RARE DISEASE
Systemic-onset juvenile idiopathic arthritis
Systemic-onset juvenile idiopathic arthritis
Systemic-onset juvenile idiopathic arthritis
Synonyms: Still disease, Systemic-onset JIA
Synonyms: Still disease, Systemic-onset JIA
Synonyms: Still disease, Systemic-onset JIA
Drug discovery
4
drugs
With orphan designations
Overview
Systemic-onset juvenile idiopathic arthritis (sJIA) is a rare autoinflammatory disease characterized by arthritis, daily spiking fevers, evanescent rash, lymphadenopathy, and systemic inflammation. Diagnosed by ILAR criteria after excluding infections/malignancies, it carries risks of macrophage activation syndrome (20% mortality) and chronic polyarthritis [1][7][12]. Treatment focuses on interleukin-1/6 blockade (anakinra, tocilizumab) to control cytokine storms, with early biologic use reducing steroid dependence [11][13][14].
Categories: rare respiratory diseases, rare systemic and rheumatological diseases, rare systemic or rheumatologic diseases of childhood, rare transplant-related disorders
Research Papers
389 drug discovery papers about Systemic-onset juvenile idiopathic arthritis, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
389 drug discovery papers about Systemic-onset juvenile idiopathic arthritis, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-07-02 | Clinical Features and Outcome Measures Across Still Disease (Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still Disease) Cohorts Worldwide: A Systematic Literature Review.
J Rheumatol 2026; doi: 10.3899/jrheum.2025-0822 The following text should be added to the acknowledgment: "The contributions of the National Institutes of Health (NIH) authors are considered works of the US government. The findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the US Department of Health and Human Services." This correction applies to the December 1 2025 First Release and February 2026 print issue. The online version has been corrected.
2026-06-20 | Predictive Factors for Relapse in Still's Disease: A Retrospective Cohort Study of Clinical and Laboratory Biomarkers.
This retrospective cohort study aimed to identify clinical and laboratory predictors of relapse in patients with Still's disease. A total of 94 patients diagnosed by Yamaguchi or Fautrel criteria across two rheumatology centers between 2012 and 2024 were evaluated, of whom 87 were eligible for analysis. Thirty-one patients (35%) experienced relapses during follow-up. Relapse was associated with higher baseline C-reactive protein (CRP > 100 mg/L), elevated neutrophil counts, and lower albumin levels. Composite ratios such as ferritin/albumin, CRP/albumin, and neutrophil/albumin were also significantly higher in the relapse group. Clinically, a joint-dominant disease phenotype and initial use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) were more common among patients who relapsed. In multivariate logistic regression, high CRP levels, joint-dominant phenotype, and csDMARD use emerged as independent predictors of relapse. These findings highlight the predictive value of widely available biomarkers and baseline clinical presentation in stratifying relapse risk in Still Disease. Early recognition of high-risk patients using these factors may guide more targeted treatment approaches, support earlier initiation of biologic therapies, and ultimately improve long-term disease outcomes.
2026-05-26 | Early intensification versus step-up biologic strategies in systemic juvenile idiopathic arthritis: a Bayesian network meta-analysis of remission and safety outcomes.
To compare the relative effects of different treatment strategies for Systemic Juvenile Idiopathic Arthritis (sJIA) on clinical inactivity (CID)/remission and safety using a Bayesian network meta-analysis and to rank the treatment options. PubMed, Embase, Web of Science, the Cochrane Library, and Scopus were systematically searched from inception to October 2025 according to PRISMA 2020 and PRISMA-NMA specifications. Randomized controlled trials (RCTs), prospective cohorts, and retrospective/registry studies were included. The primary outcome was the CID/remission rate, and the secondary outcome was the incidence of adverse events (AEs) (normalized per patient-year). Random-effects and Bayesian hierarchical network models were used. Risk of bias was assessed using ROB-2 and NOS, and the certainty of evidence was assessed using GRADE. A total of 2,408 records were retrieved. After deduplication, 1,088 records were screened for titles/abstracts, and 200 were reviewed in full text. Fifteen studies (total sample size 1,548) were ultimately included. A pooled analysis showed that approximately two-thirds of patients achieved CID/remission during follow-up (random-effects model). Stratification suggested that an early IL-1/IL-6 strategy had a more favorable response rate. A network meta-ranking analysis (SUCRA) showed that early IL-1/IL-6 blockade ranked first, followed by anakinra and canakinumab; tocilizumab was in the middle; and conventional care and mixed biologic strategies ranked last. The overall AE rate was low and consistent across studies; IL-1/IL-6 targeted drugs had a favorable safety profile. Multiple sensitivity analyses and cumulative evidence analysis supported the robustness of the conclusions. In sJIA, immediate intensive IL-1/IL-6 therapy at diagnosis is more effective than a step-up approach in achieving and maintaining CID/remission, while also having an acceptable safety profile, supporting the initial "target-to-treat (T2T)" strategy. Future prospective studies and biomarker-stratified validation of each strategy are needed.
2026-05-01 | Early C-reactive protein and ferritin kinetics after tocilizumab initiation predict macrophage activation syndrome in Still disease: a single-centre retrospective cohort study
Objectives This study aimed to evaluate the safety and effectiveness of tocilizumab (TCZ) as induction therapy in Still disease and identify early dynamic biomarkers, including C-reactive protein (CRP) and ferritin changes, for macrophage activation syndrome (MAS) risk stratification. Methods This single-centre retrospective cohort study included patients with Still disease treated from 2004 to 2024. Patients were classified by induction therapy (TCZ vs non-TCZ). MAS was defined using the 2016 European Alliance of Associations for Rheumatology/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation criteria. Early biomarker changes after prednisolone initiation were evaluated. Primary outcomes were week-4 CRP normalisation and clinically inactive disease (CID) at month 3. Associations with induction therapy were analysed using Firth's penalised logistic regression. In TCZ-treated patients, receiver operating characteristic analyses assessed laboratory biomarkers for MAS prediction. Results Among 54 patients, 12 received TCZ as initial induction therapy and 7 for relapse (19 episodes). MAS occurred in 5 episodes (26.3%). No significant differences were observed in week-4 CRP normalisation (75.0% vs 51.2%, P = .193) or month-3 CID (40.0% vs 14.6%, P = .090). After adjusting for the higher initial prednisolone dose, early TCZ exposure was independently associated with month-3 CID (odds ratio: 9.73, 95% CI: 1.25-77.50, P = .030). Week-1/baseline CRP ratio and ferritin ratios predicted MAS after TCZ induction; the week-1/baseline ferritin ratio showed the highest area under the curve (0.914), followed by the CRP ratio (0.877). Conclusions Early TCZ exposure was independently associated with CID at month 3. Insufficient early suppression of inflammatory markers, particularly higher ferritin and CRP ratios, may identify patients at higher risk of subsequent MAS.
2026-04-04 | Effectiveness of Canakinumab for First-Line Steroid-Free Treatment in Systemic-Onset Juvenile Idiopathic Arthritis and Juvenile Still Disease.
This prospective study assesses the response to canakinumab monotherapy administered as three monthly subcutaneous injections in glucocorticoid-naïve patients with newly diagnosed systemic juvenile idiopathic arthritis (sJIA) and Still disease and evaluates the durability of drug-free inactive disease for up to nine months after canakinumab cessation. In a multicenter, two-phase open-label study of newly diagnosed sJIA or Still disease, canakinumab was administered at 4 mg/kg subcutaneously every 4 weeks for 12 weeks. Thereafter, patients were followed for an additional 40 weeks. Routine care was provided to nonresponders. In total, 21 patients were recruited, and 1 was excluded due to protocol violations. Fever resolved immediately in 17/19 patients. Two nonresponders (n = 2) were managed with different strategies: one received steroids alone, and the other received steroids plus canakinumab as part of routine care. By week 12, 14 patients achieved inactive disease. Thereafter, two flares occurred at weeks 24 and 36. Macrophage activation syndrome (MAS) was diagnosed in a third patient at week 19 and responded to treatment with glucocorticoids and cyclosporine A. By week 52, 11 patients had reached drug-free inactive disease and 3 had minimal disease activity. A total of 97 adverse events were reported; four were serious (one MAS, two disease flares, and one viral infection), but none were attributed to the study drug. Canakinumab steroid-free first-line therapy in newly diagnosed sJIA induces long-lasting, drug-free inactive disease in a substantial proportion of patients. Discontinuation of canakinumab was associated with disease flares in a minority of patients.
