Type I interferon associated epistasis may contribute to early disease-onset and high disease activity in juvenile-onset lupus.

Pathologic type I interferon (T1IFN) expression is a key feature in systemic lupus erythematosus (SLE) that associates with disease activity. When compared to adult-onset disease, juvenile-onset (j)SLE is characterized by increased disease activity and damage, which likely relates to increased genetic burden. To identify T1IFN-associated gene polymorphisms (TLR7, IRAK1, miR-3142/miR-146a, IRF5, IRF7, IFIH1, IRF8, TYK2, STAT4), identify long-range linkage disequilibrium and gene:gene interrelations, 319 jSLE patients were genotyped using panel sequencing. Coupling phenotypic quantitative trait loci (QTL) analysis identified 10 jSLE QTL that associated with young age at onset (<12 years; IRAK1 [rs1059702], TLR7 [rs3853839], IFIH1 [rs11891191, rs1990760, rs3747517], STAT4 [rs3021866], TYK2 [rs280501], IRF8 [rs1568391, rs6638]), global disease activity (SLEDAI-2 K >10; IFIH1 [rs1990760], STAT4 [rs3021866], IRF8 [rs903202, rs1568391, rs6638]), and mucocutaneous involvement (TLR7 [rs3853839], IFIH1 [rs11891191, rs1990760]). This study suggests T1IFN-associated polymorphisms and gene:gene interrelations in jSLE. Genotyping of jSLE patients may allow for individualized treatment and care.

Development of CARRA/PReS-endorsed consensus Core and Expanded Datasets in childhood-onset systemic lupus erythematosus for international registry-based research.

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.

P2RX7 gene variants associate with altered inflammasome assembly and reduced pyroptosis in chronic nonbacterial osteomyelitis (CNO).

Chronic nonbacterial osteomyelitis (CNO), an autoinflammatory bone disease primarily affecting children, can cause pain, hyperostosis and fractures, affecting quality-of-life and psychomotor development. This study investigated CNO-associated variants in P2RX7, encoding for the ATP-dependent trans-membrane K+ channel P2X7, and their effects on NLRP3 inflammasome assembly. Whole exome sequencing in two related transgenerational CNO patients, and target sequencing of P2RX7 in a large CNO cohort (N = 190) were conducted. Results were compared with publicly available datasets and regional controls (N = 1873). Findings were integrated with demographic and clinical data. Patient-derived monocytes and genetically modified THP-1 cells were used to investigate potassium flux, inflammasome assembly, pyroptosis, and cytokine release. Rare presumably damaging P2RX7 variants were identified in two related CNO patients. Targeted P2RX7 sequencing identified 62 CNO patients with rare variants (32.4%), 11 of which (5.8%) carried presumably damaging variants (MAF <1%, SIFT "deleterious", Polyphen "probably damaging", CADD >20). This compared to 83 of 1873 controls (4.4%), 36 with rare and presumably damaging variants (1.9%). Across the CNO cohort, rare variants unique to one (Median: 42 versus 3.7) or more (≤11 patients) participants were over-represented when compared to 190 randomly selected controls. Patients with rare damaging variants more frequently experienced gastrointestinal symptoms and lymphadenopathy while having less spinal, joint and skin involvement (psoriasis). Monocyte-derived macrophages from patients, and genetically modified THP-1-derived macrophages reconstituted with CNO-associated P2RX7 variants exhibited altered potassium flux, inflammasome assembly, IL-1ß and IL-18 release, and pyroptosis. Damaging P2RX7 variants occur in a small subset of CNO patients, and rare P2RX7 variants may represent a CNO risk factor. Observations argue for inflammasome inhibition and/or cytokine blockade and may allow future patient stratification and individualized care.

Hypertonic saline induces inflammation in human macrophages through the NLRP1 inflammasome.

