Polyarticular-course juvenile idiopathic arthritis (pcJIA) is a chronic condition that manifests before the age of 16 years, with pathology similar to that of adult rheumatoid arthritis (RA). Sarilumab is an interleukin-6 receptor inhibitor approved for RA and pcJIA. To obtain the approval for pcJIA, a single-arm, multiple-dose phase 2 study was conducted to determine the sarilumab dose for pcJIA. The population pharmacokinetics analysis of the phase 2 dose-finding portion data showed comparable pharmacokinetics; exposure–response analyses demonstrated similar or greater efficacy (JIA-ACR30/50/70), and consistent safety (reduction in absolute neutrophil count) in patients with pcJIA compared with adult patients with RA at similar sarilumab exposure. Based on the adult-to-pediatric extrapolation concept and justifications using modeling and simulation, the phase 2 sample size was increased to generate sufficient efficacy and safety data and evidence at selected doses and the requirement for a randomized controlled study in patients with pcJIA was waived. This novel approach enabled the pcJIA dose proposal by aligning with adult RA exposures, streamlined clinical development by removing the control arm requirement and minimized children participation while ensuring robustness of sarilumab efficacy and safety evidence for approval.

Chimeric antigen receptor (CAR) T cell therapy was recently proposed as a treatment for adults with B-cell-mediated autoimmune diseases (ADs) refractory to conventional immunomodulatory therapy. We present a case series of eight children with severe/refractory AD (four systemic lupus erythematosus, three dermatomyositis, one systemic sclerosis) treated at Ospedale Pediatrico Bambino Gesù, Rome, and University Hospital Erlangen with a single infusion of 1 × 106 kg-1 point-of-care manufactured autologous CD19 CAR T cells (zorpocabtagene autoleucel), in a hospital exemption (HE) program. In Europe, the HE pathway offers the opportunity to treat patients with life-threatening or seriously debilitating disorders who lack valid therapeutic options, using an advanced therapy medicinal product (ATMP) authorized on a nonroutine, single-patient basis. In contrast to the 'compassionate use' pathway, the ATMP does not necessarily need to have undergone clinical trials or marketing authorization applications. Manufacturing was successful in all patients, yielding several drug product bags. Once infused after lymphodepletion, zorpocabtagene autoleucel cells expanded in vivo, promoting prompt B cell clearance. Grade 1 cytokine release syndrome was reported in six patients, and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in one patient. Late-hematotoxicity was limited to grade 1 in two patients. All these adverse events were manageable and no severe infections occurred. With a median follow-up of 16.5 months (range = 9-24 months), all patients experienced a clinically substantial improvement/resolution of AD, as evidenced by reduction in disease activity scores and signs of reversal of organ damage. This improvement enabled sustained discontinuation of immunomodulators, even after B cell reconstitution. The activation of formal clinical trials enrolling children and adolescents is urgently needed to confirm these preliminary results and to assess the long-term safety of this approach.

Anakinra is a recombinant human interleukin-1 receptor antagonist primarily administered by subcutaneous injection for the treatment of autoinflammatory conditions. Intravenous use of anakinra is only sparsely described in the literature. The aim of this study was to assess the safety of intravenous use of anakinra in a cohort of pediatric patients. This is a multicenter, retrospective cohort study. All patients who received intravenous anakinra from January 1st, 2017, to February 29th 2024 were enrolled. Collected data comprised: demographic characteristics, underlying clinical conditions, infusion-related data, anakinra-related adverse events and clinical response. The case series included 113 patients: 64 (56.6

