To identify predictors of clinically inactive disease (CID) and clinical remission (CR) in patients with juvenile idiopathic arthritis receiving etanercept during the 2-year, phase 3 b, open-label CLIPPER study (NCT00962741) and the 8-year extension study, CLIPPER2 (NCT01421069). Patients with extended oligoarthritis (2–17 years), enthesitis-related arthritis or psoriatic arthritis (each 12–17 years) were enrolled in CLIPPER/CLIPPER2. Predictors of CID (according to Juvenile Arthritis Disease Activity Score [JADAS] and JIA-ACR response criteria) and CR (≥6 months of CID) were identified using a multivariate stepwise logistic regression model. Two-thirds of patients met the criteria for CID at any point and 34–43% achieved CR. Height Z score >-0.74, age at onset ≤12 years, normal CRP levels, HLA-B27+ status, JADAS low disease activity (LDA) at 3 months, and ≤4 swollen joints were predictive of JADAS CID. BMI Z score >0.80, age at onset ≤12 years, normal CRP levels, and JADAS LDA at 3 months were predictors of JIA-ACR CID. JADAS LDA at 3 months was a predictor of JADAS CR, and height Z score >1.23, JADAS LDA at 3 months, and >12 swollen joints were identified as predictors of JIA-ACR CR. In patients with JIA treated with etanercept, early responses to treatment in line with treat-to-target recommendations, younger age, HLA-B27+ status and lower disease activity at baseline were associated with clinically inactive disease and clinical remission. ClinicalTrials.gov IDs: CLIPPER (NCT00962741); CLIPPER2 (NCT01421069)

BACKGROUND Newborn screening (NBS) for severe combined immunodeficiency (SCID) using T cell receptor excision circles (TREC) in dried blood spots (DBS) has been implemented in the U.S. and many other regions and countries globally. The Clinical Immunology Society (CIS) and the Association of Public Health Laboratories (APHL) jointly formed the SCID Harmonization Initiative to facilitate comparison of NBS reporting practices to promote global consensus and collaboration. OBJECTIVE To assess current NBS SCID practices using a global survey and to report the findings from the Phase 1 component. METHODS An eighteen-question survey was distributed to all known SCID screening programs worldwide. Only one response per region was analyzed. Examples of international screening algorithms were also solicited and included. RESULTS A total of 200 responses were received, of which eighty responses were unique and used for further analysis. Of the 39 non-U.S. countries, 15 (38%) reported national universal screening, and 24 (62%) reported regional, pilot, or other screening. Additional questions pertained to methodology and reporting with particular emphasis on communication of the clinical urgency of an abnormal TREC result. CONCLUSIONS This global survey confirmed that the approach to NBS SCID varies widely, underscoring the need for harmonization at multiple steps, particularly for reporting and interpretation. This is the first study to capture global NBS SCID practices, and these findings provide the basis for creation of a Phase 2 consensus reporting framework, which will be developed by the same SCID Harmonization Committee that created the current study.

To achieve consensus on the definition and clinical approach of Monogenic Inflammatory Immune Dysregulation Disorders (MIIDDs), a collective term for rare conditions marked by inflammation, immune dysregulation, and infection susceptibility. These consensus guidelines specifically apply to pathogenic (or likely pathogenic) gene mutations affecting both innate and adaptive immunity, excluding variants of unknown significance (VUS). A multi-step, evidence-based, multidisciplinary consensus process was employed, consisting of: (1) a systematic literature review across four electronic databases (Cochrane Library, Web of Science, Scopus, and MEDLINE via PubMed), updated through December 31, 2024; (2) a pre-Delphi electronic survey completed by 95 international adult and pediatric immunologists and rheumatologists; and (3) a modified online Delphi process with an international multidisciplinary expert panel, where statements were iteratively analyzed and refined until achieving consensus (≥ 80% agreement among panelists). Fifteen experts from 12 countries participated in two rounds of the Delphi process, resulting in the development of eight overarching principles and 10 consensus statements. These were categorized into five domains: (1) definitions and conceptual framework, (2) diagnostic and monitoring considerations, (3) treatment and therapeutic strategies, (4) multidisciplinary and collaborative care, and (5) patient education and support. This consensus defines MIIDDs and provides a structured clinical framework to streamline research efforts and improve patient outcomes.

