Эволюция лекарственной терапии системного ювенильного идиопатического артрита

BackgroundTreatment of juvenile idiopathic arthritis (JIA) has changed dramatically since the introduction of biological agents in 1999.ObjectiveTo evaluate trends in prescription patterns of biological agents and the subsequent outcome of...

Systemic juvenile idiopathic arthritis is a rare febrile arthritis of childhood characterized by a potentially severe course, including prolonged glucocorticoid exposure, growth failure, destructive arthritis, and life-threatening macrophage activation syndrome. Early cytokine-blocking biologic therapy may improve long-term outcomes, although some systemic juvenile idiopathic arthritis patients respond well to non-biologic treatment, leaving optimal management undefined. Consequently, treatment of new-onset systemic juvenile idiopathic arthritis by expert clinicians varies widely. To describe a pragmatic, observational comparative effectiveness study that takes advantage of diversity in the management of a rare disease: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST), comparing non-biologic and biologic consensus treatment plans for new-onset systemic juvenile idiopathic arthritis within the 60-center Childhood Arthritis and Rheumatology Research Alliance Registry (CARRA). FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) is a multicenter, prospective, non-randomized study that compares four Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans for new-onset systemic juvenile idiopathic arthritis: (1) glucocorticoids alone, (2) methotrexate, (3) interleukin-1 blockade, and (4) interleukin-6 blockade. Patients consenting to participation in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry are started on one of four Consensus Treatment Plans at the discretion of the treating physician. The outcome of primary interest is clinically inactive disease off glucocorticoids at 9 months, comparing non-biologic (Consensus Treatment Plans 1 + 2) versus biologic (Consensus Treatment Plans 3 + 4) strategies. Bayesian analytic methods will be employed to evaluate response rates, using propensity scoring to balance treatment groups for potential confounding. With 200 patients in a 2:1 ratio of biologic to non-biologic, there is a >90% probability of finding biologic consensus treatment plans more effective if the rate of clinically inactive disease is 30% higher than for non-biologic therapy. Additional outcomes include Patient-Reported Outcomes Measurement Information System measures and other parent-/patient-reported outcomes reported in real time using smartphone technology. Routine operation of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry will allow assessment of outcomes over at least 10 years. FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) began enrollment in November 2016. The observational design may not provide balance in measured and unmeasured confounders. Use of consensus treatment plan (CTP) strategies at frequencies more unbalanced than predicted could reduce the chance of finding differences in efficacy. FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) will provide the first prospective comparison of Childhood Arthritis and Rheumatology Research Alliance's (CARRA's) consensus-derived non-biologic versus biologic management strategies in systemic juvenile idiopathic arthritis, performed in a real-world setting wherein each patient receives standard-of-care treatment selected by the treating physician. Outcomes include clinician- and patient-/family-reported outcomes, empowering both physician and patient decision making in new-onset systemic juvenile idiopathic arthritis.

Эффективность ритуксимаба в терапии системного ювенильного идиопатического артрита

BackgroundJuvenile idiopathic arthritis is a heterogeneous group of diseases characterized by unknown origin arthritis under 16 years. Compared to other juvenile idiopathic arthritis subtypes, enthesitis-related arthritis has a poor prognosis...

Dysregulation of monocyte and macrophage responses are often observed in children with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS), a potentially fatal complication of chronic rheumatic diseases. Both conditions are associated with activation of TLR signaling in monocyte and macrophage lineage cells, leading to overwhelming inflammatory responses. Despite the importance of TLR engagement in activating proinflammatory macrophages, relatively little is known about activation of intrinsic negative regulatory pathways to attenuate excessive inflammatory responses. In this study, we demonstrate that loss of diacylglycerol (DAG) kinase (Dgk) ζ, an enzyme which converts DAG into phosphatidic acid, limits inflammatory cytokine production in an arthritic mouse model dependent on TLR2 signaling and in a CSS mouse model dependent on TLR9 signaling. In vitro, Dgkζ deficiency results in reduced production of TNF-α, IL-6, and IL-1β and in limited M1 macrophage polarization. Mechanistically, Dgkζ deficiency decreases STAT1 and STAT3 phosphorylation. Moreover, Dgkζ levels are increased in macrophages derived from mice with CSS or exposed to plasma from sJIA patients with active disease. Our data suggest that Dgkζ induction in arthritic conditions perpetuates systemic inflammatory responses mediated by macrophages and highlight a potential role of Dgkζ-DAG/phosphatidic acid axis as a modulator of inflammatory cytokine production in sJIA and CSS.

