OBJECTIVE:The 2023 American College of Rheumatology (ACR)/EULAR antiphospholipid syndrome (APS) classification criteria aim to identify patients with a high likelihood of APS for research. Phases I/II of our four-phase methodologic approach resulted in 27 candidate criteria organized in clinical and laboratory domains. Here, we summarize phase III efforts to reduce and refine criteria using patient scenarios. METHODS:Using standardized definitions for candidate criteria, the Steering Committee collected antiphospholipid antibody (aPL)-positive cases referred for "suspected APS." Treating physicians assessed APS case likelihood using a Likert scale. Poisson regression calculated risk ratios (RRs) and 95% confidence intervals (CIs) to quantify the direction and size of the association of candidate criteria with "highly likely" versus "equivocal or unlikely" APS, which guided Steering Committee candidate criteria refinement and organization. RESULTS:We collected 314 suspected APS cases (137 [44%] highly likely and 177 [56%] equivocal/unlikely APS). Provoking venous thromboembolism (VTE) or arterial thrombosis (AT) risk factors reduced the size of the association with highly likely APS (RR 4.31 [95% CI 2.11-8.78] to RR 1.56 [95% CI 0.89-2.75] for VTE and RR 3.48 [95% CI 1.91-6.32] to RR 1.64 [95% CI 0.77-3.51] for AT). Persistent lupus anticoagulant, anticardiolipin IgG antibody ≥40 U, and anti-β2-glycoprotein-I IgG antibody ≥40 U were positively associated with highly likely APS (all P < 0.05). Eventually, items within eight additive and independent clinical and laboratory domains were refined. CONCLUSION:Referred suspected APS cases provided insight into associations of individual candidate criteria with APS likelihood. RR analyses helped refine items and organize the draft classification system into eight additive and independent clinical and laboratory domains.

Gamma delta (γδ) T cells exhibit unique antiviral, antibacterial, and antitumor properties. Advancing the fundamental understanding of γδ T cell immunobiology and unlocking their full therapeutic potential requires detailed immunophenotypic profiling alongside optimized strategies for ex vivo activation and expansion. In this review, we synthesize current knowledge of γδ T cell immunobiology, emphasizing (i) comprehensive phenotypic characterization using flow cytometry and (ii) emerging approaches for their therapeutic implementation, with a focus on activation and ex vivo expansion methods. By integrating insights from phenotypic analysis with a comparative evaluation of expansion techniques, we provide an overview of γδ T cell immunobiology and their translational potential in immunotherapy.

Objectives:Clinical trial data are lacking for treatment of patients with juvenile systemic sclerosis (jSSc). Three published recommendations exist for jSSc but real-world data on treatment patterns are lacking. The aim of this study was to analyse treatments used in the jSSc inception cohort (jSSci) and compare to published recommendations on the treatment of jSSc. Methods:Data was extracted for patients with 24 months follow-up visits in the jSSci up until June 2023. Medications used and their association with clinical characteristics were analysed. Logistic regression analyses were performed to compare treatments between limited and diffuse cutaneous jSSc subtypes, organ involvement and time of initiation of treatment. Multilevel mixed effects logistic regression analyses were used to evaluate the change in medication use in follow-up. Treatment patterns were compared against published recommendations. Results:93 patients had 24 months follow-up data. 77% of patients were receiving disease-modifying treatment (DMARD) at enrolment, which increased to 91% at 24 months (p<0.001). Patients with diffuse cutaneous jSSc subtype had significantly more frequently active ulcerations, skin involvement and received any kind of treatment more often compared with limited (97% vs 91%, p=0.047). Methotrexate was used in 52% of patients at enrolment which decreased to 37% at 24 months (p=0.001). Mycophenolate mofetil use increased from 24% to 46% (p<0.001). Biological DMARDs increased from 5% to 22% (p<0.001). The treatment pattern strongly overlapped with the published paediatric guidance. Conclusion:This is the first report regarding the pattern of medication use in real life in the currently largest patient cohort of patients with jSSc. The observed pattern overlaps with the published recommendations.

