OBJECTIVES: Health outcomes in children and young people are known to vary by ethnicity and socioeconomic position. In juvenile idiopathic arthritis (JIA), it is unclear whether this relates to differential changes following one of the most common treatments, TNF-inhibitors (TNFi). This study investigated these factors, disease activity and treatment persistence following initial TNFi therapy in patients with JIA in the UK. METHODS: Patients with non-systemic JIA in the UK JIA Biologic Register starting their first TNFi biologic were included. Outcomes included change in disease activity between start of TNFi and 6 months, measured by JADAS-71.Multivariable linear regression was used to assess the association between ethnicity or socioeconomic position and change in JADAS. Treatment persistence was analysed using Kaplan-Meier estimates. Cox proportional hazards models compared TNFi drug persistence by ethnic group and by socioeconomic position. RESULTS: A total of 1,641 patients were included; 67% female, 90% White ethnic group (6% Asian, 2% Black, 2% Mixed), 25% in the most deprived socioeconomic group. JADAS-71 improved for all ethnic and socioeconomic groups by 6 months, with no difference in improvement by group.The proportion of patients remaining on TNFi at 12 months (67%) and the likelihood of stopping was similar between all ethnic and socioeconomic groups. CONCLUSION: Outcomes following TNFi initiation are similar between ethnic and socioeconomic groups. Based on the results of this study, ethnicity and socioeconomic position do not appear to be associated with differential change in disease activity, and there is no evidence that the effects of socioeconomic position are moderated by ethnicity or vice versa.
OBJECTIVES: Laboratory detection of myositis-specific autoantibodies (MSAs) utilises enzyme-linked immunosorbent assays (ELISA) and multianalyte line blot assays (LBA). We sought to evaluate the concordance and reliability of these two commercial assays. METHODS: Serum samples from patients with idiopathic inflammatory myopathies (IIM) were obtained from 7 countries across the Asia-Pacific region. Anti-Jo-1, anti-EJ, anti-PL-7, anti-PL-12, anti-MDA5, anti-Mi-2, and anti-TIF1-γ antibodies were centrally measured with commercial ELISA and LBA kits. The positive percentage agreement (PPA), negative percentage agreement (NPA), and Cohen's kappa were calculated by comparing the two assays. Sera with discordant results were subjected to "gold-standard" immunoprecipitation (IP) assays. RESULTS: Serum samples obtained from 485 patients with IIMs, including 180 with dermatomyositis, 44 with amyopathic dermatomyositis, 7 with juvenile dermatomyositis, 197 with polymyositis or immune-mediated necrotising myopathy, and 57 with inclusion body myositis, were subjected to ELISA and LBA. The PPA was the highest for anti-Jo-1 at 0.98, followed by 0.94 for anti-PL-7, 0.93 for anti-EJ, 0.93 for anti-MDA5, 0.89 for anti-TIF1-γ, 0.78 for anti-PL-12, and 0.67 for anti-Mi-2, whereas the NPA was high (ranging from 0.97-1 for all MSAs). Kappa values exceeded 0.80 for anti-Jo-1, anti-EJ, anti-MDA5, and anti-TIF1-γ, whereas anti-PL-7, anti-PL-12, and anti-Mi-2 exhibited low values. IP assays using sera with discordant results revealed a high rate of false positives for anti-PL-7 and anti-Mi-2 in LBA. CONCLUSION: Discrepancies in the measurement results were observed between commercially available ELISA and LBA, especially for anti-PL7 and anti-Mi-2. ELISA is more accurate than LBA.
PURPOSE OF REVIEW: Genetic and multiomics studies are reshaping our understanding of polyarticular juvenile idiopathic arthritis (JIA) and shifting the field from symptom- and phenotype-based categories toward biologically informed disease definitions. We summarize recent findings on disease risk and pathogenesis while focusing on genetic contributions to disease susceptibility and pathogenic mechanisms. RECENT FINDINGS: Classical HLA and non-HLA studies established the polygenic immune-mediated pathogenesis of JIA with distinct, partially overlapping, genetic architectures across the International League of Associations for Rheumatology categories. Rheumatoid factor (RF)-positive polyarticular JIA is increasingly considered a childhood-onset seropositive rheumatoid arthritis, whereas oligoarticular and RF-negative polyarticular JIA, although nonidentical, share substantial immunogenetic features. Recent subtype-integrative genome-wide association studies and transcriptomic and chromatin-interaction analyses prioritized candidate genes mediating lymphocyte activation, cytokine signaling, and immune regulation. Synovial atlas and spatial transcriptomic studies have further connected genetic susceptibility to immune-cell states and organized inflammatory niches, linking inherited risk to the chronic arthritis-sustaining tissue environment. SUMMARY: Genetic and multiomic studies support a shift toward biologically informed disease classification, evinced in the proposed Pediatric Rheumatology International Trials Organization framework, and provide a foundation for subtype-aware risk stratification and therapeutic target discovery in JIA. The association of genetic variations with prognosis warrants future investigation.
PURPOSE OF REVIEW: People with Down syndrome experience significant immune dysregulation, conferring elevated risk of autoimmune and inflammatory conditions. Despite the growing prevalence of adults living with Down syndrome, significant gaps remain in understanding and treating immune-mediated disease in this population. This review synthesizes current knowledge of immune dysregulation in Down syndrome, with focus on rheumatic manifestations and emerging therapeutic approaches. RECENT FINDINGS: Trisomy 21 drives constitutive, global immune remodeling characterized by mixed interferon hyperactivation, hypercytokinemia, and myeloid and lymphoid subset remodeling toward an autoimmunity-prone, pro-inflammatory state. Down syndrome associated arthritis is a distinct and aggressive entity warranting recognition separate from juvenile idiopathic and rheumatoid arthritis. People with Down syndrome face elevated risk of SJIA-associated lung disease and diffuse alveolar hemorrhage. Medication tolerance is a significant consideration, including intolerance to methotrexate and diminished response to TNF inhibitors. Early clinical trials of JAK inhibitors demonstrate promising results across multiple immune-mediated manifestations, including skin disease, arthritis, and Down syndrome regression disorder. SUMMARY: Immune dysregulation in Down syndrome is pervasive and mechanistically distinct, with interferon signaling as a central therapeutic target. Clinicians should be aware of Down syndrome specific diagnostic and management considerations, and future research should prioritize rigorous placebo-controlled trials and Down syndrome informed outcome measures.
OBJECTIVE: To investigate why, when and in which patterns decisions about changes in systemic medications were made in a cohort of juvenile idiopathic arthritis (JIA) patients. METHODS: JIA patients starting first line systemic therapy were prospectively followed in a Dutch tertiary pediatric rheumatology center. Treatment lines were constructed for the included systemic therapies (systemic corticosteroids, conventional and biological disease modifying antirheumatic drugs (cDMARDs and bDMARDs)). Each change in systemic medication and its reason was registered. Main outcomes were frequencies and timing of change reasons, across treatment lines. A Sankey diagram was used to visualize flows between change reasons over treatment lines, cumulative incidences Fine-Gray models to illustrate the frequencies of the change reasons over time. RESULTS: 551 patients were included of which 67.9% were female and oligoarticular JIA was the most common JIA diagnosis (41.9%). 1422 different systemic drug treatment lines were observed, with a median number of 2 (IQR 1-3) treatment lines per patient. Methotrexate was predominantly used as first treatment line (89.1%), while bDMARDs were mostly used as next treatment line (53.3%). JIA medication was mostly changed because of inefficacy (42.9%) in the first treatment line vs remission in the second treatment line (46.2%). CONCLUSION: JIA medication is mostly changed because of inefficacy in the first treatment line (predominantly methotrexate) vs remission in the second treatment line (roughly half on bDMARDs). This indicates that bDMARDs may be a more effective treatment than methotrexate in part of the JIA population, advocating reconsideration of current JIA treatment guidelines.
Objective To identify serum biomarkers associated with the development of uveitis in a German juvenile idiopathic arthritis (JIA) cohort. Methods A convenience sample, enriched for uveitis cases, was drawn from a prospectively followed inception cohort of newly diagnosed JIA patients (ICON). Baseline serum samples were biobanked, and each was tested for conventional and novel autoantibodies using multi-analyte array technologies. Associations between uveitis occurrence, disease outcomes, and autoantibody profiles were examined. Results Fifty-two patients with and 141 patients without uveitis were included in the analyses. At first uveitis documentation, 26% of patients presented with uveitis-related complications. Younger age at JIA diagnosis, higher ANA titers (median [IQR]: 960 [240–5120] vs. 160 [0-640]; p < 0.001), and the Anti-Cell (AC-30) immunofluorescence (IIF) staining pattern (63.5% vs. 23.4%; p < 0.001) were significantly associated with the presence of uveitis, but not with uveitis-related complications. In contrast, the AC-4 IIF staining pattern was more often present in children without uveitis. In addition, patients with uveitis showed significantly higher prefoldin subunit 5 (PFDN5) antibody titers compared to non-uveitis JIA patients (mean ± SD; 486.39 ± 495.85 vs. 321.85 ± 330.36; p = 0.010). Other tested autoantibodies, including anti-histone antibodies, were rare in both groups and did not differ significantly. Conclusions High ANA titers, the AC-30 ANA indirect immunofluorescence (IIF) pattern, and younger age at JIA onset are significantly associated with uveitis in JIA. Anti-PFDN5 antibodies show potential as a novel biomarker for JIA-associated uveitis. Combining these serological markers with clinical risk factors may improve early identification of high-risk patients and support the development of better tailored screening strategies to prevent vision-threatening complications.
A newsletter discute os desafios práticos e emocionais da maternidade em mulheres com doenças reumáticas, destacando que o cuidado médico deve transcender métricas clínicas como o DAS-28. Além disso, apresenta atualizações científicas sobre novos biomarcadores de inflamação coronariana na artrite reumatoide e a caracterização de fenótipos específicos em pacientes com anticorpos anti-CENP-B e anti-SSA.
