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
453 drug discovery papers about Systemic-onset juvenile idiopathic arthritis, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
453 drug discovery papers about Systemic-onset juvenile idiopathic arthritis, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-09-22 | Predictive molecular signatures for successful tapering of canakinumab in systemic juvenile idiopathic arthritis.
Canakinumab induces clinical remission in a substantial proportion of patients with systemic juvenile idiopathic arthritis (sJIA), although not all achieve a complete response. However, tapering and withdrawal frequently lead to disease flares. This study aimed to identify serum and transcriptomic biomarkers that predict successful or unsuccessful tapering of canakinumab in sJIA. Seventy-nine patients with sJIA in remission on canakinumab enrolled in a randomised withdrawal study were analysed; 71 had samples available for gene expression profiling. Serum biomarkers were quantified using Luminex assays. Whole-blood RNA was assessed by RNA sequencing (RNA-Seq) and a targeted 67-gene NanoString panel informed by exploratory analyses. Differential expression, hierarchical clustering, and enrichment analyses were performed. Biomarkers and gene signatures were compared between patients who later successfully withdrew canakinumab and those who experienced unsuccessful tapering. Lower serum levels of sCD163, CXCL9, interleukin (IL)-1RA, and IL-18 were associated with successful tapering. RNA-Seq showed marked differences between active and inactive sJIA and revealed that future nonresponders exhibited lower expression of type I IFN-induced and higher expression of erythopoiesis-related genes. NanoString profiling identified 9 genes (ATF6, BCL6, FAS, IL1B, MAPK1, PPARG, SLC25A37, TNFAIP3, and UBE2D1) overexpressed in patients with unsuccessful tapering, reflecting persistent inflammation and cellular stress. A composite score of these genes discriminated successful from unsuccessful discontinuation (area under curve, AUC, 0.71). Serum inflammatory markers and targeted gene expression signatures identify patients with sJIA at higher risk of flare during canakinumab tapering. Combined molecular biomarker profiling may enable individualised tapering strategies and support precision medicine approaches for Still's disease.
2026-09-01 | Persistent Interleukin-18 Fuels Expansion of CD38+HLA-DR+CD8+ T Cells in Still Disease and Macrophage Activation Syndrome.
Still disease (SD) is an autoinflammatory disorder characterized by remarkably high interleukin-18 (IL-18) levels. Increasing evidence suggests that adaptive immunity also contributes to its pathogenesis, particularly in refractory courses. Macrophage activation syndrome (MAS), one of SD's most severe complications, is associated with further IL-18 elevation and expansion of CD38+HLA-DR+CD8+ T cells. However, whether and when this population emerges during SD remains unknown. We therefore examined CD38+HLA-DR+CD8+ T cells across disease stages. CD38+HLA-DR+CD8+ T cells were analyzed longitudinally: at SD onset (therapy-naive; n = 19), during clinically inactive disease (n = 15), and before or at MAS occurrence (n = 12). Spectral flow cytometry and bulk RNA sequencing were performed. Correlations with clinical and laboratory parameters were assessed. In vitro cytokine stimulations of healthy donor (HD)-derived peripheral blood mononuclear cells and CD8+ lymphocytes were performed to explore mechanisms driving differentiation of these cells. CD38+HLA-DR+CD8+ T cells were expanded from SD onset and peaked in MAS (median: 4.61% and 31.7%, respectively, versus 0.87% in HDs). Transcriptomic profiling of these cells revealed enrichment of activation, cytotoxicity, and proliferation programs, which were confirmed at the protein level. Frequencies correlated with markers of systemic inflammation, T cell activation, and serum IL-18 levels. Sustained IL-18 stimulation in vitro induced robust and persistent expansion of CD38+HLA-DR+CD8+ cells, recapitulating key ex vivo phenotypic features. CD38+HLA-DR+CD8+ cells, previously primarily associated with MAS, are detectable early in SD. Persistent IL-18 exposure promotes their expansion. These findings identify CD38+HLA-DR+CD8+ T cells as a potential mechanistic link between SD and MAS and highlight this subset as a candidate therapeutic target.
2026-08-25 | Association between canakinumab dose and long-term remission in Still's disease: insights from the AIDA network registry.
The primary aim of this study was to assess, in Still's disease, whether the employment of canakinumab at a strictly on-label dose may increase the likelihood of treatment discontinuation due to study-defined long-term remission (LTR), compared with patients receiving lower doses. Patients were drawn from the international Autoinflammatory Disease Alliance (AIDA) Network registry dedicated to Still's disease and stratified based on the starting canakinumab dose: the on-label group received either 300 mg every 4 weeks or 150 mg every 4 weeks (corresponding to 4 mg/kg), while the underdosed group received 150 mg every 4 weeks (corresponding to a dose not exceeding 3.5 mg/kg). Bayesian regression models were implemented to estimate the probability of achieving long-term remission with subsequent canakinumab withdrawal in the two groups, as well as the mean differences in probabilities and posterior probabilities indicating whether the on-label group was superior in achieving the endpoint. In total, 131 patients (16.7%) were enrolled, 81 (61.8%) receiving the on-label posology and 50 (38.2%) the underdosed posology. The estimated marginal posterior probability of canakinumab discontinuation due to LTR was 19% (CrI 7.5%-34.6%) in the on-label group and 3.9% (CrI 0.7%-15.2%) in the underdosed group, yielding a mean difference of 15.1% (CrI 1.4%-31.4%) and a posterior probability of 98.4%. This difference remained credible, with posterior probabilities ranging from 97.9% to 99.6%, irrespective of disease course or age at disease onset. On-label canakinumab dosing appears to increase the likelihood of study-defined LTR with subsequent treatment discontinuation, compared with underdosed treatment strategies.
2026-08-11 | The Asia-Pacific League of Associations for Rheumatology Consensus Recommendations on the Management of Systemic Juvenile Idiopathic Arthritis (Juvenile Still's Disease).
The unique characteristics of the Asia Pacific called for the development of pragmatic and viable guidelines for the management of juvenile idiopathic arthritis (JIA). These consensus recommendations represent the second part of the guideline intending to offer an updated and regionally relevant framework for the management of systemic JIA (sJIA)/juvenile Still's disease. A multidisciplinary task force of 35 members from 14 countries, including pediatric and adult rheumatologists as well as patient representatives, was convened. The guideline development followed the GRADE, ADAPTE, and AGREE II frameworks. Relevant international guidelines were critically appraised, and a systematic literature review was performed to address 10 PICO questions. Draft statements were discussed and voted upon using a modified Delphi process, with consensus defined as ≥ 80% agreement. Four overarching principles and eighteen statements, including five statements addressing macrophage activation syndrome (MAS) were formulated. The recommendations align with international guidelines, advocating early use of IL-1/IL-6 inhibitors, avoidance of glucocorticoid monotherapy in sJIA without MAS, promoting tapering of glucocorticoids once inactive disease is achieved, alongside class switching for biologic refractory cases and a treat-to-target approach akin to EULAR/PReS guideline. Additional features include recommending conventional synthetic DMARD when biologics are unavailable and listing the options, acknowledging regional health system heterogeneity in the Asia Pacific, mentioning tapering strategy, discouraging NSAIDs as initial monotherapy, highlighting non-biologic salvage options, and placing less emphasis on sJIA-associated lung diseases. These recommendations provide direction for practitioners caring for sJIA patients in limited resource areas to avoid treatment delay, hence improve overall outcomes. A shared decision approach and treat-to-targets are emphasized.
