New-onset Systemic Juvenile Idiopathic Arthritis Research Articles

Recombinant Interleukin-1 Receptor Antagonist Is an Effective First-Line Treatment Strategy in New-Onset Systemic Juvenile Idiopathic Arthritis, Irrespective of HLA-DRB1 Background and IL1RN Variants.

Human leukocyte antigen (HLA)-DRB1*15:01 has been recently associated with interstitial lung disease (LD), eosinophilia, and drug reactions in systemic juvenile idiopathic arthritis (sJIA). Additionally, genetic variants in IL1RN have been linked to poor response to anakinra. We sought to reproduce these findings in a prospective cohort study of patients with new-onset sJIA treated with anakinra as first-line therapy. HLA and IL1RN risk alleles were identified via whole-genome sequencing. Treatment responses and complications were compared between carriers versus noncarriers. Seventeen of 65 patients (26%) carried HLA-DRB1*15:01, comparable with the general population, and there was enrichment for HLA-DRB1*11:01, a known risk locus for sJIA. The rates of clinical inactive disease (CID) at 6 months, 1 year, and 2 years were generally high, irrespective of HLA-DRB1 or IL1RN variants, but significantly lower in carriers of an HLA-DRB1*11:01 allele. One patient, an HLA-DRB1*15:01 carrier, developed sJIA-LD. Of the three patients with severe drug reactions to biologics, one carried HLA-DRB1*15:01. The prevalence of eosinophilia did not significantly differ between HLA-DRB1*15:01 carriers and noncarriers at disease onset (6.2% vs 14.9%, P = 0.67) nor after the start of anakinra (35.3% vs 37.5% in the first 2 years of disease). We observed high rates of CID using anakinra as first-line treatment irrespective of HLA-DRB1 or IL1RN variants. Only one of the 17 HLA-DRB1*15:01 carriers developed sJIA-LD, and of the three patients with drug reactions to biologics, only one carried HLA-DRB1*15:01. Although thorough monitoring for the development of drug hypersensitivity and refractory disease courses in sJIA, including sJIA-LD, remains important, our data support the early start of biologic therapy in patients with new-onset sJIA irrespective of HLA-DRB1 background or IL1RN variants.

Variation in Treatment of Children Hospitalized With New-Onset Systemic Juvenile Idiopathic Arthritis in the US.

Increasing evidence supports the conclusion that early initiation of biologics may dramatically improve disease course and reduce glucocorticoid exposure for children with systemic juvenile idiopathic arthritis (JIA). The present study was undertaken to characterize variation in the use of first-line biologic and glucocorticoid therapy and to identify drivers of variation in children hospitalized with new-onset systemic JIA. We conducted a retrospective cohort study of children hospitalized with new-onset systemic JIA from 2008 to 2019 utilizing a comparative pediatric database from 52 tertiary care children's hospitals. Subjects and treatment receipt were identified using International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 discharge diagnosis codes, pharmacy billing data, and clinical transaction classification codes. Mixed-effects logistic regression was used to identify patient- and hospital-level factors associated with receipt of glucocorticoids and biologics. In total, 534 children with new-onset systemic JIA hospitalized during the study period met inclusion criteria. Twenty-nine percent received biologics, and 58% received glucocorticoids. Biologic use increased over time (P < 0.001), methotrexate use decreased (P < 0.01), and glucocorticoid use remained unchanged. Biologics and glucocorticoid use varied significantly between hospitals. High annual hospital volume, intensive care unit stay, and later discharge year were significantly associated with biologic exposure. Medium-high and high annual hospital volume were significantly associated with less glucocorticoid exposure. Despite increasing evidence demonstrating improved outcomes with first-line treatment with biologics, we found significant treatment variation across hospitals with many children not receiving biologics and a persistent high rate of glucocorticoid exposure. These results underscore the need for comparative efficacy studies and improved treatment standardization.

Effect of first-line biologic initiation on glucocorticoid exposure in children hospitalized with new-onset systemic juvenile idiopathic arthritis: emulation of a pragmatic trial using observational data