Assessing the presence and degree of synovitis is the cornerstone of managing patients with arthritis. Ultrasound has been shown to be a valuable tool for this in routine care, and several scoring systems have been developed over time. Although there is an overall good validity across several different semi-quantitative scoring systems, they lack reliability when applied in the same patient cohort, emphasising the need for a consensus-based scoring system. A European Alliance of Associations for Rheumatology (EULAR) and Outcome Measures in Rheumatology (OMERACT) collaboration developed, almost 10 years ago, the consensus-based EULAR-OMERACT scoring system, which has subsequently been validated. It has face and content validity as it makes sense and allows to visualise all components constituting the synovitis complex. It has discriminant validity as it is sensitive to change during treatment, can discriminate between active treatment and placebo in clinical trials and has a moderate-to-excellent inter-observer and intra-observer reliability. It has construct validity by showing a parallel improvement in ultrasound sum scores and Disease Activity Score 28 and joint assessment, respectively. It has criterion validity with a predictive validity for biological disease-modifying antirheumatic drug (bDMARD) discontinuation and for flares while tapering bDMARDs. In addition, a correlation between the scoring system and histological inflammation was established. Finally, the EULAR-OMERACT scoring system is feasible, as a 24-joint assessment can be performed in 20 min. In conclusion, the EULAR-OMERACT scoring system is a valid scoring system that also fulfils the OMERACT 2.1 filter for instrument selection.
To measure the impact, over time, of juvenile idiopathic arthritis (JIA) on the work and daily activities of patients under age 18. Data were collected in a prospective international cohort—the Canada-Netherlands Personalized Medicine Network in Childhood Arthritis and Rheumatic Diseases which included patient- and parent-reported data collection. We used the standardized Work Productivity and Activity Impairment questionnaire (WPAI-SHP), and generalized estimating equations to model productivity loss and activity impairment over time for patients, adjusting for JIA disease activity (from cJADAS10). In addition, parents were asked about concerns of future employment for their children. We analyzed data collected up to 12 months from enrollment. The analytic sample included 154 patients who provided at least one response to WPAI-SHP over the study period (Median age = 17 years, 66% female). Patients missed on average 7% of work time due to their JIA (absenteeism). While at work, 27% of their work was impaired (presenteeism) due to their JIA. Accounting for both absenteeism and presenteeism, there was a 23% overall work impairment. In addition, patients had 29% impairment in activities. These impacts varied by disease activity, with patients with more severe JIA experiencing greater absenteeism, and work and activity impairment. Both work impairment and activity impairment were persistnent over time. This study of JIA patients of all sub-types at different points in disease history is the first to capture work productivity impairment considering both absenteeism and presenteeism, and activity impairment on JIA patients under 18. There are substantial impacts on the ability of youth to be fully productive at work, affecting overall work impairment. In addition, there was substantial impairment in usual activities. Additional research should investigate which youth are at risk of productivity
Telemedicine is a promising solution for addressing regional disparities and improving access to specialized care for patients with rheumatic diseases in Japan. This review provides a comprehensive overview of the current challenges, proposed clinical models, and future directions for implementing telemedicine for these conditions. Drawing from the European Alliance of Associations for Rheumatology (EULAR) points to consider and national surveys, we highlight the potential of hybrid care models, the importance of digital literacy, and the need for interdisciplinary collaboration in this field. We introduce innovative remote care systems currently being piloted in island regions to deliver high-quality care in underserved settings. Additionally, we discuss the outcomes of a health economic simulation, revealing the benefits and financial concerns regarding the current reimbursement structures. Key barriers-technical, clinical, patient-related, organizational, and legal-are analysed alongside proposed countermeasures. Finally, we outline a research agenda to evaluate the effectiveness, safety, and sustainability of telemedicine. With appropriate policy support and system development, telemedicine could play a pivotal role in enhancing the quality and equity of rheumatologic care in Japan.
Objective This study aimed to identify key prognostic factors for a successful transition from pediatric to adult rheumatology care. Methods A retrospective analysis was conducted of patients enrolled in the transition program at the Hamburg Centre for Pediatric and Adolescent Rheumatology between December 2014 and December 2023. Only patients who received disease-modifying antirheumatic drugs (DMARDs) during their disease course, were offered to participate in the transition program. The first two visits (T1 and T2) were conducted in presence of both specialists at the same time in the pediatric rheumatology clinic, followed by a third visit (T3) at the adult rheumatology clinic. Successful transitions were defined as attendance at the T3. Patients who decided to leave the program were excluded. Variables analyzed included demographics, diagnosis, treatment, joint count and Childhood Health Assessment Questionnaire (CHAQ) scores. Results Out of 547 included patients, 359 (65.6%) completed the transition successfully. Completion was highest in patients with uveitis (96%, with the lowest risk to discontinue the transition process (RDTP) of 0.16), biologic DMARD therapy (83.3%, with an RDTP of 0.42), and combination DMARD treatment (91.2%, with an RDTP of 0.27). The success rate among patients not receiving medication at T1 was 56.6% (RDTP of 1.48). Higher joint counts, increased disease activity, and elevated CHAQ scores are associated with a successful transition to adult care. Conclusion Higher disease activity, ongoing DMARD treatment and specific diagnoses such as uveitis are associated with better transition outcomes. Patients with no active treatment may require additional support.
ABSTRACT Introduction Juvenile spondyloarthropathies (JSpA) are a group of chronic inflammatory diseases that differ in their clinical features and course from adult spondyloarthropathies and other subtypes of juvenile idiopathic arthritis (JIA). Therefore, defining disease inactivity in JSpA requires specific criteria. This Delphi study aimed to establish a national consensus on its core clinical, laboratory, and radiological domains. Methods A total of 27 pediatric rheumatologists participated in the Delphi survey, conducted in two rounds. Participants were asked multiple‐choice and Likert‐type questions regarding their preferences for using domains including anamnesis, laboratory findings, imaging methods, and predefined disease activity scores for assessing inactivity. At the end of each round, the study coordinators determined the “strong consensus” items based on a power analysis of these parameters. Results The absence of “pain or tenderness in the peripheral joints, lower back and entheseal regions” in anamnesis domain and “tenderness in the peripheral joints, entheseal areas, and hip examination”; “swelling in the peripheral joints; tenderness on sacroiliac compression testing”; and “no reduction in hip RoM examination” in physical examination domain received the highest scores and were accepted as strong consensus. Furthermore, normalization of MRI findings of SIJ and hip/peripheral joint and “physician global score = 0” reached the specified thresholds, resulting in strong consensus following the second round. Conclusions This Delphi study highlights the need for a multidimensional approach that integrates clinical, radiological, and physician assessments to define disease inactivity in patients with JSpA. The resulting consensus provides a more specific assessment on inactivity defining JSpA patients and reflects a national consensus.
Abstract Objectives Limited information is available on patients with non-systemic juvenile idiopathic arthritis (nsJIA) receiving biologics in Japan. The types of biologics, treatment duration, prior and concomitant treatments, administration routes (intravenous [IV] or subcutaneous [SC] injection), and patient characteristics were investigated. Methods We investigated nsJIA, excluding psoriatic arthritis and ankylosing spondylitis, using data from a Japanese hospital claims database (2008–2024). Results Of the 4191 nsJIA patients in the database, 965 (23.0%) received one or more biologics. For the first biologic, the most common were antitumour necrosis factor (anti-TNF) drugs (55.3% overall; adalimumab SC, 32.1%; etanercept SC, 9.8%; infliximab IV, 9.2%; others, < 2.1% each), followed by anti-interleukin-6 (anti-IL-6) drugs (39.9% overall; tocilizumab, 39.1% [IV, 32.4%; SC, 6.6%]; others, ≤ 0.7%), abatacept IV or SC (3.7%), and canakinumab SC (1.0%). Of the patients receiving anti-TNF and anti-IL-6 drugs, 40% and 58% continued treatment for ≥1 year, respectively. The most common conventional synthetic disease-modifying antirheumatic drug (csDMARD) administered prior to anti-TNF and anti-IL-6 drugs was methotrexate [39.0% (anti-TNF) and 33.5% (anti-IL-6)], with others at ≤ 3.6%. The most common csDMARD used concomitantly was also methotrexate [66.9% (anti-TNF) and 50.4% (anti-IL-6)], with others < 8.6%. Conclusions Our study describes the real-world usage of biologics for nsJIA in Japan.
Neurodevelopmental disorders affect a substantial proportion of children and represent a major public health challenge worldwide. Emerging evidence highlights complex interactions among genetic, environmental and immune factors — particularly during the critical window of neurodevelopmental vulnerability. These insights raise the possibility that children with juvenile systemic autoimmune and autoinflammatory diseases are at an increased risk of developing neurodevelopmental disorders. Early onset and delayed treatment of these autoimmune and autoinflammatory diseases seem to increase this vulnerability. Growing awareness of these associations is transforming paediatric rheumatology, highlighting the need for early screening, multidisciplinary management, and personalized interventions that target both inflammatory disease and neurodevelopment. International research collaborations, biomarker discovery and long-term follow-up are crucial for closing knowledge gaps and subsequently advancing care and outcomes. Recognizing and tackling neurodevelopmental disorders as frequent comorbidities of juvenile systemic autoimmune and autoinflammatory diseases is vital for improving educational attainment, psychosocial wellbeing and lifelong quality of life in children with chronic inflammatory conditions.
Objective Patients with juvenile idiopathic arthritis (JIA) frequently exhibit antinuclear antibodies (ANAs), but the specific antigen target recognized by them and the presence of additional autoantibody specificities in patients with JIA remains elusive. Methods Plasma samples from 110 untreated patients with active JIA, as well as from 14 children with unspecified arthritis and 151 age‐ and sex‐matched healthy children, were analyzed with multiple modern clinical‐grade autoantibody assays, including automated indirect immunofluorescence to screen for ANAs with HEp‐2 cells, and specific immune assays to detect reactivity to individual autoantigens. In addition, a HuProt proteome microarray was used to screen for novel autoantibody targets in plasma samples from five patients with ANA‐positive JIA and four ANA‐negative healthy controls. Results Homogeneous nuclear ANA staining, indicating reactivity toward chromatin, was detected in most (61.8%) patients with JIA but rarely in healthy controls (2.6%; P < 0.0001). No antibody reactivity to specific nuclear antigens or other autoantigens associated with connective tissue diseases was detected. However, 20% of patients with JIA harbored antibodies against double‐stranded DNA (dsDNA)–nucleosome complexes (compared with 2.6% of controls, P < 0.0001). Finally, the proteome microarray revealed core histone H2A variant H2AFY, part of the nucleosome, to be the most widely recognized human protein by autoantibodies of patients with JIA. Conclusion Autoantibody reactivity in JIA primarily targets chromatin, but the epitopes targeted are likely either posttranslationally modified or multimolecule epitopes, such as dsDNA–nucleosome complexes, rather than epitopes on individual native proteins or purified dsDNA.