Nebulized hypertonic saline (3-7%) is commonly used to increase mucociliary clearance in patients with chronic airway disease and/or virus infections. However, altered salt concentrations may contribute to inflammatory responses. The aim of this study was to investigate whether 500 mM NaCl (3%) triggers inflammation in human macrophages and identify the molecular mechanisms involved. NaCl-induced pyroptosis, IL-1ß, IL-18 and ASC speck release were measured in primary human monocyte-derived macrophages. Treatment with the recombinant IL-1 receptor antagonist anakinra or the NLRP3 inhibitor MCC950 did not affect NaCl-mediated inflammasome assembly. Knock-down of NLRP1 expression, but not of NLRP3 and NLRC4, reduced NaCl-induced pyroptosis, pro-inflammatory cytokine and ASC speck release from human THP-1-derived macrophages. Data from this study suggest that 3% NaCl-induced inflammatory responses in human macrophages depend on NLRP1 and inflammasome assembly. Targeting inflammation in addition to inhalation with hypertonic saline may benefit patients with inflammatory airway disease.

cAMP responsive element modulator α promotes effector T cells in systemic autoimmune diseases.

T lymphocytes play a crucial role in adaptive immunity. Dysregulation of T cell-derived inflammatory cytokine expression and loss of self-tolerance promote inflammation and tissue damage in several autoimmune/inflammatory diseases, including systemic lupus erythematosus (SLE) and psoriasis. The transcription factor cAMP responsive element modulator α (CREMα) plays a key role in the regulation of T cell homeostasis. Increased expression of CREMα is a hallmark of the T cell-mediated inflammatory diseases SLE and psoriasis. Notably, CREMα regulates the expression of effector molecules through trans-regulation and/or the co-recruitment of epigenetic modifiers, including DNA methyltransferases (DNMT3a), histone-methyltransferases (G9a) and histone acetyltransferases (p300). Thus, CREMα may be used as a biomarker for disease activity and/or target for future targeted therapeutic interventions.

Altered DNA methylation and gene expression predict disease severity in patients with Aicardi-Goutières syndrome.

Aicardi-Goutières Syndrome (AGS) is a rare neuro-inflammatory disease characterized by increased expression of interferon-stimulated genes (ISGs). Disease-causing mutations are present in genes associated with innate antiviral responses. Disease presentation and severity vary, even between patients with identical mutations from the same family. This study investigated DNA methylation signatures in PBMCs to understand phenotypic heterogeneity in AGS patients with mutations in RNASEH2B. AGS patients presented hypomethylation of ISGs and differential methylation patterns (DMPs) in genes involved in "neutrophil and platelet activation". Patients with "mild" phenotypes exhibited DMPs in genes involved in "DNA damage and repair", whereas patients with "severe" phenotypes had DMPs in "cell fate commitment" and "organ development" associated genes. DMPs in two ISGs (IFI44L, RSAD2) associated with increased gene expression in patients with "severe" when compared to "mild" phenotypes. In conclusion, altered DNA methylation and ISG expression as biomarkers and potential future treatment targets in AGS.

Current views on lupus in children.

PURPOSE OF REVIEW: This manuscript provides an update on clinical and pathophysiological features of juvenile-onset systemic lupus erythematosis (jSLE), challenges applying adult-derived classification criteria, and recent advances in treatment and care. RECENT FINDINGS: Significant scientific advances have improved the understanding of genetic factors (both genetic causes and risk alleles) and associated phenotypic features. Panels of urine/blood biomarker candidates aid in diagnosing jSLE, monitoring disease activity and predicting treatment response. Available classification criteria have been extensively assessed, with differences in clinical and immunological phenotypes of patients across age groups and ethnicities affecting their performance in jSLE. Therapeutic options remain limited and are based on protocols for adult-onset SLE patients. International efforts to inform development of a treat-to-target (T2T) approach for jSLE have yielded cohort-level evidence that target attainment reduces the risk of severe flare and new damage, and treatment compliance. SUMMARY: Recent studies have significantly improved our understanding of jSLE pathogenesis, highlighting important differences between jSLE and adult SLE, and providing the basis of biomarker development and target-directed individualized treatment and care. Future work focused on development of a T2T approach in jSLE is eagerly awaited.

Towards development of treat to target (T2T) in childhood-onset systemic lupus erythematosus: PReS-endorsed overarching principles and points-to-consider from an international task force.