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.
cell therapies
2026-03-14 | γδ T Cells in Autoinflammatory Diseases.
Autoinflammatory diseases are characterized by inappropriate activation of innate immunity resulting in excessive or persistent inflammation in the absence of infection. γδ T cells possess innate-like properties, including rapid responsiveness to stress-induced self-molecules, phosphoantigens, and inflammasome-derived cytokines, while retaining adaptive effector functions. Neutrophils and macrophages are well-established drivers of autoinflammatory disease, but increasing evidence implicates γδ T cells as key intermediaries by linking innate immune activation to tissue-specific inflammatory pathology. Here, we review evidence that in both monogenic and multifactorial autoinflammatory diseases-including, for example, familial Mediterranean fever, hyper-immunoglobulin (Ig) D syndrome, gout, Behçet's disease, Still's disease, atherosclerosis, and neurodegenerative disorders-γδ T cells display altered frequencies, activation states, cytokine polarization, and tissue recruitment. In inflammasome-driven diseases, skewing of γδ T cells toward interleukin (IL)-17 production has been observed, often accompanied by reduced interferon (IFN)γ secretion, thereby amplifying neutrophilic inflammation and tissue damage. In other diseases, e.g., Behcet's disease, IFNγ and tumor necrosis factor (TNF)α producton predominate. Transcriptomic and tissue-based analyses support the accumulation and functional specialization of γδ T cells at sites of sterile inflammation. Collectively, these findings position γδ T cells as central amplifiers and modulators of inappropriate innate immune activation in the context of autoinflammatory diseases. Improved understanding of γδ T cell subset-specific regulation may inform novel therapeutic strategies targeting autoinflammatory diseases.
2026-03-07 | Adjunctive Therapeutic Plasma Exchange in Refractory Adult-Onset Still's Disease Complicated by Secondary Macrophage Activation Syndrome: A Single-Center Experience.
Adult-onset Still's disease (AOSD) complicated by macrophage activation syndrome (MAS) carries substantial mortality. The role of therapeutic plasma exchange (TPE) remains uncertain. We retrospectively analyzed patients with AOSD-MAS treated with TPE at a single-center. All five patients had arthralgia, a salmon-pink rash, extreme hyperferritinemia, and multiorgan dysfunction including liver dysfunction. Prior to TPE, all patients received pulse glucocorticoids; three also received calcineurin inhibitors and one tocilizumab. TPE was initiated at a median of 12.0 days after diagnosis; the patients underwent a median of six sessions without major adverse events. Following TPE, fever and rash resolved; C-reactive protein (CRP), ferritin, and liver enzyme levels decreased without further corticosteroid escalation during and immediately after TPE. At 1 month, four patients achieved CRP < 1.0 mg/dL, four recovered with tapered immunosuppression. One patient died from cytomegalovirus infection despite MAS improvement. Adjunctive TPE was associated with rapid clinical and biochemical improvement.
2025-09-01 | Allogeneic haematopoietic stem cell transplantation for severe Still's disease: a retrospective report of three paediatric patients.
Severe forms of systemic JIA (sJIA), also called paediatric-onset Still's disease are associated with two major life-threatening complications: macrophage activation syndrome (MAS) and severe lung disease. Patients are usually resistant to conventional synthetic (cs) DMARDs, biologic (b) DMARDs, and targeted synthetic (ts) DMARDs. Recently, allogeneic haematopoietic stem cell transplantation (HSCT) has been performed in a small number of patients with refractory and life-threatening disease. We aimed to report outcomes and complications of allogeneic HSCT in patients with severe, refractory sJIA treated at our centre. We conducted a retrospective, observational, single-centre study in a tertiary paediatric immunology care centre (Necker Hospital, Paris, France). We report three sJIA patients who underwent allogeneic HSCT at a median age of 3.5 years. All had recurrent MAS; two had lung disease and the HLA-DRB1*15 haplotype, associated with severe delayed hypersensitivity to IL-1/IL-6 inhibitors. Donors were matched sibling donors for the first and third patient, and matched unrelated donor for the second patient. They presented multiple post-graft complications: graft-vs-host disease, infections, thrombotic microangiopathy and severe inflammatory complications on previously affected organs, such as skin and lungs. At a median follow-up of 22 months (20-33) after transplantation, they were all in remission with full-donor chimerism and were off immunosuppressive treatment. Allogeneic HSCT can be an effective salvage therapy in patients with refractory sJIA. However, the risk of post-transplant endothelial complications and severe inflammation in previously affected organs, such as joints, skin and lungs deserves particular attention.
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.
small molecules
2026-08-21 | Expanding the therapeutic landscape of still's disease: the emerging role of JAK inhibitors.
Still's disease is a systemic inflammatory disorder characterized by a complex cytokine network involving interleukin (IL)-1, IL‑6, IL‑18 and interferon (IFN)-γ. Although IL‑1 and IL‑6 inhibitors represent the cornerstone of current targeted therapy, a subset of patients remains refractory or develops treatment-related limitations. Janus kinase inhibitors (JAKis) have emerged as a promising therapeutic strategy. We reviewed the possible role of JAKis in the management of Still's disease, with a focus on their mechanistic rationale, clinical evidence, and potential positioning within current therapeutic strategies. A narrative review was conducted through a comprehensive search of MedLine via PubMed accordingly. Preliminary evidence, mainly derived from small observational studies, suggests that JAKis may improve systemic and articular manifestations and allow glucocorticoid sparing. In addition, agents such as ruxolitinib may have a role in macrophage activation syndrome through inhibition of IFN‑γ-dependent pathways. However, incomplete modulation of IL‑1-driven and inflammasome-dependent mechanisms may represent a potential limitation in specific disease phenotypes. JAKis represent a promising addition to the therapeutic armamentarium of Still's disease, particularly in refractory cases. Further prospective studies are needed to define the role of JAKis within the treatment algorithm of Still's disease.
2026-07-12 | Successful salvage treatment with baricitinib for macrophage activation syndrome complicating adult-onset Still's disease during interleukin-6 inhibition: A case report and literature review.
Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disorder, and macrophage activation syndrome is a life-threatening hyperinflammatory complication. Interleukin-1 and interleukin-6 inhibitors have improved outcomes in refractory AOSD, but optimal management of macrophage activation syndrome, particularly when it develops during biologic therapy, remains uncertain. We report a case of a 49-year-old woman with articular-predominant AOSD who developed fulminant macrophage activation syndrome while receiving high-dose glucocorticoids, tacrolimus, and the interleukin-6 receptor inhibitor tocilizumab. At the onset of macrophage activation syndrome, she had persistent fever, cytopenia, hyperferritinemia, and liver dysfunction, and bone marrow examination revealed haemophagocytosis. Macrophage activation syndrome persisted despite two courses of intravenous methylprednisolone pulse therapy and continuation of tocilizumab. Tocilizumab was discontinued, and treatment was switched to the oral Janus kinase 1/2 inhibitor baricitinib in combination with glucocorticoids and tacrolimus. After this change, the patient experienced rapid defervescence, marked improvement in blood counts and ferritin levels, and sustained control of articular and systemic disease activity. Glucocorticoids were successfully tapered without relapse, and the patient remained in remission for more than 2 years without serious infections. To contextualise this case, we reviewed published reports on Janus kinase inhibition in AOSD, including cases complicated by macrophage activation syndrome. Multi-cytokine blockade through Janus kinase 1/2 inhibition, targeting overlapping interleukin-6, interferon-gamma, and granulocyte-macrophage colony-stimulating factor pathways, may simultaneously suppress macrophage activation and systemic inflammation. This case highlights the potential of baricitinib as a therapeutic option for refractory AOSD-associated macrophage activation syndrome during interleukin-6 inhibition.
2026-06-12 | Adult-onset Still's disease with hemophagocytic lymphohistiocytosis and minimal change disease.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by diverse etiologies and a high risk of misdiagnosis. Autoinflammatory disorders, such as adult-onset Still's disease (AOSD), are often underrecognized as contributing factors. Minimal change disease (MCD) represents an exceedingly rare renal complication in the context of HLH. This report describes the case of an adult female diagnosed with Epstein-Barr virus (EBV)-associated HLH. Initial therapy with etoposide and dexamethasone yielded a partial response; however, disease relapse occurred, accompanied by the development of significant proteinuria. Renal biopsy confirmed a diagnosis of MCD. Administration of rituximab led to complete remission of the nephrotic syndrome, although HLH activity persisted. A subsequent skin biopsy revealed perivascular infiltration composed predominantly of lymphocytes and neutrophils. In combination with clinical features such as high-grade fever and rash, these findings supported a diagnosis of AOSD. Adjustment of the treatment regimen to include corticosteroids and methotrexate resulted in complete remission of HLH. This case underscores the importance of re-evaluating the underlying cause in patients with HLH who demonstrate an inadequate therapeutic response. MCD may represent a renal manifestation of immune dysregulation associated with HLH. A multidisciplinary approach is essential for improving diagnostic precision and optimizing treatment in complex presentations of HLH.
2026-06-09 | Systemic JIA-Associated Lung Disease: A Multicenter Analysis of Clinical Features, Treatment Challenges, and Outcomes.
Systemic juvenile idiopathic arthritis (sJIA) (Still's disease) associated lung disease (sJIA-LD) is a rare but severe complication, characterized by pulmonary involvement with high morbidity and mortality rates. While the incidence of sJIA-LD has increased, its pathogenesis and risk factors remain poorly understood. This multicenter retrospective study aimed to evaluate the clinical, radiological, and laboratory features of patients with sJIA-LD, assess the impact of prior biologic treatments, and analyze treatment outcomes. Data were collected from 18 patients diagnosed with sJIA-LD between 2007 and 2024 across five pediatric rheumatology clinics in our country. Clinical features, imaging findings, and treatment regimens before and after sJIA-LD diagnosis were analyzed. HLA-DRB1*15 typing was performed in a subset of patients. The median age of sJIA-LD diagnosis was 11.21 years, with a median disease duration of 2.76 years from sJIA diagnosis. Macrophage activation syndrome (MAS) occurred in 88.9% of patients prior to the diagnosis of lung disease. Cough (100%), dyspnea (83.3%), and clubbing (50%) were the most common clinical manifestations. Ground-glass opacities were the most frequent imaging finding (61.1%). DRESS was observed in 11.1% of patients, with 27.7% experiencing adverse reactions to biologics. Treatment revision after sJIA-LD diagnosis occurred in 83.3% of patients, with JAK inhibitors demonstrating clinical improvement in some cases. The overall survival rate was 94.4%, with one death due to fulminant MAS. This study provides data from a geographically underreported population in Turkey and the Eastern Mediterranean region. In our cohort, treatment modification after sJIA-LD diagnosis was common, while biologic therapy was often continued. These findings highlight the heterogeneous course of sJIA-LD. Further prospective multicenter studies are needed to optimize treatment strategies and improve risk stratification.
2026-06-06 | Identification of a metabolic-immune crosstalk in Still's disease: monocyte/macrophage-derived immunometabolite itaconate dictates hepatic immunopathology via the CXCL10-CD8 T cell axis.
Still's disease (SD) is a chronic and systemic autoinflammatory disorder, with the possibility of resulting in life-threatening complications, including macrophage activation syndrome (MAS). The metabolic-immune interplay underlying the immunopathology of SD/MAS remains largely unexplored. In this study, we identified itaconate - a myeloid cell-specific metabolite derived from the tricarboxylic acid cycle via the enzyme ACOD1 - as a dual regulator of inflammation and chemokine-driven tissue injury in SD/MAS. Clinical metabolomics revealed elevated serum itaconate in patients with SD, attributable to peripheral blood monocytes and correlated with disease severity. This was consolidated by the identification of the Acod1-itaconate axis in monocytes and macrophages in both a mouse model of MAS and in vitro cell cultures. Although itaconate suppressed IL-1β, IL-6, CXCL1 and CCL2 in vitro, it paradoxically amplified CXCL10 secretion in vitro and in vivo. This was in line with the observations of elevated plasma CXCL10 levels in patients with MAS. In the CpG ODN 1826-induced MAS mouse model, ablation of Acod1 ameliorated disease manifestations and hepatic inflammation, accompanied by a reduced CXCL10 level as well as attenuated hepatic infiltration of CD8+ T cells. Collectively, our study reveals a previously unrecognized metabolic-immune crosstalk in AOSD/MAS, positioning monocyte/macrophage-derived itaconate as a dual regulator that suppresses canonical pro-inflammatory cytokines while licensing CXCL10-mediated CD8+ T cell-driven tissue injury. Therefore, discovery from this study calls for scrutiny of an itaconate-based anti-inflammatory strategy in chronic inflammatory diseases.
proteins
2026-09-21 | Treatment approaches to macrophage activation syndrome in real life and priorities for future research: results from the international METAPHOR project.