Background Raised concentrations of soluble intercellular adhesion molecule-1 (ICAM-1) and E-selectin (E-sel) are believed to reflect processes of their up-regulation and endothelial cell (EC) activation by various inflammatory stimuli. Resulting enhancement of cell infiltration is a pre-recquisite of tissue damage. Objectives To evaluate serum and synovial fluid (SF) concentrations of ICAM-1 and E-sel in patients with juvenile idiopathic arthritis (JIA) and in paediatric controls and to correlate them with clinical and laboratory variables. Methods Total of 33 JIA patients (mean age 10 y) were evaluated: 18 with polyarthritis (JIApoly) disease course (mean active joint count 9) and 15 with oligoarthritis (JIAoligo). Paediatric age-matched control groups consisted of 11 Henoch-Schonlein purpura (HSP) and 10 febrile (FC) patients and 28 healthy children. Current medication, ESR, CRP and FBC were recorded. Soluble ICAM-1 and E-sel in serum and SF were measured by commercially available sandwich ELISA kits. Results Significant negative correlation with age was observed for the whole group (ICAM-1: p Conclusion High concentrations of soluble ICAM-1 and E-sel in JIA patients with polyarthritis are reported here for the first time. Bloom1 and de Benedetti2 found increased ICAM-1 and E-sel levels only in systemic JIA. In our patients only 3 had systemic onset disease, none showed signs of vasculitis or infection. Our finding of correlation of both molecule levels with joint count supports the hypothesis of synovial EC origin of these molecules. It brings interesting insight in suspected disease pathogenesis in terms of endothelial activation, leucocyte migration and angiogenesis. ICAM-1 and E-sel could be a marker of aggressive disease, but their predictive value needs to be further studied. References Bloom BJ, Miller LC, Tucker LB, et al. Soluble adhesion molecules in juvenile rheumatoid arthritis. J Rheumatol. 1999;26:2044–8 De Benedetti F, Vivarelli M, Pignatti P, et al. Circulating levels of soluble E-selectin, P-selectin and intercellular adhesion molecule-1 in patients with juvenile idiopathic arthritis. J Rheumatol. 2000;27:2246–50

