needs that require new treatment options. The objective of this work was to describe and apply a modeling and simulation approach to extrapolate upadacitinib efficacy from the adult diseases, rheumatoid arthritis (RA) and psoriatic arthritis (PsA), to their respective pediatric diseases, polyarticular course JIA (pcJIA), and juvenile PsA (JPsA). A population pharmacokinetic model characterized upadacitinib pharmacokinetics in pediatric patients using data from two phase I studies in pediatric patients with pcJIA (N = 51) or atopic dermatitis (N = 33). Efficacy simulations were conducted using previously developed exposure-response models in adults with RA and PsA. Real-world pcJIA and JPsA patient databases were leveraged to construct representative patient profiles for the targeted population. Following administration of the proposed weight-based dosing regimen, the model-predicted median upadacitinib plasma exposures in pediatric patients were within 20% of those in adult RA and PsA patients receiving the approved adult regimen. Simulations demonstrate that upadacitinib efficacy in pcJIA and JPsA is predicted to be non-inferior to that in adults with RA or PsA, respectively. The results of this work enabled recent approvals of upadacitinib for the treatment of polyarticular JIA and JPsA in the United States. Upadacitinib safety in pediatrics is being further evaluated in ongoing clinical trials.

Identification of Plasma Metabolomic Biomarkers of Juvenile Idiopathic Arthritis.

Identification of disease and therapeutic biomarkers remains a significant challenge in the early diagnosis and effective treatment of juvenile idiopathic arthritis (JIA). In this study, plasma metabolomic profiling was conducted to identify disease-related metabolic biomarkers associated with JIA. Plasma samples from treatment-naïve JIA patients and non-JIA reference patients underwent global metabolomic profiling across discovery (60 JIA, 60 non-JIA) and replication (49 JIA, 38 non-JIA) cohorts. Univariate analysis identified significant metabolites (q-value ≤ 0.05), followed by enrichment analysis using ChemRICH and metabolic network mapping with MetaMapp and Cytoscape. Receiver operating characteristic (ROC) analysis determined the top discriminating biomarkers based on area under the curve (AUC) values. A total of over 800 metabolites were measured, consisting of 714 known and 155 unknown compounds. In the discovery cohort, 587 metabolites were significantly altered in JIA patients compared with the reference population (q < 0.05). In the replication cohort, 288 metabolites were significantly altered, with 78 overlapping metabolites demonstrating the same directional change in both cohorts. JIA was associated with a notable increase in plasma levels of sphingosine metabolites and fatty acid ethanolamides and decreased plasma levels of sarcosine, iminodiacetate, and the unknown metabolite X-12462. Chemical enrichment analysis identified cycloparaffins in the form of naproxen and its metabolites, unsaturated lysophospholipids, saturated phosphatidylcholines, sphingomyelins, ethanolamines, and saturated ceramides as the top discriminating biochemical clusters. ROC curve analysis identified 11 metabolites classified as highly discriminatory based on an AUC > 0.90, with the top discriminating metabolite being sphinganine-1-phosphate (AUC = 0.98). This study identifies specific metabolic changes in JIA, particularly within sphingosine metabolism, through both discovery and replication cohorts. Plasma metabolomic profiling shows promise in pinpointing JIA-specific biomarkers, differentiating them from those in healthy controls and Crohn's disease, which may improve diagnosis and treatment.

Summary of Research: Ten-Year Safety and Clinical Benefit from Open-Label Etanercept Treatment in Children and Young Adults with Juvenile Idiopathic Arthritis.

This is a summary of the original article 'Ten-year safety and clinical benefit from open label etanercept treatment in children and young adults with juvenile idiopathic arthritis'. Juvenile idiopathic arthritis (JIA) usually appears before the age of 16. JIA causes pain, swelling, and stiffness in the joints. People with JIA receive treatment for several years until the disease goes into prolonged remission. Therefore, the long-term safety of these treatments is an important topic. Etanercept is a treatment for JIA, which acts on the body's immune system to reduce arthritis. This summary of research article describes safety and how well etanercept works in children with JIA taking it for up to 10years.

