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OBJECTIVES: To identify associations between mortality in cSLE patients and their characteristics: clinical and laboratory features, disease activity and damage scores, and treatment; to evaluate risk factors associated with mortality in cSLE; and to determine the most frequent causes of death in this group of patients. METHODS: We performed a multicenter retrospective cohort using data from 1,528 cSLE patients followed in 27 pediatric rheumatology tertiary centers in Brazil. Patients' medical records were reviewed according to a standardized protocol, in which information regarding demographic and clinical features, disease activity and damage scores, and treatment were collected and compared between deceased cSLE patients and survivors. Univariate and multivariate analyses by Cox regression model were used to calculate risk factors for mortality, whereas survival rates were analyzed by Kaplan-Meier plots. RESULTS: A total of 63/1,528 (4.1%) patients deceased, 53/63 were female (84.1%), median age at death was 11.9 (9.4-13.1) years and median time interval between cSLE diagnosis and death was 3.2 (0.5-5.3) years. Sepsis was the main cause of death in 27/63 (42.8%) patients, followed by opportunistic infections in 7/63 (11.1%), and alveolar hemorrhage in 6/63 (9.5%) patients. The regression models resulted in neuropsychiatric lupus (NP-SLE) (HR = 2.56, 95% CI = 1.48-4.42) and chronic kidney disease (CKD) (HR = 4.33, 95% CI = 2.33-4.72), as risk factors significantly associated with mortality. Overall patient survival after cSLE diagnosis at 5, 10, and 15 years were 97%, 95.4%, and 93.8%, respectively. CONCLUSIONS: This study confirmed that the recent mortality rate in cSLE in Brazil is low, but still of concern. NP-SLE and CKD were the main risk factors for mortality, indicating that the magnitude of these manifestations was significantly high.

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BACKGROUND: Lupus nephritis (LN) is a frequent manifestation of childhood-onset systemic lupus erythematosus (cSLE) with a potential risk for kidney failure and poor outcomes. This study aimed to evaluate stages III, IV, and V of chronic kidney disease (CKD) and investigate risk factors for CKD in cSLE patients. METHODS: We performed a nationwide observational cohort study in 27 pediatric rheumatology centers, including medical charts of 1528 cSLE patients. Data were collected at cSLE diagnosis, during follow-up, and at last visit or death, between September 2016 and May 2019. RESULTS: Of 1077 patients with LN, 59 (5.4%) presented with CKD, 36/59 (61%) needed dialysis, and 7/59 (11.8%) were submitted for kidney transplantation. After Bonferroni's correction for multiple comparisons (p < 0.0013), determinants associated with CKD were higher age at last visit, urinary biomarker abnormalities, neuropsychiatric involvement, higher scores of disease activity at last visit and damage index, and more frequent use of methylprednisolone, cyclosporine, cyclophosphamide, and rituximab. In the regression model analysis, arterial hypertension (HR = 15.42, 95% CI = 6.12-38.83, p ≤ 0.001) and biopsy-proven proliferative nephritis (HR = 2.83, 95%CI = 1.70-4.72, p ≤ 0.001) increased the risk of CKD, while children using antimalarials had 71.0% lower CKD risk ((1.00-0.29) × 100%) than children not using them. The Kaplan-Meier comparison showed lower survival in cSLE patients with biopsy-proven proliferative nephritis (p = 0.02) and CKD (p ≤ 0.001). CONCLUSIONS: A small number of patients manifested CKD; however, frequencies of dialysis and kidney transplantation were relevant. This study reveals that patients with cSLE with hypertension, proliferative nephritis, and absence of use of antimalarials exhibited higher hazard rates of progression to CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

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BACKGROUND: Paediatric inflammatory multisystem syndrome (PIMS) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been described since mid-April 2020 with the first reports coming from Europe. Our objective was to describe the characteristics of patients among the Brazilian population. METHODS: A multicenter retrospective study was conducted with the participation of five pediatric rheumatology centers in Brazil during the period from March to November 2020. Children and adolescents with PIMS temporally associated with SARS-CoV-2 (TS) who met the definition criteria for the disease according to the Royal College of Paediatrics and Child Health were included. Demographic, clinical, laboratory, therapeutic characteristics and molecular and serological diagnosis of SARS-CoV-2 infection were described. RESULTS: Fifty-seven children and adolescents with PIMS-TS were evaluated, 54% female, with a median age of 8 (3-11) years. Most (86%) were previously healthy, with asthma being the main comorbidity, present in 10% of the patients. Fever was the main manifestation, present in all patients, followed by mucocutaneous and gastrointestinal features, present in 89% and 81% of the patients, respectively. Myocarditis occurred in 21% of the patients and in 68% of them required intensive care. The Kawasaki disease phenotype occurred in most patients (77%). All patients had elevated inflammatory markers, with elevated CRP being the most found (98%). Anemia and lymphopenia were present in 79% and 72%, respectively. Laboratory evidence of SARS-CoV-2 was found in 77% of the patients, with 39% positive RT-PCR and 84% positive serology for SARS-CoV-2. An immunomodulatory treatment was performed in 91% of the patients, with 67% receiving intravenous immunoglobulin (IVIG) associated with glucocorticoid, 21% receiving IVIG, and 3.5% receiving glucocorticoid. The median length of hospitalization was 10 days. CONCLUSIONS: This study showed a high morbidity of PIMS-TS in Brazilian children, with a prolonged length of hospitalization and a high rate of admission to pediatric intensive care unit. Multicenter prospective studies are needed to assess the morbidity of the disease in the medium and long term.

