Mariana Correia Marques

Objective: The objective of this study was to characterize the clinical, immunologic, and synovial tissue features of a patient with a systemic juvenile idiopathic arthritis (sJIA) who carries a novel heterozygous STAT5B loss‐of‐function variant (p.Gln139Ter) and whose arthritis responded markedly to interleukin‐17A (IL‐17A) inhibition. Methods: Patient blood was compared with blood from healthy donors (n = 5) for immunoblotting, phospho‐flow cytometry and immune cell profiling. Patient synovial fluid was compared with synovial fluid from seronegative oligoarticular or polyarticular juvenile idiopathic arthritis (oligo/poly JIA) (n = 5–6) for immune cell profiling. Patient synovial tissue was compared with synovial tissue from children with oligo/poly JIA (n = 11) using Xenium spatial transcriptomics. Results: CD4 ⁺ T cells from the patient exhibited impaired STAT5 phosphorylation ( z score = ‐11.1). Synovial fluid CD4 ⁺ T cells showed markedly increased IL‐17A production (z score = 34.5) and reduced FOXP3 expression ( z score = ‐2.25) in regulatory T cells. Spatial transcriptomics revealed T helper 17 (Th17) cells distributed diffusely throughout the patient's synovium, in contrast to JIA controls in which Th17 cells were largely restricted to tertiary lymphoid structures (TLS) ( z score = 3.08). The patient's severe arthritis, previously refractory to IL‐1 and IL‐6 blockade, improved markedly after IL‐17A inhibition. Conclusion: STAT5B haploinsufficiency may contribute to an sJIA phenotype characterized by Th17/IL‐17 dysregulation and an altered distribution of Th17 cells outside TLS. Integrated genetic, functional, and spatial tissue analyses may help identify therapeutic targets in refractory pediatric arthritis.

Objective: To evaluate the relationship across type I interferon (IFN‐I)–stimulated gene (ISG) expression, Still disease, and the development of lung disease (LD) and drug‐associated immune reactions (DAIR) to interleukin‐1 (IL‐1) and/or IL‐6 inhibitors. Methods: Whole blood ISG expression was quantified by NanoString array. ISG‐28 scores were calculated in consecutive patients with Still or Still‐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 is associated with LD and DAIR with high specificity, whereas absence of both biomarkers had high negative predictive value. Candidate genes from high ISG‐28 individuals were enriched in IFN‐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 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 disease with IFN‐I signature.

Objective: Lung disease (LD) in systemic juvenile idiopathic arthritis and adult-onset Still disease (Still-LD) is a severe manifestation strongly associated with HLA-DRB1*15 alleles and drug-associated immune reactions (DAIR), including eosinophilia, non–Still disease rashes, and elevated liver function tests. Despite the high morbidity and mortality of these phenomena, pathogenesis remains poorly understood. This study investigates whether Still-LD and DAIR are associated with pathogenic antigens through hypersensitivity reactions to Aspergillus fumigatus , for which HLA-DRB1*15 is a known risk allele, or drug reaction with eosinophilia and systemic symptoms (DRESS), which is frequently associated with human herpesvirus (HHV) reactivation. Methods: Pediatric and adult subjects were drawn from the National Institutes of Health Still disease cohort. Subjects with Still-LD and/or DAIR were identified by chart review. Serum samples were analyzed for anti– A. fumigatus IgE using ImmunoCap assay, and Epstein-Barr virus (EBV), cytomegalovirus (CMV), and HHV 6 (HHV-6) antibodies were analyzed by luciferase immunoprecipitation systems. Subjects were screened for EBV, CMV, and HHV-6 by nucleic acid amplification tests and/or Viral Transcript Usage Sensor (VIRTUS) analysis of whole-blood RNA sequencing data. Results: Fifty-four subjects were included in the study, 11 had LD and DAIR, and 8 had DAIR alone. Thirty-three subjects were tested for anti– A. fumigatus antibodies and all were negative. Forty-nine subjects were tested for CMV, EBV, and HHV-6; 2 were positive for EBV, both of whom did not have Still-LD or DAIR. Conclusion: The absence of anti– A. fumigatus IgE antibodies and detectable herpesvirus nucleic acids in subjects with Still-LD and DAIR does not support a mechanistic association with hypersensitivity to A. fumigatus or with HHV reactivation.