Intravenous Golimumab in the Treatment of Juvenile Idiopathic Arthritis and Its Associated Uveitis

ABSTRACT Purpose To demonstrate the efficacy and safety of intravenous golimumab infusion in treating juvenile idiopathic arthritis-associated anterior uveitis. Methods This study was a retrospective observation case series. Electronic records of patients diagnosed with juvenile idiopathic arthritis-associated anterior uveitis who received intravenous golimumab infusion were examined. Results A total of 24 eyes of 13 patients were included in this study. During 12 months before starting intravenous golimumab, the median grade of anterior chamber reaction was 1 (range: 0.5–3), and the median number of flare-ups was 1 (1–3). During 12 months following the start of intravenous golimumab, the median grade of anterior chamber reaction was 0 (range: 0–1), and the median number of flare-ups was 0 (range: 0–1). Before starting intravenous golimumab, the average number of immunomodulatory agents was 2.6 ± 1.0 with a range of 2 to 5. The average age of patients at the time of starting intravenous golimumab was 13.69 ± 5.23 years (range between 5 and 22). A total of 11 (84.6%) patients responded to intravenous golimumab. The medication was discontinued in one patient due to ineffectiveness and in another patient due to the development of psoriasis as an adverse effect. Cystoid macular edema was present in six eyes of three patients which resolved in all six eyes after starting intravenous golimumab. Conclusion Intravenous golimumab proves to be efficacious and safe for inducing and sustaining remission in JIA and JIA-associated uveitis. Nonetheless, further robust studies with larger sample sizes are needed to substantiate our findings.

Overview of the Treatment Goal, the Method of Evaluating Disease Activity/Physical Function, Activities of Daily Living, and Traditional Care for Systemic or Articular Juvenile Idiopathic Arthritis in Japan.

Juvenile idiopathic arthritis (JIA) is a chronic arthritis of unknown cause that develops in patients younger than 16 years of age and persists for at least 6 weeks. It is an important cause of short- and long-term physical and mental impairments in children. The goal of treatment for JIA is remission. A T2T (treatment-to-target) has been proposed and practiced as a means of achieving remission. The method of evaluating the disease activity of JIA depends on the disease type. For systemic JIA, disease activity is determined by comprehensively considering joint findings, systemic inflammatory findings, changes in inflammatory and synovitis markers, imaging findings, and other factors. For articular JIA other than systemic JIA, the Juvenile Arthritis Disease Activity Score (JADAS-27) is used to evaluate disease activity. The CHAQ (Childhood Health Assessment Questionnaire) and the Japanese version of the modified Rankin Scale (mRS) are mainly used to assess the physical function and ADL. The CHAQ is a global standard assessment method with the advantage that it can be transitioned to the HAQ used in adults, making it useful for international comparisons. The mRS is used to classify the severity of JIA as a chronic disease, and is an indispensable evaluation method in the specific disease procedure in Japan. It is necessary to have pediatric-specific knowledge of growth and development and routine childhood immunizations and to consider transition support tailored to the patient's situation. Ultimately, the goal is to foster the patient's independence and to provide an uninterrupted follow-up in the adult care department. Continuous follow-up will be provided during the schooling (and later, employment) period, and the relationship with the patient will be tailored to their developmental stage. It is also important to understand and communicate the importance of contraception and the drugs that cannot be used during pregnancy.

Glutathione S-Transferase Gene Polymorphisms as Predictors of Methotrexate Efficacy in Juvenile Idiopathic Arthritis.

Because of the unpredictable efficacy of methotrexate (MTX) in the treatment of juvenile idiopathic arthritis (JIA), the possibility of a favourable outcome is reduced in more than 30% of patients. To investigate the possible influence of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) gene deletion polymorphisms on MTX efficacy in patients with JIA, we determined these polymorphisms in 63 patients with JIA who did not achieve remission and 46 patients with JIA who achieved remission during MTX therapy. No significant differences were observed in the distribution of single GSTM1 or GSTT1 deletion polymorphisms or their combination between the two groups: 58.7% to 63.5%; p = 0.567, 17.4% to 22.2%; p = 0.502, and 13% to 12.7%; p = 0.966, respectively. Our results suggest that GSTM1 and GSTT1 deletion polymorphisms do not influence the efficacy of MTX in patients with JIA. Additional studies are required to determine the possible influence of GST deletion polymorphisms on MTX efficacy in patients with JIA.

Methotrexate Intolerance in Juvenile Idiopathic Arthritis: Definition, Risks, and Management.