Macrophage Activation Syndrome (MAS) is a rare, life-threatening hyperinflammatory condition complicating rheumatologic diseases, most commonly Still's disease (SD). Despite increasing awareness and emerging recommendations, MAS treatment remains heterogeneous worldwide. The METAPHOR project aimed to describe real-life therapeutic strategies for MAS, exploring differences across underlying diseases, geographic regions, physician subspecialties, and drug availability. An international web-based survey was developed by a multidisciplinary expert panel together with a patient representative, following a systematic literature review. The survey was anonymously completed through PReS/PRINTO and the Histiocyte Society networks (October-December 2023). Treatment strategies for MAS across different rheumatologic contexts were explored. Responses were analyzed descriptively and stratified by geography, subspecialty, clinical experience, and underlying disease. A total of 287 physicians from 64 countries completed the survey, the majority being pediatric rheumatologists with more than 5 years of experience. Glucocorticoids, particularly intravenous methylprednisolone, were consistently identified as 1st-line therapy across all MAS subtypes (for 44% of clinicians as monotherapy). Anakinra, ciclosporin, and intravenous immunoglobulins were the most frequently combined agents. However, their use varied markedly by underlying disease and geographical region, with anakinra preferentially used in SD-MAS. Striking global disparities in drug availability, particularly for anakinra and emapalumab, significantly influenced treatment choices and were associated with increased reliance on steroid monotherapy. MAS management remains highly heterogeneous worldwide. While glucocorticoids remain foundational, reducing steroid reliance through equitable access to immunomodulatory therapies and advancing mechanism-based strategies represent critical priorities in optimizing MAS care.
2026-08-12 | Trained immunity in autoinflammatory diseases: Cellular reprogramming across the monogenic-polygenic spectrum.
Trained immunity, an innate immunological memory induced by epigenetic and metabolic reprogramming, has changed the paradigm of host defense and pathogenesis of chronic inflammatory disease. Unlike adaptive immunological memory, trained immunity is characterized by the ability of innate immune cells and their progenitors to respond more robustly or differently to subsequent stimulations and contributes to chronic inflammatory conditions. Emerging data suggests that this process might be essential in autoinflammatory and immune-mediated inflammatory illnesses by enhancing sterile inflammation, decreasing activation thresholds, and boosting disease chronicity. This narrative review summarizes the existing evidence relating trained immunity to monogenic and polygenic autoinflammatory diseases. The greatest evidence in monogenic disease is for mevalonate kinase deficiency, where dysregulated mevalonate metabolism directly overlaps with conventional trained immunity pathways. Moderate evidence exists for familial Mediterranean fever, cryopyrin-associated periodic syndromes, and tumor necrosis factor receptor-associated periodic syndrome. For other rare hereditary autoinflammatory diseases, data are still inadequate. There is convincing evidence for a role of trained immunity in polygenic disorders like gout, atherosclerosis, obesity-associated "metaflammation", and type 2 diabetes and increasing evidence in Behçet's disease, adult-onset Still's disease, psoriasis, hidradenitis suppurativa, inflammatory bowel disease, and related inflammatory spectrum disorders. A major conceptual finding is that autoinflammatory illnesses may be a dynamic interplay between hereditary susceptibility and dysfunctional innate immune memory, rather than isolated static inflammatory abnormalities. However, information gaps still exist in reprogramming at the progenitor level, disease-specific epigenetic markers, and the reversibility of trained states. Understanding these systems may allow the development of therapeutic techniques to de-train abnormal innate immunological memory and obtain resilience for diseases.
2026-05-11 | A Diagnosis of Exclusion: Unraveling Adult-Onset Still's Disease.
Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder characterized by quotidian fevers, arthralgia, transient rash, and elevated inflammatory markers, often leading to diagnostic delay due to overlap with infectious, autoimmune, and malignant conditions. We present the case of a 60-year-old Latina woman who developed daily fevers, polyarthralgia, rash, and hypoxemic respiratory failure. Despite broad-spectrum antibiotics, her symptoms persisted, and extensive infectious and hematologic evaluations were unrevealing. A diagnosis of AOSD was established based on the Yamaguchi criteria and markedly elevated ferritin. The patient responded to corticosteroids but later developed macrophage activation syndrome (MAS), requiring anakinra in addition to high-dose steroids. This case highlights the diagnostic challenges of AOSD in older adults, the potential for atypical systemic manifestations such as pulmonary nodules and anasarca, and the importance of early cytokine-directed therapy to prevent life-threatening complications.
2026-02-02 | Still's Disease and Autoinflammation: Positioning an Inflammatory Syndrome on the Autoinflammation-Autoimmunity Spectrum.
Still's disease exemplifies systemic inflammatory disorders existing on a continuum between autoinflammation and autoimmunity. This review examines Still's disease through this spectrum lens, integrating recent advances in pathogenesis, clinical heterogeneity, and therapeutic approaches. Emerging mechanistic insights reveal complex innate-adaptive immune interactions. Type I interferon signalling and neutrophil extracellular trap formation drive inflammation, while hyperferritinemia actively perpetuates disease through Msr1-mediated signaling. mTORC1 has emerged as a central integration hub converging multiple cytokine signals. Adaptive mechanisms increasingly contribute to complications: both macrophage activation syndrome and lung disease demonstrate IFNγ-dominant pathology with T cell hyperactivation. Clinical phenotyping identifies distinct patient clusters-from hyperferritinemic monocyclic to catastrophic multiorgan phenotypes-reflecting varying innate-adaptive contributions. Current classification criteria permit considerable diagnostic latitude and may inadvertently group mechanistically distinct conditions under a single diagnostic label. IL-1 and IL-6 receptor blockade remain therapeutic cornerstones, with evidence supporting early intervention during a window of opportunity. Novel approaches including IL-18 binding protein, JAK inhibitors, and IFNγ blockade show promise in refractory disease. Still's disease predominantly reflects autoinflammatory pathology driven by innate immune dysregulation, yet adaptive mechanisms contribute meaningfully to disease heterogeneity and complications. Recognition as a spectrum disorder-with variable innate-adaptive contributions across patients and disease phases-supports unification of pediatric and adult forms, guides mechanistically targeted therapies, and emphasizes the need for biomarker-driven patient stratification to enable personalized treatment approaches.
2026-01-29 | Advancing Precision Medicine in Adult-Onset Still's Disease: Insights into Biomarkers, Therapies, and COVID-19 Impacts.
Adult-onset Still's disease (AOSD) is a rare autoinflammatory disorder characterized by spiking fevers, arthralgia, and a transient salmon-pink rash, with an incidence of 0.16-0.4 per 100,000. AOSD shares overlapping clinical and immunological features with systemic juvenile idiopathic arthritis (sJIA), supporting a disease continuum and shared treatment approaches. The COVID-19 pandemic has impacted AOSD care, with SARS-CoV-2 infection and vaccination occasionally triggering disease flares, necessitating adaptive management strategies. Driven by innate immune dysregulation and overproduction of proinflammatory cytokines (IL-1, IL-6, IL-18), AOSD presents in systemic and articular phenotypes, with severe complications like macrophage activation syndrome (MAS), fulminant hepatitis, and parenchymal lung disease. Diagnosis, based on Yamaguchi or Fautrel criteria and biomarkers (ferritin, IL-18), is challenging due to nonspecific symptoms. Biologic therapies (anakinra, canakinumab, tocilizumab) achieve remission in 80-90% of systemic cases. This review synthesises diagnostic challenges, novel biomarkers (e.g., gasdermin D), and emerging therapies (e.g., IL-18 binding protein), emphasising precision medicine and future research needs.
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
Abstract
Background:
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.
Objectives:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
REFERENCES:
NIL.
Acknowledgements:
NIL.
Disclosure of Interests:
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
2026-09-22 | Predictive molecular signatures for successful tapering of canakinumab in systemic juvenile idiopathic arthritis.