Objective: Multinational research is essential to improve recognition and management of systemic juvenile idiopathic arthritis (sJIA). Current cohorts vary in the clinical variables and outcome measures collected. Adult-onset Still disease (AOSD) and sJIA are widely considered to comprise a single disease spectrum; however, classification criteria and clinical tools differ between groups. This systematic literature review aimed to identify clinical features and outcome measures collected across sJIA and AOSD cohorts worldwide to guide the development of a minimal dataset for Still disease. Methods: A literature search was conducted from 2000 to 2024 using Ovid MEDLINE, Embase, and Wiley Cochrane Library (Trials). Included articles were in English and described sJIA or AOSD cohorts of ≥ 20 patients, reporting patient characteristics, clinical and laboratory features, and outcome measures. Results: A total of 240 articles were included (95 sJIA, 134 AOSD, 11 mixed), from 37 countries, describing 23,136 patients. International League of Associations for Rheumatology classification was used in 77.9% of sJIA studies, whereas 98.5% of AOSD studies used Yamaguchi criteria. There was no clear consensus on the definition of macrophage activation syndrome. Race and ethnicity were only reported in 11.7% of articles. Cohorts evaluated aligned on the most commonly collected laboratory items for both AOSD and sJIA, with some agreement among clinical features, whereas disease outcome measures used to evaluate and follow disease trajectory were variable. Conclusion: Data reporting across sJIA and AOSD cohorts for clinical characteristics and outcome measures is widely heterogeneous. Consensus on the identification of a standardized minimal dataset for Still disease cohorts is needed to foster future collaboration and improve patient outcomes.

Objective: Our objective was to evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH)‐associated genes among patients with systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS).Methods: Targeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in patients with sJIA from an established cohort. Sequence data from control participants were obtained in silico (database of Genotypes and Phenotypes: phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test package. Significance was defined as P < 0.05 after 100,000 permutations.Results: Sequencing data from 524 sJIA cases were jointly called and harmonized with exome‐derived target data from 3,000 controls. Quality control operations produced a set of 480 cases and 2,924 ancestrally matched control participants. RVT of cases and controls revealed a significant association with rare protein‐altering variants (minor allele frequency [MAF] < 0.01) of STXBP2 (P = 0.020) and ultrarare variants (MAF < 0.001) of STXBP2 (P = 0.006) and UNC13D (P = 0.046). A subanalysis of 32 cases with known MAS and 90 without revealed a significant difference in the distribution of rare UNC13D variants (P = 0.0047) between the groups. Additionally, patients with sJIA more often carried two or more HLH variants than did controls (P = 0.007), driven largely by digenic combinations involving LYST.Conclusion: We identified an enrichment of rare HLH variants in patients with sJIA compared with controls, driven by STXBP2 and UNC13D. Biallelic variation in HLH genes was associated with sJIA, driven by LYST. Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS. image

Objective: To evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH) genes and systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS). Methods: Targeted sequencing of HLH genes ( LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D ) was performed in sJIA subjects from an established cohort. Sequence data from control subjects were obtained in silico (dbGaP:phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test (SKAT) package. Significance was defined as pSTXBP2 (p=0.020), and ultra-rare variants (MAFSTXBP2 (p=0.007) and UNC13D (p=0.045). A subanalysis of 32 cases with known MAS and 90 without revealed significant association of rare UNC13D variants (p=0.0047). Additionally, sJIA patients more often carried ≥2 HLH variants than did controls (p=0.007), driven largely by digenic combinations involving LYST . Conclusion: We identified an enrichment of rare HLH variants in sJIA patients compared with healthy controls, driven by STXBP2 and UNC13D . Biallelic variation in HLH genes was associated with sJIA, driven by LYST . Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.

Patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD) have been under-represented in studies about safety of the COVID-19 immunization. We aimed to inquire about the safety and tolerability of COVID-19 immunization in this population. An anonymous online survey on closed Facebook groups for patients and parents with self-reported sJIA/AOSD was posted from June 27th until August 30th, 2022. Continuous variables were analyzed using t-tests or the Mann-Whitney U test if non-normally distributed. Fisher`s tests were used for categorical variables. Of a total of 167 responses, 17 were excluded. Ninety-nine patients received the COVID-19 immunization, and 51 patients did not. Patients in both immunized and unimmunized groups had a similar history of disease complications such as macrophage activation syndrome (50% vs. 49%), lung disease (17% vs. 29%), arthritis (51% vs. 50%), and pericarditis/myocarditis (10% vs. 8%). Unimmunized patients were younger (median age 8 yo vs. 12 yo, p < 0.001) and had a higher incidence of a history of disease flare or severe side effects with other immunizations (24% vs. 4%, p < 0.001). Thirty-nine patients reported mostly mild immunization side effects. Severe side effects included 6 reports of disease flare and 2 reports of cardiac side effects (pericarditis and atrial fibrillation). Seven patients reported side effects lasting ≥ 8 days. Three patients developed AOSD following COVID-19 immunization, and 2 of them had the only hospital admissions for immunization side effects. Regarding COVID-19 infection, 46 patients were infected without full immunization, and 33 were infected after 2 doses of immunization. There was one hospitalization in the immunized group, compared to one ICU admission leading to death in the non-immunized group. There was a trend (p > 0.05) toward a higher risk of disease flare after COVID-19 infection among non-immunized patients (43%), compared to immunized patients (24%). The COVID-19 immunization was well tolerated by sJIA/AOSD patients even in this group of patients with severe disease. There was a low incidence of disease flare with immunization. Most immunization side effects were mild and lasted < 7 days. The only ICU admission and death from COVID-19 infection occurred in unimmunized subjects.

Objective: Patients with undefined systemic autoinflammatory diseases (uSAIDs) are challenging to manage, as there are no guidelines or recommendations for targeted therapy. We aimed to evaluate the efficacy of empiric treatment with colchicine in our single-center uSAID population in the United States, as well as the patient characteristics associated with the most robust colchicine response. Methods: Children with uSAID 18 years old at initial evaluation during 2000-2019 were included if they received 3 months of colchicine therapy. Data on demographics, clinical features, laboratory/ genetic studies, and treatment responses were collected. Most statistics were based on chi-square analyses for categorical data. Complete response to colchicine was defined as resolution of episodes or the presence of minor residual symptoms that did not require any further therapy. A partial response was defined as a decrease in the frequency, severity, or length of episodes but still necessitating additional therapy. Patients were considered nonresponders if they did not experience any improvement with colchicine at target therapeutic dosing. Results: We identified 133 children diagnosed with uSAID who met our inclusion criteria. The median time to starting empiric colchicine was 5 months from the diagnosis of autoinflammatory disease. 92.5% (n = 123) of patients had a beneficial response to colchicine, including 46.6% (n = 62) partial responders and 45.9% (n = 61) complete responders. The presence of a nonurticarial rash was associated with an incomplete colchicine response (29.2% (n = 21) vs 13.1% (n = 8), P = .025). The presence of a heterozygous MEFV mutation in patients who did not fit Familial Mediterranean Fever diagnostic criteria (n = 25) appeared to be associated with a greater likelihood of complete colchicine response, although this was not statistically significant (62.5% (n = 14) vs 42.6% (n =11), P = .08). In MEFV mutation-negative patients, a nonurticarial rash was even more strongly associated with incomplete colchicine response, with an OR of 27.53 (CI [1.59-477], P = .023). The presence of oral ulcers also corresponded to incomplete colchicine response, although this did not reach clinical significance (38.9% (n = 28) vs 24.6% (n = 15), P = .08). There was no significant association between episode duration or frequency and colchicine response. Conclusion: Colchicine leads to clinical benefits in most children with uSAID. We, thus, recommend an early trial of colchicine in newly diagnosed patients with uSAID. Cite this article as: Marques MC, Egeli BH, Wobma H, et al. Features predicting colchicine efficacy in treatment of children with undefined systemic autoinflammatory disease: A retrospective cohort study. Eur J Rheumatol. 2022;9(3):116-121