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Ombrello, Michael J., Victoria L. Arthur, Elaine F. Remmers, Anne Hinks, Ioanna Tachmazidou, Alexei A. Grom, Dirk Foell, et al. "Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications." Annals of the Rheumatic Diseases 76, no. 5 (December 7, 2016): 906–13. http://dx.doi.org/10.1136/annrheumdis-2016-210324.
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ObjectivesJuvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA.MethodsWe performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes.ResultsThe major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes.ConclusionsThe lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways.
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Kim, Daeun, Jaeseung Song, Sora Lee, Junghyun Jung, and Wonhee Jang. "An Integrative Transcriptomic Analysis of Systemic Juvenile Idiopathic Arthritis for Identifying Potential Genetic Markers and Drug Candidates." International Journal of Molecular Sciences 22, no. 2 (January 12, 2021): 712. http://dx.doi.org/10.3390/ijms22020712.
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Systemic juvenile idiopathic arthritis (sJIA) is a rare subtype of juvenile idiopathic arthritis, whose clinical features are systemic fever and rash accompanied by painful joints and inflammation. Even though sJIA has been reported to be an autoinflammatory disorder, its exact pathogenesis remains unclear. In this study, we integrated a meta-analysis with a weighted gene co-expression network analysis (WGCNA) using 5 microarray datasets and an RNA sequencing dataset to understand the interconnection of susceptibility genes for sJIA. Using the integrative analysis, we identified a robust sJIA signature that consisted of 2 co-expressed gene sets comprising 103 up-regulated genes and 25 down-regulated genes in sJIA patients compared with healthy controls. Among the 128 sJIA signature genes, we identified an up-regulated cluster of 11 genes and a down-regulated cluster of 4 genes, which may play key roles in the pathogenesis of sJIA. We then detected 10 bioactive molecules targeting the significant gene clusters as potential novel drug candidates for sJIA using an in silico drug repositioning analysis. These findings suggest that the gene clusters may be potential genetic markers of sJIA and 10 drug candidates can contribute to the development of new therapeutic options for sJIA.
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Ombrello, Michael J., Elaine F. Remmers, Ioanna Tachmazidou, Alexei Grom, Dirk Foell, Johannes-Peter Haas, Alberto Martini, et al. "HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis." Proceedings of the National Academy of Sciences 112, no. 52 (November 23, 2015): 15970–75. http://dx.doi.org/10.1073/pnas.1520779112.
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Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10−17, odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10−5, OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10−16, OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11—HLA-DQA1*05—HLA-DQB1*03 haplotype [6.4 × 10−17, OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.
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Kaleda, M., E. Fedorov, I. Nikishina, S. Salugina, V. Matkava, M. Cherkasova, and E. Samarkina. "AB1252 RETROSPECTIVE SINGLE CENTER STUDY OF THE PREDICTIVE ROLE OF CERTAIN BIOMARKERS IN MACROPHAGE ACTIVATION SYNDROME RELATED TO SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1736.2–1737. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3328.
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BackgroundSystemic juvenile idiopathic arthritis (sJIA) is a childhood arthritis with signs of autoinflammation and high risk of macrophage activation syndrome (MAS). Immunopathogenesis of sJIA is based on excessive activation of innate immunity, which is characterized by hyperproduction of pro-inflammatory cytokines - interleukin (IL)-1 and IL-18, which play a key role in induction of synthesis of other pro-inflammatory mediators. Macrophage activation mediates the evidence of hyperferritinemia, which stimulates a pathological immune response with the development of MAS. In clinical practice, the study of the cytokine profile and its comparison with the acute-phase inflammatory response markers in patients (pts) with sJIA can make possible assessment the nature of the course process and predict the possibility of MAS.ObjectivesTo study distinctive features of some biomarkers in pts with sJA in relation with history of MAS.MethodsTotal IL-18, IP-10, IL1RA, IL1b, IL6, CRP and ferritin levels were determined in pts with sJIA and compared between between groups regarding to disease activity and history of MAS. Serum levels of cytokines, ferritin were measured using standard commercial enzyme-linked immuno-sorbent assay. CRP were estimated by commercial nephelometric method.ResultsA total of 39 pts were included to study, the ratio of boys and girls was 1:1.4. Median age of sJIA onset was 4.4 years [2.9; 6.5], age at the time of examination - 11.4 years [7.35; 13.5]. The pts were divided into 3 groups: group I - with MAS (8 pts), group II - with active sJIA without MAS (16 pts), group III - with inactive sJIA (15 pts). Total IL-18 levels were significantly higher in pts with MAS (group I) (median 6036.5 pg/ml [IQR 1932.5; 9160.3], and remained persistently elevated even in the majority of pts with inactive disease (group III) (median 1625.25 pg/ml [IQR 634.1; 2451.6]. CRP was higher in group I (CRP: median 60.6 mg/l [IQR 41.2; 109.4]), than in group II (CRP: median 15.65 mg/l; IQR 10.4; 38.4), without a statistically significant difference (p=0.5), but the level of ferritin was significantly higher in group I (median 893.25 ng/ml [IQR 253.9; 7725.25]), than in group II (median 62.1 ng/ml [IQR 19.8; 211.8], p=0.009). Generally, we observed positive correlation between CRP and ferritine (r=0.629, р˂0.05), CRP and IL-18 (r=0.352, р˂0.05), CRP and IL1RA (r=0.693, р˂0.05); between ferritin and IL-18 (r=0.566, р˂0.05), between ferritin and IL1RA (r=0.545, р˂0.05). The strongest correlation was for ferritin and overall for groups I and II. We didn’t observe significantly difference between IP-10, IL1b, IL6 between groups.ConclusionSerum levels of IL-18 were elevated in the majority of pts with sJIA regardless of activity, but were significantly higher in pts with active disease and, especially, in pts with MAS. Increased level of IL-18 may reflect increased disease activity or development of MAS, that confirms the key role of IL-18 in sJIA and MAS. According to our data, in clinical practice the measure of serum level of ferritin more useful for early detecting MAS in pts with sJIA due to more stronger correlation between the levels of proinflammatory cytokines and ferritin, than between proinflammatory cytokines and CRP. We were unable to identify a statistically significant difference in the level of IL1RA in active sJIA and MAS, despite a significant correlation between the level of CRP and IL1RA, ferritin and IL1RA, which may be associated with small number of pts.Disclosure of InterestsNone declared
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Rolfes, Elisabeth, Sae Lim von Stuckrad, and Tilmann Kallinich. "Eine neue Lungenerkrankung bei Kindern mit systemischer JIA/Still-Syndrom." Kinder- und Jugendmedizin 21, no. 05 (October 2021): 358–63. http://dx.doi.org/10.1055/a-1558-7356.
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ZUSAMMENFASSUNGIm letzten Jahrzehnt hat eine neue Komplikation der systemischen juvenilen Arthritis mehr und mehr Beachtung in Fachkreisen und als „sJIA Lung Disease“ (sJIA-LD) Einzug in die Literatur gefunden. Die Kinder mit sJIA-LD präsentieren sich mit initial oft unspezifischen respiratorischen Symptomen, Hypoxie und Hautausschlag. Ein häufiges eindrückliches erstes Zeichen sind Trommelschlegelfinger mit digitalen Erythemen. Möglicherweise scheint die sJIA-LD gehäuft aufzutreten, wenn Kinder ein junges Alter bei sJIA-Diagnose hatten sowie ein oder mehrere Makrophagen-Aktivierungssyndrome in der Vorgeschichte, hohe Interleukin-18-Spiegel im Serum und eine Unverträglichkeit gegenüber Biologika (IL-1- oder IL-6-Blocker). Die Mortalität variiert stark zwischen den einzelnen Fallsammlungen, in der größten Kohorte ist sie mit 36 % hoch 1.
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Krekhova, E. A., E. I. Alekseeva, and T. M. Dvoryakovskaya. "Predictors of response to therapy with biologicals in children with systemic juvenile idiopathic arthritis." Voprosy praktičeskoj pediatrii 16, no. 1 (2021): 64–78. http://dx.doi.org/10.20953/1817-7646-2021-1-64-78.
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Systemic juvenile idiopathic arthritis (sJIA) is a severe orphan autoimmune disease characterized by fever, polymorphic skin rash, hepatosplenomegaly, serositis, generalized lymphadenopathy, and destructive arthritis. Proinflammatory cytokines, including interleukin-1 (IL-1), IL-6, IL-17, IL-18, and tumor necrosis factor (TNF), play a key role in sJIA pathogenesis. sJIA is refractory to conventional immunosuppressive antirheumatic drugs. Before the development of biologicals, sJIA patients had to receive corticosteroids constantly. The implementation of biologicals, such as tocilizumab (IL-6 inhibitor) and canakinumab (IL-1 inhibitor) into clinical practice radically changed the disease course, reduced the need for corticosteroids, and significantly decreased the risk of disability. The administration of biologicals at sJIA onset ensured faster achievement of inactive disease or remission compared to conventional therapy, as well as more patients responding to them. Implementation of biologicals into clinical practice dictated the need to identify optimal conditions for initiating therapy in sJIA patients to improve treatment efficacy and safety. Key words: biologicals, canakinumab, predictors, systemic juvenile idiopathic arthritis, tocilizumab, cytokines
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Vankova, D. D., E. I. Alekseeva, T. M. Dvoryakovskaya, R. V. Denisova, T. V. Radygina, I. V. Zubkova, E. A. Brzhozovskaya, et al. "Activity of systemic juvenile idiopathic arthritis in children immunized with pneumococcal 13-valent conjugate vaccine: prospective cohort study." Voprosy praktičeskoj pediatrii 15, no. 5 (2020): 40–50. http://dx.doi.org/10.20953/1817-7646-2020-5-40-50.