OBJECTIVES: Application of 'treat-to-target' (T2T) in childhood-onset systemic lupus erythematosus (cSLE) may improve care and health outcomes. This initiative aimed to harmonise existing evidence and expert opinion regarding T2T for cSLE. METHODS: An international T2T Task Force was formed of specialists in paediatric rheumatology, paediatric nephrology, adult rheumatology, patient and parent representatives. A steering committee formulated a set of draft overarching principles and points-to-consider, based on evidence from systematic literature review. Two on-line preconsensus meeting Delphi surveys explored healthcare professionals' views on these provisional overarching principles and points-to-consider. A virtual consensus meeting employed a modified nominal group technique to discuss, modify and vote on each overarching principle/point-to-consider. Agreement of >80% of Task Force members was considered consensus. RESULTS: The Task Force agreed on four overarching principles and fourteen points-to-consider. It was agreed that both treatment targets and therapeutic strategies should be subject to shared decision making with the patient/caregivers, with full remission the preferred target, and low disease activity acceptable where remission cannot be achieved. Important elements of the points-to-consider included: aiming for prevention of flare and organ damage; glucocorticoid sparing; proactively addressing factors that impact health-related quality of life (fatigue, pain, mental health, educational challenges, medication side effects); and aiming for maintenance of the target over the long-term. An extensive research agenda was also formulated. CONCLUSIONS: These international, consensus agreed overarching principles and points-to-consider for T2T in cSLE lay the foundation for future T2T approaches in cSLE, endorsed by the Paediatric Rheumatology European Society.

Panel sequencing links rare, likely damaging gene variants with distinct clinical phenotypes and outcomes in juvenile-onset SLE.

OBJECTIVES: Juvenile-onset systemic lupus erythematosus (jSLE) affects 15-20% of lupus patients. Clinical heterogeneity between racial groups, age groups and individual patients suggests variable pathophysiology. This study aimed to identify highly penetrant damaging mutations in genes associated with SLE/SLE-like disease in a large national cohort (UK JSLE Cohort Study) and compare demographic, clinical and laboratory features in patient sub-cohorts with 'genetic' SLE vs remaining SLE patients. METHODS: Based on a sequencing panel designed in 2018, target enrichment and next-generation sequencing were performed in 348 patients to identify damaging gene variants. Findings were integrated with demographic, clinical and treatment related datasets. RESULTS: Damaging gene variants were identified in ∼3.5% of jSLE patients. When compared with the remaining cohort, 'genetic' SLE affected younger children and more Black African/Caribbean patients. 'Genetic' SLE patients exhibited less organ involvement and damage, and neuropsychiatric involvement developed over time. Less aggressive first line treatment was chosen in 'genetic' SLE patients, but more second and third line agents were used. 'Genetic' SLE associated with anti-dsDNA antibody positivity at diagnosis and reduced ANA, anti-LA and anti-Sm antibody positivity at last visit. CONCLUSION: Approximately 3.5% of jSLE patients present damaging gene variants associated with younger age at onset, and distinct clinical features. As less commonly observed after treatment induction, in 'genetic' SLE, autoantibody positivity may be the result of tissue damage and explain reduced immune complex-mediated renal and haematological involvement. Routine sequencing could allow for patient stratification, risk assessment and target-directed treatment, thereby increasing efficacy and reducing toxicity.

Cyclic AMP Response Element Modulator-α Suppresses PD-1 Expression and Promotes Effector CD4+ T Cells in Psoriasis.

Effector CD4+ T lymphocytes contribute to inflammation and tissue damage in psoriasis, but the underlying molecular mechanisms remain poorly understood. The transcription factor CREMα controls effector T cell function in people with systemic autoimmune diseases. The inhibitory surface coreceptor PD-1 plays a key role in the control of effector T cell function and its therapeutic inhibition in patients with cancer can cause psoriasis. In this study, we show that CD4+ T cells from patients with psoriasis and psoriatic arthritis exhibit increased production of IL-17 but decreased expression of IL-2 and PD-1. In genetically modified mice and Jurkat T cells CREMα expression was linked to low PD-1 levels. We demonstrate that CREMα is recruited to the proximal promoter of PDCD1 in which it trans-represses gene expression and corecruits DNMT3a-mediating DNA methylation. As keratinocytes limit inflammation by PD-1 ligand expression and, in this study, reported reduced expression of PD-1 on CD4+ T cells is linked to low IL-2 and high IL-17A production, our studies reveal a molecular pathway in T cells from people with psoriasis that can deserve clinical exploitation.