Background:Systemic juvenile idiopathic arthritis (SJIA) is a category of Juvenile Idiopathic Arthritis (JIA). Different clinical patterns (articular/systemic/both of them combined) have been recognized, possibly identifying distinct subpopulations. Serum biomarkers that reflect disease activity include S100A8/S100A9 (S100A8/9), however to date patterns of SJIA and their association with S100A8/9 has not been tested.Objectives:To evaluate S100A8/9 levels in a cohort of patients with SJIA. To determinate S100A8/9 inactive vs inactive visits. To distinguish patterns on SJIA and their association with S100A8/9. To compare serum levels of S100A8/9 with other JIA categories and autoinflammatory diseases.Methods:An unicenter, observational, cross sectional study was conduced. Patients with SJIA according ILAR whom S100A8/9 was measured as part of standard care were enrolled. Consecutive visits were included. Variables recorded were: clinical (systemic: fever, serositis, adenopathy, hepatomegaly, splenomegaly and arthritis); biochemical (S100A8/9, hemoglobin, platelet, erythrosedimentation, c-reactive protein, ferritin). Activity measures: Juvenile Arthritis Disease Activity Score (JADAS -10) and physician visual analogue scale (phy VAS).Visits were divided into active/inactive. Active visit was defined as at least one clinical feature.(systemjc and/or arthritis). Inactive visit no clinical symptoms neither JADAS-10> 1 and phy VAS: 0. SJIA patterns were defined as: “articular pattern”: those patients with arthritis without systemic features, “systemic pattern”: any systemic feature without arthritis, “mixed pattern”: both articular and systemic. Levels of S100A8/9 were tested using Calprotectin Elisa Kit. For comparisons others JIA: enthesitis related arthritis (ERA), polyarticular and autoinflammatory diseases who had at least one S100A8/9 determination were included. Descriptive statistics, Mann- Whitney U test and ANOVA were used as appropiate.Results:Forty-two patients with SJIA were included (25 F). Age at evaluation 13 (1-16.5) years. Clinical features at study baseline: arthritis 57 %, rash 19%, fever 15 %, adenopathies 6%, splenomegaly 4%, hepatomegaly 1.5%. Laboratory features (median): hemoglobin 12.2 gr/dl, platelet 314000 cel/mm3, erythrosedimentation 12.5 mm/h, c-reactive protein 0.7 mg/dl, ferritin 235 ng/ml. JADAS -10 ≥ 1: 62%. Number of active patients were 29 (69%). Scheduled Medical visits were 129 (active 65%, inactive 35%). Active visits were divided according patterns into: articular 54%, mixed 35%, systemic 11%.Serum Levels of S100A8/9 according to SJIA’ patterns.SJIAOverallActiveArticularSystemicMixedInactiveVisits129844692945S100A8/9 ng/mlMedian (range)7590(300-2625)16788(300-26250)10750(300-26250)5200(850-12250)25000(3290-2625)3103(1140-1010)S100A8/9 analysis revealed significant differences among active vs inactive medical visits (p: 0,00001). ANOVA test among SJIA`patterns showed, F:86.48, (p:0.00001). Mixed pattern was distinctive to others. S100A8/9 (medians ng/ml) in comparable diseases were: ERA: 4320, polyarticular: 4120, autoinflammatory: 6532. SJIA had the higher S100A8/9. SJIA was different than others comparable diseases (F: 11,62,p: 0.00001). Comparisons among SJIA`patternss and others disease found that systemic and articular pattern did not show differences (F.2.78, p:0.067)Conclusion:S100A8/9 was higher in SJIA compared to others diseases. It reflected disease activity. Mixed pattern evidenced to be different to others (systemic/articular). Mixed pattern was the unique that showed significative difference compared to other diseases. SJIA is probably not a single disease, but not only clinical patterns and biomarkers as S100A8/9, if not, genetic variants and their expression would be able to identify homogeneous groups towards tailored treatments.Disclosure of Interests:None declared

Macrophage activation syndrome is a life-threatening complication seen predominantly in children with systemic onset juvenile idiopathic arthritis. It accounts for a significant amount of the morbidity and mortality seen with systemic onset juvenile idiopathic arthritis. In this article, we will look at the new developments in the diagnosis, classification, pathogenesis and management of macrophage activation syndrome in systemic onset juvenile idiopathic arthritis patients. More work is needed to further elucidate the pathophysiology of macrophage activation syndrome in systemic onset juvenile idiopathic arthritis. This would be the key to early diagnosis using more sensitive criteria and better management.

Systemic juvenile idiopathic arthritis (SJIA) accounts for 10–15% of juvenile arthritis cases. The incidence of inflammatory bowel disease (IBD) is generally higher in SJIA patients than in the general pediatric population; however, the association of IBD with SJIA is rare. Among 65 patients with SJIA managed in two pediatric rheumatology centers, IBD was detected in 3 patients 3, 8, and 10 years from the SJIA onset. The clinical presentation of IBD in patients with SJIA is rather scanty; the diagnosis is mainly based on the colonoscopy and biopsy results. In 2 patients, Crohn's disease was diagnosed, and undifferentiated colitis in 1 patient.