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Evaluation of the safety profile of vaccines in patients with rheumatic diseases requires an assessment of their impact on disease activity. The effect of antipneumococcal vaccination on the activity of systemic juvenile idiopathic arthritis (sJIA) has not been studied so far. Objective. To evaluate the dynamics of sJIA activity after immunization with pneumococcal 13-valent conjugate vaccine (PCV13) of patients receiving biologicals. Patients and methods. This study included patients with sJIA in remission or active disease receiving biologicals during inpatient treatment and vaccinated with PCV13. To evaluate the effect of immunization on sJIA activity, we measured serum levels of high-sensitivity C-reactive protein (hs-CRP) and calprotectin. In addition to that, we assessed the number of new cases, when concentration of these markers was above the upper limit (UL) 4 weeks after PCV13 administration. Results. In 18 out of 53 patients in remission (34%) and 3 out of 25 patients with active sJIA (12%), hs-CRP levels were undetectable (0.1 mg/L) at both time-points (baseline and after 4 weeks). Among those with detectable hs-CRP levels in at least one time-point 4 weeks after vaccination, patients in remission (n = 35) had no significant changes in hs-CRP (median -0.17 mg/mL; 95% CI -0.84…0.41), whereas patients with active sJIA (n = 22) demonstrated a 3-fold decrease in hs-CRP level (median -0.94 mg/mL (95% CI -3.93…0.05). We observed no significant difference in calprotectin levels in the groups. Concentration of hs-CRP above the UL 4 weeks after vaccination was detected in 2 out of 53 sJIA patients in remission (4%) and none of the patients with active sJIA. Сoncentration of calprotectin above the UL 4 weeks after vaccination was detected in 8 out 53 (15%) and 5 out 25 (20%) sJIA patients in remission and with active disease, respectively. Conclusion. Vaccination against pneumococcal infection in patients with sJIA led to an increase in the level of highly sensitive laboratory markers of sJIA activity in 4–20% of patients. Key words: disease activity, safety, high-sensitivity C-reactive protein, biological drugs, calprotectin, juvenile idiopathic arthritis, pneumococcal 13-valent conjugate vaccine
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Zhou, Mi, Ruru Guo, Yong-Fei Wang, Wanling Yang, Rongxiu Li, and Liangjing Lu. "Application of Weighted Gene Coexpression Network Analysis to Identify Key Modules and Hub Genes in Systemic Juvenile Idiopathic Arthritis." BioMed Research International 2021 (August 13, 2021): 1–13. http://dx.doi.org/10.1155/2021/9957569.
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Systemic juvenile idiopathic arthritis (sJIA) is a severe autoinflammatory disorder with a still not clearly defined molecular mechanism. To better understand the disease, we used scattered datasets from public domains and performed a weighted gene coexpression network analysis (WGCNA) to identify key modules and hub genes underlying sJIA pathogenesis. Two gene expression datasets, GSE7753 and GSE13501, were used to construct the WGCNA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were applied to the genes and hub genes in the sJIA modules. Cytoscape was used to screen and visualize the hub genes. We further compared the hub genes with the genome-wide association study (GWAS) genes and used a consensus WGCNA to verify that our conclusions were conservative and reproducible across multiple independent datasets. A total of 5,414 genes were obtained for WGCNA, from which highly correlated genes were divided into 17 modules. The red module demonstrated the highest correlation with the sJIA module ( r = 0.8 , p = 3 e − 29 ), whereas the green-yellow module was found to be closely related to the non-sJIA module ( r = 0.62 , p = 1 e − 14 ). Functional enrichment analysis demonstrated that the red module was mostly enriched in the activation of immune responses, infection, nucleosomes, and erythrocytes, and the green-yellow module was mostly enriched in immune responses and inflammation. Additionally, the hub genes in the red module were highly enriched in erythrocyte differentiation, including ALAS2, AHSP, TRIM10, TRIM58, and KLF1. The hub genes from the green-yellow module were mainly associated with immune responses, as exemplified by the genes KLRB1, KLRF1, CD160, and KIRs. We identified sJIA-related modules and several hub genes that might be associated with the development of sJIA. Particularly, the modules may help understand the mechanisms of sJIA, and the hub genes may become biomarkers and therapeutic targets of sJIA in the future.
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Sun, Juan, Miao Feng, Fengqi Wu, Xiaolin Ma, Jie Lu, Min Kang, and Zhewei Liu. "Plasma miR-26a as a Diagnostic Biomarker Regulates Cytokine Expression in Systemic Juvenile Idiopathic Arthritis." Journal of Rheumatology 43, no. 8 (June 1, 2016): 1607–14. http://dx.doi.org/10.3899/jrheum.150593.
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Objective.We sought to identify specific microRNA (miRNA) for systemic juvenile idiopathic arthritis (sJIA) and to determine the involvement of these miRNA in regulating the expression of cytokines.Methods.Microarray profiling was performed to identify differentially expressed miRNA in sJIA plasma. Levels of candidate miRNA and mRNA were assessed by real-time PCR, and cytokines were measured by ELISA. Dual-luciferase reporter assay was used to validate the direct interaction between miR-26a and interleukin 6 (IL-6).Results.Forty-eight miRNA were differentially expressed in the plasma of patients with sJIA compared with healthy controls (HC). Five miRNA were selected for further validation. The expression level of miR-26a was exclusively elevated in the plasma of patients with sJIA as compared with 4 rheumatic diseases and 2 subtypes of JIA (oligoarticular and polyarticular). The levels of IL-6, IL-1β, and tumor necrosis factor-α in the plasma of patients with sJIA were increased, and only IL-6 presented a positive correlation with miR-26a (r = 0.539, p < 0.0001). After stimulation with IL-6, miR-26a expression was upregulated in THP-1 cells, while the supernatant level of IL-6 was downregulated by transfection of miR-26a mimics. Consistently, direct target relationship between miR-26a and IL-6 was confirmed.Conclusion.This study demonstrates that miR-26a is expressed specifically and highly in sJIA plasma and suggests that miR-26a may regulate the levels of cytokines in sJIA. Our findings highlight miR-26a as a potential biomarker for the diagnosis as well as differential diagnosis of sJIA.
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Gohar, Faekah, Angela McArdle, Melissa Jones, Niamh Callan, Belinda Hernandez, Christoph Kessel, Maria Miranda-Garcia, et al. "Molecular signature characterisation of different inflammatory phenotypes of systemic juvenile idiopathic arthritis." Annals of the Rheumatic Diseases 78, no. 8 (April 20, 2019): 1107–13. http://dx.doi.org/10.1136/annrheumdis-2019-215051.
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ObjectivesThe International League of Associations for Rheumatology classification criteria define systemic juvenile idiopathic arthritis (SJIA) by the presence of fever, rash and chronic arthritis. Recent initiatives to revise current criteria recognise that a lack of arthritis complicates making the diagnosis early, while later a subgroup of patients develops aggressive joint disease. The proposed biphasic model of SJIA also implies a ‘window of opportunity’ to abrogate the development of chronic arthritis. We aimed to identify novel SJIA biomarkers during different disease phases.MethodsChildren with active SJIA were subgrouped clinically as systemic autoinflammatory disease with fever (SJIAsyst) or polyarticular disease (SJIApoly). A discovery cohort of n=10 patients per SJIA group, plus n=10 with infection, was subjected to unbiased label-free liquid chromatography mass spectrometry (LC-MS/MS) and immunoassay screens. In a separate verification cohort (SJIAsyst, n=45; SJIApoly, n=29; infection, n=32), candidate biomarkers were measured by multiple reaction monitoring MS (MRM-MS) and targeted immunoassays.ResultsSignatures differentiating the two phenotypes of SJIA could be identified. LC-MS/MS in the discovery cohort differentiated SJIAsyst from SJIApoly well, but less effectively from infection. Targeted MRM verified the discovery data and, combined with targeted immunoassays, correctly identified 91% (SJIAsyst vs SJIApoly) and 77% (SJIAsyst vs infection) of all cases.ConclusionsMolecular signatures differentiating two phenotypes of SJIA were identified suggesting shifts in underlying immunological processes in this biphasic disease. Biomarker signatures separating SJIA in its initial autoinflammatory phase from the main differential diagnosis (ie, infection) could aid early-stage diagnostic decisions, while markers of a phenotype switch could inform treat-to-target strategies.
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Weaver, L. K. "Combining multiple biomarkers differentiates between active SJIA, SJIA-MAS and EBV-HLH." Clinical & Experimental Immunology 191, no. 3 (October 26, 2017): 253–54. http://dx.doi.org/10.1111/cei.13063.
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Gurion, R., T. J. A. Lehman, and L. N. Moorthy. "Systemic Arthritis in Children: A Review of Clinical Presentation and Treatment." International Journal of Inflammation 2012 (2012): 1–16. http://dx.doi.org/10.1155/2012/271569.
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Systemic juvenile idiopathic arthritis (sJIA) constitutes a small part of juvenile idiopathic arthritis (JIA), yet has a disproportionally higher rate of mortality. Despite being grouped under JIA, it is considered to be a multifactorial autoinflammatory disease. The objective of this paper is to review the epidemiology, pathogenesis, genetics, clinical manifestations, complications, therapy, prognosis, and outcome of sJIA. The presentation and clinical manifestations of sJIA have not changed much in the past several decades, but the collective understanding of the pathogenesis and the development of new targeted therapies (particularly the biologic agents) have transformed and improved the disease outcome for children with sJIA.
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Quartier, Pierre. "Systemic Juvenile Idiopathic Arthritis/Pediatric Still’s Disease, a Syndrome but Several Clinical Forms: Recent Therapeutic Approaches." Journal of Clinical Medicine 11, no. 5 (March 1, 2022): 1357. http://dx.doi.org/10.3390/jcm11051357.
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Background: Systemic Juvenile Idiopathic Arthritis (SJIA)/Pediatric Still’s disease is associated with different phenotypes and outcomes from currently available treatments. Methods: A review of opinion, based on personal experience in a reference pediatric rheumatology center and key publications, to explore the most important questions regarding disease heterogeneity and treatment approaches. Results: A few situations deserve particular attention: 1/patients with recent-onset SJIA who may benefit from a treat-to-target approach with a key place for interleukin (IL)-1 inhibition; 2/SJIA patients refractory to Il-1 and IL-6 antagonists in whom several options may be discussed, including thalidomide or allogeneic hematopoietic stem cell transplantation; 3/SJIA patients with macrophage activation syndrome who may benefit from both well-used classical treatment and innovative approaches, such as anti-interferon gamma therapy or Janus Kinase (JAK) inhibitors; 4/SJIA with severe lung involvement, 5/SJIA patients who achieve complete remission on treatment, with some recent evidence that treatment may be reduced in intensity but not so easily withdrawn. Conclusions: a case-by-case discussion with expert teams is recommended in this heterogeneous, often difficult-to-treat population of patients.
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Davidson, Nicole, Hemalatha G. Rangarajan, Kyla Driest, Rajinder P. S. Bajwa, Veronika Polishchuk, and Rolla F. Abu-Arja. "Allogeneic Hematopoietic Cell Transplant for Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome." Case Reports in Rheumatology 2021 (May 24, 2021): 1–3. http://dx.doi.org/10.1155/2021/9323141.
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Systemic juvenile idiopathic arthritis (sJIA) is characterized by arthritis, fever, rash, lymphadenopathy, hepatosplenomegaly, and serositis. Macrophage activation syndrome is the most feared complication of sJIA with a high risk of mortality. We report a 16-year-old female diagnosed with refractory systemic juvenile idiopathic arthritis (sJIA) complicated by recurrent macrophage activation syndrome (MAS), severe joint disease, and lung involvement requiring prolonged immunosuppressive therapy. She received a matched unrelated allogeneic hematopoietic cell transplant (Allo-HCT) using a reduced-intensity conditioning regimen and is now, 3 years after the transplant, with complete resolution of sJIA symptoms, off immunosuppressants, and with significant improvement in the quality of life.
