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Objective: This study aimed to elucidate the presence, antigen specificities, and potential clinical associations of anti-neutrophil extracellular trap (anti-NET) antibodies in a multinational cohort of antiphospholipid (aPL) antibody-positive patients who did not have lupus., Methods: Anti-NET IgG/IgM levels were measured in serum samples from 389 aPL-positive patients; 308 patients met the classification criteria for antiphospholipid syndrome. Multivariate logistic regression with best variable model selection was used to determine clinical associations. For a subset of the patients (n = 214), we profiled autoantibodies using an autoantigen microarray platform., Results: We found elevated levels of anti-NET IgG and/or IgM in 45% of the aPL-positive patients. High anti-NET antibody levels are associated with more circulating myeloperoxidase (MPO)-DNA complexes, which are a biomarker of NETs. When considering clinical manifestations, positive anti-NET IgG was associated with lesions affecting the white matter of the brain, even after adjusting for demographic variables and aPL profiles. Anti-NET IgM tracked with complement consumption after controlling for aPL profiles; furthermore, patient serum samples containing high levels of anti-NET IgM efficiently deposited complement C3d on NETs. As determined by autoantigen microarray, positive testing for anti-NET IgG was significantly associated with several autoantibodies, including those recognizing citrullinated histones, heparan sulfate proteoglycan, laminin, MPO-DNA complexes, and nucleosomes. Anti-NET IgM positivity was associated with autoantibodies targeting single-stranded DNA, double-stranded DNA, and proliferating cell nuclear antigen., Conclusion: These data reveal high levels of anti-NET antibodies in 45% of aPL-positive patients, where they potentially activate the complement cascade. While anti-NET IgM may especially recognize DNA in NETs, anti-NET IgG species appear to be more likely to target NET-associated protein antigens., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of SARS-CoV-2 infection. Recommendations are also provided for children with hyperinflammation during COVID-19, the acute, infectious phase of SARS-CoV-2 infection., Methods: The Task Force is composed of 9 pediatric rheumatologists and 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and webinar discussion. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate). Consensus was rated as low, moderate, or high based on dispersion of the votes. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, which were prespecified before voting., Results: The guidance was approved in June 2020 and updated in November 2020 and October 2021, and consists of 41 final guidance statements accompanied by flow diagrams depicting the diagnostic pathway for MIS-C and recommendations for initial immunomodulatory treatment of MIS-C., Conclusion: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion, and will be revised as further evidence becomes available., (© 2022 American College of Rheumatology.)

Objective: To provide clinical guidance to rheumatology providers who treat children with pediatric rheumatic disease (PRD) in the context of the coronavirus disease 2019 (COVID-19) pandemic., Methods: The task force, consisting of 7 pediatric rheumatologists, 2 pediatric infectious disease physicians, 1 adult rheumatologist, and 1 pediatric nurse practitioner, was convened on May 21, 2020. Clinical questions and subsequent guidance statements were drafted based on a review of the queries posed by the patients as well as the families and healthcare providers of children with PRD. An evidence report was generated and disseminated to task force members to assist with 3 rounds of asynchronous, anonymous voting by email using a modified Delphi approach. Voting was completed using a 9-point numeric scoring system with predefined levels of agreement (categorized as disagreement, uncertainty, or agreement, with median scores of 1-3, 4-6, and 7-9, respectively) and consensus (categorized as low, moderate, or high). To be approved as a guidance statement, median vote ratings were required to fall into the highest tertile for agreement, with either moderate or high levels of consensus., Results: To date, 39 guidance statements have been approved by the task force. Those with similar recommendations were combined to form a total of 33 final guidance statements, all of which received median vote ratings within the highest tertile of agreement and were associated with either moderate consensus (n = 5) or high consensus (n = 28)., Conclusion: These guidance statements have been generated based on review of the available literature, indicating that children with PRD do not appear to be at increased risk for susceptibility to SARS-CoV-2 infection. This guidance is presented as a "living document," recognizing that the literature on COVID-19 is rapidly evolving, with future updates anticipated., (© 2021, American College of Rheumatology.)