Objective Cytokine storm syndrome (CSS), commonly associated with hemophagocytic lymphohistiocytosis (HLH), is a fatal hyperinflammatory syndrome. Differentiating the underlying diseases responsible for CSS is essential for timely therapeutic decisions. This study explored the clinical usefulness of serum cytokine profiling in distinguishing underlying diseases in patients with CSS. Methods Serum samples were collected from 143 adult and pediatric patients with CSS and 22 healthy controls. The cohort included patients with various diagnoses of primary and secondary HLH and Kawasaki disease (KD)‐like hyperinflammatory syndromes. Serum levels of 48 cytokines were analyzed in 97 patients using a bead‐based multiplex immunoassay (Luminex assay). Serum levels of interferon alpha (IFN‐α), interleukin‐18 (IL‐18), IL‐6, CXCL9, and soluble tumor necrosis factor receptor II (sTNF‐RII) were measured in 165 participants using enzyme‐linked immunosorbent assay (ELISA). Results Luminex assay categorized patients with CSS into five clusters based on serum cytokine patterns. ELISA revealed distinct cytokine patterns, wherein patients with histiocytic necrotizing lymphadenitis‐associated HLH and systemic lupus erythematosus‐associated macrophage activation syndrome (MAS) showed elevated IFN‐α; systemic juvenile idiopathic arthritis–associated and adult‐onset Still's disease–associated MAS, X‐linked inhibitor of apoptosis protein deficiency with HLH, and NLRC4‐associated autoinflammatory disorder exhibited higher IL‐18 levels. Additionally, KD shock syndrome had higher IL‐6 levels than the other groups. CXCL9 was significantly elevated in patients with virus‐associated HLH, familial HLH, malignant lymphoma‐associated HLH, and KD‐MAS. Multisystem inflammatory syndrome in children and toxic shock syndrome also showed moderate elevations of CXCL9 and IL‐6 levels. Conclusion Serum cytokine profiling effectively differentiates CSS subtypes, facilitating better diagnosis and personalized treatment strategies based on specific disease backgrounds. image
Objective Methotrexate (MTX) is the first‐line therapy for juvenile idiopathic arthritis (JIA), but up to 40% of patients do not respond to it. Low inosine triphosphate pyrophosphatase (ITPA) activity has been associated with reduced clinical remission. We investigated the role and underlying mechanisms of ITPA in vitro. Methods ITPA enzymatic activity was measured by high‐performance liquid chromatography with ultraviolet detection in erythrocyte lysates from patients with JIA (enrolled in Trieste, Italy; Florence, Italy; and Kansas City, Missouri) receiving weekly MTX (10–15 mg/m 2 ) for at least 12 months. Remission was evaluated by Wallace et al criteria. ITPA rs1127354, which reduces enzyme activity, was genotyped. Immortalized human hepatocytes were transfected with either an ITPA ‐containing or empty plasmid to evaluate cytotoxicity (MTT), ADORA 2A expression (quantitative polymerase chain reaction), intracellular cyclic AMP (cAMP) (enzyme‐linked immunosorbent assay), PKA‐Cα expression (immunoblot), and extracellular adenosine metabolites (liquid chromatography–tandem mass spectrometry). Results A total of 195 patients with JIA (mean age: 8 years, range: 0–22 years, 74% female participants) were enrolled. Patients reaching remission (48%) had higher ITPA activity than nonresponders during therapy and at treatment onset (meta‐analysis: P = 0.0004 and P = 0.007, respectively). Predictive cutoffs for overall and onset measurements were identified: 181.9 and 177.8 nmol of inosine monophosphate per hour. None of the patients with variant ITPA rs1127354 achieved remission (Fisher's exact test P = 0.0063); however, 48% of wild‐type patients failed to respond. ITPA‐overexpressing cells showed elevated MTX sensitivity, cAMP levels, PKA‐Cα expression, and hypoxanthine (all P < 0.05, two‐way analysis of variance). Conclusion ITPA activity is a promising predictive biomarker for MTX response in JIA, outperforming ITPA rs1127354 genotyping. Its predictive value is evident at treatment initiation, supporting
Inborn errors of metabolism comprise a clinically diverse group of conditions that arise from the decreased activity of an enzyme or metabolite transporter and subsequent blockade in a metabolic pathway. These disorders are typically considered in the differential diagnosis of critically ill neonates or young children presenting with hypoglycaemia, metabolic acidosis or hyperammonaemia. However, beyond these classic presentations, a broader group of inborn errors of metabolism can manifest more subtly, with progressive articular and multi-systemic involvement that mimics or overlaps with typical features of rheumatological disease. Consequently, these conditions might be misdiagnosed for years as rheumatological diseases, including juvenile idiopathic arthritis, systemic sclerosis, idiopathic inflammatory myopathies and systemic lupus erythematosus. Moreover, these disorders provide unique opportunities to understand the complex interplay between metabolism and immune function. With the growing availability of disease-modifying therapies for inborn errors of metabolism, rheumatologists must be able to recognize these disorders, particularly in patients with atypical features or treatment-refractory disease.
Objective Still disease is a rare systemic inflammatory disorder of unknown origin, characterized by episodes of uncontrolled inflammation. Although natural killer (NK) cells have been implicated in Still disease pathogenesis, their precise role remains elusive. Methods Within the framework of the Immunome Project Consortium for Autoinflammatory Disorders, we performed a comprehensive NK cell phenotyping in an international cohort comprising 121 patients with distinct systemic autoinflammatory diseases (53 with Still disease, 23 with chronic recurrent multifocal osteomyelitis, 23 with familial Mediterranean fever, and 22 with inflammation of unknown origin) and 32 healthy controls. Results Our analysis revealed a unique NK cell signature in Still disease, characterized by a reduction in NK cell frequency and elevated Fas expression, rendering them more susceptible to in vitro Fas ligand–induced apoptosis. Fas ligand was expressed by Still disease monocytes and CD38 + HLA‐DR + cycling lymphocytes. Still disease NK cells displayed a hyperactivated but exhausted phenotype, including cytokine unresponsiveness, all features not observed in the other groups. This NK cell dysfunctional profile was normalized during clinical remission. Exposure of healthy NK cells to interleukin (IL)‐12, IL‐15, and IL‐18 recapitulates the Still disease–associated phenotype, suggesting an inflammation‐driven mechanism. Transcriptomic profiling identified microRNA miR‐146a as a potential regulator of this NK cell dysfunction. Conclusion Our findings establish NK cell apoptosis, exhaustion, and cytokine unresponsiveness as defining immunologic features of Still disease, distinguishing it from other inflammatory diseases in this cohort. This dysfunctional NK cell state may underlie the heightened risk of macrophage activation syndrome in Still disease and highlights inflammatory cytokines and miR‐146a as promising therapeutic targets to mitigate disease severity and prevent life‐threatening complications. image
Objective The unknown pathophysiology and the lack of specific features for systemic juvenile idiopathic arthritis and adult‐onset Still disease (collectively known as Still disease; SD) delay diagnosis and appropriate treatment. The goal of this study was to identify features and mechanisms that distinguish SD from other systemic autoinflammatory diseases (SAID). Methods Using the SomaScan assay and RNA sequencing (RNA‐Seq), we determined the plasma proteomes and immune cell microRNA (miRNA) and RNA transcriptomes of 372 patients with SAID, respectively. Proteomic findings were validated by enzyme‐linked immunosorbent assays. SD (n = 72) and non‐SD SAIDs (n = 300) were compared to identify distinguishing features of SD. We performed integrated and unbiased analyses of all data sets using weighted gene correlation network analysis to identify feature modules that characterize SD and stratify patients. Results Elevated plasma heme oxygenase 1 (HO‐1) and interleukin‐18 (IL‐18) strongly correlate and characterize SD but do not associate with general inflammation. SD was characterized by ferroptosis in plasma, type I interferon (IFN) signaling in monocyte transcriptomes, and elevated natural killer cell miRNA‐146a‐5p, which is an IL‐18 induced miRNA. Finally, we identified feature modules that distinguish SD from other SAIDs and stratified patients with SD into two distinct subgroups not attributable to disease activity or inflammation but hemophagocytosis. Conclusion This unprecedented large omics data set of SAIDs revealed that complex interactions among hemophagocytosis, IL‐18, and type I IFN signaling characterize SD. Furthermore, two distinct subgroups in patients with SD were distinguished by the degree of hemophagocytic activity. Finally, the large proteomics and RNA‐Seq data sets generated in this study can serve as an invaluable resource for the further investigation of SD and other SAIDs. image
Objective: To develop evidence-based Pan American League of Associations for Rheumatology (PANLAR) recommendations for the treatment of oligoarthritis category in juvenile idiopathic arthritis (oligo-JIA) patients. Methods: A panel of pediatric rheumatologists from Latin-America (LATAM) generated clinically meaningful questions related to the treatment of oligo-JIA patients, using Population, Intervention, Comparator, and Outcome (PICO) format. Following Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, a team of methodologists conducted a systematic literature review, extracted, summarized intervention effect estimates, and graded the evidence quality. LATAM pediatric rheumatology experts’ panel voted each PICO question, which required a minimum agreement of 70% among the voting members and developed recommendations. Results: Seven recommendations and 4 expert opinion were developed. Short-term course of NSAID and intra-articular corticosteroids was recommended as initial therapy in those with minimal disease activity with no risk factors for poor prognosis. The initiation of a nbDMARD was recommended in patients with high disease activity and risk factors for poor prognosis. For patients who achieve inactive disease state, treatment with DMARD should be maintained for a minimum of 12 months after remission. We proposed sulfasalazine or leflunomide in patients with methotrexate intolerance, or in the presence of contraindication or unavailability of bDMARD. For oligo-JIA patients with high disease activity or uveitis, anti-TNF agents are recommended as the first choice among bDMARD. Regular physical activity was also recommended for these patients. Conclusions: The first PANLAR oligo-JIA treatment guidelines provide evidence-based guidance for health care providers, treating patients with oligo-JIA in LATAM.