Abstract Objectives Two different European Reference Networks cover CTDs with paediatric onset, the European Reference Network on Rare and Complex Connective Tissue Diseases (ERN ReCONNET) and the European Reference Network on Rare Immunological Disorders (ERN RITA). The transition of care is a significant focus, with ReCONNET centres actively addressing this through updated programs. Despite these efforts, challenges persist. We aimed to inventory transitional care programs for rare CTDs across Europe. Methods In April 2023, the ERN ReCONNET Transition of Care Task Force, consisting of expert clinicians, patient advocates and coordination team members, created a survey to assess transitional care practices. The survey was distributed to ERN ReCONNET and ERN RITA centres and responses received by 15 March 2024 were analysed. Results A total of 67 responses from 59 centres across 20 European countries were collected. Paediatric rheumatologists typically initiated the transition process (49% of centres). Twenty centres had joint clinics. Despite positive self-assessments of transitional programs, significant limitations were noted. Transition policies varied, with only 40% of centres having a formal standardized policy and less than half of the centres adhering to available transition of care guidelines. Transfer readiness was evaluated using validated questionnaires in 13% of centres, while 29% transitioned patients based solely on age without any readiness assessments. The main challenges included finding adult-oriented centres and the lack of guidelines or engagement from adult centres. Adult healthcare providers also noted a lack of training in adolescent medicine. Conclusion The survey highlighted diverse transition practices and resources across centres, with challenges in readiness evaluation and the use of guidelines. Despite these obstacles, respondents rated ongoing transition processes positively. Enhancing patient perspectives in the transition process is crucial to meet their needs during this critical phase.

Objectives Childhood-onset systemic lupus erythematosus (cSLE), representing 15%–20% of individuals with SLE, has been difficult to study globally due to differences between registries. This initiative, supported by Childhood Arthritis Rheumatology Research Alliance (CARRA) and Paediatric Rheumatology European Society (PReS), aims to create Core and Expanded cSLE Datasets to standardise and enhance research worldwide. Methods 21 international cSLE experts and 4 patients participated in a Delphi process (questionnaires, 2 topic-specific focus groups and 3 virtual consensus meetings) to create 2 standardised cSLE datasets. The Core cSLE Dataset was designed to include data essential to meaningful clinical research across many settings. The Expanded cSLE Dataset was designed for centres able to consistently collect data to address broader research questions. Final data items for the Core and Expanded datasets were determined by consensus defined as >80% agreement) using an adapted nominal group technique and voting. Results The resulting Core cSLE Dataset contains 46 items, including demographics, clinical features, laboratory results, medications and significant adverse events. The Expanded cSLE Dataset adds 26 additional items and includes patient-reported outcomes. Consensus was also achieved regarding the frequency and time points for data collection: baseline, quarterly follow-up visits, annually and flare visits. Conclusion Standardised Core and Expanded cSLE Datasets for registry-based international cSLE research were defined through the consensus of global experts and patient/caregiver representatives, endorsed by CARRA and PReS. These datasets incorporate disease-specific and patient-specific features, optimised for diverse settings to facilitate international collaborative research for children and adolescents with SLE worldwide.

This is a summary of the original article ‘Ten-year safety and clinical benefit from open label etanercept treatment in children and young adults with juvenile idiopathic arthritis’. Juvenile idiopathic arthritis (JIA) usually appears before the age of 16. JIA causes pain, swelling, and stiffness in the joints. People with JIA receive treatment for several years until the disease goes into prolonged remission. Therefore, the long-term safety of these treatments is an important topic. Etanercept is a treatment for JIA, which acts on the body’s immune system to reduce arthritis. This summary of research article describes safety and how well etanercept works in children with JIA taking it for up to 10 years.

OBJECTIVES (1) characterizing a group of spondyloarthritis (SpA) patients with systemic autoinflammatory symptoms (S-SpA); (2) comparing SpA features with and without autoinflammatory symptoms; (3) comparing the autoinflammatory features of S-SpA and Still's disease (SD). METHODS Retrospective observational study. Clinical data of adult and pediatric patients with S-SpA, SD or SpA were collected retrospectively and analyzed. RESULTS 41 subjects with S-SpA, 39 with SD and 42 with SpA were enrolled. The median latency between systemic and articular manifestations in S-SpA was 4.4 (IQR 7.2) years. S-SpA and SpA had similar frequency of peripheral arthritis and enthesitis (N.S.), while tenosynovitis was more frequent (P=0.01) and uveitis less frequent (P<0.01) in S-SpA. MRI showed signs of sacroiliac inflammation and damage in both S-SpA and SpA equally (N.S.). S-SpA patients had less corner inflammatory lesions (P<0.05) and inflammation at the facet joints (P<0.01), more interspinous enthesitis (P=0.01) and interapophyseal capsulitis (P<0.01). Compared to SD, S-SpA patients had lower-grade fever (P<0.01), less rash (P<0.01) and weight loss (P<0.05), but more pharyngitis (P<0.01), gastrointestinal symptoms (P<0.01) and chest pain (P<0.05). ESR, CRP, WBC, ANC, LDH tested higher in SD (P<0.01). Resolution of systemic symptoms was less frequent in S-SpA than SD on corticosteroid (P<0.01) and methotrexate (P<0.05) treatment. When considering all SD patients, a complete response to corticosteroids in the systemic phase significantly reduced the likelihood of developing SpA (OR=0.06, coefficient -2.87 [CI -5.0 - -0.8]) Conclusions: SpA should be actively investigated in patients with autoinflammatory manifestations, including undifferentiated autoinflammatory disease and SD.