Background: Systemic Juvenile Idiopathic Arthritis (sJIA) is a unique category of juvenile arthritis in which interleukin 6 plays a major pathogenic role. This study aimed to describe the therapeutic short-term outcomes among patients with sJIA starting tocilizumab (TCZ) therapy and to identify possible predictors of treatment response.Methods: We conducted a prospective observational study including 65 patients with sJIA meeting ILAR classification criteria with active disease despite conventional therapy that were treated by TCZ between August 2019 and October 2020 as the first-line biological therapy. Clinical and serological parameters were recorded at baseline and after 1 year of TCZ therapy.Results: After 1 year, 25% of the patients achieved minimal disease activity and 35% achieved clinically inactive disease. A significant reduction of the 10-joint juvenile arthritis disease activity score and acute phase reactants was also observed. Patients with younger age (≤7 years), shorter disease duration (≤3 years), lower disease activity, and higher serum ferritin and systemic manifestations showed more favorable results.Conclusion: Patients with sJIA showed favorable disease outcomes with TCZ treatment for 1 year, especially if the drugs were administered earlier in the disease course and in younger patients with a more pronounced inflammatory status. Our results may help to define the profile of patients with sJIA who are more likely to benefit from IL-6 blockade.

PurposeTo understand the experience of adolescent systemic juvenile idiopathic arthritis (SJIA) patients and those of their parents based on their social media posts.MethodsEnglish language posts related to SJIA, Still’s disease, or juvenile arthritis were collected and analyzed.ResultsIn total, 71 posts created between 2009 and 2015 on 15 websites were identified in November 2015. Of the 32 unique authors, 17 were SJIA patients aged 13–20 years (40 posts), 7 were mothers of SJIA patients (12 posts), and 8 patients had unspecified forms of juvenile arthritis (19 posts). Many patients posted about similar diagnostic experiences marked by 5 phases: 1) early prediagnosis: pain and fatigue overlooked until crisis occurred, 2) first misdiagnosis: doctors talked about “growing pains” and psychosocial problems (“fake pains” to avoid school), 3) second misdiagnosis: severity acknowledged, but diagnosed as leukemia or another cancer, 4) tests: tests leading to diagnosis and treatment conducted, and 5) cognitive identity: patient accepted the diagnosis and its implications. Many adolescent patients, looking back at disease onset in their childhood, described themselves as a “sleeping child” rather than the typical active child. Several patients tried to hide their illness from friends, but expressed concerns openly online. Many patients described SJIA as a powerful external enemy, using terms like “bulldozer,” “dragon,” and “monster.” Many posts from patients and their mothers used superhero language/imagery to help “fight” SJIA. Some patients also posted about the risk of death.ConclusionAlthough most adolescent SJIA patients openly posted about the difficulties of their disease online, they made efforts to hide their disease in the real world. They frequently used superhero words and images in describing their fight for better health. Physicians can use these insights when counseling SJIA patients to provide a narrative that meshes with the patients’ worldview and perhaps to improve physician–patient communication to increase treatment adherence.