Objective: To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Recommendations are also provided for children with hyperinflammation during coronavirus disease 2019 (COVID-19), the acute, infectious phase of SARS-CoV-2 infection., Methods: The Task Force was composed of 9 pediatric rheumatologists and 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and webinar discussion. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate). Consensus was rated as low, moderate, or high based on dispersion of the votes. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, which were prespecified before voting., Results: The first version of the guidance was approved in June 2020, and consisted of 40 final guidance statements accompanied by a flow diagram depicting the diagnostic pathway for MIS-C. The document was revised in November 2020, and a new flow diagram with recommendations for initial immunomodulatory treatment of MIS-C was added., Conclusion: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion, and will be revised as further evidence becomes available., (© 2020, American College of Rheumatology.)

Objective: To assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN)., Methods: In a multicenter, randomized, open-label clinical trial, 43 patients with recurrent or refractory LN were treated with rituximab, cyclophosphamide (CYC), and glucocorticoids followed by weekly belimumab infusions until week 48 (RCB group), or treated with rituximab and CYC but no belimumab infusions (RC group). Patients were followed up until week 96. Percentages of total and autoreactive B cell subsets in the patients' peripheral blood were analyzed by flow cytometry., Results: Treatment with belimumab did not increase the incidence of adverse events in patients with refractory LN. At week 48, a complete or partial renal response occurred in 11 (52%) of 21 patients receiving belimumab, compared to 9 (41%) of 22 patients in the RC group who did not receive belimumab (P = 0.452). Lack of improvement in or worsening of LN was the major reason for treatment failure. B cell depletion occurred in both groups, but the percentage of B cells remained lower in those receiving belimumab (geometric mean number of B cells at week 60, 53 cells/μl in the RCB group versus 11 cells/μl in the RC group; P = 0.0012). Percentages of total and autoreactive transitional B cells increased from baseline to week 48 in both groups. However, percentages of total and autoreactive naive B cells decreased from baseline to week 48 in the belimumab group compared to the no belimumab RC group (P = 0.0349), a finding that is consistent with the observed impaired maturation of naive B cells and enhanced censoring of autoreactive B cells., Conclusion: The addition of belimumab to a treatment regimen with rituximab and CYC was safe in patients with refractory LN. This regimen diminished maturation of transitional to naive B cells during B cell reconstitution, and enhanced the negative selection of autoreactive B cells. Clinical efficacy was not improved with rituximab and CYC in combination with belimumab when compared to a therapeutic strategy of B cell depletion alone in patients with LN., (© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: The release of neutrophil extracellular traps (NETs) by hyperactive neutrophils has recently been recognized to play an important role in antiphospholipid syndrome (APS). This study was undertaken to evaluate autoantibodies targeting NETs in patients with primary APS, and to determine their potential functions and clinical associations., Methods: We measured global anti-NET activity in 76 patients with primary APS, 23 patients with systemic lupus erythematosus without antiphospholipid antibodies (aPL), 11 patients with a history of unprovoked venous thrombosis without aPL, and 44 healthy controls. The ability of APS sera to degrade NETs was also assessed., Results: We found markedly elevated levels of anti-NET IgG and IgM in patients with primary APS compared with healthy controls (for IgG, mean ± SD optical density 0.55 ± 0.34 versus 0.33 ± 0.17; for IgM, mean ± SD optical density 0.76 ± 0.51 versus 0.26 ± 0.23). This anti-NET activity did not correlate with levels of traditional aPL and was relatively stable over time. Mechanistically, anti-NET antibodies (especially of the IgG isotype) impaired the ability of patient sera to degrade NETs (r = 0.4, P = 0.003). Levels of anti-NET IgM inversely correlated with complement C4 (r = 0.4, P = 0.019). Clinically, anti-NET antibodies associated with certain APS clinical manifestations, and in particular recurrent venous thrombosis (odds ratio 4.3; P = 0.002). Interestingly, anti-NET antibody levels also appeared to be associated with unprovoked venous thrombosis in the general population (for IgM, mean ± SD optical density 0.67 ± 0.34 versus 0.26 ± 0.23)., Conclusion: Our data indicate high levels of anti-NET antibodies in patients with primary APS, which may impair NET clearance and activate the complement cascade. These findings may ultimately enable more effective risk stratification., (© 2020, American College of Rheumatology.)