Objective Phenotypic diversity of autoimmune diseases presents an ongoing diagnostic and therapeutic challenge. The discovery of mutations in RELA (encoding RELA/p65) in patients with diverse disease phenotypes suggests heterogeneous pathophysiologic mechanisms are at play, which may explain the observed phenotypic diversity. We identified seven novel/rare RELA variants in patients with autoimmune diseases and examined the functional consequences on immune signaling. Methods Whole‐exome sequencing analysis revealed seven novel/rare RELA variants. Following ectopic expression of wild type (WT) and mutant RELA proteins in HEK293 cells, NF‐ κ B/interferon‐ β (IFNβ) luciferase reporter assays were used to determine transcriptional activity. RELA expression was also assessed in transfected HEK293 cells and in patient peripheral blood mononuclear cells (PBMCs) via Western blot. NF‐ κ B and interferon‐stimulated genes in patient PBMCs were assessed via quantitative polymerase chain reaction following toll‐like receptor (TLR) activation. Results RELA I250V , RELA R295H and RELA E3* displayed a loss in NF‐κB transcriptional activity. RELA I250V and RELA R295H induced hyperactivation of the IFNβ promoter. Comparative to RELA WT , ectopically expressed RELA I250V protein levels were reduced. Collectively, an elevated IFN gene signature was not detected in patient PBMCs following TLR activation, however the patient heterozygous for I250V had elevated IFNβ transcripts after TLR7/8 activation. Conclusion We expand upon the clinical syndromes linked to RELA dysfunction and uncover rare/novel variants that have distinct functional effects on gene transcription downstream of NF‐κB and IFNβ promoter elements. These findings reinforce an important role for RELA in a range of autoimmune and autoinflammatory diseases.
Articular cartilage is crucial for joint function; however, it has limited regenerative capacity when damaged, a hallmark of many rheumatic diseases. Non-invasive imaging is essential for early diagnosis, therapeutic monitoring and prognostication. MRI remains the reference standard, offering detailed assessment of both morphological and compositional cartilage changes. Technological advances, including high-resolution and compositional MRI techniques such as T2 mapping, T1ρ, delayed gadolinium-enhanced MRI of cartilage, sodium imaging, diffusion imaging and ultra-short echo-time imaging, enable early detection of matrix alterations that precede structural breakdown. CT arthrography, although it involves radiation, serves as a valuable alternative when MRI is contra-indicated, offering high performance in the detection and evaluation of cartilage surface lesions. Emerging modalities, such as ultrasonography and PET, offer additional functional insights but are currently limited in scope. Artificial intelligence is poised to transform cartilage imaging through accelerated acquisition, automated segmentation, improved interpretation and enhanced efficiency, with growing clinical adoption. Advanced cartilage imaging will probably have an increasingly important role in clinical rheumatology, particularly for the optimization of individualized management of cartilage pathology.
Immune-mediated inflammatory arthritides (IMIA), including rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and juvenile idiopathic arthritis, are chronic immune-driven disorders in which long-term malignancy safety has become a key determinant of therapeutic decision-making. Patients with IMIA are not oncologically neutral at baseline; persistent inflammatory burden, smoking exposure, age, and cumulative immunosuppressive treatment all modify cancer susceptibility. Against this background, biologic and targeted synthetic disease-modifying antirheumatic drugs may both reduce inflammation-associated oncogenic pressure and attenuate antitumor immune surveillance. In this narrative review, we synthesize current evidence on tumor safety across major biologic classes and Janus kinase inhibitors, with emphasis on data emerging through early 2026. Overall, most biologic therapies appear broadly reassuring with respect to overall malignancy, although non-melanoma skin cancer remains the most reproducible treatment-associated signal, particularly with tumor necrosis factor inhibitors and possibly abatacept. Rituximab retains a favorable profile in patients with prior lymphoproliferative disease, whereas IL-6 and IL-17/23 pathway inhibitors appear largely neutral or reassuring in currently available datasets. By contrast, JAK inhibitors require greater caution in risk-enriched rheumatoid arthritis populations, especially older patients, smokers, and those with prior malignancy or prolonged treatment exposure. Recent register-based studies have shown that overall cancer incidence with JAK inhibitors is comparable to that with TNF inhibitors, although lung and keratinocyte cancers occur more frequently in certain risk groups; accordingly, updated 2025 EULAR guidance recommends early initiation of targeted therapy after cancer remission and tailoring drug choice to prior cancer type and patient-specific factors. We further examine tumor-type-specific patterns, major modifiers of risk, and practical risk-stratified management strategies. The central clinical message is that malignancy safety in IMIA should be interpreted through an individualized framework that balances inflammatory control against oncologic vulnerability rather
Tocilizumab (TCZ), an anti-interleukin-6 receptor (IL-6R) biologic agent, is commonly used to treat systemic juvenile idiopathic arthritis (sJIA); however, the optimal dosing strategy for susceptible children and the timing of administration for safe attenuated live vaccines remain unclear. This study aimed to determine the optimal dose-escalation regimen for TCZ in children with sJIA, as well as to investigate the recommended live-vaccine schedules for pediatric patients exposed to this drug. A physiologically-based pharmacokinetic (PBPK) model integrating a target-mediated drug disposition (TMDD) structure was built for adults and extrapolated to pediatric patients. The PBPK model successfully predicted and verified the pharmacokinetics (PKs) of TCZ in children aged < 2 years and 2-17 years. The predicted PK data were within two-fold of the observed data. According to the simulations, dose-escalation strategies were proposed to mitigate early hypersensitivity reactions: a 6-8-12 mg/kg sequence for patients weighing <30 kg, including infants aged <2 years and children aged 2-17 years, and a 4-6-8 mg/kg sequence for children aged 2-17 years weighing ≥30 kg. Furthermore, PBPK models indicated that, for pediatric patients of all ages, the advocated timing of live-attenuated vaccination is approximately 55 to 70 days after treatment cessation, provided that the underlying disease activity is closely monitored. Our study illustrated that PBPK models can provide a valuable tool to predict the PKs of large macromolecules in children across the age continuum, ultimately informing precision drug-treatment decisions and vaccination regimens for the pediatric sJIA population.
Advances in medications to treat paediatric rheumatic conditions including juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE) have transformed outcomes in well-resourced settings. Access to therapeutic agents that are an accepted standard of care in many regions of the world remains unequal. Here we review access to medications through a global paediatric rheumatology lens, examining challenges from drug development to delivery. The high cost of novel medications, combined with complex research and regulatory environments, market forces, the rarity of conditions and policy gaps, drive disparities in low- and middle-income countries (LMICs) where outcomes in children with JIA and SLE are closely linked to socioeconomic status and geography. Data concerning the prevalence of rheumatic conditions in LMICs are sparse, contributing to the under-recognition of disease burden. Clinical trials are disproportionately conducted in high-income countries, limiting global representation and knowledge of safety and efficacy across diverse populations. Additionally, medicines may technically be available, but with barriers that undermine true access. Global and regional organizations, including the Paediatric Task Force for Global Musculoskeletal Health, have advanced education, advocacy, and alignment of medicines with the WHO Essential Medicines List for children (EMLc). However, implementation at the country level remains inconsistent, and essential medicines for treating rheumatic diseases are often absent from national formularies. Addressing these inequities requires coordinated strategies: expanding and harmonizing EMLs, accelerating biosimilar approval and uptake, building a workforce and research capacity in LMICs, and embedding paediatric rheumatology within broader noncommunicable disease and universal health coverage frameworks. We summarize some strategic directions and aspirations within these 5 described arenas, that may help to address the global inequity of drug access.
Objectives To evaluate the relationship between type I interferon (IFN‐I) stimulated gene (ISG) expression, Still's disease, and the development of lung disease (LD) and drug‐associated immune reactions (DAIR) to IL‐1/IL‐6 inhibitors. Methods Whole blood ISG expression was quantified by NanoString array. ISG‐28 scores were calculated in consecutive patients with Still's or Still's‐like disease. Exome sequencing with family‐based variant prioritization identified candidate genes harboring rare candidate causative variants. Lists of candidate genes were subjected to functional enrichment analysis. Results Among 57 patients (32 children, 25 adults), 16 had elevated ISG‐28 scores. This group exhibited higher prevalence of LD (0.44 vs. 0.1, p=0.007) and DAIR (0.63 vs. 0.17, p=0.003), and lower IL‐6 inhibitor use (0 vs. 0.25, p=0.048) compared to others. No significant differences were found in the rates of macrophage activation syndrome, active disease, elevated IL‐18, or current IL‐1 inhibition. The combination of HLA‐DRB1*15 with high ISG‐28 scores associated with LD and DAIR with high specificity, while absence of both biomarkers had high negative predictive value. Candidate genes from high ISG‐28 individuals were enriched in interferon‐related pathways, including autophagy, IFN‐I production, toll‐like receptor signaling, macrophage activation, cytoskeletal organization and responses to stress. Conclusion High IFN‐I expression correlates with LD and DAIR in Still's disease, linked to rare genetic variation in immune pathways. Combining high ISG‐28 with HLA‐DRB1*15 significantly improves post‐hoc stratification of patients for these complications. If prospectively validated, these findings may guide molecular risk assessment and targeted therapies, including IFN‐I directed treatments in Still's disease with IFN‐I signature.