cell therapies
2023-10-16 | Case report: Success of allogeneic hematopoietic stem cell transplantation for refractory systemic-onset juvenile idiopathic arthritis
Objectives This study reports cases of systemic-onset juvenile idiopathic arthritis (sJIA) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center and reviews published outcomes of allo-HSCT in sJIA. Methods We present a case report of two patients with sJIA who underwent allo-HSCT at a tertiary pediatric hospital. Each patient’s disease course and allo-HSCT protocol/outcome are described. Outcomes of published cases of allo-HSCT in sJIA were compared to our experience. Results Two patients with sJIA had allo-HSCT. Both failed multiple lines of disease-modifying anti-rheumatic drugs and experienced severe disease/treatment-related complications. Despite post-HSCT complications, both recovered without sequelae. Five years post-HSCT, patient 1 is in complete remission (CR) and is off medications. Patient 2 was in CR until 11 months post-HSCT after which he developed three disease flares. At 4 years post-HSCT he is currently in CR on Adalimumab monotherapy. Engraftment was excellent with a donor chimerism of 100% for patient 1 and 93% for patient 2. In the literature, the outcome of allo-HSCT is reported in 13 sJIA patients. When merging those with our 2 patients, 1/15 patients died and 13/14 achieved CR, of which 12 are off medications (median [range] follow-up: 2.2 [0.2–7.0] years). Extended follow-up data on 11 of the 13 reported sJIA patients showed that an additional 3 patients flared at 3, 4, and 10 years post-HSCT. Conclusion We report two patients with severe/refractory sJIA who underwent successful allo-HSCT and achieved CR. Allo-HSCT is a potential curative option for severe/refractory sJIA. It should be considered only after failure of conventional sJIA treatments and when an HLA-matched donor is available in order to lower transplant-related mortality. The outcomes of reported sJIA patients who received allo-HSCT are encouraging but long-term follow-up data are needed to better characterized the risk–benefit ratio of this procedure.
2023-01-17 | Therapeutic plasma exchange in refractory macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a case-based review.
Juvenile idiopathic arthritis (JIA) is a heterogeneous group of arthritis of autoimmune aetiology. Systemic-onset juvenile idiopathic arthritis (soJIA) presents with fever, transient erythematous rash, hepatomegaly, splenomegaly, lymphadenopathy, and serositis. SoJIA presents multiple complications, and the most severe is the macrophage activation syndrome (MAS); the timely treatment of MAS must be established early and aggressively to avoid a fatal outcome. Therapeutic plasma exchange has anecdotally been used in refractory cases. A 66-month-old male with a 1-year illness characterized by evening-predominant, intermittent fever, adenomegalies, urticarial-like rash, arthralgia, and arthritis. Biochemical analysis revealed anaemia, leukocytosis, neutrophilia, hypertriglyceridemia, hyperferritinemia, and hypofibrinogenemia; bone marrow aspirate showed hemophagocytosis. He was diagnosed with SoJIA complicated with MAS. He received multiple treatments with IV human gammaglobulin, cyclosporine, dexamethasone, and tocilizumab without improvement. Plasma replacement treatment was performed. Afterwards, he presented significant improvement. After 3-year-follow-up, he remains in good general condition. We present a refractory case of soJIA complicated with MAS successfully treated with plasma exchange.
2021-07-13 | The immunoregulatory function of peripheral blood CD71+ erythroid cells in systemic-onset juvenile idiopathic arthritis
Abstract CD71 + erythroid cells (CECs) are recognized to have an immunoregulatory function via direct cell–cell interaction and soluble mediators. Circulating CECs appear in newborns or patients with hemolytic and cardiopulmonary disorders. To assess the biological role of CECs in systemic inflammation, we studied the gene expression and function in systemic-onset juvenile idiopathic arthritis (SoJIA). Peripheral blood mononuclear cells of SoJIA patients expressed upregulated erythropoiesis-related genes. It represented the largest expansion of CECs during active phase SoJIA among other inflammatory diseases. Despite the opposing roles of erythropoietin and hepcidin in erythropoiesis, both serum levels were in concert with the amounts of SoJIA-driven CECs. Circulating CECs counts in inflammatory diseases were positively correlated with the levels of C-reactive protein, IL-6, IL-18, or soluble TNF receptors. Co-culture with active SoJIA-driven CECs suppressed secretions of IL-1β, IL-6, and IL-8 from healthy donor monocytes. The top upregulated gene in SoJIA-driven CECs was ARG2 compared with CECs from cord blood controls, although cytokine production from monocytes was suppressed by co-culture, even with an arginase inhibitor. CECs are driven to the periphery during the acute phase of SoJIA at higher levels than other inflammatory diseases. Circulating CECs may control excessive inflammation via the immunoregulatory pathways, partly involving arginase-2.
2021-04-06 | Uncharted waters: Mesenchymal stem cell Treatment for Pediatric Refractory Rheumatic Diseases; A Single Center Case Series
Abstract Background: With the advent of innovative therapies including biologics and Janus kinase inhibitors, children with rheumatic diseases are more likely to have improved outcomes. Yet, despite these advances, some children do not respond, or they, or their parents fear adverse events and seek other alternatives. Increasingly, there are private companies that offer mesenchymal stem cells (MSC) as an alternative and describe it as a more natural therapy for rheumatic diseases, often insinuating that there will be a cure. Mesenchymal stem cells have immunomodulatory properties, and transplantation of these stem cells have been used to successfully treat immunologic conditions like graft-versus-host disease. More recently, MSC research in adults with lupus has been encouraging, but the clinical trials are still underway and in most, mesenchymal stem cell therapy is not a standalone treatment. This retrospective case series will highlight three cases of children with refractory autoimmune disease whose parents sought out and received MSC therapy as a self-decision without first seeking medical advice from our specialty . In our cases, the three families felt that their children were improved and in two believed that their child was cured. Mesenchymal stem cells have the potential of beneficial immunomodulation and may be a powerful tool in the therapy of rheumatic disease, but well controlled clinical trials are necessary and should be designed and monitored by experts in childhood rheumatic disease. Case Presentation: Three children with three different rheumatic diseases; systemic lupus erythematosus, mixed connective tissue disease and juvenile idiopathic arthritis were under the care of pediatric rheumatology at a large, tertiary-care, teaching institution. Multiple non-biologic and biologic disease-modifying anti-rheumatic drugs failed to significantly decrease disease activity, and as a result, the families chose to undergo MSC therapy. After transplantation, all children improved per patient and parent report and tapered off conventional immunosuppressive drugs. No serious adverse events occurred in these three patients. Conclusion: The three cases presented in this study reflect comparable beneficial outcomes and minimal risks published in adult studies. These were not controlled studies, however, and benefit was reported rather than documented. These cases suggest that MSC transplantation may prove a promising adjunctive treatment option; however, further research, development of standardized infusion therapy protocols, and well-designed and monitored clinical trials are essential.
2019-03-31 | Bone-marrow derived mesenchymal stromal cells infusion in therapy refractory juvenile idiopathic arthritis patients
Abstract Objectives To compare the total number of adverse events (AEs) before and after mesenchymal stromal cell (MSC) infusion in refractory JIA and to evaluate its effectiveness. Methods Single-centre Proof of Mechanism Phase Ib, open label intervention study in JIA patients previously failing all biologicals registered for their diagnosis. Six patients received 2 million/kg intravenous infusions of allogeneic bone-marrow derived MSC. In case of ACR-Ped30-response but subsequent loss of response one and maximal two repeated infusions are allowed. Results Six JIA patients with 9.2 years median disease duration, still active arthritis and damage were included. All had failed methotrexate, corticosteroids and median five different biologicals. MSC were administered twice in three patients. No acute infusion reactions were observed and a lower post-treatment than pre-treatment incidence in AEs was found. The one systemic onset JIA (sJIA) patient had again an evolving macrophage activation syndrome, 9 weeks after tocilizumab discontinuation and 7 weeks post-MSC infusion. Statistically significant decreases were found 8 weeks after one MSC infusion in VAS well-being (75–56), the JADAS-71 (24.5–11.0) and the cJADAS10 (18.0–10.6). Conclusion MSC infusions in six refractory JIA patients were safe, although in sJIA stopping the ‘failing’ biologic treatment carries a risk of a MAS flare, as the drug might still suppress the systemic features. Trial registration Trial register.nl, http://https://www.trialregister.nl, NTR4146.
small molecules
2026-03-19 | A Rare RIPK3 Variant Enhances Necroptosis and Promotes Inflammation in a Still Disease-Like Autoinflammatory Syndrome.