Canakinumab induces clinical remission in a substantial proportion of patients with systemic juvenile idiopathic arthritis (sJIA), although not all achieve a complete response. However, tapering and withdrawal frequently lead to disease flares. This study aimed to identify serum and transcriptomic biomarkers that predict successful or unsuccessful tapering of canakinumab in sJIA. Seventy-nine patients with sJIA in remission on canakinumab enrolled in a randomised withdrawal study were analysed; 71 had samples available for gene expression profiling. Serum biomarkers were quantified using Luminex assays. Whole-blood RNA was assessed by RNA sequencing (RNA-Seq) and a targeted 67-gene NanoString panel informed by exploratory analyses. Differential expression, hierarchical clustering, and enrichment analyses were performed. Biomarkers and gene signatures were compared between patients who later successfully withdrew canakinumab and those who experienced unsuccessful tapering. Lower serum levels of sCD163, CXCL9, interleukin (IL)-1RA, and IL-18 were associated with successful tapering. RNA-Seq showed marked differences between active and inactive sJIA and revealed that future nonresponders exhibited lower expression of type I IFN-induced and higher expression of erythopoiesis-related genes. NanoString profiling identified 9 genes (ATF6, BCL6, FAS, IL1B, MAPK1, PPARG, SLC25A37, TNFAIP3, and UBE2D1) overexpressed in patients with unsuccessful tapering, reflecting persistent inflammation and cellular stress. A composite score of these genes discriminated successful from unsuccessful discontinuation (area under curve, AUC, 0.71). Serum inflammatory markers and targeted gene expression signatures identify patients with sJIA at higher risk of flare during canakinumab tapering. Combined molecular biomarker profiling may enable individualised tapering strategies and support precision medicine approaches for Still's disease.
2026-09-01 | Persistent Interleukin-18 Fuels Expansion of CD38+HLA-DR+CD8+ T Cells in Still Disease and Macrophage Activation Syndrome.
Still disease (SD) is an autoinflammatory disorder characterized by remarkably high interleukin-18 (IL-18) levels. Increasing evidence suggests that adaptive immunity also contributes to its pathogenesis, particularly in refractory courses. Macrophage activation syndrome (MAS), one of SD's most severe complications, is associated with further IL-18 elevation and expansion of CD38+HLA-DR+CD8+ T cells. However, whether and when this population emerges during SD remains unknown. We therefore examined CD38+HLA-DR+CD8+ T cells across disease stages. CD38+HLA-DR+CD8+ T cells were analyzed longitudinally: at SD onset (therapy-naive; n = 19), during clinically inactive disease (n = 15), and before or at MAS occurrence (n = 12). Spectral flow cytometry and bulk RNA sequencing were performed. Correlations with clinical and laboratory parameters were assessed. In vitro cytokine stimulations of healthy donor (HD)-derived peripheral blood mononuclear cells and CD8+ lymphocytes were performed to explore mechanisms driving differentiation of these cells. CD38+HLA-DR+CD8+ T cells were expanded from SD onset and peaked in MAS (median: 4.61% and 31.7%, respectively, versus 0.87% in HDs). Transcriptomic profiling of these cells revealed enrichment of activation, cytotoxicity, and proliferation programs, which were confirmed at the protein level. Frequencies correlated with markers of systemic inflammation, T cell activation, and serum IL-18 levels. Sustained IL-18 stimulation in vitro induced robust and persistent expansion of CD38+HLA-DR+CD8+ cells, recapitulating key ex vivo phenotypic features. CD38+HLA-DR+CD8+ cells, previously primarily associated with MAS, are detectable early in SD. Persistent IL-18 exposure promotes their expansion. These findings identify CD38+HLA-DR+CD8+ T cells as a potential mechanistic link between SD and MAS and highlight this subset as a candidate therapeutic target.
2026-08-25 | Association between canakinumab dose and long-term remission in Still's disease: insights from the AIDA network registry.
The primary aim of this study was to assess, in Still's disease, whether the employment of canakinumab at a strictly on-label dose may increase the likelihood of treatment discontinuation due to study-defined long-term remission (LTR), compared with patients receiving lower doses. Patients were drawn from the international Autoinflammatory Disease Alliance (AIDA) Network registry dedicated to Still's disease and stratified based on the starting canakinumab dose: the on-label group received either 300 mg every 4 weeks or 150 mg every 4 weeks (corresponding to 4 mg/kg), while the underdosed group received 150 mg every 4 weeks (corresponding to a dose not exceeding 3.5 mg/kg). Bayesian regression models were implemented to estimate the probability of achieving long-term remission with subsequent canakinumab withdrawal in the two groups, as well as the mean differences in probabilities and posterior probabilities indicating whether the on-label group was superior in achieving the endpoint. In total, 131 patients (16.7%) were enrolled, 81 (61.8%) receiving the on-label posology and 50 (38.2%) the underdosed posology. The estimated marginal posterior probability of canakinumab discontinuation due to LTR was 19% (CrI 7.5%-34.6%) in the on-label group and 3.9% (CrI 0.7%-15.2%) in the underdosed group, yielding a mean difference of 15.1% (CrI 1.4%-31.4%) and a posterior probability of 98.4%. This difference remained credible, with posterior probabilities ranging from 97.9% to 99.6%, irrespective of disease course or age at disease onset. On-label canakinumab dosing appears to increase the likelihood of study-defined LTR with subsequent treatment discontinuation, compared with underdosed treatment strategies.
2026-08-11 | The Asia-Pacific League of Associations for Rheumatology Consensus Recommendations on the Management of Systemic Juvenile Idiopathic Arthritis (Juvenile Still's Disease).
The unique characteristics of the Asia Pacific called for the development of pragmatic and viable guidelines for the management of juvenile idiopathic arthritis (JIA). These consensus recommendations represent the second part of the guideline intending to offer an updated and regionally relevant framework for the management of systemic JIA (sJIA)/juvenile Still's disease. A multidisciplinary task force of 35 members from 14 countries, including pediatric and adult rheumatologists as well as patient representatives, was convened. The guideline development followed the GRADE, ADAPTE, and AGREE II frameworks. Relevant international guidelines were critically appraised, and a systematic literature review was performed to address 10 PICO questions. Draft statements were discussed and voted upon using a modified Delphi process, with consensus defined as ≥ 80% agreement. Four overarching principles and eighteen statements, including five statements addressing macrophage activation syndrome (MAS) were formulated. The recommendations align with international guidelines, advocating early use of IL-1/IL-6 inhibitors, avoidance of glucocorticoid monotherapy in sJIA without MAS, promoting tapering of glucocorticoids once inactive disease is achieved, alongside class switching for biologic refractory cases and a treat-to-target approach akin to EULAR/PReS guideline. Additional features include recommending conventional synthetic DMARD when biologics are unavailable and listing the options, acknowledging regional health system heterogeneity in the Asia Pacific, mentioning tapering strategy, discouraging NSAIDs as initial monotherapy, highlighting non-biologic salvage options, and placing less emphasis on sJIA-associated lung diseases. These recommendations provide direction for practitioners caring for sJIA patients in limited resource areas to avoid treatment delay, hence improve overall outcomes. A shared decision approach and treat-to-targets are emphasized.