BackgroundGlucocorticoid exposure is a significant driver of morbidity in children with systemic juvenile idiopathic arthritis (sJIA). We determined the effect of early initiation of biologic therapy (IL-1 or IL-6 inhibition) on glucocorticoid exposure in hospitalized patients with new-onset sJIA.MethodsWe emulated a pragmatic sequence of trials (“pseudo-trials”) of biologic initiation in children (≤ 18 years) hospitalized with new-onset sJIA utilizing retrospective data from an administrative database from 52 tertiary care children’s hospitals from 2008 to 2019. Eligibility window, treatment assignment and start of follow-up between biologic and non-biologic study arms were aligned for each pseudo-trial. Patients in the source population could meet eligibility criteria at several timepoints. Mixed-effects logistic regression was used to determine the effect of biologic initiation on in-hospital glucocorticoid exposure.ResultsFour hundred sixty-eight children met eligibility criteria, of which 19% received biologic therapy without preceding or concomitant initiation of immunomodulatory medications. This proportion significantly increased over time during the study period (p < 0.01). 1451 trial subjects were included across 4 pseudo-trials with 71 assigned to the biologic arm and 1380 assigned to the non-biologic arm. After adjustment, there was a trend toward decreased odds of glucocorticoid initiation in the biologic arm compared to the non-biologic arm (OR 0.39, 95% CI [0.13, 1.15]).ConclusionBiologic initiation in children hospitalized with new-onset sJIA significantly increased over time and may be associated with reduced glucocorticoid exposure. The increasing use of first-line biologic therapy may lead to clinically relevant reductions in treatment-related adverse effects of glucocorticoid-reliant therapeutic approaches.

Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: a cohort study.

BackgroundMultisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening hyperinflammatory syndrome that occurs after primary SARS-CoV-2 infection. The pathogenesis of MIS-C remains undefined, and whether specific inflammatory biomarker patterns can distinguish MIS-C from other hyperinflammatory syndromes, including Kawasaki disease and macrophage activation syndrome (MAS), is unknown. Therefore, we aimed to investigate whether inflammatory biomarkers could be used to distinguish between these conditions.MethodsWe studied a prospective cohort of patients with MIS-C and Kawasaki disease and an established cohort of patients with new-onset systemic juvenile idiopathic arthritis (JIA) and MAS associated with systemic JIA (JIA-MAS), diagnosed according to established guidelines. The study was done at Cincinnati Children's Hospital Medical Center (Cincinnati, OH, USA). Clinical and laboratory features as well as S100A8/A9, S100A12, interleukin (IL)-18, chemokine (C-X-C motif) ligand 9 (CXCL9), and IL-6 concentrations were assessed by ELISA and compared using parametric and non-parametric tests and receiver operating characteristic curve analysis.FindingsBetween April 30, 2019, and Dec 14, 2020, we enrolled 19 patients with MIS-C (median age 9·0 years [IQR 4·5–15·0]; eight [42%] girls and 11 [58%] boys) and nine patients with Kawasaki disease (median age 2·0 years [2·0–4·0]); seven [78%] girls and two [22%] boys). Patients with MIS-C and Kawasaki disease had similar S100 proteins and IL-18 concentrations but patients with MIS-C were distinguished by significantly higher median concentrations of the IFNγ-induced CXCL9 (1730 pg/mL [IQR 604–6300] vs 278 pg/mL [54–477]; p=0·038). Stratifying patients with MIS-C by CXCL9 concentrations (high vs low) revealed differential severity of clinical and laboratory presentation. Compared with patients with MIS-C and low CXCL9 concentrations, more patients with high CXCL9 concentrations had acute kidney injury (six [60%] of ten vs none [0%] of five), altered mental status (four [40%] of ten vs none [0%] of five), shock (nine [90%] of ten vs two [40%] of five), and myocardial dysfunction (five [50%] of ten vs one [20%] of five); these patients also had higher concentrations of systemic inflammatory markers and increased severity of cytopenia and coagulopathy. By contrast, patients with MIS-C and low CXCL9 concentrations resembled patients with Kawasaki disease, including the frequency of coronary involvement. Elevated concentrations of S100A8/A9, S100A12, and IL-18 were also useful in distinguishing systemic JIA from Kawasaki disease with high sensitivity and specificity.InterpretationOur findings show MIS-C is distinguishable from Kawasaki disease primarily by elevated CXCL9 concentrations. The stratification of patients with MIS-C by high or low CXCL9 concentrations provides support for MAS-like pathophysiology in patients with severe MIS-C, suggesting new approaches for diagnosis and management.FundingCincinnati Children's Research Foundation, National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health, the Deutsche Forschungsgemeinschaft, and The Jellin Family Foundation.

Treatment to Target Using Recombinant Interleukin-1 Receptor Antagonist as First-Line Monotherapy in New-Onset Systemic Juvenile Idiopathic Arthritis: Results From a Five-Year Follow-Up Study.