Abstract Introduction Juvenile idiopathic arthritis–associated uveitis (JIA-U) is an important cause of childhood and adult visual impairment. Advances in surveillance approaches and treatment have improved outcomes, yet delayed detection and treatment-refractory disease remain substantial challenges. This review summarises recent developments across disease stratification, imaging, pharmacologic management, and psychosocial support, following the natural history of disease from inception to adulthood. Main body Risk-stratified screening based on antinuclear antibody status, JIA subtype, and age at arthritis onset is now standard, but many cases present outside screening windows. Novel biomarkers, including S100A8/A9, S100A12, and genetic risk alleles, offer promise for earlier identification. Ocular imaging modalities such as anterior segment optical coherence tomography and optical coherence tomography angiography enable objective, child-friendly detection of inflammation and subclinical vascular changes, potentially extending specialist-level assessment to community settings. Early initiation of immunomodulatory therapy in children with JIA is now prevalent care, reducing uveitis incidence and improving outcomes in childhood, although the consequence may be new challenges later in the lifecourse. Anti-tumour necrosis factor therapy has changed the management of JIA-U for the better, although precision strategies, such as anti-drug antibody monitoring, dose individualisation, and tapering approaches are needed to further optimise care. For refractory disease, biologics and other emerging therapies are under investigation, but new therapeutic targets are needed. Beyond ocular health, JIA-U imposes a heavy psychosocial burden on children and families, exacerbated by treatment side-effects and frequent medical visits. Validated tools, such as the EYE-Q questionnaire, and co-developed educational and self-management resources will be key to addressing mental health and quality-of-life concerns. Conclusion JIA-U remains a lifelong, vision-threatening condition despite advances in screening, diagnostics, and treatment. Integration of biomarker-based risk stratification, advanced imaging, and precision pharmacology
Background Treatment of childhood chronic idiopathic uveitis (cCIU) is predominantly based on studies in Juvenile Idiopathic Arthritis associated uveitis and expert opinion. Our aim was to report the treatment outcomes of our cohort of cCIU. Methods Retrospective multicenter study involving the rheuma/ophthalmology units at Florence and Bristol. We included children with cCIU, who received at least one systemic treatment. Ocular inflammation and treatment response were assessed according to the standardized Uveitis Nomenclature (SUN). Findings 116 cCIU received at least one systemic treatment (93 methotrexate, 22 adalimumab, 1 mycophenolate), while 60 of them received an additional second‐line (45 adalimumab, 14 mycophenolate and 1 tocilizumab). Children treated with adalimumab (+/‐methotrexate) as first‐line were more likely to achieve remission than methotrexate alone (χ 2 31.35 p<0.001), furthermore children treated with methotrexate as first‐line relapsed earlier (χ 2 4.35 p0.043). Children receiving adalimumab were more likely to stop treatment for remission than methotrexate (χ 2 25.9 p<0.001). Regarding second‐line, children who started adalimumab(±methotrexate) were more likely to achieve remission than mycophenolate (χ 2 14.66 p0.005). Children with non‐anterior uveitis, conversely to the others, were more likely to achieve remission with adalimumab as first‐line than methotrexate (χ 2 32.3 p<0.001). Children with non‐anterior uveitis, but not children with anterior uveitis, were more likely to stop the first‐line treatment when receiving adalimumab than methotrexate (χ 2 18.56 p0.001) due to persistent remission. Interpretations Adalimumab shows promise as a potential first‐line therapy for cCIU, particularly for posterior segment uveitis. Although effective in anterior uveitis, methotrexate leads children to relapse earlier than adalimumab. image
Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease most commonly affecting children and young people. CNO can cause bone pain, hyperostosis and fractures, thereby significantly impacting on patients' wellbeing. The molecular pathophysiology of CNO is characterized by NLRP3 inflammasome activation and a pronounced imbalance between pro- and anti-inflammatory cytokines. In the absence of clinical trials, treatment of CNO remains empiric and is based on personal experience and published case series. This project systematically reviewed the available literature in pediatric CNO following 'Preferred Reporting Items for Systematic Reviews and Meta-Analyses' (PRISMA) guidance accessing Medline, Embase, NCBI PubMed, Cochrane Library Clinical Trials, ClinicalTrials.gov, and WHO ICTRP. Nonsteroidal anti-inflammatory drugs are usually used as first-line treatment. They facilitate pain control and induce early remission in some patients but also associate with later flares. Conventional disease modifying antirheumatic drugs (DMARDs) have been used with mixed success and may be helpful in patients with associated arthritis, skin inflammation, and/or inflammatory bowel disease. Biologic DMARDs, namely TNF inhibitors, are effective for the treatment of bone and associated skin and/or bowel disease. Bisphosphonates induce rapid remission in most patients but may associate with higher relapse rates when compared to TNF inhibitors. The longstanding absence of diagnostic and, until recently, classification criteria as well as defined study endpoints, the small sample size and variable therapeutic approaches challenge interpretation of studies and comparisons between treatments. Prospective randomised controlled trials are urgently needed to improve the evidence base, resulting in approval of treatments for CNO.
To present updated evidence-based recommendations with a range of therapeutic options for children in Africa with oligoarticular juvenile idiopathic arthritis (JIA), adopting the treat to-target approach. This study was conducted by the Paediatric Society of the African League Against Rheumatism (PAFLAR) to reach a consensus for recommendations regarding diagnosis and management of oligoarticular JIA suitable for application among different African countries. The Delphi technique was used to reach a consensus of 15 key questions identified by the steering committee. According to the PICO (patient/population, intervention, comparison, outcome) approach, a voting process among 22 African and international clinicians and experts in the field of pediatric rheumatology was performed after intensive systematic review of literature. A consensus was reached for 15 recommendations for diagnosis, monitoring, management of the disease, and its complications, intervention, and when to discontinue treatment of oligoarticular JIA patients with high level of agreement (ranging between 85 and 95%) who agreed or strongly agreed, and the response rate was 100%. These recommendations focus on the early diagnosis and multidisciplinary management of oligoarticular JIA and its complications with high levels of consensus and agreement, improving practice consistency among healthcare providers. Key Points • A panel of experts created a consensus about the early diagnosis of oligoarticular JIA • Consensus-based recommendations to the management of oligoarticular JIA • These guidelines emphasized on the oligoarticular JIA-specific characteristics, severity factors, and treatment alternatives.
Objective To evaluate the timeline for resolution of sacroiliac joint (SIJ) inflammation, changes in structural lesions, and their correlation with patient‐reported outcomes (PROs) in youth with axial juvenile spondyloarthritis (axJSpA) initiating tumor necrosis factor inhibitor (TNFi). Methods This prospective, multicenter study included youth aged 8 to 18 years with a clinical diagnosis of axJSpA starting TNFi. Assessments were conducted at baseline and 12 weeks, including clinical evaluation, magnetic resonance imaging (MRI), and PROs. Participants with persistent SIJ inflammation at 12 weeks were reassessed at 24 weeks. Three blinded reviewers evaluated MRIs using Spondyloarthritis Research Consortium of Canada SIJ inflammation scores (SIS) and SIJ structural scores. Results Of 75 enrolled participants, 73 completed baseline visits, and 62 had MRI‐confirmed axJSpA. Fifty‐seven completed a 12‐week follow‐up; 89% (51 of 57) showed SIS improvement, and 63% (36 of 57) achieved inflammation resolution (SIS <2). Median SIS change from baseline to 12 weeks was −8 (interquartile range: −18 to −3). Among those with persistent inflammation at 12 weeks (n = 26), 85% reported at least moderate clinical improvement. At 24 weeks, 56% (14 of 25) had ongoing inflammation. A total of 84% of SIS improvement occurred within the first 12 weeks. In patients with at least two scans, structural lesion scores decreased, increased, or stayed the same from baseline to the 12‐week scan for erosions (58%/25%/18%), sclerosis (21%/9%/70%), fat metaplasia (0%/30%/70%), and backfill (4%/28%/68%). Conclusion Most participants showed early imaging response to TNFi, with most improvement occurring within 12 weeks. Despite residual inflammation persisting in nearly half of patients, most reported symptom improvement, underscoring both the rapid impact of TNFi and the heterogeneity of treatment effects. image
Objective To evaluate the prognostic utility of circulating interleukin‐18 (IL‐18) levels in predicting disease activity, macrophage activation syndrome (MAS), and disease course in patients with Still disease (SD) receiving first‐line IL‐1 inhibitors (IL‐1i). Methods We retrospectively analyzed 66 biologic‐naive patients with SD who received first‐line treatment with IL‐1i. Plasma IL‐18 levels were measured at baseline and at 3, 6, and 12 months after IL‐1i initiation. Associations between IL‐18 levels and clinical outcomes were assessed using mixed‐effects models, receiver operating characteristic (ROC) curve analysis, and multivariate logistic regression. Results Median baseline IL‐18 levels were 61,425 pg/mL (interquartile range 16,194–235,746) and declined significantly after IL‐1 blockade ( P 45,000 pg/mL predicted active disease at 12 months (area under the curve [AUC] 0.82; P = 0.0002), MAS development within 24 months (AUC 0.78; P = 0.01), and a chronic–persistent course (AUC 0.73; P = 0.007). In multivariate models, elevated baseline IL‐18 and delayed IL‐1i initiation for more than three months independently predicted adverse outcomes. Strikingly, at three months, IL‐18 >15,000 pg/mL was a stronger predictor of chronic–persistent course (AUC 0.92; P < 0.0001), independent of clinical disease activity (odds ratio 25.6; P = 0.01), with the multivariate model explaining 67% of variance (AUC 0.95). Conclusion In biologic‐naive patients with SD, IL‐18 levels, especially reassessed three months after IL‐1i initiation, robustly predict long‐term disease activity, MAS risk, and chronic–persistent trajectory. Early measurement and dynamic monitoring of IL‐18 may enable risk stratification and guide timely therapeutic escalation or treatment adjustment to improve outcomes. image
A newsletter destaca as principais atualizações do ACR 2025, focando na emergência dos T Cell Engagers (TCEs) como uma terapia celular mais acessível para o tratamento de doenças autoimunes graves. O conteúdo também revisa a falta de evidências robustas para terapias alternativas na osteoartrite de joelho e compila novos guidelines para o manejo de lúpus, gota e artrite idiopática juvenil.
A newsletter discute o potencial do baricitinibe em pacientes com uveíte associada à AIJ refratários a biológicos e destaca como a mudança para equações de função pulmonar neutras em relação à raça altera significativamente a classificação de gravidade na esclerose sistêmica. Além disso, aborda evidências recentes sobre a eficácia do adalimumabe na Síndrome de Behçet e os benefícios metabólicos e inflamatórios dos agonistas de GLP-1 na artrite reumatoide.
This study aimed to compare the risk of developing systemic autoimmune diseases (SADs) among pediatric patients with juvenile idiopathic arthritis (JIA) treated with tumor necrosis factor inhibitors (TNFi) versus interleukin-6 inhibitors (IL-6i), based on real-world data. We conducted a retrospective real-world cohort study using the TriNetX Research Network, which contains data from over 122 million patients. Individuals ≤18 years of age with a diagnosis of JIA who initiated TNFi or IL-6i therapy between January 1, 2013, and December 31, 2024, were included. Propensity score matching (1:1) was performed to balance baseline characteristics. The primary outcome was the incidence of SADs. Hazard ratios (HRs) were estimated using Cox proportional hazards models, and subgroup and sensitivity analyses were conducted to assess robustness. After matching, 1,192 patients were included in each cohort. The TNFi group demonstrated a significantly lower incidence of SADs than the IL-6i group (17 vs. 45 events; HR = 0.37, 95% CI: 0.20-0.63). Subgroup analyses showed consistent protective effects of TNFi across age, sex, and concomitant medication strata. Sensitivity analyses across three adjusted models confirmed the robustness of the findings, yielding HRs ranging from 0.28 to 0.46. Among pediatric patients with JIA, TNF inhibitor therapy was associated with a substantially lower risk of developing systemic autoimmune diseases compared with IL-6 inhibitor therapy. These findings may inform biologic selection and long-term safety considerations in pediatric rheumatologic practice.