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Ishikawa, S., T. Mima, C. Aoki, N. Yoshio-Hoshino, Y. Adachi, T. Imagawa, M. Mori, et al. "Abnormal expression of the genes involved in cytokine networks and mitochondrial function in systemic juvenile idiopathic arthritis identified by DNA microarray analysis." Annals of the Rheumatic Diseases 68, no. 2 (April 3, 2008): 264–72. http://dx.doi.org/10.1136/ard.2007.079533.
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Objectives:Systemic juvenile idiopathic arthritis (sJIA) is a rheumatic disease in childhood characterised by systemic symptoms and a relatively poor prognosis. Peripheral leukocytes are thought to play a pathological role in sJIA although the exact cause of the disease is still obscure. In this study, we aimed to clarify cellular functional abnormalities in sJIA.Methods:We analysed the gene expression profile in peripheral leukocytes from 51 patients with sJIA, 6 patients with polyarticular type JIA (polyJIA) and 8 healthy children utilising DNA microarrays. Gene ontology analysis and network analysis were performed on the genes differentially expressed in sJIA to clarify the cellular functional abnormalities.Result:A total of 3491 genes were differentially expressed in patients with sJIA compared to healthy individuals. They were functionally categorised mainly into a defence response group and a metabolism group according to gene ontology, suggesting the possible abnormalities in these functions. In the defence response group, molecules predominantly constituting interferon (IFN)γ and tumour necrosis factor (TNF) network cascades were upregulated. In the metabolism group, oxidative phosphorylation-related genes were downregulated, suggesting a mitochondrial disorder. Expression of mitochondrial DNA-encoded genes including cytochrome c oxidase subunit 1(MT-CO1) and MT-CO2 were suppressed in patients with sJIA but not in patients with polyJIA or healthy children. However, nuclear DNA-encoded cytochrome c oxidases were intact.Conclusion:Our findings suggest that sJIA is not only an immunological disease but also a metabolic disease involving mitochondria disorder.
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Villarreal, M. G., S. Bonaldi, L. Perez, and M. Katsikas. "AB1007 SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS: ARE DIFFERENT CLINICAL PATTERNS ASSOCIATED WITH S100A8/S100A9 SERUM LEVELS?" Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1797.1–1797. http://dx.doi.org/10.1136/annrheumdis-2020-eular.5094.
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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
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Rossi-Semerano, Linda, and Isabelle Koné-Paut. "Is Still's Disease an Autoinflammatory Syndrome?" International Journal of Inflammation 2012 (2012): 1–5. http://dx.doi.org/10.1155/2012/480373.
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Systemic juvenile idiopathic arthritis (sJIA), formerly called Still's disease, is officially classified as a subset of juvenile idiopathic arthritis (JIA). Beside arthritis, it is characterized by prominent systemic features and a marked inflammatory response. Even if it is still included in the group of juvenile arthritides, sJIA is set apart from all the other forms of JIA. This disorder has markedly distinct clinical and laboratory features suggesting a different pathogenesis. sJIA does not show any association with HLA genes or with autoantibodies and is characterised by an uncontrolled activation of phagocytes with hypersecretion of IL-1 and IL-6. Based on clinical and laboratory features, as well as on new acquisitions on the pathogenesis, it seems evident that sJIA is an autoinflammatory disease related to abnormality in innate immune system. The new insights on the pathogenesis of sJIA have therefore dramatically changed the approach to treatment, with the development of targeted treatments (anti-IL-1 and anti-IL-6 agents) more effective and safer than earlier medications.
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Macaubas, Claudia, Khoa Nguyen, Ariana Peck, Elizabeth Wong, Julia Buckingham, Yael Goertz, Chetan Deshpande, et al. "Monocyte phenotypes in systemic juvenile idiopathic arthritis (44.13)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 44.13. http://dx.doi.org/10.4049/jimmunol.186.supp.44.13.
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Abstract Systemic juvenile idiopathic arthritis (SJIA) is a chronic autoinflammatory condition of childhood, characterized by remitting fever, transient rash, and relapsing arthritis. The association of macrophage activation syndrome with SJIA and clinical evidence implicating monocyte-derived cytokines IL-1 and IL-6 suggest a key role for monocyte in SJIA pathogenesis. We have previously found monocyte expansion during disease activity (flare), and a normal distribution of the monocyte subsets CD14hiCD16- and CD14loCD16+. We also observed elevated expression of monocyte surface markers CD14 and CD16 in the respective CD14hiCD16- and CD14loCD16+ monocyte subpopulations during disease flare and inactivity (quiescence), suggesting phenotypic alteration of monocytes in SJIA, independent of clinical status. We further analyzed phenotypic and functional alterations of SJIA monocytes in relation to disease activity and in comparison to age- and ethnicity-matched controls, specifically regarding development towards a M1- or M2- polarized phenotype. Gene expression profile, flow-cytometry based analysis of surface markers, baseline and LPS-induced production of cytokines and phosphorylation patterns in response to cytokine stimulation indicate that SJIA monocytes have a mixed M1/M2 phenotype during disease flare. Disease quiescence is associated not with normalization, but with an M2 phenotype, suggesting the existence of a state of compensated inflammation that is broke during disease flare.
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Minoia, Francesca, Francesca Bovis, Sergio Davì, AnnaCarin Horne, Michel Fischbach, Michael Frosch, Adam Huber, et al. "Development and initial validation of the MS score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis." Annals of the Rheumatic Diseases 78, no. 10 (July 11, 2019): 1357–62. http://dx.doi.org/10.1136/annrheumdis-2019-215211.
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ObjectiveTo develop and validate a diagnostic score that aids in identifying macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (sJIA).MethodsThe clinical and laboratory features of 362 patients with sJIA-associated MAS and 404 patients with active sJIA without evidence of MAS were collected in a multinational collaborative project. Eighty percent of the study population was used to develop the score and the remaining 20% constituted the validation sample. A Bayesian Model Averaging approach was used to assess the role of each clinical and laboratory variables in the diagnosis of MAS and to obtain the coefficients of selected variables. The final score, named MAS/sJIA (MS) score, resulted from the linear combination of these coefficients multiplied by the values of each variable. The cut-off that best discriminated MAS from active sJIA was calculated by means of receiver operating characteristic (ROC) curve analysis. Score performance was evaluated in both developmental and validation samples.ResultsThe MS score ranges from −8.4 to 41.8 and comprises seven variables: central nervous system dysfunction, haemorrhagic manifestations, active arthritis, platelet count, fibrinogen, lactate dehydrogenase and ferritin. A cut-off value ≥−2.1 revealed the best performance in discriminating MAS from active sJIA, with a sensitivity of 0.85, a specificity of 0.95 and a kappa value of 0.80. The good performance of the MS score was confirmed in the validation sample.ConclusionThe MS score is a powerful and feasible tool that may assist practitioners in making a timely diagnosis of MAS in patients with sJIA.
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Alekseeva, Ekaterina I., Dariya D. Van’kova, Margarita A. Soloshenko, Tatyana M. Dvoryakovskaya, Kseniya B. Isaeva, Rina V. Denisova, Anna V. Mamutova, Aleksandra M. Chomahidze, Nikolay A. Mayanskiy, and Natalya E. Tkachenko. "Pneumococcal Vaccine in Patients with Systemic Juvenile Idiopathic Arthritis Receiving Biologic Therapy: International Practice Review." Current Pediatrics 18, no. 2 (June 23, 2019): 101–8. http://dx.doi.org/10.15690/vsp.v18i2.2012.
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International practice of immunization against pneumococcus in patients with systemic juvenile idiopathic arthritis (SJIA) receiving biological therapy is generalized in this review. High efficiency and safety of pneumococcal vaccines in children with SJIA is presented. Numerous researches show the adequate immune response after vaccination as well as alongside with genetically engineered biologic drugs therapy. Prevention of pneumococcal disease in patients with SJIA reduces the risk of development of pneumococcal diseases severe complications.
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Petrongari, Duilio, Paola Di Filippo, Francesco Misticoni, Giulia Basile, Sabrina Di Pillo, Francesco Chiarelli, and Marina Attanasi. "Lung Involvement in Systemic Juvenile Idiopathic Arthritis: A Narrative Review." Diagnostics 12, no. 12 (December 8, 2022): 3095. http://dx.doi.org/10.3390/diagnostics12123095.
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Systemic juvenile idiopathic arthritis associated with lung disorders (sJIA-LD) is a subtype of sJIA characterized by the presence of chronic life-threatening pulmonary disorders, such as pulmonary hypertension, interstitial lung disease, pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia, which were exceptionally rare before 2013. Clinically, these children show a striking dissociation between the relatively mild clinical manifestations (tachypnoea, clubbing and chronic cough) and the severity of the pulmonary inflammatory process. Our review describes sJIA-LD as having a reported prevalence of approximately 6.8%, with a mortality rate of between 37% and 68%. It is often associated with an early onset (<2 years of age), macrophage activation syndrome and high interleukin (IL)-18 circulating levels. Other risk factors may be trisomy 21 and a predisposition to adverse reactions to biological drugs. The most popular hypothesis is that the increase in the number of sJIA-LD cases can be attributed to the increased use of IL-1 and IL-6 blockers. Two possible explanations have been proposed, named the “DRESS hypothesis” and the “cytokine plasticity hypothesis”. Lung ultrasounds and the intercellular-adhesion-molecule-5 assay seem to be promising tools for the early diagnosis of sJIA-LD, although high resolution computed tomography remains the gold standard. In this review, we also summarize the treatment options for sJIA-LD, focusing on JAK inhibitors.
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Saper, Vivian E., Guangbo Chen, Gail H. Deutsch, R. Paul Guillerman, Johannes Birgmeier, Karthik Jagadeesh, Scott Canna, et al. "Emergent high fatality lung disease in systemic juvenile arthritis." Annals of the Rheumatic Diseases 78, no. 12 (September 27, 2019): 1722–31. http://dx.doi.org/10.1136/annrheumdis-2019-216040.
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ObjectiveTo investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).MethodsIn a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.ResultsLD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features.ConclusionsA rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.
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Ailioaie, Laura Marinela, Constantin Ailioaie, and Gerhard Litscher. "Biomarkers in Systemic Juvenile Idiopathic Arthritis, Macrophage Activation Syndrome and Their Importance in COVID Era." International Journal of Molecular Sciences 23, no. 21 (October 22, 2022): 12757. http://dx.doi.org/10.3390/ijms232112757.