Systemic lupus erythematosus - Are children miniature adults?

Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease that can affect any organ system and cause significant damage and organ failure. Disease-onset during childhood (juvenile-onset SLE) is associated with less typical autoantibody patterns, diffuse organ involvement, more damage already at diagnoses, and a higher need of immunomodulating treatment, including corticosteroids, when compared to adult-onset SLE. Differences in the molecular pathophysiology within SLE, and over-representation of patients with "genetic SLE" contribute to differences in clinical presentation and treatment responses between children and adults. This manuscript summarizes currently available literature focusing on parallels and differences between clinical pictures, known pathomechanisms, and available treatment options in juvenile- versus adult-onset SLE.

Longitudinal analysis of urinary proteins in lupus nephritis - A pilot study.

Approximately 30% of adult-onset systemic lupus erythematosus (SLE) patients develop lupus nephritis (LN). The gold standard for LN detection involves renal biopsies, invasive procedures not suitable for routine disease monitoring. A urinary biomarker panel comprised of lipocalin-like prostaglandin D synthase (LPGDS), transferrin, alpha-1-acid glycoprotein (AGP-1), ceruloplasmin, monocyte chemoattractant protein 1 (MCP-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) has shown promise to predict LN and response to rituximab at baseline. Whether these proteins predict LN during longitudinal sampling, however, remained unknown. Here, we quantified aforementioned urinary proteins at baseline (N = 25), six and twelve months (N = 17 each) after rituximab treatment. Urine MCP-1 (at six and twelve months) and AGP-1 (at twelve months) levels varied between patients with active vs mildly active/inactive LN. Findings support the use of urinary proteins to detect active LN in ongoing disease monitoring in adult-onset SLE patients, but need to be validated in larger cohorts.

RIP2-deficiency induces inflammation in response to SV40 Large T induced genotoxic stress through altered ROS homeostasis.

Deciphering signaling pathways that regulate the complex interplay between inflammation and cell death is a key challenge in understanding innate immune responses. Over recent years, receptor interacting protein (RIP) kinases have been described to regulate the interplay between inflammation and cell death. Whereas RIP1 and 3, the most well described members of the RIP kinase family, play important roles in necroptosis, RIP2's involvement in regulating inflammation, cell death processes and cancer is less well described and controversially discussed. Here, we demonstrate that RIP2 exerts immune regulatory functions by regulating mitochondrial damage and mitochondrial superoxide production in response to SV40 LT-induced genotoxic stress by the induction of ULK1-phosphorylation, therefore regulating the expression of interferon stimulated genes (ISGs) and NLRP3-inflammasome dependent IL-1ß release. Because RIP2 is upregulated and/or activated in autoimmune/inflammatory disease and cancer, observations from this study promise implications of RIP kinases in human disease.

Real world treatment of juvenile-onset systemic lupus erythematosus: Data from the UK JSLE cohort study.

BACKGROUND: In the absence of clinical trials evidence, Juvenile-onset Systemic Lupus Erythematosus (JSLE) treatment plans vary. AIM: To explore 'real world' treatment utilising longitudinal UK JSLE Cohort Study data. METHODS: Data collected between 07/2009-05/2020 was used to explore the choice/sequence of immunomodulating drugs from diagnosis. Multivariate logistic regression determined how organ-domain involvement (pBILAG-2004) impacted treatment choice. RESULT: 349 patients met inclusion criteria, median follow-up 4-years (IQR:2,6). Mycophenolate mofetil (MMF) was most commonly used for the majority of organ-domains, and significantly associated with renal involvement (OR:1.99, 95% CI:1.65-2.41, pc < 0.01). Analyses assessing the sequence of immunomodulators focused on 197/349 patients (meeting relevant inclusion/exclusion criteria). 10/197 (5%) solely recieved hydroxychloroquine/prednisolone, 62/197 (31%) received a single-immunomodulator, 69/197 (36%) received two, and 36/197 patients (28%) received ≥three immunomodulators. The most common first and second line immunomodulator was MMF. Rituximab was the most common third-line immunomodulator. CONCLUSIONS: Most UK JSLE patients required ≥two immunomodulators, with MMF used most commonly.

Attainment of low disease activity and remission targets reduces the risk of severe flare and new damage in childhood lupus.