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.
cell therapies
2026-03-14 | γδ T Cells in Autoinflammatory Diseases.
Autoinflammatory diseases are characterized by inappropriate activation of innate immunity resulting in excessive or persistent inflammation in the absence of infection. γδ T cells possess innate-like properties, including rapid responsiveness to stress-induced self-molecules, phosphoantigens, and inflammasome-derived cytokines, while retaining adaptive effector functions. Neutrophils and macrophages are well-established drivers of autoinflammatory disease, but increasing evidence implicates γδ T cells as key intermediaries by linking innate immune activation to tissue-specific inflammatory pathology. Here, we review evidence that in both monogenic and multifactorial autoinflammatory diseases-including, for example, familial Mediterranean fever, hyper-immunoglobulin (Ig) D syndrome, gout, Behçet's disease, Still's disease, atherosclerosis, and neurodegenerative disorders-γδ T cells display altered frequencies, activation states, cytokine polarization, and tissue recruitment. In inflammasome-driven diseases, skewing of γδ T cells toward interleukin (IL)-17 production has been observed, often accompanied by reduced interferon (IFN)γ secretion, thereby amplifying neutrophilic inflammation and tissue damage. In other diseases, e.g., Behcet's disease, IFNγ and tumor necrosis factor (TNF)α producton predominate. Transcriptomic and tissue-based analyses support the accumulation and functional specialization of γδ T cells at sites of sterile inflammation. Collectively, these findings position γδ T cells as central amplifiers and modulators of inappropriate innate immune activation in the context of autoinflammatory diseases. Improved understanding of γδ T cell subset-specific regulation may inform novel therapeutic strategies targeting autoinflammatory diseases.
2026-03-07 | Adjunctive Therapeutic Plasma Exchange in Refractory Adult-Onset Still's Disease Complicated by Secondary Macrophage Activation Syndrome: A Single-Center Experience.
Adult-onset Still's disease (AOSD) complicated by macrophage activation syndrome (MAS) carries substantial mortality. The role of therapeutic plasma exchange (TPE) remains uncertain. We retrospectively analyzed patients with AOSD-MAS treated with TPE at a single-center. All five patients had arthralgia, a salmon-pink rash, extreme hyperferritinemia, and multiorgan dysfunction including liver dysfunction. Prior to TPE, all patients received pulse glucocorticoids; three also received calcineurin inhibitors and one tocilizumab. TPE was initiated at a median of 12.0 days after diagnosis; the patients underwent a median of six sessions without major adverse events. Following TPE, fever and rash resolved; C-reactive protein (CRP), ferritin, and liver enzyme levels decreased without further corticosteroid escalation during and immediately after TPE. At 1 month, four patients achieved CRP < 1.0 mg/dL, four recovered with tapered immunosuppression. One patient died from cytomegalovirus infection despite MAS improvement. Adjunctive TPE was associated with rapid clinical and biochemical improvement.
2025-09-01 | Allogeneic haematopoietic stem cell transplantation for severe Still's disease: a retrospective report of three paediatric patients.
Severe forms of systemic JIA (sJIA), also called paediatric-onset Still's disease are associated with two major life-threatening complications: macrophage activation syndrome (MAS) and severe lung disease. Patients are usually resistant to conventional synthetic (cs) DMARDs, biologic (b) DMARDs, and targeted synthetic (ts) DMARDs. Recently, allogeneic haematopoietic stem cell transplantation (HSCT) has been performed in a small number of patients with refractory and life-threatening disease. We aimed to report outcomes and complications of allogeneic HSCT in patients with severe, refractory sJIA treated at our centre. We conducted a retrospective, observational, single-centre study in a tertiary paediatric immunology care centre (Necker Hospital, Paris, France). We report three sJIA patients who underwent allogeneic HSCT at a median age of 3.5 years. All had recurrent MAS; two had lung disease and the HLA-DRB1*15 haplotype, associated with severe delayed hypersensitivity to IL-1/IL-6 inhibitors. Donors were matched sibling donors for the first and third patient, and matched unrelated donor for the second patient. They presented multiple post-graft complications: graft-vs-host disease, infections, thrombotic microangiopathy and severe inflammatory complications on previously affected organs, such as skin and lungs. At a median follow-up of 22 months (20-33) after transplantation, they were all in remission with full-donor chimerism and were off immunosuppressive treatment. Allogeneic HSCT can be an effective salvage therapy in patients with refractory sJIA. However, the risk of post-transplant endothelial complications and severe inflammation in previously affected organs, such as joints, skin and lungs deserves particular attention.
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.
small molecules
2026-08-21 | Expanding the therapeutic landscape of still's disease: the emerging role of JAK inhibitors.
Still's disease is a systemic inflammatory disorder characterized by a complex cytokine network involving interleukin (IL)-1, IL‑6, IL‑18 and interferon (IFN)-γ. Although IL‑1 and IL‑6 inhibitors represent the cornerstone of current targeted therapy, a subset of patients remains refractory or develops treatment-related limitations. Janus kinase inhibitors (JAKis) have emerged as a promising therapeutic strategy. We reviewed the possible role of JAKis in the management of Still's disease, with a focus on their mechanistic rationale, clinical evidence, and potential positioning within current therapeutic strategies. A narrative review was conducted through a comprehensive search of MedLine via PubMed accordingly. Preliminary evidence, mainly derived from small observational studies, suggests that JAKis may improve systemic and articular manifestations and allow glucocorticoid sparing. In addition, agents such as ruxolitinib may have a role in macrophage activation syndrome through inhibition of IFN‑γ-dependent pathways. However, incomplete modulation of IL‑1-driven and inflammasome-dependent mechanisms may represent a potential limitation in specific disease phenotypes. JAKis represent a promising addition to the therapeutic armamentarium of Still's disease, particularly in refractory cases. Further prospective studies are needed to define the role of JAKis within the treatment algorithm of Still's disease.
2026-07-12 | Successful salvage treatment with baricitinib for macrophage activation syndrome complicating adult-onset Still's disease during interleukin-6 inhibition: A case report and literature review.
Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disorder, and macrophage activation syndrome is a life-threatening hyperinflammatory complication. Interleukin-1 and interleukin-6 inhibitors have improved outcomes in refractory AOSD, but optimal management of macrophage activation syndrome, particularly when it develops during biologic therapy, remains uncertain. We report a case of a 49-year-old woman with articular-predominant AOSD who developed fulminant macrophage activation syndrome while receiving high-dose glucocorticoids, tacrolimus, and the interleukin-6 receptor inhibitor tocilizumab. At the onset of macrophage activation syndrome, she had persistent fever, cytopenia, hyperferritinemia, and liver dysfunction, and bone marrow examination revealed haemophagocytosis. Macrophage activation syndrome persisted despite two courses of intravenous methylprednisolone pulse therapy and continuation of tocilizumab. Tocilizumab was discontinued, and treatment was switched to the oral Janus kinase 1/2 inhibitor baricitinib in combination with glucocorticoids and tacrolimus. After this change, the patient experienced rapid defervescence, marked improvement in blood counts and ferritin levels, and sustained control of articular and systemic disease activity. Glucocorticoids were successfully tapered without relapse, and the patient remained in remission for more than 2 years without serious infections. To contextualise this case, we reviewed published reports on Janus kinase inhibition in AOSD, including cases complicated by macrophage activation syndrome. Multi-cytokine blockade through Janus kinase 1/2 inhibition, targeting overlapping interleukin-6, interferon-gamma, and granulocyte-macrophage colony-stimulating factor pathways, may simultaneously suppress macrophage activation and systemic inflammation. This case highlights the potential of baricitinib as a therapeutic option for refractory AOSD-associated macrophage activation syndrome during interleukin-6 inhibition.