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Systemic juvenile idiopathic arthritis (sJIA) and its complication, macrophage activation syndrome (sJIA-MAS), are rare but sometimes very serious or even critical diseases of childhood that can occasionally be characterized by nonspecific clinical signs and symptoms at onset—such as non-remitting high fever, headache, rash, or arthralgia—and are biologically accompanied by an increase in acute-phase reactants. For a correct positive diagnosis, it is necessary to rule out bacterial or viral infections, neoplasia, and other immune-mediated inflammatory diseases. Delays in diagnosis will result in late initiation of targeted therapy. A set of biomarkers is useful to distinguish sJIA or sJIA-MAS from similar clinical entities, especially when arthritis is absent. Biomarkers should be accessible to many patients, with convenient production and acquisition prices for pediatric medical laboratories, as well as being easy to determine, having high sensitivity and specificity, and correlating with pathophysiological disease pathways. The aim of this review was to identify the newest and most powerful biomarkers and their synergistic interaction for easy and accurate recognition of sJIA and sJIA-MAS, so as to immediately guide clinicians in correct diagnosis and in predicting disease outcomes, the response to treatment, and the risk of relapses. Biomarkers constitute an exciting field of research, especially due to the heterogeneous nature of cytokine storm syndromes (CSSs) in the COVID era. They must be selected with utmost care—a fact supported by the increasingly improved genetic and pathophysiological comprehension of sJIA, but also of CSS—so that new classification systems may soon be developed to define homogeneous groups of patients, although each with a distinct disease.
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Kaleda, M., I. Nikishina, V. Matkava, A. Shapovalenko, E. Fedorov, and S. Salugina. "AB0725 MACROPHAGE ACTIVATION SYNDROME IN CHILDREN WITH RHEUMATIC DISEASES: ANALYSIS OF CASE SERIES." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1393.3–1394. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2098.
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Background:Macrophage activation syndrome (MAS) is a rare, but severe life-threatening complication of chronic rheumatic disease (RD) in children, which associated with high risks of the multiple organ failure and mortality.Objectives:Tо analyze demographic, clinical and laboratory parameters, timing of MAS and disease outcome in patients (pts) with MAS and RD.Methods:The study included all pts of single center with RD, who developed the MAS. The diagnosis was recognized according to Classification criteria for MAS in sJIA [1].Results:We observed 52 pts with RD and MAS: 31 (59.6%) with sJIA, 19 (36.5%) – SLE, 1(1.9%) – juvenile dermatomyositis (JDM), 1 (1.9%) – overlap syndrome (JIA+JDM). Pts with MAS accounted of 26% of all pts with sJIA, 7.6% of all pts with SLE. The mean age of pts at onset of sJIA was 2.6 y [1.5; 5.75], at onset of SLE – 11.8 y [8.6; 13.95]. The patient with JDM was 6.5 years old, pts with overlap syndrome – 3.5 years old. Male to female ratio was 1:1,7. A total of 63 episodes of MAS was recorded (41 – in sJIA, 20 – SLE, 1 – JDM, 1 - overlap syndrome). 23 pts (44.2%) had MAS at onset, 26 pts (50%) – “classic” MAS (during the course of disease), 3 pts (5.8%) – recurrent MAS. The clinical manifestations of MAS included fever (90.4%), hepatomegaly (50%), pericarditis (46.2%), hemorrhagic rash (32.7%), neurologic involvement (42.3%), lung involvement (34.6%). We found hyperferritinemia in 98%, thrombocytopenia in 78.8%, increased transaminases in 88.5%, hypofibrinogenemia in 40.4%, hypertriglyceridemia in 42.3 % of pts. Most severe course of MAS was established in pts with ferritin levels >1500 ng/ml and with hypertriglyceridemia more than 6.0 mmol/l at an early stage. Bone marrow investigation was performed in 21 pts, and the evidence of haemophagocytosis was confirmed in 8 pts (38%). First features of MAS were fever, sleepiness, lower platelet counts, high TA. Lesions of the skin and mucous were mainly represented by point hemorrhages at an early stage in pts with SLE and MAS, the development of a bright rash with itching was typical for pts with sJIA and MAS. There are no principal differences between course of MAS in sJIA and other RD in children, but mild “subclinical” cases of MAS were observed only in pts with sJIA on biologics. For treatment of MAS all pts were administered high dose of glucocorticoids (per os+iv). Pts with SLE received: cyclophosphamide iv - 5 (26.3%), cyclosporine per os 1 (5.2%), IVIGs - 6 (31.6%), rituximab - 2 pts (10.5%). Pts with sJIA received: cyclosporine per os - 20 (64.5%), IVIGs - 25 (80.6%), 1 etoposide - (3.2%). Patient with overlap syndrome received cyclosporine per os. 8 pts (15.4%) died from MAS (3 with sJIA, 5 – with SLE).Conclusion:MAS can develop in various children’s RD, but more often in pts with sJIA. In our observation more pts had MAS during the course of disease, not at onset. Rapid recognition of MAS can improve treatment outcomes and prognosis.References:[1]Ravelli A, Minoia F, Davì S, et al. 2016.Disclosure of Interests:None declared
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Alekseeva, E., R. Denisova, S. Valieva, T. Bzarova, T. Sleptsova, E. Mitenko, and K. Isayeva. "P02-029 - CAPS or SJIA." Pediatric Rheumatology 11, Suppl 1 (2013): A136. http://dx.doi.org/10.1186/1546-0096-11-s1-a136.
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Kathmann, Wiebke. "Hoffnung für Patienten mit SJIA." pädiatrie hautnah 25, no. 2 (March 21, 2013): 117. http://dx.doi.org/10.1007/s15014-013-0071-z.
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Kostik, Mikhail Mikhaylovich, Tatyana Serafimovna Likhacheva, Irina Aleksandrovna Chikova, Natal’ya Valer’yevna Buchinskaya, Natal’ya Nikolaevna Abramova, Olga Valeryevna Kalashnikova, Randy Q. Cron, and Vyacheslav Grigoryevich Chasnyk. "Higher-dose canakinumab therapy for refractory macrophage activation syndrome in children with systemic juvenile idiopathic arthritis: two case reports." Pediatrician (St. Petersburg) 5, no. 4 (December 15, 2014): 14–19. http://dx.doi.org/10.17816/ped5414-19.
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Macrophage activation syndrome (MAS) is a life-threatening, potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA) appears in non-remitted fever, cytopenia, coagulopathy, liver and CNS dysfunctions. Triggers of MAS could be disease activity, infections and medications. Known IL-1 is the key cytokine in pathogenesis of MAS and SJIA, and disease flare associated with increased amounts of different cytokines, especially IL-1β. Many cases of MAS are medically-refractory to traditional doses of cytokine inhibition and may require increased dosing of biologic cytokine blockade. Interleukin-1 (IL-1) is typically a key cytokine in the pathogenesis of sJIA and associated MAS. When MAS occurs in the setting of sJIA treated with IL-1 inhibitors, then increased dosing of IL-1 blockers may be beneficial. This has been shown for anakinra, an IL-1 receptor antagonist, but this drug is currently not available worldwide. Another IL-1 blocker, canakinumbab (CKB), is a monoclonal antibody that blocks IL-1β, but does not also block IL-1α like anakinra. Herein, we describe 2 sJIA patients who developed MAS on standard doses of CKB (4 mg/kg). Both patients received an increased dose of CKB: 150 mg (7.5 and 12.5 mg/kg, respectively) with rapid and complete resolution of MAS. Later the CKB doses was tapered to normal regimen. No side effects or adverse events were noticed during usage of increased CKB doses. Increased dosing of CKB should be considered for CKB-treated sJIA patients who develop MAS on standard dosing.
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Lee, Pui Y., Grant S. Schulert, Scott W. Canna, Yuelong Huang, Jacob Sundel, Ying Li, Kacie J. Hoyt, et al. "Adenosine deaminase 2 as a biomarker of macrophage activation syndrome in systemic juvenile idiopathic arthritis." Annals of the Rheumatic Diseases 79, no. 2 (November 9, 2019): 225–31. http://dx.doi.org/10.1136/annrheumdis-2019-216030.
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ObjectiveMacrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterised by a vicious cycle of immune amplification that can culminate in overwhelming inflammation and multiorgan failure. The clinical features of MAS overlap with those of active sJIA, complicating early diagnosis and treatment. We evaluated adenosine deaminase 2 (ADA2), a protein of unknown function released principally by monocytes and macrophages, as a novel biomarker of MAS.MethodsWe established age-based normal ranges of peripheral blood ADA2 activity in 324 healthy children and adults. We compared these ranges with 173 children with inflammatory and immune-mediated diseases, including systemic and non-systemic JIA, Kawasaki disease, paediatric systemic lupus erythematosus and juvenile dermatomyositis.ResultsADA2 elevation beyond the upper limit of normal in children was largely restricted to sJIA with concomitant MAS, a finding confirmed in a validation cohort of sJIA patients with inactive disease, active sJIA without MAS or sJIA with MAS. ADA2 activity strongly correlated with MAS biomarkers including ferritin, interleukin (IL)-18 and the interferon (IFN)-γ-inducible chemokine CXCL9 but displayed minimal association with the inflammatory markers C reactive protein and erythrocyte sedimentation rate. Correspondingly, ADA2 paralleled disease activity based on serial measurements in patients with recurrent MAS episodes. IL-18 and IFN-γ elicited ADA2 production by peripheral blood mononuclear cells, and ADA2 was abundant in MAS haemophagocytes.ConclusionsThese findings collectively identify the utility of plasma ADA2 activity as a biomarker of MAS and lend further support to a pivotal role of macrophage activation in this condition.
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Roth, Johannes. "Komplizierter Verlauf einer systemischen JIA." Arthritis und Rheuma 42, no. 02 (April 2022): 114–19. http://dx.doi.org/10.1055/a-1781-8225.
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ZUSAMMENFASSUNGDie systemische juvenile idiopathische Arthritis (sJIA) kann sehr behandlungsresistent sein und es können erhebliche Komplikationen einschließlich einer interstitiellen Lungenerkrankung auftreten. Anhand der Fallgeschichte einer sJIA-Patientin mit fortgeschrittener Lungenerkrankung werden molekulardiagnostische Methoden, neue Behandlungsoptionen und ethische Überlegungen bei der Versorgung komplexer Patienten diskutiert.
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Canny, Susan, and Elizabeth Mellins. "New frontiers in the treatment of systemic juvenile idiopathic arthritis." F1000Research 6 (June 22, 2017): 971. http://dx.doi.org/10.12688/f1000research.11327.1.