OBJECTIVES: To assess the achievability and effect of attaining low disease activity (LDA) or remission in childhood-onset SLE (cSLE). METHODS: Attainment of three adult-SLE derived definitions of LDA (LLDAS, LA, Toronto-LDA), and four definitions of remission (clinical-SLEDAI-defined remission on/off treatment, pBILAG-defined remission on/off treatment) was assessed in UK JSLE Cohort Study patients longitudinally. Prentice-Williams-Petersen gap recurrent event models assessed the impact of LDA/remission attainment on severe flare/new damage. RESULTS: LLDAS, LA and Toronto-LDA targets were reached in 67%, 73% and 32% of patients, after a median of 18, 15 or 17 months, respectively. Cumulatively, LLDAS, LA and Toronto-LDA was attained for a median of 23%, 31% and 19% of total follow-up-time, respectively. Remission on-treatment was more common (61% cSLEDAI-defined, 42% pBILAG-defined) than remission off-treatment (31% cSLEDAI-defined, 21% pBILAG-defined). Attainment of all target states, and disease duration (>1 year), significantly reduced the hazard of severe flare (P < 0.001). As cumulative time in each target increased, hazard of severe flare progressively reduced. LLDAS attainment reduced the hazard of severe flare more than LA or Toronto-LDA (P < 0.001). Attainment of LLDAS and all remission definitions led to a statistically comparable reduction in the hazards of severe flare (P > 0.05). Attainment of all targets reduced the hazards of new damage (P < 0.05). CONCLUSIONS: This is the first study demonstrating that adult-SLE-derived definitions of LDA/remission are achievable in cSLE, significantly reducing risk of severe flare/new damage. Of the LDA definitions, LLDAS performed best, leading to a statistically comparable reduction in the hazards of severe flare to attainment of clinical remission.

[Systemic lupus erythematosus-are children small adults?] / Systemischer Lupus erythematodes ­ sind Kinder kleine Erwachsene?

Systemic lupus erythematosus (SLE) is a systemic inflammatory disease that can affect any organ of the human body and cause significant damage. As compared to patients with adult-onset SLE, children and young people (juvenile SLE) more frequently experience extensive diffuse organ involvement, more organ damage at diagnoses, and resistance to immunomodulatory treatment. This manuscript emphasizes parallels and differences between the clinical pictures, known pathomechanisms, and available treatment options of juvenile and adult-onset SLE.

Cardiac pathology and outcomes vary between Kawasaki disease and PIMS-TS.

Overlapping clinical features promoted the discussion of whether Kawasaki disease (KD) and PIMS-TS share pathophysiological features and disease outcomes. Medical records from English patients with KD (2015-02/20, N = 27) and PIMS-TS (02/2020-21, N = 34) were accessed to extract information. Children with PIMS-TS were older and more frequently of minority ethnicity background. They patients more commonly exhibited cytopenias and hyperferritinemia, which associated with diffuse cardiac involvement and functional impairment. In some PIMS-TS cases, cardiac pathology developed late, but outcomes were more favorable. In both, KD and PIMS-TS, baseline coronary diameter was a predictor of outcomes. PIMS-TS treatment more frequently included respiratory and cardiovascular support, and corticosteroids with IVIG. Cardiac involvement in PIMS-TS may be the result of a cytokine storm. Though more severe and diffuse when compared to KD, cardiac involvement of PIMS-TS has a more favorable prognosis, which may, after recovery, mitigate the need for long-term follow up.

Serum protein signatures differentiate paediatric autoimmune/inflammatory disorders.

Because of their rarity, limited awareness among non-specialists, and significant overlaps in their clinical presentation, childhood autoimmune/inflammatory conditions represent a diagnostic and therapeutic challenge. Juvenile idiopathic arthritis (JIA), with its 7 sub-forms, is the most common paediatric "rheumatic" disease. Juvenile-onset systemic lupus erythematosus (jSLE) is a severe autoimmune/inflammatory disease that can affect any organ system and shares clinical features with JIA. To overcome issues around diagnostic approaches in the context of clinical overlap, we aimed at the definition of disease sub-form specific cytokine and chemokine profiles. Serum samples from patients with JIA (n = 77) and jSLE (n = 48), as well as healthy controls (n = 30), were collected. Samples were analysed using the Meso Scale Discovery (MSD) U-PLEX Biomarker Group 1 (hu) panel. Distinct serum protein signatures associate with JIA vs jSLE disease groups. Proteins with high discriminatory ability include IL-23, MIP-1ß, MCP-1, M-CSF and MDC. Furthermore, serum IL-18, MIF, MIP-5 and YKL-40 discriminate between systemic JIA and other JIA subtypes. Thus, simultaneous quantification of serum proteins in a panel format may provide an avenue for the diagnosis and monitoring of childhood autoimmune/inflammatory conditions.