Pediatric uveitis, though accounting for less than 10% of all uveitis cases, presents significant diagnostic and therapeutic challenges due to its asymptomatic onset and potential for severe, vision-threatening complications. Despite known associations with autoimmune diseases, data on risk factors in Asian pediatric populations remain limited. This study aimed to quantify the risk of uveitis in Taiwanese children with autoimmune diseases, identify key comorbidities, and evaluate the effects of immunosuppressive therapies. Using Taiwan's National Health Insurance Research Database (2009-2019), we conducted a nationwide retrospective cohort study of 3,643 pediatric patients with autoimmune diseases matched 1:1 to controls. Patients were followed for up to 12 years, with uveitis risk assessed through Cox proportional hazards models and cumulative incidence analyzed using Kaplan-Meier curves. During a mean follow-up of 5.5 years, autoimmune diseases were associated with increased uveitis risk (adjusted HR [aHR] = 2.65 [95% CI, 1.67-4.19]), with juvenile idiopathic arthritis showing the highest risk (aHR = 25.70 [95% CI, 7.41-89.22]). Risk was significant only in adolescents aged 10-14 years (aHR = 2.58 [95% CI, 1.29-5.14]) and 15-18 years (aHR = 2.60 [95% CI, 1.27-5.31]) and was notably higher in patients without diabetes (aHR = 6.88 [95% CI, 2.54-18.61]) compared with those with diabetes (aHR = 1.67 [95% CI, 0.98-2.82]). In medication analysis, sulfasalazine use (aHR = 2.00 [95% CI, 1.04-3.84]) and high-daily dose prednisolone (≥30 mg/day; aHR = 2.25 [95% CI, 1.12-4.53]) were associated with increased risk, while moderate cumulative prednisolone doses were associated with a lower risk compared with low-dose exposure (aHR = 0.32 [95% CI, 0.13-0.79]). This cohort study identified distinct patterns of uveitis risk across specific autoimmune diseases and age groups. These findings suggest the need for risk-stratified ophthalmologic screening
Rheumatoid arthritis (RA) is a chronic autoimmune arthritis that predominantly affects adults, whereas juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of childhood-onset arthritides defined by age at onset, clinical phenotype, and immunological profile. Although RA and JIA are classified as distinct diseases, they share overlapping clinical and immunological features, and the nosological relationship between RA and some JIA subtypes remains debated. The global burden of RA and JIA in young people, and the similarities and differences in their underlying immunogenetic features, remain incompletely understood. We utilized GBD 2021 data to describe trends in incidence, prevalence, and disability-adjusted life years for RA in individuals aged 0-19 years, as defined within the GBD framework, from 1990 to 2021. In parallel, we performed two-sample Mendelian randomization (MR) using genome-wide association study summary statistics from European-ancestry cohorts to assess associations of genetically proxied levels of 731 immune-cell traits, 91 circulating inflammatory proteins, and 1,400 serum metabolites with RA and JIA risk. From 1990 to 2021, global age-standardized incidence and prevalence of RA in individuals aged 0-19 years increased, whereas disability-adjusted life years declined slightly. The aggregated burden was higher in females and in high-sociodemographic index regions. MR identified overlapping genetically proxied immune-cell and inflammatory protein traits for RA and JIA, including CD28 on CD8+CD45RA+ T cells, CD25 on memory B cells, signaling lymphocytic activation molecule, and Fms-like tyrosine kinase 3 ligand, whereas higher genetically predicted levels of activated regulatory T cells and HLA-DR on dendritic cells were associated with lower risk in both diseases. Our study highlights a rising global burden of GBD-defined RA among children and adolescents and delineates shared and distinct patterns of genetically predicted immune-cell, inflammatory protein, and metabolite traits
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.
jMCTD share the same clinical characteristics as aMCTD patients, but less frequently have puffy fingers. Outcomes appear more favorable in jMCTD than aMCTD, with higher remission rates, albeit at the cost of more intensive treatment.
Myositis specific antibodies are clinically useful biomarkers in inflammatory myositis. Although immunoprecipitation is regarded as the gold standard, line immune assay (LIA) is widely used in practice. However, LIA is limited by multiple MSA positivity in up to 15% of patients, which limits its applicability in diagnosis and prognostication. We sought to interrogate the subset of patients with multiple antibody positivity on LIA to determine a new positive control band index with high specificity for the diagnosis of myositis. We retrospectively reviewed all samples tested for MSA (EUROLINE DL 1530-1601-4G) between April 2023 to April 2025. We calculated the PCBI (test reading/positive control) and compared it with optimal cutoffs as per EUROLINE and how it impacted multiple antibody positivity. Diagnosis of myositis subtype was confirmed by 2 rheumatologists. We retrieved records of 235 patients, 59.6% females with a mean age of 46.1 years. The underlying diagnosis was dermatomyositis (8.5%), juvenile dermatomyositis (2.1%), anti-synthetase syndrome (7.7%), necrotizing myopathy (2.6%), malignancy associated (4, 1.7%), MSA negative IIM or polymyositis (8, 3.4%) and CTD associated myositis (12, 5.1%) and ILD for IPAF evaluation (139, 59.1%). Multiple MSA positivity was seen in 25 patients (10.6%) with EuroLine, Using the revised PCBI cutoffs, we could discriminate between 14 of these MSA's and 11 remained positive for multiple antibodies. On correspondence analysis, both Euroline cutoffs and PCBI showed association between antibody positivity and clinical diagnosis (Chisq p values < 0.001). However, using the PCBI, 73.4% of the variability in the data compared to 69.13% with Euroline cutoffs. Rather than a single uniform cut off for all patients, a phenotype specific cut off for each clinical phenotype at the time of clinical assessment might offer a higher specificity for MSA with line
Juvenile idiopathic arthritis (JIA) is one of the most common chronic rheumatic diseases and requires coordinated and targeted treatment strategies to avoid long-term disability. Existing guidelines from Western countries may not address region-specific factors, including genetic heterogeneity, limited treatment availability, and limitations in healthcare infrastructure, in the Asia Pacific region. The aim of this systematic literature review (SLR) and meta-analysis was to provide up-to-date evidence for the Asia Pacific League of Associations for Rheumatology (APLAR) recommendations for managing polyarticular course JIA (pcJIA) and temporomandibular joint (TMJ) arthritis. This systematic review followed PRISMA guidelines, with searches conducted on MEDLINE, Embase, Web of Science, Scopus, and CENTRAL through January 2025. Included studies addressed pharmacologic or non-pharmacologic treatments for pcJIA and TMJ involvement. Studies were limited to publications not already covered in existing guidelines. The Cochrane Rob2 tool and GRADE approach were used to assess quality and evidence certainty. Meta-analyses were performed where applicable. Of the initial 9424 records, 86 studies were included in the qualitative analysis. Methotrexate remains the csDMARD of choice, and subcutaneous administration may be more advantageous. Biological DMARDs, particularly abatacept and tocilizumab, have evidence for good efficacy and acceptable safety profiles. Emerging evidence supports the use of JAK inhibitors. Biosimilars were reported to have efficacy and safety comparable to those of originator biologics in observational studies. Limited evidence suggests that gradual medication tapering after achieving inactive disease status reduces the risk of flares. Evidence for physiotherapy, occupational therapy, and complementary medicine was of very low certainty due to methodological heterogeneity. This SLR offers new evidence to support region-specific clinical practice in JIA. While many findings support global recommendations, important evidence gaps remain, particularly in tapering, biosimilar use, TMJ management,
Juvenile idiopathic arthritis (JIA) is one of the most common childhood rheumatic diseases. In the Asia-Pacific region, access to pediatric rheumatology services and therapies remains variable. To address regional disparities and promote evidence-based yet practical care, the APLAR developed consensus recommendations for the management of polyarticular-course JIA (pcJIA), temporomandibular joint (TMJ) arthritis, and non-pharmacologic interventions. A multidisciplinary task force of 34 members from 14 countries, including pediatric and adult rheumatologists and patient representatives, was convened. The guideline development followed the GRADE, ADAPTE, and AGREE II frameworks. Existing international guidelines were critically appraised, and a systematic literature review was performed to address 26 PICO questions. Draft statements were discussed and voted upon using a modified Delphi process, with consensus defined as ≥ 80% agreement. Four overarching principles and 32 statements were finalized: 16 for pcJIA treatment, 10 for TMJ arthritis, 3 for non-pharmacologic therapies, 2 for imaging, and 1 for disease monitoring. Key recommendations that diverge from Western guidelines include: (1) stronger recommendation for methotrexate as initial therapy before biologic DMARDs; (2) explicit advocacy for TNF inhibitors, including biosimilars, when escalation is required; (3) cautious allowance of short-term systemic glucocorticoids where DMARDs are limited; (4) emphasis on treat-to-target using cJADAS-10; (5) stronger endorsement for physical and occupational therapy; and (6) conditional allowance of traditional and complementary medicine practices under professional supervision. These consensus statements provide regionally adapted, evidence-based recommendations to improve access, standardize management, and promote equitable care for patients with JIA across the Asia-Pacific region.
Chronic autoimmune inflammatory rheumatic diseases (AIRD), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), juvenile idiopathic arthritis, systemic sclerosis (SSc), psoriatic arthritis (PsA), and ankylosing spondylitis (AS), are characterized by the dysregulation of the immune system and that of the neuroendocrine immune networks, leading to chronic inflammation and tissue damage. Perturbations of T, B, and macrophage cells result in uncontrolled inflammation. Traditional therapeutic approaches have focused on immunosuppressive drugs but more recently the use of biologics targeting specific cytokines or receptors on immune cells, and intracellular JAK pathways has been employed. However, these therapies often have limited efficacy and significant side effects. Moreover, they are not globally accessible due to high drug costs especially in poor as well as low- to middle-income countries. Cell immunotherapy, such as CAR-T and CAR-M cell therapy based on chimeric antigen receptor (CAR) technology, is opening up novel potential avenues for a precision approach to managing AIRD. This area is still experimental and in the research phase. This paper reviews the potential of CAR-M immunotherapy in AIRDs, highlighting its mechanisms of action and therapeutic applications.