ObjectiveSystemic juvenile idiopathic arthritis (JIA) is a multifactorial autoinflammatory disease with a historically poor prognosis. With current treatment regimens, approximately half of patients still experience active disease after 1 year of therapy. This study was undertaken to evaluate a treat‐to‐target approach using recombinant interleukin‐1 receptor antagonist (rIL‐1Ra; anakinra) as first‐line monotherapy to achieve early inactive disease and prevent damage.MethodsIn this single‐center, prospective study, patients with new‐onset systemic JIA with an unsatisfactory response to nonsteroidal antiinflammatory drugs received rIL‐1Ra monotherapy according to a treat‐to‐target strategy. Patients with an incomplete response to 2 mg/kg rIL‐1Ra subsequently received 4 mg/kg rIL‐1Ra or additional prednisolone, or switched to alternative therapy. For patients in whom inactive disease was achieved, rIL‐1Ra was tapered after 3 months and subsequently stopped.ResultsForty‐two patients, including 12 who had no arthritis at disease onset, were followed up for a median of 5.8 years. The median time to achieve inactive disease was 33 days. At 1 year, 76% had inactive disease, and 52% had inactive disease while not receiving medication. High neutrophil counts at baseline and a complete response after 1 month of rIL‐1Ra were highly associated with inactive disease at 1 year. After 5 years of follow‐up, 96% of the patients included had inactive disease, and 75% had inactive disease while not receiving medication. Articular or extraarticular damage was reported in <5%, and only 33% of the patients received glucocorticoids. Treatment with rIL‐1Ra was equally effective in systemic JIA patients without arthritis at disease onset.ConclusionTreatment to target, starting with first‐line, short‐course monotherapy with rIL‐1Ra, is a highly efficacious strategy to induce and sustain inactive disease and to prevent disease‐ and glucocorticoid‐related damage in systemic JIA.

Pilot study comparing the Childhood Arthritis & Rheumatology Research Alliance (CARRA) systemic Juvenile Idiopathic Arthritis Consensus Treatment Plans

ObjectivesTo assess the feasibility of studying the comparative effectiveness of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans (CTPs) for systemic Juvenile Idiopathic Arthritis (JIA) using an observational registry.MethodsUntreated systemic JIA patients enrolled in the CARRA Registry were begun on one of 4 CTPs chosen by the treating physician and patient/family (glucocorticoid [GC] alone; methotrexate [MTX] ± GC; IL1 inhibitor [IL1i] ± GC; IL6 inhibitor [IL6i] ± GC). The primary outcome of clinical inactive disease (CID) without current GC use was assessed at 9 months. Trial registration: clinicaltrials.gov NCT01697254; first registered 9/28/12 (retrospectively enrolled).ResultsThirty patients were enrolled at 13 sites; eight patients were started on a non-biologic CTP (2 GC, 6 MTX) and 22 patients on a biologic CTP (12 IL1i, 10 IL6i) at disease onset. Demographic and disease features were similar between CTP groups. CTP choice appeared to segregate by site preference. CID off GC was achieved by 37% (11 of 30) including 11/22 (50%) starting a biologic CTP compared to 0/8 starting a non-biologic CTP (p = 0.014). There were four serious adverse events: two infections, one appendicitis and one macrophage activation syndrome.ConclusionsThe CARRA systemic JIA CTP pilot study demonstrated successful implementation of CTPs using the CARRA registry infrastructure. Having demonstrated feasibility, a larger study using CTP response to better determine the relative effectiveness of treatments for new-onset systemic JIA is now underway.

AB0695 Cyclosporine usage in resistant systemic jia-an experience from india

BackgroundThe mainstay of treatment of Systemic JIA (sJIA) are corticosteroids(1,2), with majority being well responsive to steroids. But stopping steroids is really challenging as many relapse on tapering off or...

Development of consensus best treatment plans for new-onset systemic juvenile idiopathic arthritis

Purpose Currently, there is significant variability in the therapeutic approaches to new onset systemic Juvenile Idiopathic Arthritis (sJIA), as evidenced by surveys using case presentations administered to Childhood Arthritis and Rheumatology Research Alliance (CARRA) members. Understanding the comparative effectiveness of these diverse therapeutic approaches would likely result in better health outcomes. We therefore aimed to derive consensus based treatment plans, standardized assessment intervals and data collection plans for clinical use to facilitate comparative effectiveness studies for new-onset sJIA. Eligible patients may be enrolled into any of the treatment plans at the treating physician’s discretion. Methods To develop eligibility criteria and consensus approaches to therapeutic management, the CARRA sJIA Core Workgroup convened regularly for workgroup meetings, hosted a 2-day CARRA consensus conference in April 2010, and conducted surveys of the CARRA membership. Results The CARRA sJIA Core Workgroup developed formal eligibility criteria for patient enrollment, standardized treatment approaches, and a recommended schedule of visits and monitoring parameters. Entry criteria include age 6m18y and probable sJIA determined by defined criteria. The