Still disease represents a prototypical polygenic systemic autoinflammatory disease, characterized by recurrent systemic inflammation and dysregulation of innate immunity. Despite extensive clinical characterization, familial clustering Still disease remains unreported. This study investigates a novel variant underlying a distinct Still disease-like autoinflammatory syndrome. Whole-exome sequencing was performed in a three-generation family with three affected individuals. Functional analyses were conducted to assess the impact of the receptor-interacting protein kinase 3 (RIPK3) p.Q134K variant on kinase activity, necroptosis, and inflammatory signaling. Transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) and in vitro cytokine assays were used to characterize inflammatory responses. A heterozygous RIPK3 p.Q134K variant was identified in all affected individuals. Functional analyses demonstrated that this variant exhibits gain-of-function activity, characterized by enhanced RIPK3 kinase activity and increased RIPK3 self-association, which in turn promote mixed-lineage kinase domain-like protein phosphorylation and necroptosis. RNA sequencing of PBMCs from one patient revealed marked up-regulation of NF-κB and MAPK signaling pathways and elevated expression of interleukin-6, and tumor necrosis factor-α, which was effectively suppressed by pharmacologic inhibition of RIPK3. This study describes a familial Still disease-like autoinflammatory syndrome caused by a gain-of-function RIPK3 variant. Our findings establish aberrant RIPK3 activation as a driver of autoinflammation and expand the spectrum of human RIPK3-associated diseases.
2026-03-13 | Efficacy of combined JAK1/2 inhibition and cyclosporine in paediatric-onset Still's disease with lung involvement: a case report.
BACKGROUND: Paediatric-onset Still’s disease is a severe autoinflammatory disorder marked by high fever, systemic inflammation, rash, organomegaly, and arthritis. Pulmonary complications, once anecdotally reported, have been increasingly observed in paediatric Still’s disease. A more severe lung involvement, Still-associated lung disease, has emerged in the last ten years, including interstitial lung disease, pulmonary hypertension, and pulmonary alveolar proteinosis (PAP). This complication carries significant morbidity and mortality. Its mechanism remains poorly understood; current biologic therapies targeting interleukin (IL)-1 and IL-6 often prove insufficient, supporting the need for innovative approaches or combined treatment. CASE PRESENTATION: A 10-year-old girl with Still’s disease developed PAP and pulmonary hypertension. After several treatment failures and ongoing oxygen dependency, she responded favourably to a combination of baricitinib and cyclosporine. This allowed for gradual corticosteroid tapering and eventual discontinuation, achieving sustained disease control without further oxygen supplementation. Pulmonary assessment, echocardiography, cardiac catheterization, bronchoalveolar lavage, and lung biopsy were performed, along with immunological profiling, HLA typing, and genetic analysis. The type I IFN signature was closely monitored, with normalization observed after reaching the therapeutic dose of baricitinib. CONCLUSION: This case provides evidence of the long-term efficacy and safety of baricitinib combined with cyclosporine in managing Still-LD, offering a promising option for this severe complication.
2025-10-02 | Pruritic eruption in a young woman with fever.
A 29-year-old woman presented with 3 weeks of fever, arthralgia and pruritic rashes on her trunk and limbs. She had no significant medical history and denied occurrence of muscle weakness, dysphagia, mouth ulcers, alopecia and sicca symptoms. Physical examination revealed erythematous, oedematous papules and plaques on the anterior sternum, upper to mid-back, arms, flanks and lateral aspect of the proximal thighs. Antinuclear antibody and anti-double-stranded DNA were negative. Complements, creatine kinase and myositis panel were normal. Her erythrocyte sediment rate and ferritin levels were elevated at 48 mm h-1 and 580 µg L-1, respectively. Histological examination of the plaque on her upper back revealed epidermal dyskeratosis, with a mixed perivascular infiltrate of neutrophils, lymphocytes and histiocytes within the superficial dermis. There was prominent nuclear dust, red cell extravasation and increased dermal mucin. Direct immunofluorescence was negative. She was eventually diagnosed with persistent pruritic eruption (PPE) of adult-onset Still disease (AOSD) and was treated with oral etoricoxib with resolution of her fever and symptoms. The entity of PPE in AOSD is associated with the striking histological feature of dyskeratotic keratinocytes in the upper one-third of the epidermis. This is in contrast to other conditions such as cutaneous lupus or dermatomyositis, where the dyskeratotic keratinocytes are found in the lower epidermis instead. This case highlights the importance of clinicopathological correlation and recognition of PPEs in AOSD in view of the associated poorer prognosis due to associated conditions such as secondary macrophage activation syndrome.
2025-09-05 | Tofacitinib as an adjuvant treatment for pediatric Still's disease.
To describe the efficacy and safety of tofacitinib for pediatric Still's disease, also referred to as systemic-onset juvenile idiopathic arthritis (sJIA). Traditional non-biological drugs and drugs targeting the interleukin-1 and interleukin-6 pathways benefit some patients, but others show inadequate responses. We retrospectively analyzed ten patients with pediatric Still's disease who were treated with tofacitinib and had at least one follow-up visit. Data on patient history, laboratory findings, and treatments were collected at disease onset, at the initiation of tofacitinib, and during follow-up. Tofacitinib led to complete remission in six patients, partial remission in three patients, and loss of efficacy in one patient. Among the nine patients with remission, two discontinued corticosteroids entirely and seven used lower dosages of corticosteroids; these patients also used fewer concurrent medications (1 or 2) after tofacitinib initiation. The one patient who experienced loss of efficacy continued to require a higher dosage of corticosteroids and received five different additional medications. The other nine patients received tocilizumab and had a decreased frequency of these injections after tofacitinib initiation. Tofacitinib was well-tolerated, with only one reported instance of an upper respiratory tract infection. Tofacitinib appears to be an effective adjunct therapy for management of pediatric Still's disease, particularly for patients with unstable clinical conditions and adverse reactions to corticosteroids.
2025-08-20 | Table 1_Tofacitinib as an adjuvant treatment for pediatric Still's disease.docx
Objective To describe the efficacy and safety of tofacitinib for pediatric Still's disease, also referred to as systemic-onset juvenile idiopathic arthritis (sJIA). Traditional non-biological drugs and drugs targeting the interleukin-1 and interleukin-6 pathways benefit some patients, but others show inadequate responses. Methods We retrospectively analyzed ten patients with pediatric Still's disease who were treated with tofacitinib and had at least one follow-up visit. Data on patient history, laboratory findings, and treatments were collected at disease onset, at the initiation of tofacitinib, and during follow-up. Results Tofacitinib led to complete remission in six patients, partial remission in three patients, and loss of efficacy in one patient. Among the nine patients with remission, two discontinued corticosteroids entirely and seven used lower dosages of corticosteroids; these patients also used fewer concurrent medications (1 or 2) after tofacitinib initiation. The one patient who experienced loss of efficacy continued to require a higher dosage of corticosteroids and received five different additional medications. The other nine patients received tocilizumab and had a decreased frequency of these injections after tofacitinib initiation. Tofacitinib was well-tolerated, with only one reported instance of an upper respiratory tract infection. Conclusions Tofacitinib appears to be an effective adjunct therapy for management of pediatric Still's disease, particularly for patients with unstable clinical conditions and adverse reactions to corticosteroids.
proteins
2026-01-01 | Rescue Therapy With Continuous Intravenous Anakinra Infusion and Plasma Exchange in Refractory Cytokine Storm of Systemic JIA: A Case Report.
Macrophage activation syndrome (MAS) is one of the most common fatal complications of inflammatory diseases in children. In recent studies, Interleukin 1 inhibitors have been shown to be effective in suppressing the cytokine storm in MAS. There is limited literature describing the role of plasmapheresis in the cytokine storm syndromes as in MAS. A six-year-old boy presented with a 1-month history of daily fever, arthritis, cervical lymphadenopathy, skin rash, and elevated inflammatory markers. After multidisciplinary evaluation, he was diagnosed with systemic onset Juvenile Idiopathic Arthritis (sJIA) and started on IV methylprednisolone and SC anakinra. He later developed status epilepticus, required intubation, and progressed to multiorgan failure, needing inotropes and dialysis. Following a brief afebrile period, he worsened again, and labs confirmed MAS relapse with ferritin levels peaking at 26,000. Escalated treatment included switching to IV continuous anakinra, adding ciclosporin, and starting plasmapheresis. After three sessions of plasma exchange, he significantly improved, was extubated, and weaned off inotropes. However, attempts to switch anakinra back to SC failed twice, with recurrence of fever, rash, and elevated ferritin. He remained in PICU on IV continuous anakinra for over 3 weeks. When ferritin dropped to 900, an IV bolus regimen was trialed for a week, followed by a successful switch to SC anakinra. The child was discharged home asymptomatic with normalized labs. Anakinra has been used off-label in critically ill patients with MAS, thrombocytopenia, subcutaneous edema, and neurological dysfunction. Tapering from intravenous Anakinra to subcutaneous was challenging. This case taught us that tapering must begin at the right time to avoid hiccups or unfavorable outcomes. As reported in a few studies, plasmapheresis combined with immunosuppressants can reduce MAS-associated mortality by rapidly removing cytokines from the body.