2026-06-12 | Adult-onset Still's disease with hemophagocytic lymphohistiocytosis and minimal change disease.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by diverse etiologies and a high risk of misdiagnosis. Autoinflammatory disorders, such as adult-onset Still's disease (AOSD), are often underrecognized as contributing factors. Minimal change disease (MCD) represents an exceedingly rare renal complication in the context of HLH. This report describes the case of an adult female diagnosed with Epstein-Barr virus (EBV)-associated HLH. Initial therapy with etoposide and dexamethasone yielded a partial response; however, disease relapse occurred, accompanied by the development of significant proteinuria. Renal biopsy confirmed a diagnosis of MCD. Administration of rituximab led to complete remission of the nephrotic syndrome, although HLH activity persisted. A subsequent skin biopsy revealed perivascular infiltration composed predominantly of lymphocytes and neutrophils. In combination with clinical features such as high-grade fever and rash, these findings supported a diagnosis of AOSD. Adjustment of the treatment regimen to include corticosteroids and methotrexate resulted in complete remission of HLH. This case underscores the importance of re-evaluating the underlying cause in patients with HLH who demonstrate an inadequate therapeutic response. MCD may represent a renal manifestation of immune dysregulation associated with HLH. A multidisciplinary approach is essential for improving diagnostic precision and optimizing treatment in complex presentations of HLH.
2026-06-09 | Systemic JIA-Associated Lung Disease: A Multicenter Analysis of Clinical Features, Treatment Challenges, and Outcomes.
Systemic juvenile idiopathic arthritis (sJIA) (Still's disease) associated lung disease (sJIA-LD) is a rare but severe complication, characterized by pulmonary involvement with high morbidity and mortality rates. While the incidence of sJIA-LD has increased, its pathogenesis and risk factors remain poorly understood. This multicenter retrospective study aimed to evaluate the clinical, radiological, and laboratory features of patients with sJIA-LD, assess the impact of prior biologic treatments, and analyze treatment outcomes. Data were collected from 18 patients diagnosed with sJIA-LD between 2007 and 2024 across five pediatric rheumatology clinics in our country. Clinical features, imaging findings, and treatment regimens before and after sJIA-LD diagnosis were analyzed. HLA-DRB1*15 typing was performed in a subset of patients. The median age of sJIA-LD diagnosis was 11.21 years, with a median disease duration of 2.76 years from sJIA diagnosis. Macrophage activation syndrome (MAS) occurred in 88.9% of patients prior to the diagnosis of lung disease. Cough (100%), dyspnea (83.3%), and clubbing (50%) were the most common clinical manifestations. Ground-glass opacities were the most frequent imaging finding (61.1%). DRESS was observed in 11.1% of patients, with 27.7% experiencing adverse reactions to biologics. Treatment revision after sJIA-LD diagnosis occurred in 83.3% of patients, with JAK inhibitors demonstrating clinical improvement in some cases. The overall survival rate was 94.4%, with one death due to fulminant MAS. This study provides data from a geographically underreported population in Turkey and the Eastern Mediterranean region. In our cohort, treatment modification after sJIA-LD diagnosis was common, while biologic therapy was often continued. These findings highlight the heterogeneous course of sJIA-LD. Further prospective multicenter studies are needed to optimize treatment strategies and improve risk stratification.
2026-06-06 | Identification of a metabolic-immune crosstalk in Still's disease: monocyte/macrophage-derived immunometabolite itaconate dictates hepatic immunopathology via the CXCL10-CD8 T cell axis.
Still's disease (SD) is a chronic and systemic autoinflammatory disorder, with the possibility of resulting in life-threatening complications, including macrophage activation syndrome (MAS). The metabolic-immune interplay underlying the immunopathology of SD/MAS remains largely unexplored. In this study, we identified itaconate - a myeloid cell-specific metabolite derived from the tricarboxylic acid cycle via the enzyme ACOD1 - as a dual regulator of inflammation and chemokine-driven tissue injury in SD/MAS. Clinical metabolomics revealed elevated serum itaconate in patients with SD, attributable to peripheral blood monocytes and correlated with disease severity. This was consolidated by the identification of the Acod1-itaconate axis in monocytes and macrophages in both a mouse model of MAS and in vitro cell cultures. Although itaconate suppressed IL-1β, IL-6, CXCL1 and CCL2 in vitro, it paradoxically amplified CXCL10 secretion in vitro and in vivo. This was in line with the observations of elevated plasma CXCL10 levels in patients with MAS. In the CpG ODN 1826-induced MAS mouse model, ablation of Acod1 ameliorated disease manifestations and hepatic inflammation, accompanied by a reduced CXCL10 level as well as attenuated hepatic infiltration of CD8+ T cells. Collectively, our study reveals a previously unrecognized metabolic-immune crosstalk in AOSD/MAS, positioning monocyte/macrophage-derived itaconate as a dual regulator that suppresses canonical pro-inflammatory cytokines while licensing CXCL10-mediated CD8+ T cell-driven tissue injury. Therefore, discovery from this study calls for scrutiny of an itaconate-based anti-inflammatory strategy in chronic inflammatory diseases.
proteins
2026-09-21 | Treatment approaches to macrophage activation syndrome in real life and priorities for future research: results from the international METAPHOR project.
Macrophage Activation Syndrome (MAS) is a rare, life-threatening hyperinflammatory condition complicating rheumatologic diseases, most commonly Still's disease (SD). Despite increasing awareness and emerging recommendations, MAS treatment remains heterogeneous worldwide. The METAPHOR project aimed to describe real-life therapeutic strategies for MAS, exploring differences across underlying diseases, geographic regions, physician subspecialties, and drug availability. An international web-based survey was developed by a multidisciplinary expert panel together with a patient representative, following a systematic literature review. The survey was anonymously completed through PReS/PRINTO and the Histiocyte Society networks (October-December 2023). Treatment strategies for MAS across different rheumatologic contexts were explored. Responses were analyzed descriptively and stratified by geography, subspecialty, clinical experience, and underlying disease. A total of 287 physicians from 64 countries completed the survey, the majority being pediatric rheumatologists with more than 5 years of experience. Glucocorticoids, particularly intravenous methylprednisolone, were consistently identified as 1st-line therapy across all MAS subtypes (for 44% of clinicians as monotherapy). Anakinra, ciclosporin, and intravenous immunoglobulins were the most frequently combined agents. However, their use varied markedly by underlying disease and geographical region, with anakinra preferentially used in SD-MAS. Striking global disparities in drug availability, particularly for anakinra and emapalumab, significantly influenced treatment choices and were associated with increased reliance on steroid monotherapy. MAS management remains highly heterogeneous worldwide. While glucocorticoids remain foundational, reducing steroid reliance through equitable access to immunomodulatory therapies and advancing mechanism-based strategies represent critical priorities in optimizing MAS care.