The assessment of long-term outcome of functional disability and disease activeness in adult patients with juvenile idiopathic arthritis appears to be complicated due to the absence of a unified approach to the classification and estimation of disease activeness, as well as the loss of supervision over a patient because of remission or his/her transition from pediatric to adult rheumatic service. The objective of the research was to determine how adults with the history of juvenile idiopathic arthritis fulfill the classification criteria for adult rheumatic diseases, as well as to assess activeness of these diseases, the degree of functional disorders, and social activeness of patients in Ukraine. Materials and methods. Patients with juvenile idiopathic arthritis older than 18 years and with more than 3 years of disease duration living in different parts of Ukraine were included into the study. Data regarding sociodemographic features, fulfillment of adult classification criteria, Health Assessment Questionnaire, articular and extra-articular Juvenile Arthritis Damage Index and disease activity were analyzed.Results. We observed 122 adult patients with the history of juvenile idiopathic arthritis irrespective of the presence of active inflammation at the moment of the examination. This group included patients from different regions of Ukraine diagnosed with juvenile idiopathic arthritis during 1984-2013. An adult rheumatologist examined all patients and the diagnosis was revised according to the adult classification of rheumatic diseases. Typical diagnostic criteria for rheumatoid arthritis were estimated in 32.8% of patients, ankylosing spondylitis – in 31.1% of patients, undifferentiated arthritis – in 13.9% of patients, Still’s disease – in 4.9% of patients, psoriatic arthritis – in 0.8% of patients, steady clinical laboratory remission – in 16.5% of patients. Most patients (81.8%) with rheumatoid factor positive polyarticular juvenile idiopathic arthritis fell under rheumatoid arthritis criteria in adulthood, and in 85% of patients with enthesitis-related arthritis as well as 53.8% of patients with extended oligoarthritis ankylosing spondylitis developed in adulthood. 68.8% of patients with systemic juvenile idiopathic arthritis, 68% of patients with rheumatoid factor negative polyarthritic subtype and 55% of patients with enthesitis-related arthritis had disability and incapacitation. Minimal disorders of the patients’ general condition according to the Health Assessment Questionnaire in adult age were found in most subtypes of juvenile idiopathic arthritis classified according to the International League of Associations for Rheumatology (extended and persistent oligoarthritis, rheumatoid factor positive polyarthritis, systemic subtype); moderate disorders of the general condition were found in enthesitis-related arthritis and rheumatoid factor negative polyarthritis. Side effects of juvenile idiopathic arthritis according to the articular Juvenile Arthritis Damage Index included severe articular damage being most frequently found in systemic and rheumatoid factor positive polyarthritis subtypes of juvenile idiopathic arthritis, while side effects of juvenile idiopathic arthritis according to the extra-articular Juvenile Arthritis Damage Index included extra-articular damage being found in systemic and rheumatoid factor negative polyarthritis subtypes of juvenile idiopathic arthritis, that was confirmed by the assessment of physical health according to the Short Form Health Survey-36, which was the worst in patients with systemic (40.3±12.6) and rheumatoid factor negative polyarthritis (38.9±9.4) subtypes of juvenile idiopathic arthritis.Conclusions. Further research of remote consequences of juvenile idiopathic arthritis in adult age and long-term observation of such patients require a detailed study to improve diagnostics and provide adequate treatment of rheumatic diseases with juvenile onset in adult age.

BackgroundA decrease in bone mass has been described in a high percentage with increased risk of osteoporosis in JIA subtypes. The pathogenesis of bone loss in active JIA is complex,...