Consensus treatment plans for new‐onset systemic juvenile idiopathic arthritis

There is wide variation in therapeutic approaches to systemic juvenile idiopathic arthritis (JIA) among North American rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available for treatment of systemic JIA can result in better health outcomes. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans and standardized assessment schedules for use in clinical practice to facilitate such studies. Case-based surveys were administered to CARRA members to identify prevailing treatments for new-onset systemic JIA. A 2-day consensus conference in April 2010 employed modified nominal group technique to formulate preliminary treatment plans and determine important data elements for collection. Followup surveys were employed to refine the plans and assess clinical acceptability. The initial case-based survey identified significant variability among current treatment approaches for new-onset systemic JIA, underscoring the utility of standardized plans to evaluate comparative effectiveness. We developed 4 consensus treatment plans for the first 9 months of therapy, as well as case definitions and clinical and laboratory monitoring schedules. The 4 treatment regimens included glucocorticoids only, or therapy with methotrexate, anakinra, or tocilizumab, with or without glucocorticoids. This approach was approved by >78% of the CARRA membership. Four standardized treatment plans were developed for new-onset systemic JIA. Coupled with data collection at defined intervals, use of these treatment plans will create the opportunity to evaluate comparative effectiveness in an observational setting to optimize initial management of systemic JIA.

RE: Reactive macrophage activation syndrome (MAS) in a patient with parvovirus B19 infection, lymphocytic lichenoid vasculitis, urticaria and angioedema

lettersRE: Reactive macrophage activation syndrome (MAS) in a patient with parvovirus B19 infection, lymphocytic lichenoid vasculitis, urticaria and angioedema Luis Gonzalez-Granado Luis Gonzalez-Granado Search for more papers by this author Published Online:3 Jun 2010https://doi.org/10.4103/0256-4947.62827SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutIntroductionTo the Editor: I read with keen interest the article published by Soldo-Juresa et al in the last issue of the journal.1 I would like to make some comments: First, Still disease should be kept in mind whenever macrophage activation syndrome is considered in a patient with the clinical picture shown. In fact the patient's condition fulfills the criteria published by Yamagushi for Still disease.2 I would like to remark that the measurement of soluble IL-2R (also known as CD25s) could be helpful in distinguishing between Still disease and MAS.3 Furthermore, the development of MAS in Still disease is not infrequent and intravenous gamma globulins have shown promising results in treatment.4,5 Second, as the authors rule out a C1q-linked vasculitis, C4 and alternative complement pathway activity should be measured. It is well known that in esterase inhibitor type II levels of C1-inhibitor esterase are normal although C4 is decreased due to low functional C1-inhibitor levels.6 Hypocomplementemic vasculitis has been also described in patients with factor I deficiency.7 I have attended recently a patient with vasculitis secondary to factor I deficiency. This factor was not measured by the author in this patient. Third, the authors recognize that DNA of parvovirus B-19 can persist in bone marrow for years. This is why we should distinguish between MAS secondary to viral infection or underlying Still disease that needs long-term treatment and follow-up.ARTICLE REFERENCES:1. Soldo-Juresa D, Radman M, Pejsa V, Bozikov V. "Reactive macrophage activation syndrome in a patient with parvovirus B19 infection, lymphocytic lichenoid vasculitis, urticaria and angioedema" . Ann Saudi Med. 2010; 30:88-9. Google Scholar2. Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, Kashiwazaki S, Tanimoto K, Matsumoto Y, Ota T. "Preliminary criteria for classification of adult Stills disease" . J Rheumatol. 1992; 19:424-430. Google Scholar3. Bleesing J, Prada A, Siegel DM, Villanueva J, Olson J, Ilowite NT, Brunner HI, Griffin T, Graham TB, Sherry DD, Passo MH, Ramanan AV, Filipovich A, Grom AA. "The diagnostic significance of soluble CD163 and soluble interleukine-2 receptor a -chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis" . Arthritis Rheum. 2007; 56:965-71. Google Scholar4. García-Consuegra Molina J, Merino Muñoz R, de Inocencio Arocena J. "Grupo de Estudio del Síndrome de Activación Macrofágica y Artritis Idiopática Juvenil de la Sociedad Española de Reumatología Pediátrica. Macrophage activation syndrome and juvenile idiopathic arthritis. A multicenter study" . An Pediatr (Barc). 2008; 68:110-6. Google Scholar5. Vignes S, Wechsler B, Amoura Z, Papo T, Francès C, Huong DL, Veyssier P, Godeau P, Piette JC. "Intravenous immunoglobulin in adult Still's disease refractory to non-steroidal anti-inflammatory drugs" . Clin Exp Rheumatol. 1998; 16:295-8. Google Scholar6. Zuraw BL, Christiansen SC. "Pathogenesis and laboratory diagnosis of hereditary angioedema" . Allergy Asthma Proc. 2009; 30:487-92. Google Scholar7. Sadallah S, Gudat F, Laissue JA, Spath PJ, Schifferli JA. "Glomerulonephritis in a patient with complement factor I deficiency" . Am J Kidney Dis. 199906 33(6):1153-7. Google Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 30, Issue 3May–Jun 2010 Metrics History Published online3 June 2010 InformationCopyright © 2010, Annals of Saudi MedicineThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.PDF download