To determine the prevalence of depressive and anxiety symptoms among young people 7 years and 9 years after inclusion in the multicentre, prospective inception cohort (ICON) of newly diagnosed patients with juvenile idiopathic arthritis (JIA) in Germany, and to identify factors associated with mental health problems at study inclusion and in the course of the disease. Patients and controls (healthy peers, eg, friends of the same age and sex) from the ICON cohort (both ≥13 years) were assessed for mental health using the Patient Health Questionnaire-9 and the Generalised Anxiety Disorder Scale-7 at 7-year and 9-year follow-ups. Demographic and clinical characteristics, treatments and health-related quality of life (HRQoL) (Pediatric Quality of Life Inventory (PedsQL)) were documented at baseline and follow-up visits. Cross-sectional (analysis of variance or χ² tests at 7-year/9-year follow-up) and longitudinal analyses (generalised linear mixed models for PedsQL in follow-up from baseline) were conducted, respectively. A total of 344 patients (age 18.7±3.5 years, disease duration 9.2±1.8 years, 42% polyarthritis) and 224 controls (age 18.2±3.6 years) were evaluated. Moderate to severe symptoms of depression and anxiety were present in 13% and 10% of patients, respectively, compared with 7% and 2% of controls. Patients with moderate to severe psychological distress did not exhibit significantly higher physician-reported disease activity at inclusion and follow-up but reported worse patient-reported outcomes. These patients already showed reduced emotional functioning 3 months after diagnosis (p<0.001) and reported lower physical and emotional functioning (p<0.001) after the first year of specialised care compared with those without relevant mental health problems at long-term follow-up. Poor emotional functioning at the start of care for JIA may be an indicator of future mental health issues. Therefore, HRQoL should be routinely assessed at
Juvenile idiopathic arthritis (JIA) is the most common chronic pediatric rheumatic disease. Early referral to a specialized center is crucial for prompt diagnosis and treatment. This study aims to develop and validate a scoring system to assist clinicians in efficiently identifying and referring patients suspected of having non-systemic JIA. We conducted a cohort study with a mixed design (retrospective and prospective), involving consecutive patients presenting with joint complaints who were referred for the first time to the Pediatric Rheumatology Unit at ASST G. Pini-CTO Hospital. The model was developed using multivariate logistic regression with bootstrap resampling and the Lasso (Least Absolute Shrinkage and Selection Operator) method for variable selection. A total of 342 patients were included, of whom 61 (18%) were diagnosed with JIA. The selected variables for the model were: type of joint (large), daily symptoms, joint swelling, activity as a precipitating factor, a positive squeeze test of the metatarsophalangeal/metacarpophalangeal (MTP/MCP) joints, normal bending of the interphalangeal (IF) joints of the hands, morning limping and/or stiffness, and sacroiliac tenderness. The ROC curve, based on the model's regression score, showed an AUC of 0.92 with an overall accuracy of 0.88 (95% CI: 0.84-0.91) using a cutoff of 3 points, yielding a sensitivity of 95% and a specificity of 71%. Initial internal validation of the model revealed an AUC of 0.92 (95% CI: 0.89-0.95). This study presents and initially validates a simple and efficient scoring system to aid clinicians in the early referral of patients suspected of having non-systemic JIA. Not applicable.
To describe diagnostic framework classification, treatment patterns and outcomes in Kawasaki disease-associated macrophage activation syndrome (KD-MAS) using a single-centre cohort and a structured descriptive synthesis of published cases to inform hypothesis generation and future refinement of diagnostic and management strategies for KD-MAS. We performed a retrospective single-centre cohort study. MAS was classified by haemophagocytic lymphohistiocytosis (HLH)-2004, HLH-2009 or 2016 systemic juvenile idiopathic arthritis (sJIA)-MAS criteria. Data were abstracted around a prespecified MAS window; severity was indexed by haemophagocytic syndrome diagnostic score (HScore) and the association between HScore and treatment escalation was assessed using Firth's logistic regression. In parallel, we conducted a literature review. In our centre, incidence was 0.6% (22/3786); mean age was 3.72 years; coronary involvement was 77.2%. The proportions of clinician-diagnosed KD-MAS cases fulfilling each framework were HLH-2004 14/22, HLH-2009 18/22 and 2016 sJIA-MAS 20/22; 11 met all three. Cytopenias, liver dysfunction and coagulopathy were frequent; management followed stepwise escalation from intravenous immunoglobulin (IVIG) or corticosteroid monotherapy to IVIG plus corticosteroids and, when required, to adjunct immunosuppressive/biologic therapy; similar patterns appeared in the literature. HScore was higher with intensified therapy than with standard therapy (median 274 vs 199; p=0.020). Each 10-point HScore increase was associated with higher odds of escalation (OR 1.44 univariable; 1.37 adjusted). The 2016 sJIA-MAS criteria demonstrate the highest proportion fulfilling criteria in our cohort for KD-MAS. Treatment in our cohort and in published cases generally reflected a stepwise, typically progressing from IVIG±glucocorticoids to adjunct immunosuppressants/biologics. Higher HScores co-occurred with escalation, suggesting they capture baseline severity; prospective multicentre studies are needed to test incremental value and risk-stratification thresholds.
Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disorder, characterized by chronic idiopathic joint inflammation in children under sixteen years of age. Emerging evidence suggests that food allergens- particularly cow's milk proteins may modulate inflammatory pathways, and that their elimination could potentially ameliorate disease activity. This study aimed to evaluate through a randomized controlled clinical trial whether eliminating cow's milk protein from the diet influences disease activity and symptom severity in children with JIA. In this randomized controlled trial, 120 children with controlled juvenile idiopathic arthritis (JIA) receiving stable standard therapy were randomly allocated to either a cow's milk protein-free diet (intervention group, n = 60) or an unrestricted diet (control group, n = 60) for one month. Disease activity was assessed at baseline and post-intervention using subjective measures (patient- and physician-reported Visual Analog Scale [VAS]) and objective parameters, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), active joint count, morning stiffness duration, fever. Compared with baseline, the intervention group demonstrated statistically significant improvements in multiple outcomes, including patient VAS (2.9 ± 1.9 to 1.7 ± 1.4; P < 0.001), physician VAS (2.5 ± 1.8 to 1.6 ± 1.3; P < 0.001), ESR (14.6 ± 13.7 to 9.4 ± 7.3 mm/hr; P < 0.001), CRP (7.3 ± 13.7 to 2.5 ± 3.6 mg/dL; P = 0.011), morning stiffness duration (6.1 to 0.6 min; P = 0.002), active joint count (0.55 to 0.11; P < 0.001), and Disease Activity Score (5.53 ± 4.44 to 3.0 ± 2.6; P < 0.001). In contrast, the control group exhibited only minor or non-significant changes. In children with well-controlled JIA, a cow's milk protein-free diet was associated with modest short-term improvements in pain and disease activity. These findings suggest a potential adjunctive benefit alongside standard therapy, but the short duration, low baseline disease activity, and reliance on parental self-report warrant cautious interpretation. The protocol of this clinical trial has been registered in the Iranian Clinical Trial
BACKGROUND: Children and adolescents with juvenile idiopathic arthritis (JIA) are at increased risk for long-term physical and psychosocial complications, making physical activity (PA) and sedentary behaviour (SB) key modifiable lifestyle factors. Although increasingly acknowledged as relevant, data on the daily distribution of these behaviours in JIA remain scarce. This study aimed to (1) describe the time-use composition of SB and PA intensities in young people with JIA, (2) identify correlates of greater relative time spent in SB, and (3) compare movement behaviour patterns to matched population controls using a compositional data analysis (CoDA) approach. METHODS: Patients aged 10–20 years with JIA and individually matched population controls wore hip-worn accelerometers (ActiGraph wGT3X-BT) for eight consecutive days. Movement behaviours were categorized into SB, light-intensity PA, and moderate-to-vigorous PA (MVPA) using validated, age-specific cut-points. CoDA with log-ratio transformations was used to model associations and compare groups. Diifferences in movement composition were assessed using adjusted multivariate analysis of variance (MANOVA). RESULTS: Data from 126 matched pairs (mean age: 15.0 ± 2.1 years; 67% female) were analysed. Patients spent, on average, 86% of waking time in SB, 8% in light-intensity PA, and 6% in MVPA. Overall, 76% did not meet the WHO recommendation of an average of ≥ 60 min of MVPA per day. Among those who did, 87% still spent ≥ 75% of their wear time sedentary. A greater proportion of SB relative to PA was associated with female gender (B = 0.13; p = 0.042), higher age (B = 0.06; p < 0.001), and higher BMI (B = 0.01; p = 0.049). Compared to controls, patients spent more time in SB, less in light-intensity PA, and slightly more in vigorous PA (all p < 0.001). Group differences remained significant after adjustment and were consistent across weekdays and weekends. CONCLUSIONS: Young people with well-controlled
This study aimed to retrospectively evaluate the provisional Paediatric Rheumatology International Trials Organisation (PRINTO) criteria in patients with juvenile idiopathic arthritis (JIA) classified according to the International League of Associations for Rheumatology (ILAR) criteria. This retrospective cohort study was conducted at a single tertiary pediatric rheumatology center. In total, 310 patients with nonsystemic JIA were classified according to both ILAR and provisional PRINTO criteria. Demographic, clinical, and laboratory features were recorded, and the distribution of JIA categories under both classification systems was analyzed. The mean age at study enrollment was 169.8 (SD 59.2) months. Using ILAR criteria, 136 patients (43.9%) were categorized as having oligoarticular JIA, 73 (23.5%) enthesitis-related arthritis, 34 (11%) rheumatoid factor (RF)-negative polyarticular JIA, 12 (3.9%) psoriatic arthritis (PsA), 7 (2.3%) RF-positive polyarticular JIA, and 48 (15.5%) undifferentiated JIA. The provisional PRINTO criteria classified 107 (34.5%) patients with early-onset antinuclear antibody-positive JIA, 93 (30%) other JIA, 88 (28.4%) enthesitis/spondylitis-related JIA, 17 (5.5%) RF-positive JIA, and 5 (1.6%) unclassified JIA. The other JIA category included 93 patients, consisting of those with oligoarticular JIA (54.8%), RF-negative polyarticular JIA (21.5%), undifferentiated JIA (11.8%), enthesitis-related arthritis (6.5%), and PsA (5.4%) under the ILAR classification system. The provisional PRINTO criteria successfully reclassified a substantial proportion of previously undifferentiated JIA cases, improving diagnostic categorization by addressing some ILAR classification limitations. However, the high number of patients in the other JIA group highlights a potential limitation of the new system, warranting further investigation.