Objective: To provide clinical guidance to rheumatology providers who treat children with pediatric rheumatic disease (PRD) in the context of the coronavirus disease 2019 (COVID-19) pandemic., Methods: The task force, consisting of 7 pediatric rheumatologists, 2 pediatric infectious disease physicians, 1 adult rheumatologist, and 1 pediatric nurse practitioner, was convened on May 21, 2020. Clinical questions and subsequent guidance statements were drafted based on a review of the queries posed by the patients as well as the families and healthcare providers of children with PRD. An evidence report was generated and disseminated to task force members to assist with 3 rounds of asynchronous, anonymous voting by email using a modified Delphi approach. Voting was completed using a 9-point numeric scoring system with predefined levels of agreement (categorized as disagreement, uncertainty, or agreement, with median scores of 1-3, 4-6, and 7-9, respectively) and consensus (categorized as low, moderate, or high). To be approved as a guidance statement, median vote ratings were required to fall into the highest tertile for agreement, with either moderate or high levels of consensus., Results: The task force drafted 33 guidance statements, which were voted upon during the second and third rounds of voting. Of these 33 statements, all received median vote ratings within the highest tertile of agreement and were associated with either moderate consensus (n = 6) or high consensus (n = 27). Statements with similar recommendations were combined, resulting in 27 final guidance statements., Conclusion: These guidance statements have been generated based on review of the available literature, indicating that children with PRD do not appear to be at increased risk for susceptibility to SARS-CoV-2 infection. This guidance is presented as a "living document," recognizing that the literature on COVID-19 is rapidly evolving, with future updates anticipated., (© 2020, American College of Rheumatology.)

Objective: To provide guidance on the management of multisystem inflammatory syndrome in children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and to provide recommendations for children with hyperinflammation during coronavirus disease 2019 (COVID-19), the acute, infectious phase of SARS-CoV-2 infection., Methods: A multidisciplinary task force was convened by the American College of Rheumatology (ACR) to provide guidance on the management of MIS-C associated with SARS-CoV-2 and hyperinflammation in COVID-19. The task force was composed of 9 pediatric rheumatologists, 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved 2 rounds of anonymous voting and 2 webinars. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate), and consensus was rated as low, moderate, or high based on dispersion of the votes along the numeric scale. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, as prespecified prior to voting., Results: The ACR task force approved a total of 128 guidance statements addressing the management of MIS-C and hyperinflammation in pediatric COVID-19. These statements were refined into 40 final clinical guidance statements, accompanied by a flow diagram depicting the diagnostic pathway for MIS-C., Conclusion: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. The guidance provided in this "living document" reflects currently available evidence, coupled with expert opinion, and will be revised as further evidence becomes available., (© 2020, American College of Rheumatology.)

Objective: Systemic lupus erythematosus (SLE) and other autoimmune diseases cause significant morbidity. Identifying populations at risk of developing SLE is essential for curtailing irreversible inflammatory damage. The aim of this study was to identify factors associated with transition to classified disease that would inform our understanding of the risk of SLE., Methods: Previously identified blood relatives of patients with SLE, who had <4 American College of Rheumatology (ACR) classification criteria for SLE at baseline, were enrolled in this follow-up study (n = 409 unaffected relatives). Participants provided detailed family, demographic, and clinical information, including the SLE-specific portion of the Connective Tissue Disease Screening Questionnaire (SLE-CSQ). Serum and plasma samples were tested for the presence of lupus-associated autoantibodies and 52 soluble mediators. Generalized estimating equations (GEEs) were applied to identify factors predictive of disease transition., Results: Of the 409 unaffected relatives of SLE patients, 45 (11%) had transitioned to classified SLE at follow-up (mean time to follow-up 6.4 years). Relatives who transitioned to SLE displayed more lupus-associated autoantibody specificities and higher SLE-CSQ scores (P < 0.0001) at baseline than did relatives who did not transition. Importantly, those who had developed SLE during the follow-up period also had elevated baseline plasma levels of inflammatory mediators, including B lymphocyte stimulator, stem cell factor (SCF), and interferon-associated chemokines (P ≤ 0.02), with concurrent decreases in the levels of regulatory mediators, transforming growth factor β (TGFβ), and interleukin-10 (P ≤ 0.03). GEE analyses revealed that baseline SLE-CSQ scores or ACR scores (number of ACR criteria satisfied) and plasma levels of SCF and TGFβ, but not autoantibodies, were significant and independent predictors of SLE transition (P ≤ 0.03)., Conclusion: Preclinical alterations in levels of soluble mediators may predict transition to classified disease in relatives of SLE patients. Thus, immune perturbations precede SLE classification and can help identify high-risk relatives for rheumatology referral and potential enrollment in prevention trials., (© 2016, American College of Rheumatology.)