Introduction Haploinsufficiency of A20 (HA20) is a monogenic disease caused by heterozygous TNFAIP3 variants. Despite the marked clinical variability, no genotype–phenotype correlation or validated laboratory biomarkers have been identified so far. Neurobehavioural abnormalities have been reported in murine models, but their prevalence in humans remains unclear.Objectives To describe a cohort of patients with HA20 from two centres, evaluating age-related clinical variability; to assess the prevalence of neuropsychiatric symptoms; to explore the inflammatory profile of the patients, including interferon (IFN)-γ-inducible chemokines (CXCL9/10) and type 1 IFN signature (IS), as well as the therapies administered.Methods Clinical and laboratory data of 17 subjects from six families heterozygous for TNFAIP3 variants (American College of Medical Genetics and Genomics class 4–5) were retrospectively collected. Disease activity, treatments, CXCL9/10 and IS levels were collected. Continuous variables were expressed as medians (IQR). Age at onset was compared using the Kruskal-Wallis test, and groups were compared through the Wilcoxon test or Fisher’s exact test.Results Clinical manifestations included oral aphthosis (88%), recurrent fever (53%), gastrointestinal inflammation (53%), autoimmunity (47%), genital ulcers (47%), neuropsychiatric symptoms (41%), arthritis/tenosynovitis (18%) and skin inflammation (12%). Disease onset before 5 years of age was associated with a higher prevalence of neuropsychiatric symptoms during lifetime (p=0.004), whereas arthritis was more common in patients with later onset. The median age at onset differed significantly according to the type of clinical manifestation (p<0.001). Higher IS levels were found in patients with active disease (p<0.01).Conclusions HA20 shows marked clinical heterogeneity both between and within families. Clinical manifestations appear age-related and early disease onset was associated with increased neuropsychiatric involvement lifetime. Finally, type 1 IS may represent a potential biomarker of disease activity in HA20.

OBJECTIVE:We evaluated the immunogenicity of SARS-CoV-2 mRNA vaccines in patients with juvenile idiopathic arthritis (JIA), focusing on the generation of spike-specific memory B cells (MBCs) and of neutralizing antibodies, and assessed the impact of disease-modifying antirheumatic drugs, particularly tumor necrosis factor inhibitors (TNFi). METHODS:This study enrolled 35 adolescent and young adult patients with JIA. Data concerning disease characteristics and SARS-CoV-2 vaccination and infection were collected. We analyzed the frequency of low-affinity spike-specific and high-affinity spike-specific MBCs by flow cytometry. We measured total anti-spike antibodies levels using a chemiluminescence microparticle immunoassay and assessed neutralizing antibody titers with a microneutralization assay. RESULTS:Patients with JIA showed a reduced frequency of high-affinity MBCs compared to controls, with a notably poorer response among those receiving TNFi treatment. Additionally, their ability to bind the Omicron variant was significantly lower, particularly among TNFi-treated patients. SARS-CoV-2 infection alone was not able to generate high-affinity MBCs and neutralizing antibodies in patients with JIA. After receiving three vaccine doses, 43% of patients with JIA exhibited a reduced frequency of high-affinity MBCs and neutralizing antibodies. CONCLUSION:Patients with JIA undergoing treatment with TNFi demonstrated a diminished immunogenic response to SARS-CoV-2 vaccination, with lower frequencies of high-affinity MBCs and decreased neutralizing antibody titers. These findings underscore the need for customized vaccination protocols, including the potential use of booster doses, to enhance immunoprotection in this group. Additionally, the development of reliable biomarkers to distinguish between patients with and without adequate protective immunity is imperative to refine therapeutic interventions and ensure optimal patient outcomes.

BACKGROUND:Type I interferon-mediated diseases present diagnostic challenges due to heterogeneous clinical manifestations and limitations of current molecular diagnostics, such as the type I interferon score (IS). OBJECTIVES:We sought to evaluate SIGLEC-1 expression on monocytes as a practical biomarker for type I interferon activation. METHODS:We conducted a combined retrospective (n = 47) and prospective (n = 62) study of patients with suspected interferon-mediated diseases. SIGLEC-1 expression was quantified by flow cytometry as mean fluorescence intensity (MFI) and percentage of SIGLEC-1+ monocytes. Analytical robustness was assessed in 52 paired samples comparing whole blood versus PBMCs and 2 cytometers (BD Fortessa vs BD Lyric). Fold-change normalization was evaluated to reduce interinstrument variability. RESULTS:In the retrospective cohort, SIGLEC-1 MFI and percentage of SIGLEC-1+ monocytes strongly correlated with the type I IS (R2 = 0.76; P < .0001), with excellent diagnostic accuracy (area under the curve [AUC] = 0.99 and 0.98). In 11 patients with paired samples (high and low IS), SIGLEC-1 decreased in parallel with the IS. In the prospective cohort, optimized MFI and percentage cutoffs (2307 and 40.65) perfectly discriminated patients with interferonopathies from those with alternative diagnoses (AUC = 1.0). Analytical validation showed that although absolute values differed between PBMCs and whole blood, correlations were strong (R2 > 0.97) and diagnostic classification was maintained. Similarly, Lyric values were lower than Fortessa but remained highly correlated (R2 > 0.93) with stable classification. Fold-change normalization (cutoffs: 4.7 for MFI; 12 for %) minimized platform variability while preserving 100% sensitivity and specificity. CONCLUSIONS:Flow-cytometric SIGLEC-1 is a robust, cost-effective, and reproducible surrogate of type I IS, supporting its implementation for diagnosis, patient stratification, and longitudinal monitoring.