Juvenile arthritis with systemic onset (syn: systemic juvenile idiopathic arthritis; SJIA) is the most complex in pathogenesis, severe in course and unfavorable in prognosis variant of juvenile arthritis. The course of SJIA is characterized by the development of severe life-threatening complications, which in the future may lead to the progression of functional and multiple organ failure, delayed physical development and disability of the patient, therefore it is very important to diagnose this disease at an early stage, for which children with suspicion of SJIA must be examined in accordance with the Procedure for providing medical care for children in the profile "Rheumatology" in rheumatology departments of multidisciplinary hospitals, where it is possible to perform the entire complex of diagnostic measures, these are indicated in the clinical recommendations, since at the stage of diagnosis it is very important to exclude diseases appearing in the guise of SJIA, including infectious diseases, These are indicated in the clinical recommendations, because at the stage of diagnosis it is very important to exclude diseases appearing under the guise of SJIA, including infectious, oncologic, oncohematologic, lymphoproliferative, inflammatory bowel, autoinflammatory syndromes and other rheumatic diseases. Federal districts (FD) of the Russian Federation (RF) differ significantly in demographic, climatic, natural-geographical, sociocultural parameters, which cannot but determine differences in the processes of providing medical care to children in the profile of rheumatology. The analysis of these processes is a necessary condition for improving the quality of early diagnosis of juvenile arthritis in pediatric patients. Objective. To carry out a comparative assessment of compliance with clinical recommendations of the scope of examination performed in the Russian Federation at the stage of primary diagnosis of juvenile arthritis with systemic onset, according to the Federal Register of the Ministry of Health of the Russian Federation. Patients and Methods. A retrospective study of discharge records of 927 patients diagnosed with SJIA, receiving genetically engineered biological drugs, included in the Federal Register of persons with hemophilia, cystic fibrosis, pituitary nanism, Gaucher disease, malignant neoplasms of lymphoid, hematopoietic and related tissues, multiple sclerosis, hemolytic-uremic syndrome, juvenile arthritis with systemic onset, mucopolysaccharidosis types I, II and VI, persons after organ and/or tissue transplantation (Register). Results. Our study found that there were significant differences between the Russian Federation regions in the volume of investigations performed at the stage of diagnosis of SJIA and their compliance with clinical recommendations. In all regions of the Russian Federation we found a reliable dynamics of improvement in the quality of examination associated with the improvement of the regulatory and legal framework for the organization of medical care for children in the profile of rheumatology. Conclusion. Our study confirms the need for continuous monitoring of the work of pediatric rheumatology service of the FD, which will optimize the algorithms of early diagnosis of SJIA and other rheumatic diseases in children in order to timely start treatment, including on the basis of the introduction and modernization of digital health technologies, in particular, the system of electronic registers. Key words: Federal Register, juvenile arthritis with systemic onset, diagnosis, federal district, clinical recommendations

Objective To analyze the clinical features and laboratory data of 10 patients with macrophage activation syndrome (MAS) complicating systemic onset juvenile idiopathic arthritis (soJIA), which were characterized by acute severe liver injury. Methods Data of 10 patients with soJIA/MAS from Nanjing Children's Hospital were collected retrospectively. The clinical features, laboratory findings, treatment, out-comes and prognosis were analyzed. Results In the total 10 patients, female (6/10) outnumbered male. Their age ranged from 1.5 to 9.5 years old (average 5.2±2.6). The most remarkable clinical manifestations were severe liver injury without systemic features, representing as hepatomegaly (10/10), splenomegaly (2/10) and strikingly increased transaminase (10/10, median: ALT 1 445 U/L, AST 885 U/L). Central nervous system dysfunction and hemorrhages were recorded in 20% of the patients. Two patients had pulmonary infection. Laboratory data showed that platelet count was less than normal or precaution value (10/10, ≤262×109/L). Hyperferritinaemia (10/10, median: 17 329 mg/ml) and soluble CD25 elevation (median: 3 140 U/ml) were common in the soJIA/MAS patients. Evidence of macrophage hemophagocytosis was found in 90% of the patients (9/10) who underwent bone marrow aspiration. Pathological findings of liver biopsy from 1 patient revealed massive infiltration of mononuclear cells in the portal tracts. Nearly all patients (9/10) received intravenous pulse methylprednisolone therapy, combined with cyclosporine A and high-dose intravenous immunoglobulin. Eight patients had good outcome. Only 2 patients were complicated with severe interstitial lung disease during 12-months follow-up. Conclusion MAS should be considered when patients with soJIA represents acute severeliver injury without systemic features combined with other laboratory data. Intravenous pulse methylprednisolone and cyclosporine A therapy may improve the prognosis of soJIA/MAS. Key words: Macrophage activation syndrome; Systemic onset juvenile idiopathic arthritis; Severe liver injury; Corticosteroids; Cyclosporine A.