2025-11-07 | Anakinra treatment for systemic onset juvenile idiopathic arthritis in Libyan Children
Systemic onset juvenile idiopathic arthritis (SoJIA) is a rare inflammatory disorder. It is the severest form of juvenile idiopathic arthritis, and complications occur most commonly in this type. Non-responsiveness to standard therapy with corticosteroids and disease-modifying antirheumatic drugs is not uncommon. Interleukin-1 beta (Il-1β) has been shown to be a main contributor to the pathogenesis of SoJIA. Anakinra, a recombinant Il-1β receptor antagonist, was shown to be effective in small cohorts of therapy-resistant adult and pediatric still's patients. This study aimed to evaluate the real-world efficacy, steroid-sparing effect, and safety profile of anakinra in patients with SoJIA at a tertiary care center in Libya. A retrospective case series was conducted on patients with SoJIA treated with anakinra at the Tripoli Children's Hospital between 2010 and 2017. Data on demographic characteristics, disease activity, corticosteroid dosage, concomitant medications, and adverse events were collected at baseline and at 1-, 3-, 6-, and 12-month post-treatment. 13 patients were treated with anakinra with a mean age of 9.4±4.6 years at anakinra initiation and a female-to-male ratio of 2: 1. All patients were on corticosteroids and 92.3% on methotrexate at treatment initiation. The proportion of patients achieving inactive disease (Jadas 10=0) increased over time. A marked steroid-sparing effect was observed: the number of patients requiring high-dose steroids (>0.5 mg/kg/day) decreased from 100% at baseline to 7.6% at 12 months, and 53.8% successfully discontinued corticosteroids entirely. All patients experienced injection site reaction, and macrophage activation syndrome occurred in 15.4% as a side effect after treatment initiation. But no severe infections or fatalities occurred. Reasons for discontinuation included remission (46.1%), drug unavailability (23.0%), inefficacy (15.3%), and side effects (15.3%). Anakinra demonstrated significant efficacy in inducing rapid disease control and reducing corticosteroid dependence in patients with refractory SoJIA, with a manageable safety profile.
2025-07-26 | Use of Intravenous Anakinra for Management of Pediatric Cytokine Storm Syndromes at an Academic Medical Center
Background: Off-label intravenous (IV) route of anakinra is increasingly recognized to enable higher and faster maximal plasma concentrations than subcutaneous route for treatment of cytokine storm syndromes. Objective: To describe off-label indications of IV anakinra, corresponding dosing and safety profiles, particularly during the coronavirus disease 19 (COVID-19) pandemic. Methods: A retrospective, single-cohort study was conducted at an academic medical center to evaluate use of IV anakinra in hospitalized pediatric patients (age ≤21 years). Institutional Review Board review was considered exempt. The primary endpoint was the primary indication(s) for IV anakinra. The key secondary endpoints were dosing of IV anakinra, previous immunomodulatory therapies, and adverse events. Results: Of 14 pediatric patients, 8 (57.1%) received IV anakinra for treatment of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, whereas 3 and 2 were treated for hemophagocytic lymphohistiocytosis (HLH) and flares of systemic onset juvenile idiopathic arthritis (SoJIA), respectively. The initial dosing regimen of IV anakinra for MIS-C associated with COVID-19 was a median dose of 2.25 mg/kg/dose with a median dosing interval of 12 hours for a median initial treatment duration of 3.5 days. Eleven (78.6%) patients received previous immunomodulatory therapies (IV immune globulin [n = 10; 71.4%] and steroids [n = 9; 64.3%]). No adverse drug events were documented. Conclusion: IV anakinra was used off-label for treatment of MIS-C associated with COVID-19, HLH and SoJIA flares in critically ill patients with no adverse drug events documented. This study helped ascertain the off-label indications of IV anakinra and corresponding patient characteristics.
2024-09-30 | MYOCARDITISREVEALING AN ADULTSTILLONSETDISEASE
A 21-year-old male patient presented with a combination of fever, palpitations, a maculopapular rash, and pharyngitis. Laboratory tests revealed an elevated high-sensitivity troponin I concentration of 3000 ng/L, indicating potential cardiac involvement. A transthoracic echocardiogram demonstrated a reduction in global longitudinal strain, suggesting impaired cardiac function. Further investigation with cardiac magnetic resonance imaging confirmed the diagnosis of acute myocarditis. After a thorough clinical evaluation, the patient was diagnosed with adult-onset Stills disease. Treatment was promptly initiated, consisting of intravenous corticosteroids and Kineret (anakinra), aimed at managing the inflammatory response and preventing further complications.
2023-07-17 | IL-18 in Autoinflammatory Diseases: Focus on Adult Onset Still Disease and Macrophages Activation Syndrome.
Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine that is involved in various innate and adaptive immune processes related to infection, inflammation, and autoimmunity. Therefore, it is described as a key mediator of autoinflammatory diseases associated with the development of macrophage activation syndrome (MAS), including systemic juvenile idiopathic arthritis and adult-onset Still's disease. This review focuses on the role of IL-18 in inflammatory responses, placing emphasis on autoinflammatory diseases associated with chronic excess of serum IL-18, which correlate with clinical and biological signs of the disease. Therefore, it is useful for the diagnosis and monitoring of disease activity. Researchers are currently investigating IL-18's role as a therapeutic target for the treatment of inflammatory diseases. The inhibition of IL-18 signaling through recombinant human IL-18BP (IL-18 binding protein) seems to be an effective therapeutic strategy, though further studies are necessary to clarify its importance as a therapeutic target.
other
2025-06-01 | POS1430 GENETIC LANDSCAPE OF ADULT-ONSET STILL'S DISEASE WITH MACROPHAGE ACTIVATION SYNDROME: IDENTIFYING KEY RISK LOCI FOR DISEASE MECHANISMS AND PERSONALIZED TREATMENT
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are severe, life-threatening systemic hyperinflammatory syndromes. They can arise from genetic defects as well as various triggers, including infections, malignancies, and autoimmune diseases. MAS is most recognised and best studied in systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still disease (AOSD). Currently, research on the underlying pathogenesis of MAS and its treatment options remains insufficient. Recently, the field of genomics has garnered increasing attention. The objective of this study is to identify the genetic variants associated with AOSD-MAS susceptibility and to elucidate their connections to specific target genes. Such insights are critical for advancing the clinical translation of genetic discoveries, thereby enhancing the accuracy of diagnostic genetic screenings and informing personalized therapeutic strategies. In this study, we performed whole-exome sequencing (WES) on a cohort of AOSD patients to identify potential genetic variations, followed by Sanger sequencing for validation. RNA sequencing (RNA-seq) was conducted to explore gene expression profiles. Statistical analyses were carried out using Fisher's exact test (two-sided) to assess associations, and survival analysis was employed to evaluate outcomes. This study investigated the genetic predisposition of AOSD-MAS, highlighting the critical involvement of known causative genes for primary HLH (pHLH-KG) and the candidate genes in AOSD-MAS. Among the 72 AOSD-MAS patients, 19 individuals (19/72, 26.39%) harbored mutations in pHLH-KG genes, including LYST, PRF1, STX11, UNC13D, NLRC4, STXBP2, AP3B1, CTPS1, RASGRP1, NCKAP1L, and RC3H1. Gene level comparisons demonstrated that ADGRE2, TGFB1, C6, IKZF3, MPO, POLD1, LIFR, IL15RA, and FANCC were significantly enriched in AOSD-MAS compared to AOSD without MAS (AOSD-nMAS), with notable differences (log2OR > 1 or infinite, p-value < 0.05). At the variant level, significant differences were observed for LYST p.I2666N, STX11 p.A125V, POLA1 p.V539M, LRBA p.E88A, ERCC4 p.G912R, and ADGRE2 p.C29Y (p-value < 0.05). These findings strongly suggest that ADGRE2 plays a pivotal role in the pathogenesis of AOSD-MAS. Additionally, we also conducted gene-phenotype correlation analysis, which revealed that CSF2RB and MECOM were significantly more prominent in refractory AOSD-MAS. In conclusion, the potential synergistic interactions among these genes may contribute critically to the development of AOSD-MAS. Our study identified mutations in known HLH-associated genes as well as new candidate genes in AOSD-MAS through WES. Gene-phenotype correlation analysis revealed differences in gene profiles across different clinical phenotypes, providing insights for the precision therapies for AOSD-MAS. NIL. NIL. None declared. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.
antibodies
2026-07-02 | Clinical Features and Outcome Measures Across Still Disease (Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still Disease) Cohorts Worldwide: A Systematic Literature Review.