BACKGROUND:Nerve growth factor (NGF) is upregulated in psoriatic skin, and increasing evidence indicates that its receptor, p75 neurotrophin receptor (p75NTR), promotes inflammatory responses. However, the contribution of p75NTR and its ligand, pro-nerve growth factor (proNGF), in psoriasis inflammation remains unclear. OBJECTIVES:To investigate the role of p75NTR in the inflammatory response of skin fibroblasts derived from plaques from patients with psoriasis, to unravel possible novel interactions. METHODS:Plasma levels of proNGF and p75NTR extracellular domain (ECD) were measured in 54 patients with psoriasis and 25 healthy donors (HDs). p75NTR and tropomyosin receptor kinase A expression were evaluated in skin biopsies and dermal fibroblasts from patients with psoriasis and from HDs. Protein–protein interaction (PPI) analysis was used to prioritize potential p75NTR interactors. The effects of cytokines related to psoriasis [interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-22, IL-17A] on receptor expression were examined in skin biopsies and fibroblasts. Pharmacological inhibition of p75NTR with LM11A-31 (p75i) or RNA interference was used to assess effects on intracellular signalling, inflammatory gene expression (IL6, PTGS2, CCL2, CCL20) and molecular interactions using reverse transcription quantitative polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay and proximity ligation assay (PLA). RESULTS:p75NTR expression was increased in the dermal layer of skin biopsies from psoriasis plaques, and plasma levels of p75NTR ECD and proNGF were enhanced in patients with psoriasis and correlated with disease severity. Psoriasis fibroblasts showed high basal p75NTR expression, which was inducible by the cytokine mix (IFN-γ, TNF-α, IL-22, IL-17A) in HD fibroblasts and blocked by LM11A-31. In fibroblasts from HDs and from patients with psoriasis, p75NTR inhibition significantly reduced cytokine-induced inflammatory gene expression and prevented nuclear translocation of nuclear factor-κB. Similar effects were seen after inhibition of Toll-like receptor 4 (TLR4). PPI analysis identified the alarmins high mobility group box 1 (HMGB1) and nucleophosmin as potential connectors between p75NTR and TLR4. These interactions were confirmed by PLA. Treatment with the cytokine mix enhanced p75NTR–TLR4–alarmin interactions, which were prevented by the p75i. Moreover, nucleophosmin and HMGB1 inhibition decreased p75NTR–TLR4 interaction and inflammatory gene expression. In psoriasis fibroblasts, p75NTR inhibition consistently reduced cytokine mix or lipopolysaccharide-induced extracellular release of nucleophosmin and HMGB1. CONCLUSION:p75NTR upregulation and signalling contribute to alarmin release and amplification of the TLR4–NF-κB inflammatory pathway in psoriasis. p75NTR can be considered a sensor of inflammation required for full activation of TLR4-dependent inflammatory signalling. Thus, p75NTR targeting may represent a novel therapeutic strategy to counteract chronic inflammation in psoriasis.

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 < 0.0001). Higher IL-18 levels persisted in patients with active disease (P < 0.0001). Baseline IL-18 >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.