Juvenile idiopathic arthritis is the most common rheumatic disorder in childhood and adolescence posing a significant threat of short-term and long-term disability if left untreated. Methotrexate is a folic acid analog with various immunomodulatory properties. It has demonstrated significant efficacy for the treatment of juvenile idiopathic arthritis, often considered the preferred first-line disease-modifying anti-rheumatic drug given as monotherapy or in combination with biological drugs. Despite this, there is a considerable risk for treatment disruptions owing to the high prevalence of methotrexate intolerance, with symptoms such as nausea, stomach ache, vomiting, and behavioral symptoms. Many different risk factors for the intolerance have been proposed including gender, age, disease activity, treatment duration, dosing and administration, and genetic and psychological factors. As the studies have shown contradictory results, many questions are left unanswered. Therefore, a consensus regarding outcome measures and reporting is crucial. In this review, we describe the identification and assessment of methotrexate intolerance and evaluate potential risk factors, genetic associations as well as management strategies.

Markers associated with the development of osteoporosis in children with juvenile idiopathic arthritis

Background. The purpose of the study was to investigate the association between bone mineralization le­vel in children with juvenile idiopathic arthritis (JIA) and various exogenous and endogenous factors. Materials and ­me­thods. The study group consisted of 162 children diagnosed with JIA. Medical history, clinical features, and treatment of JIA were studied. Disease activity was evaluated using the Juvenile Arthritis Disease Activity Score (JADAS-27), health status — with the Childhood Health Assessment Questionnaire (CHAQ). Complete blood count with erythrocyte sedimentation rate, biochemical analysis (C-reactive protein, total and ionized calcium) were performed, and instrumental methods (ultrasound densitometry, X-ray and ultrasound examination of joints) were used. Serum levels of osteocalcin, 25-hydroxyvitamin D (25(OH)D), and parathyroid hormone were evaluated using an enzyme-linked immunosorbent assay on an ER500 analyzer (Sinnowa, China). Results. According to our study, osteoporosis was observed in 19 patients (11 girls and 8 boys) out of 162 children with JIA, accounting for 11.7 %. It was significantly more frequent in patients with polyarthritis (73.7 %) compared to those with oligoarthritis (26.3 %) (p &lt; 0.05). Conclusions. Osteoporosis can develop in children with JIA who do not receive systemic glucocorticoid therapy. The main markers associated with osteoporosis in children with JIA include non-infectious disease onset trigger, cervical joint involvement at disease onset, involvement of more than 3 joint groups at onset, gait disturbances, high JADAS-27 and CHAQ scores, signs of systemic inflammatory process, including elevated erythrocyte sedimentation rate.

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

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

Validation of new medication use algorithms as proxies for worsening disease activity in patients with juvenile idiopathic arthritis.

To facilitate claims-based research on populations with juvenile idiopathic arthritis (JIA), we sought to validate an algorithm of new medication use as a proxy for worsening JIA disease activity. Using electronic health record data from three pediatric centers, we defined new JIA medication use as (re)initiation of disease-modifying antirheumatic drugs or glucocorticoids (oral or intra-articular). Data were collected from 201 randomly selected subjects with (101) or without (100) new medication use. We assessed the positive predictive value (PPV) and negative predictive value (NPV) based on a reference standard of documented worsening of JIA disease activity. The algorithm was refined to optimize test characteristics. Overall, the medication-based algorithm had suboptimal performance in representing worsening JIA disease activity (PPV 69.3%, NPV 77.1%). However, algorithm performance improved for definitions specifying longer times after JIA diagnosis (≥1-year post-diagnosis: PPV 82.9%, NPV 80.0%) or after initiation of prior JIA treatment (≥1-year post-treatment: PPV 89.7%, NPV 80.0%). An algorithm for new JIA medication use appears to be a reasonable proxy for worsening JIA disease activity, particularly when specifying new use ≥1 year since initiating a prior JIA medication. This algorithm will be valuable for conducting research on JIA populations within administrative claims databases.

Evaluation of medication withdrawal in patients with non-systemic juvenile idiopathic arthritis in Japan using a web-based survey.

Although treatments for juvenile idiopathic arthritis (JIA) have seen considerable advancements, there remains a lack of clear guidelines on withdrawing medications. This study aimed to investigate the current strategies for discontinuing non-systemic JIA treatment. A web-based questionnaire was distributed to members of the Pediatric Rheumatology Association of Japan. According to 126 responses, the most significant factors influencing JIA treatment tapering were the duration of clinically inactive disease, medication toxicity, and a history of arthritis flares. Respondents were often cautious about discontinuing medication if symptoms, e.g. 'morning stiffness' or 'intermittent joint pain', persisted. Among subtypes, oligoarticular JIA was more amenable to treatment tapering, whereas rheumatoid factor-positive polyarticular JIA proved less amenable. Most respondents started medication tapering after a continuous clinical inactive duration exceeding 12 months, and >50% of them required >6 months to achieve treatment discontinuation. Additionally, 40% of the respondents consistently underwent imaging before treatment tapering. The relative risks of treatment continuation and withdrawal should be considered, and decisions should be made accordingly. To obtain improved understanding of and more robust evidence for the optimal strategies for safely discontinuing JIA treatment, it is crucial to continue investigations including long-term outcomes.