J Rheumatol 2026; doi: 10.3899/jrheum.2025-0822 The following text should be added to the acknowledgment: "The contributions of the National Institutes of Health (NIH) authors are considered works of the US government. The findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the US Department of Health and Human Services." This correction applies to the December 1 2025 First Release and February 2026 print issue. The online version has been corrected.
2026-06-20 | Predictive Factors for Relapse in Still's Disease: A Retrospective Cohort Study of Clinical and Laboratory Biomarkers.
This retrospective cohort study aimed to identify clinical and laboratory predictors of relapse in patients with Still's disease. A total of 94 patients diagnosed by Yamaguchi or Fautrel criteria across two rheumatology centers between 2012 and 2024 were evaluated, of whom 87 were eligible for analysis. Thirty-one patients (35%) experienced relapses during follow-up. Relapse was associated with higher baseline C-reactive protein (CRP > 100 mg/L), elevated neutrophil counts, and lower albumin levels. Composite ratios such as ferritin/albumin, CRP/albumin, and neutrophil/albumin were also significantly higher in the relapse group. Clinically, a joint-dominant disease phenotype and initial use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) were more common among patients who relapsed. In multivariate logistic regression, high CRP levels, joint-dominant phenotype, and csDMARD use emerged as independent predictors of relapse. These findings highlight the predictive value of widely available biomarkers and baseline clinical presentation in stratifying relapse risk in Still Disease. Early recognition of high-risk patients using these factors may guide more targeted treatment approaches, support earlier initiation of biologic therapies, and ultimately improve long-term disease outcomes.
2026-05-26 | Early intensification versus step-up biologic strategies in systemic juvenile idiopathic arthritis: a Bayesian network meta-analysis of remission and safety outcomes.
To compare the relative effects of different treatment strategies for Systemic Juvenile Idiopathic Arthritis (sJIA) on clinical inactivity (CID)/remission and safety using a Bayesian network meta-analysis and to rank the treatment options. PubMed, Embase, Web of Science, the Cochrane Library, and Scopus were systematically searched from inception to October 2025 according to PRISMA 2020 and PRISMA-NMA specifications. Randomized controlled trials (RCTs), prospective cohorts, and retrospective/registry studies were included. The primary outcome was the CID/remission rate, and the secondary outcome was the incidence of adverse events (AEs) (normalized per patient-year). Random-effects and Bayesian hierarchical network models were used. Risk of bias was assessed using ROB-2 and NOS, and the certainty of evidence was assessed using GRADE. A total of 2,408 records were retrieved. After deduplication, 1,088 records were screened for titles/abstracts, and 200 were reviewed in full text. Fifteen studies (total sample size 1,548) were ultimately included. A pooled analysis showed that approximately two-thirds of patients achieved CID/remission during follow-up (random-effects model). Stratification suggested that an early IL-1/IL-6 strategy had a more favorable response rate. A network meta-ranking analysis (SUCRA) showed that early IL-1/IL-6 blockade ranked first, followed by anakinra and canakinumab; tocilizumab was in the middle; and conventional care and mixed biologic strategies ranked last. The overall AE rate was low and consistent across studies; IL-1/IL-6 targeted drugs had a favorable safety profile. Multiple sensitivity analyses and cumulative evidence analysis supported the robustness of the conclusions. In sJIA, immediate intensive IL-1/IL-6 therapy at diagnosis is more effective than a step-up approach in achieving and maintaining CID/remission, while also having an acceptable safety profile, supporting the initial "target-to-treat (T2T)" strategy. Future prospective studies and biomarker-stratified validation of each strategy are needed.
2026-05-01 | Early C-reactive protein and ferritin kinetics after tocilizumab initiation predict macrophage activation syndrome in Still disease: a single-centre retrospective cohort study
Objectives This study aimed to evaluate the safety and effectiveness of tocilizumab (TCZ) as induction therapy in Still disease and identify early dynamic biomarkers, including C-reactive protein (CRP) and ferritin changes, for macrophage activation syndrome (MAS) risk stratification. Methods This single-centre retrospective cohort study included patients with Still disease treated from 2004 to 2024. Patients were classified by induction therapy (TCZ vs non-TCZ). MAS was defined using the 2016 European Alliance of Associations for Rheumatology/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation criteria. Early biomarker changes after prednisolone initiation were evaluated. Primary outcomes were week-4 CRP normalisation and clinically inactive disease (CID) at month 3. Associations with induction therapy were analysed using Firth's penalised logistic regression. In TCZ-treated patients, receiver operating characteristic analyses assessed laboratory biomarkers for MAS prediction. Results Among 54 patients, 12 received TCZ as initial induction therapy and 7 for relapse (19 episodes). MAS occurred in 5 episodes (26.3%). No significant differences were observed in week-4 CRP normalisation (75.0% vs 51.2%, P = .193) or month-3 CID (40.0% vs 14.6%, P = .090). After adjusting for the higher initial prednisolone dose, early TCZ exposure was independently associated with month-3 CID (odds ratio: 9.73, 95% CI: 1.25-77.50, P = .030). Week-1/baseline CRP ratio and ferritin ratios predicted MAS after TCZ induction; the week-1/baseline ferritin ratio showed the highest area under the curve (0.914), followed by the CRP ratio (0.877). Conclusions Early TCZ exposure was independently associated with CID at month 3. Insufficient early suppression of inflammatory markers, particularly higher ferritin and CRP ratios, may identify patients at higher risk of subsequent MAS.
2026-04-04 | Effectiveness of Canakinumab for First-Line Steroid-Free Treatment in Systemic-Onset Juvenile Idiopathic Arthritis and Juvenile Still Disease.
This prospective study assesses the response to canakinumab monotherapy administered as three monthly subcutaneous injections in glucocorticoid-naïve patients with newly diagnosed systemic juvenile idiopathic arthritis (sJIA) and Still disease and evaluates the durability of drug-free inactive disease for up to nine months after canakinumab cessation. In a multicenter, two-phase open-label study of newly diagnosed sJIA or Still disease, canakinumab was administered at 4 mg/kg subcutaneously every 4 weeks for 12 weeks. Thereafter, patients were followed for an additional 40 weeks. Routine care was provided to nonresponders. In total, 21 patients were recruited, and 1 was excluded due to protocol violations. Fever resolved immediately in 17/19 patients. Two nonresponders (n = 2) were managed with different strategies: one received steroids alone, and the other received steroids plus canakinumab as part of routine care. By week 12, 14 patients achieved inactive disease. Thereafter, two flares occurred at weeks 24 and 36. Macrophage activation syndrome (MAS) was diagnosed in a third patient at week 19 and responded to treatment with glucocorticoids and cyclosporine A. By week 52, 11 patients had reached drug-free inactive disease and 3 had minimal disease activity. A total of 97 adverse events were reported; four were serious (one MAS, two disease flares, and one viral infection), but none were attributed to the study drug. Canakinumab steroid-free first-line therapy in newly diagnosed sJIA induces long-lasting, drug-free inactive disease in a substantial proportion of patients. Discontinuation of canakinumab was associated with disease flares in a minority of patients.
cell therapies
2023-10-16 | Case report: Success of allogeneic hematopoietic stem cell transplantation for refractory systemic-onset juvenile idiopathic arthritis
Objectives This study reports cases of systemic-onset juvenile idiopathic arthritis (sJIA) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center and reviews published outcomes of allo-HSCT in sJIA. Methods We present a case report of two patients with sJIA who underwent allo-HSCT at a tertiary pediatric hospital. Each patient’s disease course and allo-HSCT protocol/outcome are described. Outcomes of published cases of allo-HSCT in sJIA were compared to our experience. Results Two patients with sJIA had allo-HSCT. Both failed multiple lines of disease-modifying anti-rheumatic drugs and experienced severe disease/treatment-related complications. Despite post-HSCT complications, both recovered without sequelae. Five years post-HSCT, patient 1 is in complete remission (CR) and is off medications. Patient 2 was in CR until 11 months post-HSCT after which he developed three disease flares. At 4 years post-HSCT he is currently in CR on Adalimumab monotherapy. Engraftment was excellent with a donor chimerism of 100% for patient 1 and 93% for patient 2. In the literature, the outcome of allo-HSCT is reported in 13 sJIA patients. When merging those with our 2 patients, 1/15 patients died and 13/14 achieved CR, of which 12 are off medications (median [range] follow-up: 2.2 [0.2–7.0] years). Extended follow-up data on 11 of the 13 reported sJIA patients showed that an additional 3 patients flared at 3, 4, and 10 years post-HSCT. Conclusion We report two patients with severe/refractory sJIA who underwent successful allo-HSCT and achieved CR. Allo-HSCT is a potential curative option for severe/refractory sJIA. It should be considered only after failure of conventional sJIA treatments and when an HLA-matched donor is available in order to lower transplant-related mortality. The outcomes of reported sJIA patients who received allo-HSCT are encouraging but long-term follow-up data are needed to better characterized the risk–benefit ratio of this procedure.