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Systemic juvenile idiopathic arthritis (sJIA) and its most significant complication, macrophage activation syndrome (MAS), have traditionally been treated with steroids and non-steroidal anti-inflammatory medications. However, the introduction of biologic medications that inhibit specific cytokines, such interleukins 1 and 6, has changed the treatment paradigm for sJIA patients. In this review, we discuss the therapies currently used in the treatment of sJIA as well as novel targets and approaches under consideration, including mesenchymal stromal cell therapy and JAK inhibitors. We also discuss targeting cytokines that have been implicated in MAS, such as interferon gamma and interleukin 18.
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Krekhova, E., E. Alexeeva, T. Dvoryakovskaya, K. Isaeva, R. Denisova, O. Lomakina, A. Mamutova, et al. "POS1312 DRUG SURVIVAL FOR IL-6 INHIBITOR TOCILIZUMAB: DATA FROM A SINGLE-CENTER OBSERVATION." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 938–39. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2255.
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Background:The efficacy of tocilizumab for treatment patients with systemic juvenile idiopathic arthritis (sJIA) was demonstrated before. We want to describe tocilizumab drug survival based on data from a single-center observation.Objectives:To analyze the drug survival of tocilizumab in patients with sJIA treated at the National Medical Research Center of Children`s health, Moscow, Russia.Methods:Medical records from sJIA patients treated with tocilizumab (TOC) were analyzed retrospectively from the National Medical Research Center of Children`s health, Moscow, Russia.Results:One hundred ninety-two patients presenting with sJIA were included in this observation, with a median age at treatment initiation of 7,2 (interquartile range, IQR 3,9-10,8) years and a median disease duration of 1,9 (IQR 0,4-5,9) years. All patients had been bio-naive. TOC therapy was highly effective in patients with sJIA. At 6 month of follow-up 148/172 (86%) patients achieved inactive disease according the criteria C. Wallace, disease activity persisted in 24/172 (14%) patients. At 1 year of medication 139/150 (92%) patients had inactive disease. We analyzed the reason of TOC withdrawal retrospectively. A total of 82/192 drug withdrawals were performed. TOC was discontinued due to primary ineffectiveness in 4 patients, due to secondary ineffectiveness in 39 patients. 33 patients achieved drug-free remission. Six patients developed side effects that required discontinuation of TOC therapy (4 patients had allergic reactions, 1 patient developed tuberculosis, 1 patient had severe neutropenia). 47/82 patients were switched on other biologic drug: on canakinumab (31), on TNF-inhibitors (11), on rituximab (5). In summary, TOC was canceled in 49/192 (25%) patients due to ineffectiveness or AEs in our cohort.Conclusion:These results demonstrated that TOC is highly effective as the first biologic drug in patients with sJIA. Our observations have shown a good tolerability and survival of the IL-6 inhibitor TOC in patients with sJIA treated in a real-world clinical setting.Disclosure of Interests:None declared
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Alexeeva, Ekaterina I., Dariya D. Vankova, Tatyana M. Dvoryakovskaya, Ksenia B. Isaeva, Rina V. Denisova, Anna V. Mamutova, Aleksandra M. Chomakhidze, et al. "Efficacy of Pneumococcal Polysaccharide Conjugate Vaccine (13-valent, Adsorbed) in Patients with Systemic Juvenile Idiopathic Arthritis Treated with Genetically Engineered Biologic Drugs (Tocilizumab or Canakinumab): Prospective Cohort Study." Current Pediatrics 19, no. 3 (August 10, 2020): 190–99. http://dx.doi.org/10.15690/vsp.v19i3.2114.
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Background. Immunological potency of 13-valent pneumococcal vaccine (PCV-13) in children with systemic juvenile idiopathic arthritis (SJIA) is still unstudied. Estimates of the genetically engineered biologic drugs (GEBD) effects on pneumococcal vaccination results also remain controversial.Objective. The aim of the study was to explore the PCV-13 efficacy in patients with SJIA and who is on treatment with monoclonal antibodies against interleukin 6 receptor (tocilizumab) and interleukin 8 receptor beta (canakinumab).Methods. The study included patients under the age of 18 with SJIA in remission or active form of disease vaccinated with PCV-13. The vaccine was administered in single dose of 0.5 ml intramuscularly in patients on treatment with GEBD or 3 weeks before GEBD administration for the first time (for patients with active disease). Vaccination was considered effective at achievement of the minimum protective level of antibodies to capsular polysaccharide of pneumococcus (anti-SPP IgG; ≥ 7 U/ml) or increase of anti-SPP IgG level ≥ 2 times in 4 weeks after vaccination. The anti-SPP IgG levels were measured with enzyme immunoassay.Results. The study included 53 patients (27 girls) in remission of SJIA and 25 (16 girls) in active disease. Median age was 13.3 and 10.8 years respectively. Tocilizumab/canakinumab was administrated in 43/10 and 18/7 patients respectively. Minimum significant anti-SPP IgG level and two-fold increase in anti-SPP IgG level were recorded in 49/53 (92%) and 32/53 (60%) patients with SJIA in remission, as well as in 22/25 (88%) and 18/25 (72%) patients in active disease respectively. PCV-13 immunological potency in patients with SJIA in remission and in active disease (in those who were initially administrated and who did not receive GEBD) did not differ.Conclusion. PCV-13 vaccination allows to achieve protective antibodies level in most of the patients with SJIA in children population regardless of the disease stage and the history of GEBD administration.
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Worley, Emily, Weijie Li, and Jordan T. Jones. "Atypical Presentation of Systemic Arthritis in a Toddler with Down Syndrome." Case Reports in Pediatrics 2021 (August 11, 2021): 1–4. http://dx.doi.org/10.1155/2021/6567770.
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Systemic juvenile idiopathic arthritis (sJIA) is a chronic, inflammatory disease of childhood, which is characterized by the combination of arthritis, serositis, daily, high-spiking fevers, and evanescent macular rash and can present with the life-threatening complication of macrophage activation syndrome (MAS). Children with Down syndrome (DS) have complex medical challenges related to abnormalities in their immune system, which can cause a broad spectrum of disease manifestations, which can occur atypically. Children with DS are at increased risk for arthritis and interstitial lung disease (ILD) associated with sJIA that has high mortality. This case report outlines an atypical presentation of sJIA in a 21-month-old male with DS in which fever was not part of the initial presentation of sJIA and then later developed MAS and ILD. Due to broad spectrum of disease and atypical presentation in children with DS, this case report was created to increase awareness of atypical presentations of rheumatic disease in children with DS.
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Cepika, Alma-Martina, Romain Banchereau, Elodie Segura, Marina Ohouo, Brandi Cantarel, Kristina Goller, Victoria Cantrell, et al. "A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis." Journal of Experimental Medicine 214, no. 11 (September 21, 2017): 3449–66. http://dx.doi.org/10.1084/jem.20170412.
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The etiology of sporadic human chronic inflammatory diseases remains mostly unknown. To fill this gap, we developed a strategy that simultaneously integrates blood leukocyte responses to innate stimuli at the transcriptional, cellular, and secreted protein levels. When applied to systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory disease of unknown etiology, this approach identified gene sets associated with specific cytokine environments and activated leukocyte subsets. During disease remission and off treatment, sJIA patients displayed dysregulated responses to TLR4, TLR8, and TLR7 stimulation. Isolated sJIA monocytes underexpressed the IL-1 inhibitor aryl hydrocarbon receptor (AHR) at baseline and accumulated higher levels of intracellular IL-1β after stimulation. Supporting the demonstration that AHR down-regulation skews monocytes toward macrophage differentiation, sJIA monocytes differentiated in vitro toward macrophages, away from the dendritic cell phenotype. This might contribute to the increased incidence of macrophage activation syndrome in these patients. Integrated analysis of high-dimensional data can thus unravel immune alterations predisposing to complex inflammatory diseases.
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Gorelik, Mark, Ndate Fall, Mekibib Altaye, Michael G. Barnes, Susan D. Thompson, Alexei A. Grom, and Raphael Hirsch. "Follistatin-like Protein 1 and the Ferritin/Erythrocyte Sedimentation Rate Ratio Are Potential Biomarkers for Dysregulated Gene Expression and Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis." Journal of Rheumatology 40, no. 7 (May 15, 2013): 1191–99. http://dx.doi.org/10.3899/jrheum.121131.
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Objective.Follistatin-like protein 1 (FSTL-1) is a secreted glycoprotein overexpressed in certain inflammatory diseases. Our objective was to correlate FSTL-1 levels with gene expression, known biomarkers, and measures of disease activity in systemic juvenile idiopathic arthritis (sJIA), including macrophage activation syndrome (MAS).Methods.FSTL-1 serum levels were measured by ELISA in 28 patients with sJIA, including 7 patients who developed MAS, and 30 healthy controls. Levels were correlated with erythrocyte sedimentation rate (ESR), ferritin, and soluble interleukin-2 receptor-α (sIL-2Rα). Gene expression based on FSTL-1 levels was analyzed in peripheral blood mononuclear cells (PBMC).Results.Serum levels of FSTL-1 were elevated at time of presentation of sJIA (mean 200.7 ng/ml) and decreased to normal (mean 133.7 ng/ml) over 24 months (p < 0.01). FSTL-1 levels were markedly elevated during acute MAS (mean 279.8 ng/ml) and decreased to normal following treatment (p < 0.001). FSTL-1 levels correlated with serum markers of inflammation, including sIL-2Rα and ferritin. Ferritin/ESR ratio was superior to ferritin, sIL-2Rα, and FSTL-1 in discriminating MAS from new-onset sJIA. PBMC from patients with FSTL-1 levels > 200 ng/ml showed altered expression of genes related to innate immunity, erythropoiesis, and natural killer cell dysfunction. Two patients with the highest FSTL-1 levels at disease onset (> 300 ng/ml) ultimately developed MAS.Conclusion.Elevated pretreatment serum FSTL-1 levels in sJIA are associated with dysregulated gene expression suggestive of occult MAS, and may have utility in predicting progression to overt MAS. Ferritin/ESR ratio may be superior to ferritin alone in discriminating overt MAS from new-onset sJIA.
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de Zegher, Francis, Nele Reynaert, Lien De Somer, Carine Wouters, and Mathieu Roelants. "Growth Failure in Children with Systemic Juvenile Idiopathic Arthritis and Prolonged Inflammation despite Treatment with Biologicals: Late Normalization of Height by Combined Hormonal Therapies." Hormone Research in Paediatrics 90, no. 5 (2018): 337–43. http://dx.doi.org/10.1159/000489778.