Safety and efficacy of biologic immunosuppressive treatment in juvenile idiopathic arthritis associated with inborn errors of immunity.

This study aims to describe clinical features, therapeutic outcomes, and safety profiles in patients affected by juvenile idiopathic arthritis (JIA) and inborn errors of immunity (IEI) treated with biological Disease-modifying antirheumatic drugs (DMARDs). We enrolled three patients who were followed in the Pediatric Rheumatology Unit at Meyer Children's Hospital in Florence; these patients were affected by JIA, according to ILAR criteria, and IEI, according to the IUIS Phenotypical Classification for Human Inborn Errors of Immunity. Among them, two patients had 22q11.2 deletion syndrome (22q11.2DS) and one patient had X-linked agammaglobulinemia (XLA). Case 1: A 6-year and 2-month-old boy was affected by 22q11.2DS, associated with oligoarticular JIA, at the age of 2 years. He was treated with non-steroidal anti-inflammatory drugs (NSAIDs) and methotrexate, along with oral glucocorticoids but with no benefits. Treatment with etanercept allowed him to achieve remission after 10 months. Case 2: A 6-year and 2-month-old girl was affected by 22q11.2DS, associated with oligoarticular JIA, at the age of 3 years and 11 months. She was treated with NSAIDs, joint injections, and methotrexate but without clinical response. Treatment with Adalimumab allowed her to achieve remission after 6 months. Case 3: A 12-year and 2-month-old boy was affected by XLA, associated with polyarticular JIA, at the age of 9 years and 11 months. He was treated with NSAIDs, methotrexate, joint injections, and oral glucocorticoids with no benefits. He failed to respond to anti-TNF-alpha, tocilizumab, and abatacept. Currently, he is undergoing therapy with sirolimus plus abatacept, which allowed him to achieve remission after 4 months. Results suggest that the use of immunosuppressive biological therapies can control disease activity in these patients. No adverse drug-related reactions were observed during the follow-up.

Treatment of non-systemic juvenile idiopathic arthritis.

In the past two decades, the treatment of juvenile idiopathic arthritis (JIA) has evolved markedly, owing to the availability of a growing number of novel, potent and relatively safe therapeutic agents and the shift of management strategies towards early achievement of disease remission. However, JIA encompasses a heterogeneous group of diseases that require distinct treatment approaches. Furthermore, some old drugs, such as methotrexate, sulfasalazine and intraarticular glucocorticoids, still maintain an important therapeutic role. In the past 5 years, information on the efficacy and safety of drug therapies for JIA has been further enriched through the accomplishment of several randomized controlled trials of newer biologic and synthetic targeted DMARDs. In addition, a more rational therapeutic approach has been fostered by the promulgation of therapeutic recommendations and guidelines. A multinational collaborative effort has led to the development of the recommendations for the treat-to-target strategy in JIA. There is currently increasing interest in establishing the optimal time and modality for discontinuation of treatment in children with JIA who achieve sustained clinical remission. The aim of this Review is to summarize the current evidence and discuss the therapeutic approaches to the management of non-systemic phenotypes of JIA, including oligoarthritis, polyarthritis, enthesitis-related arthritis and psoriatic arthritis.

Algorithm for Growth Evaluation in Juvenile Idiopathic Arthritis.

Juvenile Idiopathic Arthritis (JIA) includes a range of inflammatory conditions that exhibit chronic arthritis with various clinical presentations. The disease's heterogeneity leads to different impacts on children's health, both short and long-term. Compromised growth, seen as growth retardation and delayed puberty, is a common complication in children with JIA, severely impacting their quality of life. This impairment is linked to disease duration and activity, with severe cases in systemic and polyarticular subtypes. Literature reports growth retardation incidence from 8% to 41%, but data on pubertal impairment is lacking. Growth in children is influenced by systemic and local mechanisms. Chronic inflammation, prolonged glucocorticosteroid (GCS) use, and nutritional issues contribute to growth stunting and pubertal delays. Chronic inflammation in JIA flattens growth curves, while steroid treatment impairs growth and causes weight gain. Disruption of the GH/IGF1 axis is known, but data on systemic hormonal resistance in JIA are insufficient. Optimizing JIA treatment, including biological therapies, is expected to improve growth velocity and reduce long-term impacts by better disease control and reduced GCS doses. Thyroid function also influences growth and puberty, but comprehensive studies on thyroid involvement in JIA are lacking. Given the early onset of chronic inflammatory consequences, preventive auxological screening measures are necessary for children with JIA. Early detection of developmental disorders can enhance therapeutic management. This article summarizes information from a cohort study on growth in children with JIA and proposes a diagnostic algorithm for clinical use.