Gene expression profiling of peripheral blood from patients with untreated new‐onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome

Systemic juvenile idiopathic arthritis (JIA) is frequently associated with the development of macrophage activation syndrome. This study was undertaken to better understand the relationship between systemic JIA and macrophage activation syndrome. Gene expression profiles were examined in 17 patients with untreated new-onset systemic JIA, 5 of whom showed evidence of subclinical macrophage activation syndrome (of whom 2 eventually developed overt macrophage activation syndrome). Peripheral blood mononuclear cells (PBMCs) were separated on Ficoll gradients, and purified RNA was analyzed using Affymetrix GeneChip expression arrays. A fraction of the PBMCs were used for flow cytometry to define the cellular composition of the samples. Two hundred twenty-five differentially expressed genes (P < 0.05) that distinguished patients with systemic JIA from healthy controls (n = 30) were identified. Clustering analysis indicated that expression patterns correlated with serum ferritin levels. Three main clusters distinguished systemic JIA patients with highly elevated ferritin levels (including those with subclinical macrophage activation syndrome) from those with normal or only moderately elevated ferritin levels. The first cluster comprised genes involved in the synthesis of hemoglobins and structural proteins of erythrocytes. This transcriptional profile was consistent with immature nucleated red blood cells, likely reflective of high red blood cell turnover. Also included were transcripts indicating immature granulocytes. The second cluster was enriched for genes involved in cell cycle regulation. The third cluster was enriched for genes involved in innate immune responses, including those involved in the negative regulation of Toll-like receptor/interleukin-1 receptor-triggered inflammatory cascades and markers of the alternative pathway of macrophage differentiation. Additional differentially expressed genes of interest were those involved in the cytolytic pathway, including SH2D1A and Rab27a. These data indicate that gene expression profiling can be a useful tool for identifying early macrophage activation syndrome in patients with systemic JIA.

The diagnostic significance of soluble CD163 and soluble interleukin‐2 receptor α‐chain in macrophage activation syndrome and untreated new‐onset systemic juvenile idiopathic arthritis

Macrophage activation syndrome is characterized by an overwhelming inflammatory reaction driven by excessive expansion of T cells and hemophagocytic macrophages. Levels of soluble interleukin-2 receptor alpha (sIL-2Ralpha) and soluble CD163 (sCD163) may reflect the degree of activation and expansion of T cells and macrophages, respectively. This study was undertaken to assess the value of serum sIL-2Ralpha and sCD163 in diagnosing acute macrophage activation syndrome complicating systemic juvenile idiopathic arthritis (JIA). Enzyme-linked immunosorbent assay was used to assess sIL-2Ralpha and sCD163 levels in sera from 7 patients with acute macrophage activation syndrome complicating systemic JIA and 16 patients with untreated new-onset systemic JIA. The results were correlated with clinical features of established macrophage activation syndrome, including ferritin levels. The median level of sIL-2Ralpha in the patients with macrophage activation syndrome was 19,646 pg/ml (interquartile range [IQR] 18,128), compared with 3,787 pg/ml (IQR 3,762) in patients with systemic JIA (P = 0.003). Similarly, the median level of sCD163 in patients with macrophage activation syndrome was 23,000 ng/ml (IQR 14,191), compared with 5,480 ng/ml (IQR 2,635) in patients with systemic JIA (P = 0.017). In 5 of 16 patients with systemic JIA, serum levels of sIL-2Ralpha or sCD163 were comparable with those in patients with acute macrophage activation syndrome. These patients had high inflammatory activity associated with a trend toward lower hemoglobin levels (P = 0.11), lower platelet counts, and significantly higher ferritin levels (P = 0.02). Two of these 5 patients developed overt macrophage activation syndrome several months later. Levels of sIL-2Ralpha and sCD163 are promising diagnostic markers for macrophage activation syndrome. They may also help identify patients with subclinical macrophage activation syndrome.