2026-08-12 | Trained immunity in autoinflammatory diseases: Cellular reprogramming across the monogenic-polygenic spectrum.
Trained immunity, an innate immunological memory induced by epigenetic and metabolic reprogramming, has changed the paradigm of host defense and pathogenesis of chronic inflammatory disease. Unlike adaptive immunological memory, trained immunity is characterized by the ability of innate immune cells and their progenitors to respond more robustly or differently to subsequent stimulations and contributes to chronic inflammatory conditions. Emerging data suggests that this process might be essential in autoinflammatory and immune-mediated inflammatory illnesses by enhancing sterile inflammation, decreasing activation thresholds, and boosting disease chronicity. This narrative review summarizes the existing evidence relating trained immunity to monogenic and polygenic autoinflammatory diseases. The greatest evidence in monogenic disease is for mevalonate kinase deficiency, where dysregulated mevalonate metabolism directly overlaps with conventional trained immunity pathways. Moderate evidence exists for familial Mediterranean fever, cryopyrin-associated periodic syndromes, and tumor necrosis factor receptor-associated periodic syndrome. For other rare hereditary autoinflammatory diseases, data are still inadequate. There is convincing evidence for a role of trained immunity in polygenic disorders like gout, atherosclerosis, obesity-associated "metaflammation", and type 2 diabetes and increasing evidence in Behçet's disease, adult-onset Still's disease, psoriasis, hidradenitis suppurativa, inflammatory bowel disease, and related inflammatory spectrum disorders. A major conceptual finding is that autoinflammatory illnesses may be a dynamic interplay between hereditary susceptibility and dysfunctional innate immune memory, rather than isolated static inflammatory abnormalities. However, information gaps still exist in reprogramming at the progenitor level, disease-specific epigenetic markers, and the reversibility of trained states. Understanding these systems may allow the development of therapeutic techniques to de-train abnormal innate immunological memory and obtain resilience for diseases.
2026-05-11 | A Diagnosis of Exclusion: Unraveling Adult-Onset Still's Disease.
Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder characterized by quotidian fevers, arthralgia, transient rash, and elevated inflammatory markers, often leading to diagnostic delay due to overlap with infectious, autoimmune, and malignant conditions. We present the case of a 60-year-old Latina woman who developed daily fevers, polyarthralgia, rash, and hypoxemic respiratory failure. Despite broad-spectrum antibiotics, her symptoms persisted, and extensive infectious and hematologic evaluations were unrevealing. A diagnosis of AOSD was established based on the Yamaguchi criteria and markedly elevated ferritin. The patient responded to corticosteroids but later developed macrophage activation syndrome (MAS), requiring anakinra in addition to high-dose steroids. This case highlights the diagnostic challenges of AOSD in older adults, the potential for atypical systemic manifestations such as pulmonary nodules and anasarca, and the importance of early cytokine-directed therapy to prevent life-threatening complications.
2026-02-02 | Still's Disease and Autoinflammation: Positioning an Inflammatory Syndrome on the Autoinflammation-Autoimmunity Spectrum.
Still's disease exemplifies systemic inflammatory disorders existing on a continuum between autoinflammation and autoimmunity. This review examines Still's disease through this spectrum lens, integrating recent advances in pathogenesis, clinical heterogeneity, and therapeutic approaches. Emerging mechanistic insights reveal complex innate-adaptive immune interactions. Type I interferon signalling and neutrophil extracellular trap formation drive inflammation, while hyperferritinemia actively perpetuates disease through Msr1-mediated signaling. mTORC1 has emerged as a central integration hub converging multiple cytokine signals. Adaptive mechanisms increasingly contribute to complications: both macrophage activation syndrome and lung disease demonstrate IFNγ-dominant pathology with T cell hyperactivation. Clinical phenotyping identifies distinct patient clusters-from hyperferritinemic monocyclic to catastrophic multiorgan phenotypes-reflecting varying innate-adaptive contributions. Current classification criteria permit considerable diagnostic latitude and may inadvertently group mechanistically distinct conditions under a single diagnostic label. IL-1 and IL-6 receptor blockade remain therapeutic cornerstones, with evidence supporting early intervention during a window of opportunity. Novel approaches including IL-18 binding protein, JAK inhibitors, and IFNγ blockade show promise in refractory disease. Still's disease predominantly reflects autoinflammatory pathology driven by innate immune dysregulation, yet adaptive mechanisms contribute meaningfully to disease heterogeneity and complications. Recognition as a spectrum disorder-with variable innate-adaptive contributions across patients and disease phases-supports unification of pediatric and adult forms, guides mechanistically targeted therapies, and emphasizes the need for biomarker-driven patient stratification to enable personalized treatment approaches.
2026-01-29 | Advancing Precision Medicine in Adult-Onset Still's Disease: Insights into Biomarkers, Therapies, and COVID-19 Impacts.
Adult-onset Still's disease (AOSD) is a rare autoinflammatory disorder characterized by spiking fevers, arthralgia, and a transient salmon-pink rash, with an incidence of 0.16-0.4 per 100,000. AOSD shares overlapping clinical and immunological features with systemic juvenile idiopathic arthritis (sJIA), supporting a disease continuum and shared treatment approaches. The COVID-19 pandemic has impacted AOSD care, with SARS-CoV-2 infection and vaccination occasionally triggering disease flares, necessitating adaptive management strategies. Driven by innate immune dysregulation and overproduction of proinflammatory cytokines (IL-1, IL-6, IL-18), AOSD presents in systemic and articular phenotypes, with severe complications like macrophage activation syndrome (MAS), fulminant hepatitis, and parenchymal lung disease. Diagnosis, based on Yamaguchi or Fautrel criteria and biomarkers (ferritin, IL-18), is challenging due to nonspecific symptoms. Biologic therapies (anakinra, canakinumab, tocilizumab) achieve remission in 80-90% of systemic cases. This review synthesises diagnostic challenges, novel biomarkers (e.g., gasdermin D), and emerging therapies (e.g., IL-18 binding protein), emphasising precision medicine and future research needs.
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
Abstract
Background:
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.
Objectives:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
REFERENCES:
NIL.
Acknowledgements:
NIL.
Disclosure of Interests:
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 | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
upadacitinib | small molecules | FDA | AbbVie, Inc. | |
interleukin-1 receptor antagonist anakinra | proteins | FDA | Swedish Orphan Biovitrum AB | |
Canakinumab [Ilaris] | antibodies | EMA | Novartis Europharm Limited | |
Interleukin-1 Trap | proteins | FDA | Regeneron Pharmaceuticals, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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