Simple Summary Patients with chronic lymphocytic leukemia (CLL) are more susceptible to infections, which are also the most common cause of death in these patients. Previous studies in patients with CLL described elevated levels of FOXP3+ regulatory T cells (Tregs), which also correlated with decreased T cell responses to microbial antigens. As the activation of the STAT5 transcription factor induces the expression of FOXP3 and human CD4+FOXP3+ T cells that also contain nonsuppressive T cells, we analyzed STAT5 phosphorylation (pSTAT5) and suppressive subpopulations, including activated Tregs (aTregs). We found a significantly increased frequency of aTregs in patients with advanced stages, which significantly correlated with the total tumor mass score. aTreg expansion in vitro was associated with significantly higher aTreg pSTAT5 responses to SARS-CoV-2 antigen-specific stimulation in vitro. Finally, a subgroup of patients characterised by an increased aTreg percentage among CD4+FOXP3+ T cells experienced a more severe disease course with serious grade ≥3 infections during follow-up. Abstract Introduction: Advanced chronic lymphocytic leukemia (CLL) is accompanied by increased circulating regulatory T cells (Tregs) and increased susceptibility to severe infections, which were also shown to entail a striking induction of FOXP3 expression in Tregs. As homeostasis of the most suppressive CD45RA−FOXP3high activated Treg (aTreg) subset differs, it is critical to analyse homeostatic signalling in Treg subsets. Materials and Methods: In this study, by using conventional and imaging flow cytometry, we monitored STAT5 signalling/phosphorylation (pSTAT5) and investigated Treg subsets in relation to the Binet stage, the total tumor mass score (TTM) and the disease course during a follow-up of 37 patients with CLL. Results: The aTreg percentage was significantly increased among CD4+ T cells from patients with advanced disease and significantly correlated with the TTM. A subgroup of patients with higher aTreg percentages among CD4+FOXP3+ T cells at the start of therapy was characterised by more frequent episodes of severe infections during follow-up. Conclusions: The results suggesting that an aTreg fraction could represent a possible marker of a severe disease course with infectious complications. Augmented homeostatic STAT5 signalling could support aTreg expansion, as higher pSTAT5 levels were significantly correlated with an increased aTreg frequency among CD4+FOXP3+ T cells during the follow-up of patients on therapy, as well as following SARS-CoV-2 antigen-specific stimulation in vitro.

The 2023 American College of Rheumatology/EULAR antiphospholipid syndrome (APS) classification criteria development, which aimed to identify patients with high likelihood of APS for research, employed a four‐phase methodology. Phase I and II resulted in 27 proposed candidate criteria, which are organized into laboratory and clinical domains. Here, we summarize the last stage of phase III efforts, employing a consensus‐based multicriteria decision analysis (MCDA) to weigh candidate criteria and identify an APS classification threshold score.

Paediatric patients with autoimmune rheumatic diseases (pARD) have a dysregulated immune system, so infections present a major threat to them. To prevent severe COVID-19 infections we aimed to vaccinate them as soon as possible. Studies have shown that the BNT162b2 vaccine is safe, effective, and immunogenic, however, in a short observation period, only. The main objective was to compare the serological response between three groups of pARD: after SARS-CoV-2 infection, after vaccination against COVID-19 with two doses of the BNT162b2 vaccine, and after experiencing both events. Data on demographics, diagnosis, therapy, and serology (anti-SARS-CoV-2 IgG/IgA) were collected from March 2020 to April 2022. For statistical analysis ANOVA, Mann-Whitney U test, Chi-square test and Fisher’s exact test were applied. To compare adverse events (AE) after vaccination we included a control group of healthy adolescents. We collected data from 115 pARD; from 92 after infection and 47 after vaccination. Twenty-four were included in both groups. Serological data were available for 47 pARD after infection, 25 after vaccination, and 21 after both events. Serological response was better after vaccination and after both events compared to after infection only. No effect of medication on the antibody levels was noted. The safety profile of the vaccine was good. Systemic AE after the first dose of the vaccine were more common in healthy adolescents compared to pARD. In the observation period of 41.3 weeks, 60% of vaccinated pARD did not experience a symptomatic COVID-19 infection. IgG and IgA anti-SARS-CoV-2 levels were higher after vaccination and after both events compared to after infection only. Six months after vaccination we observed an increase in antibody levels, suggesting that pARD had been exposed to SARS-CoV-2 but remained asymptomatic. The study was approved by the Medical Ethics Committee of the Republic of Slovenia (document number: 0120–485/2021/6).