OBJECTIVE:This study assessed sarilumab in treating patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). METHODS:This phase 2b, open-label study (NCT02776735) consisted of three sequential parts (each with a core-treatment and extension phase). During part 1, three doses were assessed in two weight groups (group A/B: ≥30-60 kg/≥10 to <30 kg) to select the optimal dose with regard to pharmacokinetics, safety and efficacy were evaluated in latter parts. During the extension phase of part 1, patients initially assigned to the selected optimal dose continued on this dose; the remaining patients were switched to this selected dose. Patients in parts 2 and 3 received the selected dose from baseline. The primary endpoint was pharmacokinetic exposure (area under the serum concentration versus time curve during a dose interval Շ of 2 weeks [AUC0-Շ], maximum serum concentration observed [Cmax], and concentrations observed before treatment administration during repeated dosing [Ctrough]). Safety and efficacy were assessed. RESULTS:The mean age of treated patients (N = 101; 76.2% female) was 9.4 years. Of the evaluated doses in part 1, dose 2 (group A/B: 3.0/4.0 mg/kg every 2 weeks [q2w]) was selected. In patients receiving the selected dose from baseline (n = 73), Cmax, AUC0-14 days and Ctrough at steady state in group A/B were 27.1/40.4 mg/L, 276/395-day*mg/L, and 9.57/14.4 mg/L, respectively. At week 48, the JIA-American College of Rheumatology 30%, 50%, 70%, and 90% improvement criteria rates were 100%, 100%, 93.8%, and 76.6%, respectively. Adverse events were reported in 70 of 73 patients (95.9%). Twenty-seven patients (37%) experienced grade 3/4 neutropenia; there were no associated infections. No deaths occurred. CONCLUSION:In patients with pcJIA receiving the selected dose from baseline, pharmacokinetic exposure was comparable to a dose of 200 mg q2w for adults with rheumatoid arthritis. Clinically relevant improvements were observed in disease activity, with safety being consistent with the known profile of sarilumab.

BACKGROUND:Juvenile idiopathic arthritis (JIA) is an autoimmune disease that can involve the temporomandibular joint (TMJ). OBJECTIVES:To investigate the association between clinical signs and symptoms of temporomandibular disorders (TMD) and TMJ inflammation, as detected by magnetic resonance imaging (MRI) in children and adolescents with JIA. METHODS:Monocentric cross-sectional observational study. Consecutive JIA patients underwent clinical dental examination following the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and performed MRI examination when the presence of signs and/or symptoms was detected. TMJ involvement was assessed using MRI parameters. Data were analysed with descriptive statistics, using parametric statistical tests for normally distributed data and non-parametric statistical tests for other variables. Associations between TMD signs/symptoms and MRI findings were investigated using appropriate statistical tests. Adjustment for multiple comparisons was performed using a false discovery rate approach. A p-value < 0.05 after correction was considered statistically significant. RESULTS:Seventy-six JIA patients were included. In unadjusted analyses, multiple associations emerged between clinical findings and MRI signs of TMJ involvement. After correction for multiple comparisons, TMJ sounds remained significantly associated with protrusion limitation, and mandibular deviation patterns were significantly associated with inflammatory MRI findings, particularly synovial thickening and bone marrow edema. Other associations did not retain statistical significance after adjustment and should be considered exploratory. CONCLUSIONS:Dental and TMD evaluations revealed correlations with MRI findings of TMJ involvement. Application of TMD screening at JIA onset might make it possible to detect TMJ-related early signs of arthritis in patients with JIA.

OBJECTIVE:Information is limited on the natural history and current treatment patterns in macrophage activation syndrome (MAS), a life-threatening hyperinflammatory syndrome complicating Still's disease (systemic juvenile idiopathic arthritis [sJIA] and adult-onset Still's disease [AOSD]). AMETHYST aimed to describe real-world treatment patterns and outcomes in glucocorticoid (GC)-refractory MAS complicating Still's disease. METHODS:In this retrospective cohort study, medical data from January 1, 2012, to March 31, 2023, were abstracted from charts of all eligible patients across eight sites in Europe, Canada, and the US for index MAS episodes (occurring between January 1, 2012, and September 30, 2022, and meeting eligibility criteria). RESULTS:Overall, 55/64 (86%) included patients had sJIA and 9/64 (14%) had AOSD. Most patients (53/64 [82.8%]) were children at index (median age: 7.0 years). MAS was characterized by rash (60.4%), fever (52.8%), and hepatic involvement (49.1%). All patients received GCs; most were also treated with anakinra (48/64 [75%]) and/or ciclosporin (33/64 [51.6%]). Normalization of 7 (complete MAS laboratory remission) or ≥3 (partial remission) prespecified laboratory parameters occurred in 7/64 (10.9%) and 41/64 (64.1%) patients, respectively. GCs were tapered in 50/64 (78.1%) patients (median: 39.9 days). Per investigator assessment of clinical signs/symptoms for the index MAS episode, 24/64 (37.5%) and 26/64 (40.6%) patients had a complete and partial response, respectively. MAS recurred in 20/64 (31.3%) patients. There were 7/64 (10.9%) deaths; estimated 1-year survival probability was 93.75%. CONCLUSIONS:Low MAS laboratory remission rates and toxicities of high-dose GCs combined with other treatments highlight the need for safer, more effective therapies.