BACKGROUND:Newborn screening (NBS) for severe combined immunodeficiency (SCID) using T-cell receptor excision circles in dried blood spots has been implemented in the United States and many other regions and countries globally. The Clinical Immunology Society and the Association of Public Health Laboratories 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 18-question survey was distributed to all known SCID screening programs worldwide. Only 1 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 80 responses were unique and used for further analysis. Of the 39 non-US 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 T-cell receptor excision circle 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.

OBJECTIVES: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 3b, open-label CLIPPER study (NCT00962741) and the 8-year extension study, CLIPPER2 (NCT01421069). METHODS: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. RESULTS: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. CONCLUSION: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. TRIAL REGISTRATION:ClinicalTrials.gov IDs: CLIPPER (NCT00962741); CLIPPER2 (NCT01421069).

Background:Anakinra, an interleukin-1 receptor antagonist (IL-1 Ra), is a treatment option for recurrent pericarditis refractory to conventional therapy. However, some patients cannot discontinue anakinra treatment without relapse. This is of particular concern for women of childbearing age, as data on its safety during pregnancy and lactation is limited. Case summary:We report the case of a 36-year-old White woman with recurrent pericarditis of an inflammatory phenotype. Pericardial biopsy revealed virus-negative fibro-productive pericarditis, and genetic testing showed no identifiable cause. Despite treatment with non-steroidal anti-inflammatory drugs, colchicine, and corticosteroids, the patient experienced multiple recurrences and developed corticosteroid-related side effects. Introduction of anakinra resulted in immediate clinical improvement and allowed corticosteroid withdrawal. However, several attempts to discontinue anakinra led to pericarditis recurrences. The patient tested positive for neutralizing anti-IL-1Ra antibodies. During the stable phase of the disease, as confirmed by cardiac magnetic resonance imaging, and while on anakinra and colchicine, she conceived spontaneously. She maintained anakinra treatment throughout the full-term pregnancy and breastfeeding, with no impact on foetal or child development. Discussion:Our paper provides evidence supporting the safe use of anakinra in pregnancy and lactation in a patient with recurrent pericarditis. It also reports the first case of anti-IL-1Ra antibodies in a patient receiving anakinra for recurrent pericarditis, which may help explain the dependency on the medication. The potential role of these antibodies as biomarkers for anakinra dependency or tools for optimizing immunosuppressive treatment warrants further research. A patient-centred counselling and a multidisciplinary approach are essential for achieving optimal outcomes.

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

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.

Objective: To evaluate safety, long-term effectiveness and immunogenicity of varicella vaccination in children with JIA, treated with biologic disease-modifying antirheumatic drugs (bDMARDs). Methods: This is a prospective case-control study. VZV-naive patients with JIA on selected bDMARDs (TNFi, IL-6 and IL-1 inhibitors), who were at risk for contracting varicella, had stable disease and normal values of immunoglobulins and lymphocyte populations, were vaccinated against varicella. Adverse events (AEs) and disease activity were followed after vaccination. VZV-specific humoral (VZV-IgG) and cell-mediated immunity (VZV-CMI) were measured at predetermined time points after vaccination by Liaison and intracellular cytokine staining, respectively. Two healthy control (HC) groups comprised 52 healthy children after varicella vaccination and 69 healthy children after varicella infection. Results: 17 patients were vaccinated against varicella (12 on TNFi, 4 on IL-6 inhibitors and 1 on IL-1 inhibitor), of whom 14 patients received both the first and second dose on bDMARDs. No vaccine-strain infections or other serious AEs occurred after vaccination. Disease activity increased in 3/17 (18 %) patients following vaccination. Four out of 17 (24 %) patients developed mild breakthrough varicella (BV) 4 months-4.5 years after vaccination, and none of the HC. Fourteen out of 17 (82 %) patients and 50/52 (96 %) vaccinated HC were seropositive after second vaccination and 8/11 (72 %) patients and 42/43 (98 %) vaccinated HC developed VZV-CMI, which persisted longer compared to VZV-IgG. Patients presented lower antibody levels compared to HC. The rate of VZV-IgG decline was comparable between patients and HC after vaccination or infection. Five patients received the third vaccine dose due to primary or secondary vaccine failure, and none of them developed BV. Conclusions: Varicella vaccination was safe and largely immunogenic in our cohort of JIA patients treated with bDMARDs. Although the vaccination was not always fully effective, it prevented severe disease in all vaccinated patients.