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Background: Biologicals targeting the interleukin (IL)-1β or IL-6 pathway are becoming prime choices for the treatment of children with systemic juvenile idiopathic arthritis (sJIA). Up to 1 in 3 sJIA children receiving such treatment continues to have inflammatory activity and to require supra-physiological glucocorticoid doses which may reduce growth velocity for years and may lead to an extremely short stature for age, if not for life. Currently, there is no long-term proposal to normalize the adult height of these children with sJIA. Methods and Results: We present long-term (up to 10 years), proof-of-concept evidence that the adult stature and adipose body composition of short sJIA children can be normalized with a hormonal combination strategy: (i) pubertal onset is postponed with a gonadotropin-releasing hormone analog (triptorelin) until a minimum height is reached, or until prepubertal growth is exhausted, and (ii) height gain is promoted with growth hormone (≈50 μg/kg/day), once inflammation is under control and high glucocorticoid doses are no longer needed. The latter treatment takes advantage of the window of relative glucocorticoid deficiency, which is known to open after prolonged glucocorticoid administration, and to be uniquely favorable to height gain. Conclusion: A long-term combination of biological and hormonal treatments for short sJIA children can be guided by a simple concept that involves (i) postponement of pubertal development and (ii) growth-promoting therapy after the episodes of major inflammation and high-dose glucocorticoid treatment. Limited long-term experience in short sJIA children suggests that this strategy leads consistently – albeit late – to a normal adult stature.
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Yasin, Shima, Ndate Fall, Rachel A. Brown, Maggie Henderlight, Scott W. Canna, Charlotte Girard-Guyonvarc’h, Cem Gabay, Alexei A. Grom, and Grant S. Schulert. "IL-18 as a biomarker linking systemic juvenile idiopathic arthritis and macrophage activation syndrome." Rheumatology 59, no. 2 (July 20, 2019): 361–66. http://dx.doi.org/10.1093/rheumatology/kez282.
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Abstract Objectives Systemic juvenile idiopathic arthritis (sJIA) is a childhood arthritis with features of autoinflammation and high risk of macrophage activation syndrome (MAS). IL-18 has been shown to have key roles in sJIA and MAS. We aimed to examine IL-18 levels in sJIA in relation to disease activity and history of MAS and other disease biomarkers namely S100 proteins and CXCL9. Methods Total IL-18, CXCL9 and S100 proteins levels were determined in 40 sJIA patients, and IL-18 levels were compared between patients with regards to disease activity, history of MAS, and other biomarkers. Results Total IL-18 levels were significantly higher in patients with active sJIA (median 16 499 pg/ml; interquartile range (IQR) 4816–61 839), and remained persistently elevated even in the majority of patients with inactive disease (1164 pg/ml; IQR 587–3444). Patients with history of MAS had significantly higher IL-18 levels (13 380 pg/ml; IQR 4212–62 628) as compared with those without MAS history (956.5 pg/ml; IQR 276.3–4262.5). Total IL-18 performed well with area under the curve of 0.8145 and 0.84 in predicting disease activity and history of MAS, respectively. We observed moderate correlation between IL-18 and CXCL9 (R = 0.56), S100A8/A9 (R = 0.47) and S100A12 (R = 0.46). The correlation was stronger for ferritin (R = 0.74) and overall for those with active disease. Conclusion Total IL-18 levels were elevated in the majority of sJIA patients regardless of clinical features, but were higher in patients with active disease and history of MAS. Change in IL-18 may reflect increased disease activity or development of MAS.
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Alexeeva, E., E. Krekhova, T. Dvoryakovskaya, K. Isaeva, A. Chomakhidze, E. Chistyakova, O. Lomakina, et al. "THU0506 LONG-TERM EFFECTIVENESS AND SAFETY OF CANAKINUMAB AS A SECOND BIOLOGIC AFTER TOCILIZUMAB IN CHILDREN WITH EARLY AND LATE JIA WITH ACTIVE SYSTEMIC FEATURES." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 491.2–492. http://dx.doi.org/10.1136/annrheumdis-2020-eular.5706.
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Background:Canakinumab (CAN) is often used as second biologics in juvenile idiopathic arthritis with active systemic features (sJIA). However, there are little information about its long-term efficacy and safety.Objectives:To evaluate the long-term effectiveness and safety of CAN as a second biologics after tocilizumab (TOC) in sJIA patients depending on the duration of the disease.Methods:Thirty-one patients were enrolled in this study: the group of early sJIA (with duration shorter than 2 years, 19 patients) and the group of late sJIA (with duration longer than 2 years, 12 patients). At the baseline, information was collected on the characteristics of the onset of the disease, previous therapy and its success. At each visit at least 1 time per year clinical and laboratory characteristics of sJIA severity were assessed. Response to therapy was assessed using the ACRPedi 30/50/70/90 criteria and the C.Wallace criteria for inactive disease (WID) and clinical remission.Results:The most common reason for withdrawal of previous TOC was secondary ineffectiveness (22 cases, 71%); in 6 cases (19.4%) allergic reaction was observed; in two cases (6.5%) primary non-effectiveness appeared; and in one case (3.2%) there was marked infusion reaction.At CAN initiation, sJIA activity was as follows: 15 (12: 23) for JADAS-71; 45 (36.5: 72) and 58 (45: 81) for physician’s and patient’s global assessment VAS; and 0.25 (0: 0.62) for the CHAQ disability index.After 12-month treatment, 22 (71%) patients reached WID: 21 on CAN therapy and 1 – after CAN withdrawal due to administrative reason and stable WID. ACR50/70/90 response was achieved by 84.2%/84.2%/64.7% patients in early arthritis group and in 83.3%/75%/75% patients in late arthritis group (p=0.792).However, 42.1% of patients with early sJIA achieved remission in the first 1.5 years without any further relapse during all the studied period and only 16.7% of patients with late arthritis (p=0.239). In multivariable analysis, it was found that age of sJIA onset (OR (2.5-97.5 CI) 0.353 (0.13 - 0.72), p=0.015), number of joints with active arthritis at sJIA onset (2.308 (1.26-5.73), p=0.025), and JADAS-71 at sJIA onset (0.664 (0.44-0.88), p=0.016) were associated with successful treatment with rapid achievement of stable remission.During the 76.7 patient-years follow-up period, 18 of 31 (58.1%) patients were able to achieve a stable clinical remission and 27 (87.1%) – WID. Two patients have achieved successfully drug-off remission. Serious adverse event (SAE) was reported in one (3.2%) patient (enteritis).Conclusion:Long-term canakinumab therapy proved to be effective and safe as a second biologics after tocilizumab for any duration of the disease. However, patients with early arthritis are more likely to quickly achieve stable remission without further relapse. Younger onset of sJIA with polyarthritis involvement and low disease activity are predictors of rapid and stable remission.Disclosure of Interests:Ekaterina Alexeeva Grant/research support from: Roche, Pfizer, Centocor, Novartis, Speakers bureau: Roche, Novartis, Pfizer., Elizaveta Krekhova: None declared, Tatyana Dvoryakovskaya: None declared, Ksenia Isaeva: None declared, Aleksandra Chomakhidze: None declared, Evgeniya Chistyakova: None declared, Olga Lomakina: None declared, Rina Denisova: None declared, Anna Mamutova: None declared, Anna Fetisova: None declared, Marina Gautier: None declared, Dariya Vankova: None declared, Meyri Shingarova: None declared, Alina Alshevskaya: None declared, Andrey Moskalev: None declared, Ivan Kriulin: None declared
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Pardeo, Manuela, Jianmei Wang, Nicolino Ruperto, Ekaterina Alexeeva, Vyacheslav Chasnyk, Rayfel Schneider, Gerd Horneff, et al. "Neutropenia During Tocilizumab Treatment Is Not Associated with Infection Risk in Systemic or Polyarticular-course Juvenile Idiopathic Arthritis." Journal of Rheumatology 46, no. 9 (March 1, 2019): 1117–26. http://dx.doi.org/10.3899/jrheum.180795.
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Objective.To determine whether neutropenia is associated with increased risk for infection in patients with systemic juvenile idiopathic arthritis (sJIA) and polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with tocilizumab (TCZ).Methods.Data up to Week 104 from 2 phase III trials of intravenous TCZ in sJIA (n = 112;ClinicalTrials.gov,NCT00642460) and pcJIA (n = 188;ClinicalTrials.gov,NCT00988221) were pooled. Worst common toxicity criteria grade and lowest observed absolute neutrophil count (ANC) were identified for each patient. Associations between patient characteristics and lowest observed ANC were tested using univariate regression analysis. Infection and serious infection rates per 100 patient-years (PY) in periods associated with grades 1/2 and 3/4 neutrophil counts were compared with rates associated with normal neutrophil counts.Results.ANC decreased to grade ≥ 3 in 25.0% and 5.9% of sJIA and pcJIA patients, respectively, and decreases were transient. Young age (p = 0.047) and methotrexate use (p = 0.012) were positively associated with neutropenia in patients with sJIA but not in patients with pcJIA. The rate of serious infections in patients with sJIA (10.9/100 PY; 95% CI 6.8–16.5) tended to be higher than in patients with pcJIA (5.2/100 PY; 95% CI 3–8.5). No increase in rates of serious or nonserious infections was observed during periods of neutropenia in either trial.Conclusion.Patients with JIA treated with TCZ experienced transient neutropenia that was not associated with an increased number of infections.
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R, N., A. Jain, H. Muhammed, A. Aggarwal, V. Agarwal, L. Gupta, D. Misra, A. Lawrence, and R. Misra. "SAT0230 MACROPHAGE ACTIVATION SYNDROME IN SLE AND SYSTEMIC ONSET JIA: SIMILAR OR DISSIMILAR." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1057.2–1058. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4469.