2023-01-17 | Therapeutic plasma exchange in refractory macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a case-based review.
Juvenile idiopathic arthritis (JIA) is a heterogeneous group of arthritis of autoimmune aetiology. Systemic-onset juvenile idiopathic arthritis (soJIA) presents with fever, transient erythematous rash, hepatomegaly, splenomegaly, lymphadenopathy, and serositis. SoJIA presents multiple complications, and the most severe is the macrophage activation syndrome (MAS); the timely treatment of MAS must be established early and aggressively to avoid a fatal outcome. Therapeutic plasma exchange has anecdotally been used in refractory cases. A 66-month-old male with a 1-year illness characterized by evening-predominant, intermittent fever, adenomegalies, urticarial-like rash, arthralgia, and arthritis. Biochemical analysis revealed anaemia, leukocytosis, neutrophilia, hypertriglyceridemia, hyperferritinemia, and hypofibrinogenemia; bone marrow aspirate showed hemophagocytosis. He was diagnosed with SoJIA complicated with MAS. He received multiple treatments with IV human gammaglobulin, cyclosporine, dexamethasone, and tocilizumab without improvement. Plasma replacement treatment was performed. Afterwards, he presented significant improvement. After 3-year-follow-up, he remains in good general condition. We present a refractory case of soJIA complicated with MAS successfully treated with plasma exchange.
2021-07-13 | The immunoregulatory function of peripheral blood CD71+ erythroid cells in systemic-onset juvenile idiopathic arthritis
Abstract CD71 + erythroid cells (CECs) are recognized to have an immunoregulatory function via direct cell–cell interaction and soluble mediators. Circulating CECs appear in newborns or patients with hemolytic and cardiopulmonary disorders. To assess the biological role of CECs in systemic inflammation, we studied the gene expression and function in systemic-onset juvenile idiopathic arthritis (SoJIA). Peripheral blood mononuclear cells of SoJIA patients expressed upregulated erythropoiesis-related genes. It represented the largest expansion of CECs during active phase SoJIA among other inflammatory diseases. Despite the opposing roles of erythropoietin and hepcidin in erythropoiesis, both serum levels were in concert with the amounts of SoJIA-driven CECs. Circulating CECs counts in inflammatory diseases were positively correlated with the levels of C-reactive protein, IL-6, IL-18, or soluble TNF receptors. Co-culture with active SoJIA-driven CECs suppressed secretions of IL-1β, IL-6, and IL-8 from healthy donor monocytes. The top upregulated gene in SoJIA-driven CECs was ARG2 compared with CECs from cord blood controls, although cytokine production from monocytes was suppressed by co-culture, even with an arginase inhibitor. CECs are driven to the periphery during the acute phase of SoJIA at higher levels than other inflammatory diseases. Circulating CECs may control excessive inflammation via the immunoregulatory pathways, partly involving arginase-2.
2021-04-06 | Uncharted waters: Mesenchymal stem cell Treatment for Pediatric Refractory Rheumatic Diseases; A Single Center Case Series
Abstract Background: With the advent of innovative therapies including biologics and Janus kinase inhibitors, children with rheumatic diseases are more likely to have improved outcomes. Yet, despite these advances, some children do not respond, or they, or their parents fear adverse events and seek other alternatives. Increasingly, there are private companies that offer mesenchymal stem cells (MSC) as an alternative and describe it as a more natural therapy for rheumatic diseases, often insinuating that there will be a cure. Mesenchymal stem cells have immunomodulatory properties, and transplantation of these stem cells have been used to successfully treat immunologic conditions like graft-versus-host disease. More recently, MSC research in adults with lupus has been encouraging, but the clinical trials are still underway and in most, mesenchymal stem cell therapy is not a standalone treatment. This retrospective case series will highlight three cases of children with refractory autoimmune disease whose parents sought out and received MSC therapy as a self-decision without first seeking medical advice from our specialty . In our cases, the three families felt that their children were improved and in two believed that their child was cured. Mesenchymal stem cells have the potential of beneficial immunomodulation and may be a powerful tool in the therapy of rheumatic disease, but well controlled clinical trials are necessary and should be designed and monitored by experts in childhood rheumatic disease. Case Presentation: Three children with three different rheumatic diseases; systemic lupus erythematosus, mixed connective tissue disease and juvenile idiopathic arthritis were under the care of pediatric rheumatology at a large, tertiary-care, teaching institution. Multiple non-biologic and biologic disease-modifying anti-rheumatic drugs failed to significantly decrease disease activity, and as a result, the families chose to undergo MSC therapy. After transplantation, all children improved per patient and parent report and tapered off conventional immunosuppressive drugs. No serious adverse events occurred in these three patients. Conclusion: The three cases presented in this study reflect comparable beneficial outcomes and minimal risks published in adult studies. These were not controlled studies, however, and benefit was reported rather than documented. These cases suggest that MSC transplantation may prove a promising adjunctive treatment option; however, further research, development of standardized infusion therapy protocols, and well-designed and monitored clinical trials are essential.
2019-03-31 | Bone-marrow derived mesenchymal stromal cells infusion in therapy refractory juvenile idiopathic arthritis patients
Abstract Objectives To compare the total number of adverse events (AEs) before and after mesenchymal stromal cell (MSC) infusion in refractory JIA and to evaluate its effectiveness. Methods Single-centre Proof of Mechanism Phase Ib, open label intervention study in JIA patients previously failing all biologicals registered for their diagnosis. Six patients received 2 million/kg intravenous infusions of allogeneic bone-marrow derived MSC. In case of ACR-Ped30-response but subsequent loss of response one and maximal two repeated infusions are allowed. Results Six JIA patients with 9.2 years median disease duration, still active arthritis and damage were included. All had failed methotrexate, corticosteroids and median five different biologicals. MSC were administered twice in three patients. No acute infusion reactions were observed and a lower post-treatment than pre-treatment incidence in AEs was found. The one systemic onset JIA (sJIA) patient had again an evolving macrophage activation syndrome, 9 weeks after tocilizumab discontinuation and 7 weeks post-MSC infusion. Statistically significant decreases were found 8 weeks after one MSC infusion in VAS well-being (75–56), the JADAS-71 (24.5–11.0) and the cJADAS10 (18.0–10.6). Conclusion MSC infusions in six refractory JIA patients were safe, although in sJIA stopping the ‘failing’ biologic treatment carries a risk of a MAS flare, as the drug might still suppress the systemic features. Trial registration Trial register.nl, http://https://www.trialregister.nl, NTR4146.
small molecules
2026-03-19 | A Rare RIPK3 Variant Enhances Necroptosis and Promotes Inflammation in a Still Disease-Like Autoinflammatory Syndrome.
Still disease represents a prototypical polygenic systemic autoinflammatory disease, characterized by recurrent systemic inflammation and dysregulation of innate immunity. Despite extensive clinical characterization, familial clustering Still disease remains unreported. This study investigates a novel variant underlying a distinct Still disease-like autoinflammatory syndrome. Whole-exome sequencing was performed in a three-generation family with three affected individuals. Functional analyses were conducted to assess the impact of the receptor-interacting protein kinase 3 (RIPK3) p.Q134K variant on kinase activity, necroptosis, and inflammatory signaling. Transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) and in vitro cytokine assays were used to characterize inflammatory responses. A heterozygous RIPK3 p.Q134K variant was identified in all affected individuals. Functional analyses demonstrated that this variant exhibits gain-of-function activity, characterized by enhanced RIPK3 kinase activity and increased RIPK3 self-association, which in turn promote mixed-lineage kinase domain-like protein phosphorylation and necroptosis. RNA sequencing of PBMCs from one patient revealed marked up-regulation of NF-κB and MAPK signaling pathways and elevated expression of interleukin-6, and tumor necrosis factor-α, which was effectively suppressed by pharmacologic inhibition of RIPK3. This study describes a familial Still disease-like autoinflammatory syndrome caused by a gain-of-function RIPK3 variant. Our findings establish aberrant RIPK3 activation as a driver of autoinflammation and expand the spectrum of human RIPK3-associated diseases.