Chronic pain and psychiatric comorbidities in juvenile idiopathic arthritis (JIA) persist even during disease remission, suggesting central nervous system (CNS) alterations. This study used proton magnetic resonance spectroscopy (1H-MRS) to investigate neurometabolic changes in the right hippocampus of JIA patients across active and inactive disease phases. A cohort of 248 JIA patients (61 treatment-naïve patients with active JIA and 187 patients with inactive JIA) and 57 healthy controls (HCs) underwent 1H-MRS of the right hippocampus. Metabolite ratios of total N-acetylaspartate (tNAA), total choline (tCho), myo-inositol (mI), glutamate (Glu), and glutamate-glutamine complex (Glx) relative to total creatine (tCr) were quantified. Associations with systemic inflammation (ESR and CRP) and clinical indices (JADAS-27 and CHAQ) were evaluated. Compared with HCs, both JIA groups showed elevated mI/tCr and reduced Glu/tCr and Glx/tCr in the inactive JIA group (all, P < 0.05). mI/tCr was positively correlated with ESR (rho = 0.269) and CRP (rho = 0.287) in active JIA patients. However, the results did not survive the rigid multiple correction. Notably, tNAA/tCr, tCho/tCr, Glu/tCr and Glx/tCr showed no significant correlations with systemic inflammation and clinical indices for treatment-naïve and inactive JIA patients. Sustained hippocampal neuroinflammation (indicated by elevated mI/tCr) and the subsequent glutamatergic synaptic dysfunction (indicated by reduced Glu/tCr and Glx/tCr) were identified in JIA patients. Peripheral inflammation may drive microglial activation during active disease, highlighting the hippocampus as a vulnerable CNS target in chronic inflammatory states.
JIA affects ∼1-2/2000 children in the UK. Adults with inflammatory arthritis have ∼10% increased malignancy risk. JIA malignancy rates in Nordic data are 3-5/10 000 person years, with conflicting evidence on comparative risk. This study calculated malignancy rates in England of patients with JIA, vs matched controls and general population estimates. Using UK Primary Care data (CPRD) Aurum, this retrospective cohort study matched patients with JIA (diagnosed <16 years) 4-to-1 with non-JIA controls in England by birth year, gender and practice. Malignancies were identified from (i) NHS-linked hospitalization data and (ii) CPRD read codes. Exposure started at first JIA code date (or matched date for controls), 1 January 2000, or CPRD entry date, whichever was latest. Follow-up continued until end of follow-up of JIA-matched patient (for controls), end of CPRD follow-up, 31 December 2018, first malignancy or death, whichever was first. Cox-proportional hazards models compared malignancy rates. Standardized incidence ratios (SIRs) were calculated against ONS general population estimates by calendar year, age and gender. A total of 3714 patients with JIA and 10 858 matched controls were identified; demographics were similar. Malignancy rates were 6.8 per 10 000 (95% CI: 4.4-10.7) in JIA and 3.1 per 10 000 person years (95% CI: 2.0-4.6) in controls; HR 2.2 (95% CI: 1.2-4.1). Both cohorts had raised SIRs compared with ONS general population estimates. This study found that those with JIA had a doubling risk for malignancies compared with the matched control population. However, it is important to note that malignancy in this JIA patient population is extremely rare with the absolute risk remaining very low.
To update the existing European Alliance of Associations for Rheumatology (EULAR) points to consider (PtC) for use of antirheumatic drugs in reproduction, pregnancy, and lactation, including additional drugs and adverse outcomes as well as paternal drug safety. According to the EULAR standardised operating procedures, an international task force (TF) defined the questions for a systematic literature review, followed by formulation of the updated statements. A predefined voting process was applied to each overarching principle and statement. Level of evidence and strength of recommendation were assigned, and participants finally provided their level of agreement for each item. The TF proposes 5 overarching principles and 12 recommendations for the use of antirheumatic drugs before and during pregnancy, through lactation, and in male patients. The current evidence indicates that synthetic disease-modifying antirheumatic drugs (DMARDs) compatible with pregnancy include antimalarials, azathioprine, colchicine, cyclosporine, sulfasalazine, and tacrolimus. Regarding nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, a more restrictive approach to their use during pregnancy is recommended. Based on an individualised risk-benefit assessment, all tumour necrosis factor inhibitor (TNFi) biologic DMARDs (bDMARDs) can be used throughout pregnancy, and non-TNFi bDMARDs may be used if needed. In relation to lactation, compatible drugs include antimalarials, azathioprine, colchicine, cyclosporine, glucocorticoids, intravenous immunoglobulin (IVIG), NSAIDs, sulfasalazine, and tacrolimus. All bDMARDs are considered compatible with breastfeeding. Concerning the use of drugs in men, compatible options include antimalarials, azathioprine, colchicine, cyclosporine, IVIG, leflunomide, methotrexate, mycophenolate, NSAIDs, glucocorticoids, sildenafil, sulfasalazine, tacrolimus, and bDMARDs. The updated recommendations provide consensus guidance and will help to improve the quality of care of patients during the phases of reproduction, pregnancy, and lactation.
We aimed to conduct a meta-analysis of randomized controlled trials (RCTs) to examine the efficacy of biologic DMARDs in improving the clinical response of patients with polyarticular JIA. The literature and relevant reviews were searched for published clinical studies comparing the efficacy of standard therapy without biologic DMARDs to that of biologic DMARDs in patients with polyarticular JIA. The focus was on the minimal clinical effectiveness criteria of the pediatric American College of Rheumatology (pedACR30-100), time to disease flare, remission clinical, inactive disease, and pedACR30/flare. This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. In total, 9 randomized controlled trials were included in the study. Compared with standard therapy, treatment with biologics significantly improved PedACR70 (relative risk [RR] 1.68; 95% confidence interval [CI] 1.43-1.96; p < 0.00001). Similarly, PedACR30 (RR 1.37; CI 1.19-1.58; p < 0.0001), PedACR50 (RR 1.49; CI 1.25-1.77; p < 0.00001), PedACR90 (RR 1.67; CI 1.34-2.09; p < 0.00001) and PedACR100 (RR 1.88; CI 1.05-3.35; p = 0.03) were also significantly improved with biologic treatment. However, patients on standard therapy had worse flare outcomes, as determined by the PedACR30/Flare (RR 0.56; CI 95% 0.45-0.70; p < 0.00001). Additionally, the time to disease flare was significantly shorter with standard therapy (hazard ratio [HR] 0.38; 95% CI 0.27-0.54; p < 0.00001). Compared with standard therapy, biologic DMARDs lead to significant and long-term improvements in signs and symptoms in polyarticular JIA patients. This meta-analysis was registered in PROSPERO under the registration number CRD42023494938 on December 18, 2023.
Rheumatic diseases may impair reproductive success and pregnancy outcomes, but systematic evaluations across diseases are lacking. We conducted a nationwide cohort study to examine the impact of rheumatic diseases on reproductive health measures, comparing the impacts with those of other immune-mediated diseases (IMDs). Out of all of the 5 339 804 Finnish citizens, individuals born 1964-1984 and diagnosed with any of the 19 IMDs before age 30 (women) or 35 (men) were matched with 20 controls by birth year, sex, and education. We used data from nationwide health registers to study the impact of IMDs on reproductive health measures, such as reproductive success and, for women, ever having experienced adverse maternal and perinatal outcomes. Several of the rheumatic diseases, particularly SLE, JIA, and seropositive RA, were associated with higher rates of childlessness and fewer children. The risks for pre-eclampsia, newborns being small for gestational age, preterm delivery, non-elective Caesarean sections, and need of neonatal intensive care were increased in many IMDs. Particularly, SLE, SS, type 1 diabetes, and Addison's disease showed >2-fold risks for some of these outcomes. In most rheumatic diseases, moderate (1.1-1.5-fold) risk increases were observed for diverse adverse pregnancy outcomes, with similar effects in IBD, celiac disease, asthma, ITP, and psoriasis. Rheumatic diseases have a broad impact on reproductive health, with effects comparable with that of several other IMDs. Of the rheumatic diseases, SLE and SS conferred the largest risk increases on perinatal adverse event outcomes.
Live vaccines are generally contraindicated in patients treated with biological agents. However, they are often needed in this patient population. This prospective study aimed to evaluate the immunogenicity and safety of the live attenuated varicella vaccine in patients receiving tumor necrosis factor-alpha (TNF-α) inhibitors. This single-center, prospective study was conducted at the National Center for Child Health and Development and registered with the Japan Registry of Clinical Trials in accordance with the Japanese Clinical Trials Act. Patients receiving TNF-α inhibitors were enrolled. Those with varicella-specific immunoglobulin G (IgG) levels <4.0 who also met predefined criteria of cellular and humoral immunity were eligible. A single dose of the varicella vaccine was administered, and varicella-specific IgG levels were measured before and after vaccination. Participants were monitored for adverse events for up to 6 months following vaccination. Ten pediatric patients (five with juvenile idiopathic arthritis and 5 with inflammatory bowel disease) were enrolled. Of these, 5 achieved seroconversion (defined as a varicella-specific IgG level of 4.0 or more) after a single vaccination (seroconversion rate: 50%). Three patients received a booster vaccination, and 1 subsequently achieved seroconversion. Adverse events were nonspecific, and none were related to the varicella vaccine. The varicella vaccine may be acceptable in patients receiving TNF-α inhibitors. However, due to the small sample size, neither the efficacy nor safety can be definitively established in this pilot study. A larger-scale study is warranted to further evaluate immunogenicity and safety.
Systemic glucocorticoids are commonly used as short-term bridging treatment to control disease activity in juvenile idiopathic arthritis (JIA). This study aimed to analyze the factors affecting the use of systemic glucocorticoid treatment and cumulative dose during the first year after JIA diagnosis. This retrospective study included children who were diagnosed with JIA according to the International League for Rheumatology (ILAR) classification criteria, excluding systemic JIA, and followed up for at least 1 year. All systemic glucocorticoid treatments administered during follow-up were converted to prednisolone-equivalent doses, and the total cumulative dose was calculated for each patient. The study included 164 patients (53% female), of whom 110 (67.1%) received systemic glucocorticoid treatment. Higher baseline Juvenile Arthritis Disease Activity Score-71 (JADAS-71) scores (OR: 1.149, 95% CI: 1.003-1.316, p=0.045) and ankle joint involvement (OR: 5.740, 95% CI: 1.134-29.050, p=0.035) were associated with an increased use of systemic glucocorticoid treatment, while enthesitis-related arthritis (ERA) was associated with a decreased use (OR: 0.132, 95% CI: 0.036-0.487, p=0.002). Ankle involvement (β: 1.434, 95% CI: 0.328-2.539, p=0.012), antinuclear antibody (ANA) positivity (β: 1.232, 95% CI: 0.181-2.283, p=0.022), and higher baseline JADAS-71 scores (β: 0.101, 95% CI: 0.001-0.202, p=0.046) were strongly associated with increased cumulative systemic glucocorticoid dose. To our knowledge, this is the first study to comprehensively evaluate the factors influencing the use of systemic glucocorticoid treatment and cumulative dose in patients with JIA. Our findings emphasize disease subtypes, specific joint involvements, ANA positivity, and disease activities in this regard.