Specific Features of Juvenile Idiopathic Arthritis Patients' Cytokine Profile.

Juvenile idiopathic arthritis (JIA) is a systemic autoimmune disease that affects the joints, leading to disability. Cytokines and signaling molecules expressed by the immune system cells play a key role in JIA pathogenesis. Understanding how their content changes during pathology development can open up new opportunities for its diagnosis and treatment. The blood plasma of 30 patients with JIA (14 males and 16 females with a mean age of 12.2 ± 4.1) and 20 relatively healthy individuals (10 males and 10 females with a mean age of 10.20 ± 5.85) was analyzed to determine the levels of cytokines using the MILLIPLEX® kit. An increase in interleukins (IL)-1α, 1β, 2, 4, 5, 6, 7, 8, 9, 10, 13, 15, 17F, 22, and 27 and a decrease in IL-3 levels have been shown in patients with JIA. Levels of cytokines, which are important for B-cell activation and proliferation, are increased, while levels of T-cell activating factors remained similar to the control group. Based on our results, it can be assumed that the use of combination therapy aimed at inhibiting both nonspecific interleukins and cytokines that activate B-cells will be more effective for the treatment of JIA.

Towards stratified treatment of JIA: machine learning identifies subtypes in response to methotrexate from four UK cohorts

Methotrexate (MTX) is the gold-standard first-line disease-modifying anti-rheumatic drug for juvenile idiopathic arthritis (JIA), despite only being either effective or tolerated in half of children and young people (CYP). To facilitate stratified treatment of early JIA, novel methods in machine learning were used to i) identify clusters with distinct disease patterns following MTX initiation; ii) predict cluster membership; and iii) compare clusters to existing treatment response measures. Discovery and verification cohorts included CYP who first initiated MTX before January 2018 in one of four UK multicentre prospective cohorts of JIA within the CLUSTER consortium. JADAS components (active joint count, physician (PGA) and parental (PGE) global assessments, ESR) were recorded at MTX start and over the following year. Clusters of MTX 'response' were uncovered using multivariate group-based trajectory modelling separately in discovery and verification cohorts. Clusters were compared descriptively to ACR Pedi 30/90 scores, and multivariate logistic regression models predicted cluster-group assignment. The discovery cohorts included 657 CYP and verification cohorts 1241 CYP. Six clusters were identified: Fast improvers (11%), Slow Improvers (16%), Improve-Relapse (7%), Persistent Disease (44%), Persistent PGA (8%) and Persistent PGE (13%), the latter two characterised by improvement in all features except one. Factors associated with clusters included ethnicity, ILAR category, age, PGE, and ESR scores at MTX start, with predictive model area under the curve values of 0.65-0.71. Singular ACR Pedi 30/90 scores at 6 and 12 months could not capture speeds of improvement, relapsing courses or diverging disease patterns. Six distinct patterns following initiation of MTX have been identified using methods in artificial intelligence. These clusters demonstrate the limitations in traditional yes/no treatment response assessment (e.g., ACRPedi30) and can form the basis of a stratified medicine programme in early JIA. Medical Research Council, Versus Arthritis, Great Ormond Street Hospital Children's Charity, Olivia's Vision, and the National Institute for Health Research.