2026-03-13 | Efficacy of combined JAK1/2 inhibition and cyclosporine in paediatric-onset Still's disease with lung involvement: a case report.
BACKGROUND: Paediatric-onset Still’s disease is a severe autoinflammatory disorder marked by high fever, systemic inflammation, rash, organomegaly, and arthritis. Pulmonary complications, once anecdotally reported, have been increasingly observed in paediatric Still’s disease. A more severe lung involvement, Still-associated lung disease, has emerged in the last ten years, including interstitial lung disease, pulmonary hypertension, and pulmonary alveolar proteinosis (PAP). This complication carries significant morbidity and mortality. Its mechanism remains poorly understood; current biologic therapies targeting interleukin (IL)-1 and IL-6 often prove insufficient, supporting the need for innovative approaches or combined treatment. CASE PRESENTATION: A 10-year-old girl with Still’s disease developed PAP and pulmonary hypertension. After several treatment failures and ongoing oxygen dependency, she responded favourably to a combination of baricitinib and cyclosporine. This allowed for gradual corticosteroid tapering and eventual discontinuation, achieving sustained disease control without further oxygen supplementation. Pulmonary assessment, echocardiography, cardiac catheterization, bronchoalveolar lavage, and lung biopsy were performed, along with immunological profiling, HLA typing, and genetic analysis. The type I IFN signature was closely monitored, with normalization observed after reaching the therapeutic dose of baricitinib. CONCLUSION: This case provides evidence of the long-term efficacy and safety of baricitinib combined with cyclosporine in managing Still-LD, offering a promising option for this severe complication.
2025-10-02 | Pruritic eruption in a young woman with fever.
A 29-year-old woman presented with 3 weeks of fever, arthralgia and pruritic rashes on her trunk and limbs. She had no significant medical history and denied occurrence of muscle weakness, dysphagia, mouth ulcers, alopecia and sicca symptoms. Physical examination revealed erythematous, oedematous papules and plaques on the anterior sternum, upper to mid-back, arms, flanks and lateral aspect of the proximal thighs. Antinuclear antibody and anti-double-stranded DNA were negative. Complements, creatine kinase and myositis panel were normal. Her erythrocyte sediment rate and ferritin levels were elevated at 48 mm h-1 and 580 µg L-1, respectively. Histological examination of the plaque on her upper back revealed epidermal dyskeratosis, with a mixed perivascular infiltrate of neutrophils, lymphocytes and histiocytes within the superficial dermis. There was prominent nuclear dust, red cell extravasation and increased dermal mucin. Direct immunofluorescence was negative. She was eventually diagnosed with persistent pruritic eruption (PPE) of adult-onset Still disease (AOSD) and was treated with oral etoricoxib with resolution of her fever and symptoms. The entity of PPE in AOSD is associated with the striking histological feature of dyskeratotic keratinocytes in the upper one-third of the epidermis. This is in contrast to other conditions such as cutaneous lupus or dermatomyositis, where the dyskeratotic keratinocytes are found in the lower epidermis instead. This case highlights the importance of clinicopathological correlation and recognition of PPEs in AOSD in view of the associated poorer prognosis due to associated conditions such as secondary macrophage activation syndrome.
2025-09-05 | Tofacitinib as an adjuvant treatment for pediatric Still's disease.
To describe the efficacy and safety of tofacitinib for pediatric Still's disease, also referred to as systemic-onset juvenile idiopathic arthritis (sJIA). Traditional non-biological drugs and drugs targeting the interleukin-1 and interleukin-6 pathways benefit some patients, but others show inadequate responses. We retrospectively analyzed ten patients with pediatric Still's disease who were treated with tofacitinib and had at least one follow-up visit. Data on patient history, laboratory findings, and treatments were collected at disease onset, at the initiation of tofacitinib, and during follow-up. Tofacitinib led to complete remission in six patients, partial remission in three patients, and loss of efficacy in one patient. Among the nine patients with remission, two discontinued corticosteroids entirely and seven used lower dosages of corticosteroids; these patients also used fewer concurrent medications (1 or 2) after tofacitinib initiation. The one patient who experienced loss of efficacy continued to require a higher dosage of corticosteroids and received five different additional medications. The other nine patients received tocilizumab and had a decreased frequency of these injections after tofacitinib initiation. Tofacitinib was well-tolerated, with only one reported instance of an upper respiratory tract infection. Tofacitinib appears to be an effective adjunct therapy for management of pediatric Still's disease, particularly for patients with unstable clinical conditions and adverse reactions to corticosteroids.
2025-08-20 | Table 1_Tofacitinib as an adjuvant treatment for pediatric Still's disease.docx
Objective To describe the efficacy and safety of tofacitinib for pediatric Still's disease, also referred to as systemic-onset juvenile idiopathic arthritis (sJIA). Traditional non-biological drugs and drugs targeting the interleukin-1 and interleukin-6 pathways benefit some patients, but others show inadequate responses. Methods We retrospectively analyzed ten patients with pediatric Still's disease who were treated with tofacitinib and had at least one follow-up visit. Data on patient history, laboratory findings, and treatments were collected at disease onset, at the initiation of tofacitinib, and during follow-up. Results Tofacitinib led to complete remission in six patients, partial remission in three patients, and loss of efficacy in one patient. Among the nine patients with remission, two discontinued corticosteroids entirely and seven used lower dosages of corticosteroids; these patients also used fewer concurrent medications (1 or 2) after tofacitinib initiation. The one patient who experienced loss of efficacy continued to require a higher dosage of corticosteroids and received five different additional medications. The other nine patients received tocilizumab and had a decreased frequency of these injections after tofacitinib initiation. Tofacitinib was well-tolerated, with only one reported instance of an upper respiratory tract infection. Conclusions Tofacitinib appears to be an effective adjunct therapy for management of pediatric Still's disease, particularly for patients with unstable clinical conditions and adverse reactions to corticosteroids.
proteins
2026-01-01 | Rescue Therapy With Continuous Intravenous Anakinra Infusion and Plasma Exchange in Refractory Cytokine Storm of Systemic JIA: A Case Report.
Macrophage activation syndrome (MAS) is one of the most common fatal complications of inflammatory diseases in children. In recent studies, Interleukin 1 inhibitors have been shown to be effective in suppressing the cytokine storm in MAS. There is limited literature describing the role of plasmapheresis in the cytokine storm syndromes as in MAS. A six-year-old boy presented with a 1-month history of daily fever, arthritis, cervical lymphadenopathy, skin rash, and elevated inflammatory markers. After multidisciplinary evaluation, he was diagnosed with systemic onset Juvenile Idiopathic Arthritis (sJIA) and started on IV methylprednisolone and SC anakinra. He later developed status epilepticus, required intubation, and progressed to multiorgan failure, needing inotropes and dialysis. Following a brief afebrile period, he worsened again, and labs confirmed MAS relapse with ferritin levels peaking at 26,000. Escalated treatment included switching to IV continuous anakinra, adding ciclosporin, and starting plasmapheresis. After three sessions of plasma exchange, he significantly improved, was extubated, and weaned off inotropes. However, attempts to switch anakinra back to SC failed twice, with recurrence of fever, rash, and elevated ferritin. He remained in PICU on IV continuous anakinra for over 3 weeks. When ferritin dropped to 900, an IV bolus regimen was trialed for a week, followed by a successful switch to SC anakinra. The child was discharged home asymptomatic with normalized labs. Anakinra has been used off-label in critically ill patients with MAS, thrombocytopenia, subcutaneous edema, and neurological dysfunction. Tapering from intravenous Anakinra to subcutaneous was challenging. This case taught us that tapering must begin at the right time to avoid hiccups or unfavorable outcomes. As reported in a few studies, plasmapheresis combined with immunosuppressants can reduce MAS-associated mortality by rapidly removing cytokines from the body.