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:To develop and validate a European Alliance of Associations for Rheumatology (EULAR) disease activity score in antiphospholipid syndrome (EAPSDAS). METHODS:Twenty-four Task Force members and an international group of 53 antiphospholipid syndrome (APS) experts/collaborators, 65 patients with primary APS, and 21 healthcare professionals participated. EAPSDAS development proceeded in 4 phases: (i) item generation using a systematic literature review and 2 surveys; (ii) item reduction by rating items on their importance to be included in EAPSDAS and using Delphi methodology; (iii) item scoring based on real-world clinical vignettes and using as criterion standard the physician global assessment (PhysGA); and (iv) validation. RESULTS:One hundred seventy items representing APS activity were generated, and 140 deduplicated candidate items were rated by participants. Using a ≥75% vote threshold and Delphi consensus among Task Force members, 24 items were included in the EAPSDAS thrombotic/microvascular/nonthrombotic (TMN) scale and 6 in the obstetric scale. Item scoring was based on ratings of 3 versions of 60 vignettes with new/worsening manifestations (30 single TMN or obstetric manifestations, 26 combinations of 2 TMN manifestations, 2 inactive cases, 2 testing cases) by physicians. Item scores were calculated as the adjusted mean PhysGA in linear regression analysis. A 1-month time frame was defined for the TMN scale and the entire pregnancy for the obstetric scale. Scores for stable or improved TMN manifestations were also included. High face and content validity, construct validity (internal/external standard), and reliability were demonstrated using real-world clinical vignettes. CONCLUSIONS:Using data-driven and consensus methodology, EAPSDAS was developed and initial validation was performed. Further validation in prospective studies is warranted.

An international multi-disciplinary initiative resulted in the development of 2023 ACR/EULAR Antiphospholipid Syndrome (APS) Classification Criteria to identify patients with high likelihood of APS for research. Phase I/II resulted in 27 candidate criteria organized into six clinical and laboratory domains. Here, we summarize early Phase III efforts to better define and structure candidate criteria within clinical and laboratory domains. Using comprehensive literature reviews and expert consensus, domain subcommittees developed definitions for candidate criteria. Prevalence information was incorporated when available. Definitions were finalized and approved by the Steering Committee for future use during real-world case collection (derivation cohort), multi-criteria decision analysis, and validation. Clinical domain items defined were: (a) macrovascular thrombosis (venous thromboembolism including superficial venous thrombosis, arterial thrombosis, and transient ischemic attack) and associated provoking risk factors; (b) microvascular disease (livedo racemosa, livedoid vasculopathy, antiphospholipid-antibody-nephropathy, diffuse alveolar hemorrhage, cardiac microthrombosis, adrenal hemorrhage, and acute ischemic encephalopathy); (c) pregnancy morbidity (pre-fetal death, fetal death, and pre-eclampsia and placental insufficiency with severe features); (d) cardiac valve disease (thickening or vegetation); and (e) thrombocytopenia. Laboratory domain items defined were coagulation-based functional assay (lupus anticoagulant) and solid phase-based assays (anticardiolipin antibody IgG/M and anti-β2-Glycoportein-I antibody IgG/M). Based on comprehensive literature review and Steering Committee consensus, we defined and structured APS clinical and laboratory domains. Preliminary definitions were subsequently evaluated and confirmed in late Phase III using the derivation cohort and multicriteria decision analysis prior to validation the 2023 ACR/EULAR APS Classification Criteria.