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Background:Macrophage activation syndrome (MAS) is a serious complication in rheumatic disease. Fever and hyperferritinemia are common in systemic onset JIA and cytopenias are common in SLE thus recognising MAS in them is a challenge.Objectives:We compared clinical, laboratory parameters, various classification criteria for MAS, and its outcome in SLE and sJIA.Methods:Clinical and laboratory data were extracted from clinician diagnosed cases of MAS with SLE/sJIA who were admitted between 2004-2018 at a tertiary care hospital. Percentage of patients satisfying Ravelli, International consensus, HLH 2004 and criteria proposed by Parodi et al1were calculated.Results:Among 33 patients (18 females) with MAS 19 had SLE and 14 had sJIA. MAS was more likely to be the presenting manifestation of disease in SLE as compared to sJIA (p<0.05). There were no differences in the clinical features among these two diseases. EBV and CMV were identified in 2 patients each as the trigger for MAS.Patients with SLE had lower baseline TLC and platelet whereas patients with sJIA-MAS had significantly higher median CRP (p = 0.002), fall in TLC (p=0.012) and delta ESR/CRP ratio (p=0.02) and lower fibrinogen level (p=0.006). Neutrophil to lymphocyte ratio, Ferritin/CRP ratio and number of patients with Ferritin/ESR >80 were similar. Bone Marrow hemophagocytosis was seen in only in 21% of patients.Only 6/33 fulfilled HLH criteria but criteria meant for sJIA or SLE performed well for both diseases and majority of patients could be diagnosed using them. Treatment included steroids(100%), cyclosporine(30%), Tacrolimus(21%), cyclophosphamide(21%), etoposide(3%) and thalidomide(12%). Mortality was similar in both groups.Table 1.Agreement amongst MAS/HLH criteria in SLE and sJIA MASSLE-MASHLHRavelli et alConsensusParodi et alHLH4444Ravelli et al4191918Consensus4191918Parodi et al4181818sJIA-MASHLHRavelli et alConsensusParodi et alHLH2222Ravelli et al2121112Consensus2111212Parodi et al2121214Table 2.Comparison with various other cohortsMinoia et alsJIAn (%)Our studysJIA, n (%)Our Study SLE, n (%)SLE, n (%) Ai-Chun Liu et alJuvenile SLE n (%)Parodi et alNumber36214193238MAS as presenting feature (%)80 (22)4 (28)12 (63)NA24 (63)Most common manifestation (%)Fever (96)Fever (100)Fever (89)Fever (96)Fever (89)Most common triggerDisease activityDisease activityDisease activityDisease activityDisease activityBM done251 (72.3)8 (57)12 (63)32 (96)38 (100)BM hemophagocytosis150 (60.7)2 (25)5 (41)32 (100)20 (52)Mortality28 (8)2 (14)2 (10.5)4 (12.5)4 (11.4)Patients meeting JIA criteria %NA-100NA100Patients meeting HLH criteria %NA1419NA66Conclusion:MAS is more likely to be presenting manifestation in SLE compared to sJIA. Though lab parameters are significantly different in MAS associated with SLE & sJIA, criteria meant for MAS in sJIA or SLE MAS performed equally well in both diseases.References:[1]Parodi A et al, Macrophage activation syndrome in juvenile systemic lupus erythematosus: a multinational multicenter study of thirty-eight patients. Arthritis Rheum. 2009 Nov;60(11):3388-99.Disclosure of Interests:None declared
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Batulevičiūtė, Lina, Violeta Radžiūnienė, Ramunė Vankevičienė, Odeta Kinčinienė, and Violeta Panavienė. "VAIKŲ NEAIŠKIOS KILMĖS KARŠČIAVIMAS." Medicinos teorija ir praktika 20, no. 4 (February 20, 2014): 376–81. http://dx.doi.org/10.15591/mtp.2014.067.
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Reikšminiai žodžiai: neaiškios kilmės karščiavimas, sisteminis jaunatvinis idiopatinis artritas, vaikai. Santrumpos: sJIA – sisteminis jaunatvinis idiopatinis artritas, MAS – makrofagų aktyvacijos sindromas, NKK – neaiškios kilmės karščiavimas. Neaiškios kilmės karščiavimas – karščiavimas ≥ 38,3 °C, trunkantis ilgiau nei 8 dienas, kai, įvertinus anamnezę, klinikinės apžiūros bei pradinių laboratorinių tyrimų duomenis, priežastis lieka nenustatyta. Pagrindinės karščiavimo priežastys vaikų amžiuje yra infekcijos, autoimuninės ligos ir navikai. Tarp reumatinių ligų dažniausias yra sisteminis jaunatvinis idiopatinis artritas. sJIA būdinga ne trumpiau kaip 2 savaites, mažiausiai 3 dienas iš eilės trunkantis karščiavimas, trumpalaikis bėrimas, difuzinė limfadenopatija, hepatosplenomegalija, serozitas ir, žinoma, artritas ar artralgija [1]. Ligos pradžioje apie trečdaliui sJIA sergančių pacientų dar nebūna artrito, o tai neretai sukelia diagnostinių sunkumų. Laboratorinių ir vaizdinių tyrimo metodų duomenys yra nespecifiniai. Nustatant diagnozę, remiamasi klinikiniais simptomais, kurie pasižymi didele įvairove bei vertinimo subjektyvumu. Diferencinei diagnostikai svarbiausia ekskliuduoti kitas ligas: infekciją, leukemiją, neuroblastomą, periodinius karščiavimo sindromus, vaskulitus, sistemines jungiamojo audinio ligas [1]. Makrofagų aktyvacijos sindromas (MAS) – gyvybei grėsminga sJIA komplikacija. Nediagnozavus laiku, paciento ligos išeitis fatališka. Naujausias gydymas pagrįstas citokinų (IL-1, IL-6) slopinimu. Šiame straipsnyje bus nagrinėjamas NKK atvejis, kurio priežastis buvo jaunatvinis idiopatinis artritas.
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RUSSO, RICARDO A. G., and MARÍA M. KATSICAS. "Patients with Very Early-onset Systemic Juvenile Idiopathic Arthritis Exhibit More Inflammatory Features and a Worse Outcome." Journal of Rheumatology 40, no. 3 (January 15, 2013): 329–34. http://dx.doi.org/10.3899/jrheum.120386.
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Objective.Systemic juvenile idiopathic arthritis (SJIA) frequently leads to disability and damage. Predictive factors for a poor outcome include persistent systemic features and younger age at onset. We describe and analyze disease features in patients with early-onset (EO) SJIA (disease onset before age 18 mo) and compare them to patients with later-onset (LO) disease.Methods.Clinical features at onset, activity measures (occurrence of macrophage activation syndrome, remission), and outcome measures for disability [Childhood Health Assessment Questionnaire (CHAQ) ≥ 0.5] and damage [radiographic joint destruction, Juvenile Arthritis Damage Index (JADI) score, growth retardation] observed during followup were analyzed retrospectively in patients with SJIA followed for ≥ 3 years since disease onset.Results.In total 132 patients were included. SJIA started at age ≤ 18 months in 19 (14%) patients and at a later age in 113 (86%) children. At onset, serositis (p < 0.01) and hepatomegaly (p < 0.05) were more frequent in EO patients, who also exhibited lower hemoglobin levels (p < 0.03) and higher platelet counts (p < 0.03) than patients with LO. Macrophage activation syndrome occurred in 20 patients (11 EO and 9 LO; p < 0.0001). Remission was achieved by 49 patients (37%; 4 EO and 45 LO). At last visit, destructive hip disease (p < 0.04), growth retardation (p < 0.01), radiographic damage (p < 0.02), and disability (p < 0.04) were more frequent in patients with EO disease, who had higher JADI scores (p < 0.003).Conclusion.Patients with EO exhibited a more aggressive and destructive disease course than patients with LO SJIA.
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Bracaglia, Claudia, Kathy de Graaf, Denise Pires Marafon, Florence Guilhot, Walter Ferlin, Giusi Prencipe, Ivan Caiello, et al. "Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis." Annals of the Rheumatic Diseases 76, no. 1 (June 13, 2016): 166–72. http://dx.doi.org/10.1136/annrheumdis-2015-209020.
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ObjectivesInterferon-γ (IFNγ) is the pivotal mediator in murine models of primary haemophagocytic lymphohistiocytosis (pHLH). Given the similarities between primary and secondary HLH (sec-HLH), including macrophage activation syndrome (MAS), we investigate the involvement of the IFNγ pathway in MAS by evaluating levels of IFNγ and of the induced chemokines, and their relation with laboratory parameters of MAS in systemic juvenile idiopathic arthritis (sJIA) patients with MAS and in a murine MAS model.MethodsThe Luminex multiplexing assay was used to assess serum levels of interleukin (IL)-1β, IL-6, IFNγ and of the IFNγ-induced chemokines CXCL9, CXCL10 and CXCL11 in patients with sec-HLH (n=11) and in patients with sJIA (n=54), of whom 20 had active MAS at sampling. Expression of IFNγ-induced chemokines was assessed in IL-6 transgenic mice in which MAS is induced by TLR4 stimulation with lipopolysaccharide.ResultsLevels of IFNγ and of IFNγ-induced chemokines were markedly elevated during active MAS and sec-HLH and were significantly higher in patients with MAS compared with active sJIA without MAS. Levels in patients with active sJIA without MAS were comparable to those of patients with clinically inactive sJIA. During MAS, ferritin and alanine transferase levels and neutrophil and platelet counts were significantly correlated with serum levels of IFNγ and CXCL9. In murine MAS, serum levels of ferritin were significantly correlated with mRNA levels of Cxcl9 in liver and spleen.ConclusionsThe high levels of IFNγ and of IFNγ-induced chemokines and their correlation with the severity of laboratory abnormalities of MAS suggest a pivotal role of IFNγ in MAS.
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Zimmermann, Wolfgang. "Dauerhafte Symptomreduktion bei CAPS und sJIA." pädiatrie: Kinder- und Jugendmedizin hautnah 28, no. 1 (February 2016): 66. http://dx.doi.org/10.1007/s15014-016-0637-7.
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Onuora, Sarah. "Multi-pronged approach uncovers sJIA mechanisms." Nature Reviews Rheumatology 13, no. 11 (October 12, 2017): 631. http://dx.doi.org/10.1038/nrrheum.2017.173.
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Kriulin, I. A., E. I. Alexeeva, I. Yu Shilkrot, and T. M. Dvoryakovskaya. "Secondary hemophagocytic lymphohistiocytosis: prognostic model and early markers in patients with systemic juvenile idiopathic arthritis. Results of a cohort retrospective study." Voprosy praktičeskoj pediatrii 17, no. 6 (2022): 17–24. http://dx.doi.org/10.20953/1817-7646-2022-6-17-24.