2025-11-07 | Anakinra treatment for systemic onset juvenile idiopathic arthritis in Libyan Children
Systemic onset juvenile idiopathic arthritis (SoJIA) is a rare inflammatory disorder. It is the severest form of juvenile idiopathic arthritis, and complications occur most commonly in this type. Non-responsiveness to standard therapy with corticosteroids and disease-modifying antirheumatic drugs is not uncommon. Interleukin-1 beta (Il-1β) has been shown to be a main contributor to the pathogenesis of SoJIA. Anakinra, a recombinant Il-1β receptor antagonist, was shown to be effective in small cohorts of therapy-resistant adult and pediatric still's patients. This study aimed to evaluate the real-world efficacy, steroid-sparing effect, and safety profile of anakinra in patients with SoJIA at a tertiary care center in Libya. A retrospective case series was conducted on patients with SoJIA treated with anakinra at the Tripoli Children's Hospital between 2010 and 2017. Data on demographic characteristics, disease activity, corticosteroid dosage, concomitant medications, and adverse events were collected at baseline and at 1-, 3-, 6-, and 12-month post-treatment. 13 patients were treated with anakinra with a mean age of 9.4±4.6 years at anakinra initiation and a female-to-male ratio of 2: 1. All patients were on corticosteroids and 92.3% on methotrexate at treatment initiation. The proportion of patients achieving inactive disease (Jadas 10=0) increased over time. A marked steroid-sparing effect was observed: the number of patients requiring high-dose steroids (>0.5 mg/kg/day) decreased from 100% at baseline to 7.6% at 12 months, and 53.8% successfully discontinued corticosteroids entirely. All patients experienced injection site reaction, and macrophage activation syndrome occurred in 15.4% as a side effect after treatment initiation. But no severe infections or fatalities occurred. Reasons for discontinuation included remission (46.1%), drug unavailability (23.0%), inefficacy (15.3%), and side effects (15.3%). Anakinra demonstrated significant efficacy in inducing rapid disease control and reducing corticosteroid dependence in patients with refractory SoJIA, with a manageable safety profile.
2025-07-26 | Use of Intravenous Anakinra for Management of Pediatric Cytokine Storm Syndromes at an Academic Medical Center
Background: Off-label intravenous (IV) route of anakinra is increasingly recognized to enable higher and faster maximal plasma concentrations than subcutaneous route for treatment of cytokine storm syndromes. Objective: To describe off-label indications of IV anakinra, corresponding dosing and safety profiles, particularly during the coronavirus disease 19 (COVID-19) pandemic. Methods: A retrospective, single-cohort study was conducted at an academic medical center to evaluate use of IV anakinra in hospitalized pediatric patients (age ≤21 years). Institutional Review Board review was considered exempt. The primary endpoint was the primary indication(s) for IV anakinra. The key secondary endpoints were dosing of IV anakinra, previous immunomodulatory therapies, and adverse events. Results: Of 14 pediatric patients, 8 (57.1%) received IV anakinra for treatment of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, whereas 3 and 2 were treated for hemophagocytic lymphohistiocytosis (HLH) and flares of systemic onset juvenile idiopathic arthritis (SoJIA), respectively. The initial dosing regimen of IV anakinra for MIS-C associated with COVID-19 was a median dose of 2.25 mg/kg/dose with a median dosing interval of 12 hours for a median initial treatment duration of 3.5 days. Eleven (78.6%) patients received previous immunomodulatory therapies (IV immune globulin [n = 10; 71.4%] and steroids [n = 9; 64.3%]). No adverse drug events were documented. Conclusion: IV anakinra was used off-label for treatment of MIS-C associated with COVID-19, HLH and SoJIA flares in critically ill patients with no adverse drug events documented. This study helped ascertain the off-label indications of IV anakinra and corresponding patient characteristics.
2024-09-30 | MYOCARDITISREVEALING AN ADULTSTILLONSETDISEASE
A 21-year-old male patient presented with a combination of fever, palpitations, a maculopapular rash, and pharyngitis. Laboratory tests revealed an elevated high-sensitivity troponin I concentration of 3000 ng/L, indicating potential cardiac involvement. A transthoracic echocardiogram demonstrated a reduction in global longitudinal strain, suggesting impaired cardiac function. Further investigation with cardiac magnetic resonance imaging confirmed the diagnosis of acute myocarditis. After a thorough clinical evaluation, the patient was diagnosed with adult-onset Stills disease. Treatment was promptly initiated, consisting of intravenous corticosteroids and Kineret (anakinra), aimed at managing the inflammatory response and preventing further complications.
2023-07-17 | IL-18 in Autoinflammatory Diseases: Focus on Adult Onset Still Disease and Macrophages Activation Syndrome.
Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine that is involved in various innate and adaptive immune processes related to infection, inflammation, and autoimmunity. Therefore, it is described as a key mediator of autoinflammatory diseases associated with the development of macrophage activation syndrome (MAS), including systemic juvenile idiopathic arthritis and adult-onset Still's disease. This review focuses on the role of IL-18 in inflammatory responses, placing emphasis on autoinflammatory diseases associated with chronic excess of serum IL-18, which correlate with clinical and biological signs of the disease. Therefore, it is useful for the diagnosis and monitoring of disease activity. Researchers are currently investigating IL-18's role as a therapeutic target for the treatment of inflammatory diseases. The inhibition of IL-18 signaling through recombinant human IL-18BP (IL-18 binding protein) seems to be an effective therapeutic strategy, though further studies are necessary to clarify its importance as a therapeutic target.
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2025-06-01 | POS1430 GENETIC LANDSCAPE OF ADULT-ONSET STILL'S DISEASE WITH MACROPHAGE ACTIVATION SYNDROME: IDENTIFYING KEY RISK LOCI FOR DISEASE MECHANISMS AND PERSONALIZED TREATMENT
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are severe, life-threatening systemic hyperinflammatory syndromes. They can arise from genetic defects as well as various triggers, including infections, malignancies, and autoimmune diseases. MAS is most recognised and best studied in systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still disease (AOSD). Currently, research on the underlying pathogenesis of MAS and its treatment options remains insufficient. Recently, the field of genomics has garnered increasing attention. The objective of this study is to identify the genetic variants associated with AOSD-MAS susceptibility and to elucidate their connections to specific target genes. Such insights are critical for advancing the clinical translation of genetic discoveries, thereby enhancing the accuracy of diagnostic genetic screenings and informing personalized therapeutic strategies. In this study, we performed whole-exome sequencing (WES) on a cohort of AOSD patients to identify potential genetic variations, followed by Sanger sequencing for validation. RNA sequencing (RNA-seq) was conducted to explore gene expression profiles. Statistical analyses were carried out using Fisher's exact test (two-sided) to assess associations, and survival analysis was employed to evaluate outcomes. This study investigated the genetic predisposition of AOSD-MAS, highlighting the critical involvement of known causative genes for primary HLH (pHLH-KG) and the candidate genes in AOSD-MAS. Among the 72 AOSD-MAS patients, 19 individuals (19/72, 26.39%) harbored mutations in pHLH-KG genes, including LYST, PRF1, STX11, UNC13D, NLRC4, STXBP2, AP3B1, CTPS1, RASGRP1, NCKAP1L, and RC3H1. Gene level comparisons demonstrated that ADGRE2, TGFB1, C6, IKZF3, MPO, POLD1, LIFR, IL15RA, and FANCC were significantly enriched in AOSD-MAS compared to AOSD without MAS (AOSD-nMAS), with notable differences (log2OR > 1 or infinite, p-value < 0.05). At the variant level, significant differences were observed for LYST p.I2666N, STX11 p.A125V, POLA1 p.V539M, LRBA p.E88A, ERCC4 p.G912R, and ADGRE2 p.C29Y (p-value < 0.05). These findings strongly suggest that ADGRE2 plays a pivotal role in the pathogenesis of AOSD-MAS. Additionally, we also conducted gene-phenotype correlation analysis, which revealed that CSF2RB and MECOM were significantly more prominent in refractory AOSD-MAS. In conclusion, the potential synergistic interactions among these genes may contribute critically to the development of AOSD-MAS. Our study identified mutations in known HLH-associated genes as well as new candidate genes in AOSD-MAS through WES. Gene-phenotype correlation analysis revealed differences in gene profiles across different clinical phenotypes, providing insights for the precision therapies for AOSD-MAS. NIL. NIL. None declared. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.
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Drug Discovery Landscape
4 orphan drug designations for Systemic-onset juvenile idiopathic arthritis.
4 orphan drug designations for Systemic-onset juvenile idiopathic arthritis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
upadacitinib | small molecules | FDA | 2017-08-16 | — | AbbVie, Inc. |
interleukin-1 receptor antagonist anakinra | proteins | FDA | 2015-09-15 | — | Swedish Orphan Biovitrum AB |
Canakinumab [Ilaris] | antibodies | EMA | 2008-02-04 | — | Novartis Europharm Limited |
Interleukin-1 Trap | proteins | FDA | 2005-04-04 | — | Regeneron Pharmaceuticals, Inc. |
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