A panel of urinary proteins predicts active lupus nephritis and response to rituximab treatment.

OBJECTIVES: ∼30% of patients with SLE develop LN. Presence and/or severity of LN are currently assessed by renal biopsy, but biomarkers in serum or urine samples may provide an avenue for non-invasive routine testing. We aimed to validate a urinary protein panel for its ability to predict active renal involvement in SLE. METHODS: A total of 197 SLE patients and 48 healthy controls were recruited, and urine samples collected. Seventy-five of the SLE patients had active LN and 104 had no or inactive renal disease. Concentrations of lipocalin-like prostaglandin D synthase (LPGDS), transferrin, alpha-1-acid glycoprotein (AGP-1), ceruloplasmin, monocyte chemoattractant protein 1 (MCP-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were quantified by MILLIPLEX® Assays using the MAGPIX Luminex platform. Binary logistic regression was conducted to examine whether proteins levels associate with active renal involvement and/or response to rituximab treatment. RESULTS: Urine levels of transferrin (P <0.005), AGP-1 (P <0.0001), MCP-1 (P <0.001) and sVCAM-1 (P <0.005) were significantly higher in SLE patients when compared with healthy controls. Furthermore, levels of transferrin, AGP-1, ceruloplasmin, MCP-1 and sVCAM-1 (all P <0.0001) were higher in SLE patients with active LN when compared with patients without active LN. A combination of five urine proteins, namely LPGDS, transferrin, ceruloplasmin, MCP-1 and sVCAM-1 was a good predictor of active LN (AUC 0.898). A combined model of LPGDS, transferrin, AGP-1, ceruloplasmin, MCP-1 and sVCAM-1 predicted response to rituximab treatment at 12 months (AUC 0.818). CONCLUSIONS: Findings support the use of a urinary protein panel to identify active LN and potentially predict response to treatment with rituximab in adult SLE patients. Prospective studies are required to confirm findings.

Limited sensitivity and specificity of the ACR/EULAR-2019 classification criteria for SLE in JSLE?-observations from the UK JSLE Cohort Study.

OBJECTIVES: This study aimed to test the performance of the new ACR and EULAR criteria, that include ANA positivity as entry criterion, in JSLE. METHODS: Performance of the ACR/EULAR-2019 criteria were compared with Systemic Lupus International Collaborating Clinics (SLICC-2012), using data from children and young people (CYP) in the UK JSLE Cohort Study (n = 482), with the ACR-1997 criteria used as reference standard. An unselected cohort of CYP positive for ANA (n = 129) was used to calculate positive/negative predictive values of the criteria. RESULTS: At both first and last visits, the number of patients fulfilling the different classification criteria varied significantly (P < 0.001). The sensitivity of the SLICC-2012 criteria was higher when compared with that of the ACR/EULAR-2019 criteria at first and last visits (98% vs 94% for first visit, and 98% vs 96% for last visit; P < 0.001), when all available CYP were considered. The ACR/EULAR-2019 criteria were more specific when compared with the SLICC-2012 criteria (77% vs 67% for first visit, and 81% vs 71% for last visit; P < 0.001). Significant differences between the classification criteria were mainly caused by the variation in ANA positivity across ages. In the unselected cohort of ANA-positive CYP, the ACR/EULAR-2019 criteria produced the highest false-positive classification (6/129, 5%). CONCLUSION: In CYP, the ACR/EULAR-2019 criteria are not superior to those of the SLICC-2012 or ACR-1997 criteria. If classification criteria are designed to include CYP and adult populations, paediatric rheumatologists should be included in the consensus and evaluation process, as seemingly minor changes can significantly affect outcomes.