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Background. Secondary hemophagocytic lymphohistiocytosis (sHLH) is a potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA) characterized by hyperinflammation and a variety of clinical and laboratory manifestations. This condition is also referred to as macrophage activation syndrome (MAS) in patients with rheumatic diseases, including those with sJIA. In this article, we use the term sHLH. Approximately 40% of sHLH cases are asymptomatic, especially in patients who receive biologicals. Thus, the development of a prognostic model and identification of early sHLH markers in sJIA patients will enable timely initiation of anti-inflammatory and immunosuppressive therapy. Objective. To develop a prognostic model and identify early sHLH markers in sJIA patients. Methods. This study included 100 sJIA patients who were examined and treated in the Department of Rheumatology, National Medical Research Center for Children's Health between August 2010 and May 2021. A total of 114 sHLH episodes were registered among study participants. We analyzed medication history, as well as clinical and laboratory parameters reflecting the activity of sHLH and sJIA as potential early markers of sHLH. Multivariate logistic regression analysis was used to assess the predictive value of these markers for sHLH development. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each factor to evaluate its significance. Receiver operating characteristic (ROC) curves were constructed to assess the sensitivity and specificity of the model. Results. We analyzed a number of factors as potential early sHLH markers, including medication history (treatment with oral or injectable glucocorticoids (GCs) before sHLH, immunosuppressants (methotrexate, cyclosporine, or leflunomide), and biologicals (tocilizumab, canakinumab, adalimumab, etanercept)), clinical signs (fever, rash, hepatomegaly, splenomegaly, lymphadenopathy, myalgia, hemorrhagic syndrome, central nervous system (CNS) lesions, kidney lesions, lung lesions, heart lesions), and laboratory parameters (hemoglobin, absolute count of red blood cells (RBCs), white blood cells (WBCs), neutrophils, lymphocytes, and platelets, erythrocyte sedimentation rate (ESR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), creatinine, blood urea, c-reactive protein (CRP), ferritin, triglycerides, procalcitonin (PCT), total protein, albumin, blood electrolytes (sodium, potassium, chlorides, iron), coagulation parameters (Quick prothrombin, thrombin time, prothrombin time, international normalized ratio (INR), partial thromboplastin time (APTT), D-dimer, fibrinogen, fibrin monomer, von Willebrand factor, protein S, and protein C). Our prognostic model demonstrated that the following variables were significant predictors of sHLH in sJIA patients: lymphadenopathy, red blood cell count <4.34 × 106 cells/mL, platelets <208 × 103 cells/mL, serum chlorides <101.9 mmol/L, and serum lactate dehydrogenase >412 Units/L. The specificity of the model was 98.0%; the overall accuracy was 95.6%. The area under the ROC-curve (AUC) was 0.954 ± 0.027 (95% CI 0.902–1.000; р < 0.001). Conclusion. The most reliable prognostic markers of sHLH in sJIA patients are undoubtedly heterozygous mutations in the genes of primary (familial) hemophagocytic lymphohistiocytosis. In addition to that, lymphadenopathy, decreased RBC and platelet count, decreased serum level of chloride, and elevated serum LDH in sJIA patients can be interpreted as early sHLH markers and, therefore, considered as an indication to enhance anti-inflammatory and immunosuppressive therapy. Key words: secondary hemophagocytic lymphohistiocytosis, systemic juvenile idiopathic arthritis, early markers, prognostic model
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Kaleda, M. I., I. P. Nikishina, S. O. Salugina, E. S. Fedorov, and E. V. Nikolaeva. "MACROPHAGE ACTIVATION SYNDROME IN RHEUMATIC DISEASES IN CHILDREN: A RETROSPECTIVE STUDY." Pediatria. Journal named after G.N. Speransky 100, no. 5 (October 11, 2021): 53–61. http://dx.doi.org/10.24110/0031-403x-2021-100-5-53-61.
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Macrophage activation syndrome (MAS) is a rare life-threatening complication of rheumatic diseases (RD) that requires early recognition and adequate immediate treatment. Objective of the study: to identify the features of onset of RD in patients who developed MAS, the clinical and laboratory characteristics of the MAS, possible trigger factors and the timing of development. Materials and methods of research: 57 patients (20 boys and 37 girls) with RD who developed MAS were included in a retrospective continuous non-randomized study: 36 (63%) with systemic juvenile idiopathic arthritis (sJIA), 19 (33%) with Systemic lupus erythematosus (SLE), 1 (2%) – with juvenile dermatomyositis (JDM), one (2%) – with overlapping syndrome. Results: in the structure of patients with sJIA, patients with a history of MAS accounted for 28%, among patients with SLE – 7,6%. The median age at the time of sJIA debut in the study group was 2,6 years [1,5; 5,75], patients with SLE – 11,8 years [8,6; 13,95]. The ratio of boys and girls in the study group was 1:1,85. 70 MAS episodes were recorded: 48 – with sJIA, 20 – with SLE, one episode each for JDM and crossover syndrome. A single episode of MAS at the onset had 22% of patients with sJIA, 47% – with SLE, MAS during the course of the disease – 55% and 47%, repeated episodes of MAS – 25% and 5% of patients, respectively. Clinical manifestations of MAS included fever in 91% of children, hepatomegaly in 54%, pericarditis in 51%, skin lesions in 68%, CNS damage in 44%, lung damage in 33%, hyperferritinemia in 96%, thrombocytopenia – in 79%, increased aminotransferases – in 89%, hypertriglyceridemia – in 53%. Patients with sJIA and MAS had statistically significantly earlier onset (p=0,047), a greater number of systemic manifestations (p=0,012), a typical exanthema (p<0,0001), and a smaller number of active joints (p=0,041). 83% of them had episodes of MAS before the initiation of therapy with biological disease-modifying antirheumatic drugs (bDMARDs). There was no statistically significant relationship between the development of MAS with the use of bDMARDs with a clear positive relationship with the violation of the therapy regimen. 19% of patients with sJIA and MAS had a history of infusion reaction to tocilizumab, 8% later had interstitial lung damage. Patients with SLE and MAS at the onset were statistically significantly more likely to have serositis (p=0,0028), ulcers of the oral mucosa (p<0,0001), neuropsychiatric disorders (p=0,0024), positive Coombs' test (p=0,026). All patients received glucocorticoid therapy; experience with the use of GIBP in the study group was limited. Conclusion: MAS in children develops more often with sJIA; the dominant provoking factor is the activity of the underlying disease. The overwhelming majority of patients developed MAS during the course of the disease, less often at the onset. Patients with a history of MAS with sJIA are characterized by an earlier age of onset, a predominance of systemic manifestations, the need for early administration of bDMARDs therapy, and a tendency to infusion reaction to tocilizumab. Against the background of bDMARDs, a subclinical course of MAS with the absence of fever is possible. The risk of developing MAS along with SLE is higher in patients with onset of serositis, ulcers of the oral mucosa, neuropsychiatric disorders, and a positive Coombs' test. MAS cases were detected with high SLE activity at the onset, violation of the treatment protocol.
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Limenis, Elizaveta, Brian M. Feldman, Camille Achonu, Michelle Batthish, Bianca Lang, Marjorie Mclimont, Sylvia Ota, et al. "Proposed Core Set of Items for Measuring Disease Activity in Systemic Juvenile Idiopathic Arthritis." Journal of Rheumatology 45, no. 1 (August 1, 2017): 115–21. http://dx.doi.org/10.3899/jrheum.161534.
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Objective.To date, there are no standardized disease activity tools for systemic juvenile idiopathic arthritis (sJIA). We developed a core set of disease activity measures for sJIA.Methods.We conducted a validation study in patients with sJIA recruited from 3 Canadian institutions. Disease activity scores were based on questionnaires, clinical factors, and laboratory measures. The physician’s global assessment was our criterion standard. We determined the strength of association of each item with the criterion standard. We then surveyed international experts to determine the top 10 items. Finally, we used the experts’ responses to generate a proposed core set of disease activity measures.Results.We enrolled 57 subjects — 26 with moderately or severely active disease, and 31 with mildly active or inactive disease. Items that most strongly correlated with the criterion standard were number of active joints (r = 0.79), parent’s global assessment of disease activity (r = 0.53), erythrocyte sedimentation rate (ESR; r = 0.62), and C-reactive protein (CRP; r = 0.61). The response rate from international experts was 82% (154/187). Items with the most votes, in descending order, were number of active joints, number of days with fever in the preceding 2 weeks, patient’s and parent’s global assessments of disease activity, sJIA rash, ESR, CRP, and hemoglobin level.Conclusion.We propose a core set of items for measuring disease activity in sJIA. Future research should be aimed at further validation of this core set in the international context.
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Tajkia, Gule, Syed Khairul Amin, Shamim Rima, Soma Halder, and Fabia Hannan. "Systemic Onset Juvenile Idiopathic Arthritis (sJIA) or Still's Disease: A Diagnostic Challenge; while Presented as Fever of Unknown Origin. 2 Cases." Anwer Khan Modern Medical College Journal 10, no. 1 (October 20, 2019): 84–88. http://dx.doi.org/10.3329/akmmcj.v10i1.43667.
Full textAbstract:
Systemic-onset juvenile idiopathic arthritis (sJIA) or Still's disease is a chronic inflammatory disease of unknown etiology belongs to the group of Juvenile Idiopathic Arthritis. In contrast to other JIA patients in whom the joint disease usually overshadows the more general symptomatology, in Systemic-onset juvenile idiopathic arthritis (sJIA) extra-articular features such as spiking fever, hepatosplenomegaly, lymphadenopathy, rash, pleurisy, or pericarditis, and vasculopathy are most prominent. Thus the onset of disease can be vary nonspecific and may suggest bacterial or viral infection, malignancy or other rheumatic disease. As it is highly characterized by its extra-articular systemic illness features, in some ways, it resembles a fever of unknown origin. We present 2 cases of fever of unknown origin, initially presented with fever and other extra-articular features, without any arthritis, but after several months develops arthritis and finally diagnosed as Systemic-onset juvenile idiopathic arthritis (sJIA) or Still's disease .
Anwer Khan Modern Medical College Journal Vol. 10, No. 1: Jan 2019, P 84-88
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Kirchner, M., B. Robinson, L. Strothmann, A. Sonnenschein, and W. Mannhardt-Laakmann. "In-vitro-Einfluss von Adalimumab und Anakinra auf das Zytokin-netzwerk bei Patienten mit oJIA und sJIA." Arthritis und Rheuma 35, no. 05 (2015): 323–30. http://dx.doi.org/10.1055/s-0037-1618388.
Full textAbstract:
ZusammenfassungEinleitung: Die oJIA gilt als Autoimmun-erkrankung der adaptiven Immunität, die sJIA wird als Autoinflammationserkrankung gewertet. Bei beiden Verlaufsformen werden die proinflammatorischen Zytokine IL-1, IL-6 und TNF-α hochreguliert. Daher gilt die Inhibition proinflammatorischer Zytokine als geeignete therapeutische Strategie. Die Autoren untersuchten, welchen Einfluss die Blockade eines einzelnen Zytokins auf das Gleichgewicht des gesamten Zytokinsystems nimmt.Methoden: Hierzu wurde die Zytokinsekretion nach In-vitro-LPS-Stimulation und Hemmung von IL-1 und TNF-[uni03B1] bei Patienten mit oJIA, sJIA und gesunden Probanden analysiert.Resultate: Anakinra hemmt unselektiv alle untersuchten proinflammatorischen Zytokine. Adalimumab verhindert sehr selektiv die Wirkung von TNF-α. Adalimumab und Anakinra unterdrücken die Sekretion des antiinflammatorischen IL-10 bei sJIA-Patienten und Gesunden. Beide Biologika supprimieren IFN-γ signifikant. Die Autoren zeigten, dass Biologika nicht nur die Zielzytokine, sondern auch andere Zytokine unselektiv blockieren.Diskussion: Es bleibt zu klären, ob die reduzierte IFN-γ-Sekretion als Folge der Biologikatherapie der JIA verantwortlich für die erhöhte Infektanfälligkeit gegenüber opportunistischen Erregern ist.