BackgroundProtein biomarkers such as interleukin 18 (IL-18), CXCL9, and the S100A alarmin proteins are increasingly used in the diagnosis and treatment of juvenile idiopathic arthritis (JIA) and Still's Disease (SD). Reported values for these biomarkers vary considerably among different testing platforms at different centers, representing a barrier to their clinical application as well as international research collaborations. We undertook a systematic evaluation of measurement comparability across different platforms in Europe (EU) and North America (NoA).MethodsRecombinant proteins including IL-18, CXCL9, S100A8/9, and S100A12 spiked into donor human serum were distributed in blinded fashion to participating centers in NoA and EU for determination of sample concentration on each center's measurement platform. Assay-specific mathematical correction formulas were calculated based on spike recovery data. Next, samples from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) First-line Options for Systemic JIA Treatment (FROST) study were utilized for validation on selected platforms. Comparisons between measurement platforms before and after mathematical correction were analyzed.ResultsIn the spiked samples, while overall strong correlation was observed for IL-18 measurements across different platforms, the percent recovery revealed significant analytical variation ranging between approximately 50-400%. Similar variation in recovery was also observed for CXCL9, S100A8/9, and S100A12 across different measurement platforms. Analysis of real-world samples from the FROST study revealed strong correlation in IL-18 and CXCL9 values when comparing the same bead-based platforms at two different centers. Significant differences and systematic bias in measurement of FROST samples were uncovered when comparing ELISA or Ella platforms to commercial Luminex platforms. The application of regression-based mathematical correction factors generated from the spike recovery assays could only partly resolve these inter-platform differences.ConclusionsThis is the first systematic analysis of the comparability of biomarker measurements used in JIA and SD across different platforms including ELISA, Luminex, and Ella. We demonstrate substantial differences in the quantification of standardized biomarker concentrations both between assay types and across testing sites. In contrast, analyses of real-world samples from sJIA patients showed high concordance between two independent Ella platforms, indicating that this platform could improve clinical and research standardization.

OBJECTIVE:To assess current treatment in macrophage activation syndrome (MAS) worldwide and to highlight any areas of major heterogeneity of practice. METHODS:A systematic literature search was performed in both EMBASE and PubMed databases. Paper screening was done by two independent teams based on agreed criteria. Data extraction was standardized following the PICO framework. A panel of experts assessed paper validity, using the Joanna Briggs Institute appraisal tools and category of evidence (CoE) according to EULAR procedure. RESULTS:Fifty-seven papers were finally included (80% retrospective case-series), describing 1148 patients with MAS: 889 systemic juvenile idiopathic arthritis (sJIA), 137 systemic lupus erythematosus (SLE), 69 Kawasaki disease (KD) and 53 other rheumatological conditions. Fourteen and 11 studies specified data on MAS associated to SLE and KD, respectively. All papers mentioned glucocorticoids (GCs), mostly methylprednisolone and prednisolone (90%); dexamethasone was used in 7% of patients. Ciclosporin was reported in a wide range of patients according to different cohorts. Anakinra was used in 179 MAS patients, with a favourable outcome in 83% of sJIA-MAS. Etoposide was described by 11 studies, mainly as part of HLH-94/04 protocol. Emapalumab was the only medication tested in a clinical trial in 14 sJIA-MAS, with 93% of MAS remission. Ruxolitinib was the most reported Janus kinase inhibitor in MAS. CONCLUSION:High-dose GCs together with IL-1 and IFNγ inhibitors have shown efficacy in MAS, especially in sJIA-associated MAS. However, the global level of evidence on MAS treatment, especially in other conditions, is still poor and requires standardized studies to be confirmed.