Безопасность долгосрочного применения ритуксимаба у пациентов с ювенильным идиопатическим артритом: результаты когортного ретроспективного исследования

Juvenile idiopathic arthritis (JIA) is the most frequent rheumatic disease of childhood. The goal of juvenile arthritis therapy is to achieve durable clinical and laboratory remission and a good quality of life. Various groups of drugs are used in the treatment of JIA, one of which is the anti-CD20 drug rituximab. Rituximab causes B-cell depletion, which may lead to decreased immunoglobulin levels, decreased antigen-presenting function of B-lymphocytes and impaired T-cell response. The main side effects of rituximab administration are infusion reactions, hypogammaglobulinaemia, neutropenia and infectious complications. Safety studies of rituximab use have been conducted mainly in adult patients with rheumatoid arthritis, in paediatric patients with oncological diseases and diffuse connective tissue diseases. There have been no long-term safety studies of rituximab in children with JIA. Objective. To evaluate the safety of long-term use of rituximab in patients with juvenile idiopathic arthritis. Patients and methods. A cohort retrospective study of patients with JIA aged from 2 to 17 years with evaluation of adverse events on the background of rituximab therapy was carried out; the maximum duration of follow-up was 165 months. Rituximab was administered by intravenous drip at a dose of 375 mg/m2 body surface area by 4 weekly injections (61% of all courses given) or 2 injections of 1000 mg 2 weeks apart (29%). 4% had 1 administration per course; 6% had 3 consecutive weekly administrations. The indication for repeat rituximab administration and the number of administrations were determined on an individual basis. Safety was assessed by registration of adverse events (AEs) according to medical records; AEs registered during the patient's hospitalisation and anamnestic data on AEs during the interhospital period were taken into account; infectious, infusion and other AEs were considered separately. Results. Rituximab demonstrated a sufficiently high safety profile: 88/102 (86%) patients did not report any serious AEs (grade ≥3); life-threatening AEs (grade 4-5) were reported in 7/102 (7%) patients, included 4 episodes of severe pneumonia, 3 episodes of sepsis; their incidence was 2.5 cases per 100 PY. The incidence of infectious AEs was 57.4/100 patient-years; 85% of them corresponded to mild severity; most often infectious AEs were registered in the first year of rituximab therapy; pneumonia (16/100 PY) and ENT infections (11.3/100 PY) prevailed in the structure. Infusion reactions developed with an incidence of 34.8/100 PY, most frequently registered at the first rituximab administration and manifested as influenza-like syndrome (18.4/100 PY) and rash (10.3/100 PY). The incidence of neutropenia was 17/100 PY, erythropenia 0.7/100 patient-years; decreased blood immunoglobulin levels (IgA – 5.3 episodes, IgM – 6.7, IgG – 3.4/100 patient-years), increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity – 3.9/100 PY, 1 episode of increased serum urea levels. Conclusion. The use of rituximab in patients with JIA may be accompanied by the development of AEs, which include infusion reactions, infectious complications, cytopenias, decreased level of immunoglobulins in blood, increased activity of ALT and AST. Implementation of the algorithm for the management of patients with JIA under rituximab treatment into clinical practice will allow to ensure monitoring of AEs, their detection at early stages, timely initiation of adequate therapy to prevent the development of severe complications. Key words: juvenile idiopathic arthritis, safety of therapy, rituximab, adverse events, infusion reactions, infectious complications

ВЛИЯНИЕ ПРИМЕНЕНИЯ МЕТОТРЕКСАТА НА СОСТОЯНИЕ МИЕЛОПОЭЗА И ТРОМБОЦИТОПОЭЗА У ДЕТЕЙ С ИДИОПАТИЧЕСКИМ АРТРИТОМ

Methotrexate is the mainstay drug in the treatment of juvenile idiopathic arthritis (JIA). The effect of methotrexate on the hematopoietic system manifests itself in the form of its inhibition, contributing to the development of aplastic anemia, leukopenia, neutropenia and thrombocytopenia. The purpose of the study was to study the effect of methotrexate on the state of the leukocyte and megakaryocyte pool of cells in patients with JIA. Material and methods. The study was carried out on the basis of the 2nd City Children's Clinical Hospital in Minsk. A study of the state of hematopoiesis was carried out in 82 children with JIA who received only methotrexate. The comparison group consisted of 40 patients who were diagnosed with JIA and had a complete blood count performed before starting methotrexate therapy. Results. Statistically significant differences were identified in both the megakaryocyte and leukocyte series. Against the background of an increase in the number of platelets before the start of basic therapy, there was a decrease in the average volume of platelets (p&lt;0.01) and, accordingly, the distribution of platelets by volume (p&lt;0.001). Changes in the white blood cell count (WBC) were manifested in a gradual decrease in the number of leukocytes during long-term use of methotrexate (p &lt; 0.001). Conclusion. The use of methotrexate in patients with JIA contributes to a significant decrease in the content of platelets, leukocytes, neutrophils, lymphocytes, and monocytes, which is due to the relief of the inflammatory process. The duration of methotrexate administration did not affect the content of lymphocytes and basophils.