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Pediatric antiphospholipid syndrome (APS) is a rare acquired multisystem autoimmune thromboinflammatory condition characterized by thrombotic and non-thrombotic clinical manifestations. APS in children and adolescents typically presents with large-vessel thrombosis, thrombotic microangiopathy, and, rarely, obstetric morbidity. Non-thrombotic clinical manifestations are frequently seen in pediatric APS and may be present even before the vascular thrombotic events occur. We review insights into the pathogenesis of APS and discuss potential targets for therapy. The identification of multiple immunologic abnormalities in patients with APS reveals molecular targets for current or future treatment. Management strategies, especially for APS in adolescents, require screening for additional prothrombotic risk factors and consideration of counseling regarding contraceptive strategies, lifestyle recommendations, treatment adherence, and mental health issues associated with this autoimmune thrombophilia. The main goal of therapy in pediatric APS is the prevention of thrombosis. The management of acute thrombosis events in children and adolescents is the same as for primary APS, which involves isolated occurrences, and secondary APS, which is seen in association with another autoimmune disease, e.g., systemic lupus erythematosus. A pediatric hematologist should be consulted so other differential thrombophilic conditions can be eliminated. Therapy includes unfractionated heparin or low-molecular-weight heparin followed by vitamin K antagonists. Treatment of catastrophic APS involves triple therapy (anticoagulation, intravenous corticosteroid pulse therapy, and plasma exchange) and may include intravenous immunoglobulin for children and adolescents with this condition. New drugs such as eculizumab and sirolimus seem to be promising drugs for APS.

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Abstract Background: Paediatric inflammatory multisystem syndrome (PIMS) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been described since mid-April 2020 with the first reports coming from Europe. Our objective was to describe the characteristics of patients among the Brazilian population. Methods: A multicenter retrospective study was conducted with the participation of five pediatric rheumatology centers in Brazil during the period from March to November 2020. Children and adolescents with PIMS temporally associated with SARS-CoV-2 (TS) who met the definition criteria for the disease according to the Royal College of Paediatrics and Child Health were included. Demographic, clinical, laboratory, therapeutic characteristics and molecular and serological diagnosis of SARS-CoV-2 infection were described. Results: Fifty-seven children and adolescents with PIMS-TS were evaluated, 54% female, with a median age of 8 (3-11) years. Most (86%) were previously healthy, with asthma being the main comorbidity, present in 10% of the patients. Fever was the main manifestation, present in all patients, followed by mucocutaneous and gastrointestinal features, present in 89% and 81% of the patients, respectively. Myocarditis occurred in 21% of the patients and in 68% of them required intensive care. The Kawasaki disease phenotype occurred in most patients (77%). All patients had elevated inflammatory markers, with elevated CRP being the most found (98%). Anemia and lymphopenia were present in 79% and 72%, respectively. Laboratory evidence of SARS-CoV-2 was found in 77% of the patients, with 39% positive RT-PCR and 84% positive serology for SARS-CoV-2. An immunomodulatory treatment was performed in 91% of the patients, with 67% receiving intravenous immunoglobulin (IVIG) associated with glucocorticoid, 21% receiving IVIG, and 3.5% receiving glucocorticoid. The median length of hospitalization was 10 days. Conclusions: This study showed a high morbidity of PIMS-TS in Brazilian children, with a prolonged length of hospitalization and a high rate of admission to pediatric intensive care unit. Multicenter prospective studies are needed to assess the morbidity of the disease in the medium and long term.

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OBJECTIVE: To evaluate if the 2019-European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) criteria at diagnosis of childhood-onset systemic lupus erythematosus (cSLE) are associated with higher rates of early damage scored by Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI). METHODS: This retrospective multicenter study included 670 cSLE patients with ≤5 years of disease duration. All patients fulfilled both 2019-EULAR/ACR and 1997-ACR classification criteria. Total score of 2019-EULAR/ACR criteria and each of its specific domains were assessed at diagnosis as predictors of damage accrual at the last visit, according to the presence of any organ damage (defined by SDI ≥ 1). RESULTS: Median disease duration was 2.8 (IQR 1.8-3.8) years and 200 (29.9%) patients had at least one organ damage (SDI ≥ 1). The most frequent domains were neuropsychiatric (12%), renal (7%), and musculoskeletal (6%). There was a higher frequency of renal (58% vs 43%, p = 0.0004) and neuropsychiatric domain (21% vs 7%, p < 0.0001) of 2019-EULAR/ACR criteria in patients with damage (SDI ≥ 1) compared to those without damage (SDI = 0). Patients scoring renal or neuropsychiatric domains of the 2019-EULAR/ACR criteria at diagnosis were associated with renal damage (odds ratio 9.701, 95% confidence interval 3.773-24.941, p < 0.001) or neuropsychiatric damage (OR 9.480, 95% CI 5.481-16.399, p<0.0001) at latest visit, respectively. cSLE patients with positive anti-dsDNA at diagnosis were also associated with renal damage by the latest visit (OR 2.438, 95% CI 1.114-5.3381, p = 0.021). Constitutional, hematologic, mucocutaneous, serosal, and musculoskeletal domains and specific criteria as well as other immunologic criteria were not associated with damage accrual. Median of SLEDAI-2K was significantly higher in patients with global damage (19.5 (2-51) vs 14 (0-51), p<0.001). 2019-EULAR/ACR score >25 was associated with more overall (SDI ≥ 1) (38% vs 25%, p = 0.0002) and renal damage (11% vs 5%, p = 0.023). CONCLUSIONS: The 2019-EULAR/ACR criteria at diagnosis were associated with a higher rate of early damage in cSLE patients, especially for renal and neuropsychiatric damage. Of note, damage was particularly associated with high disease activity at diagnosis and 2019-EULAR/ACR score >25.

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OBJECTIVE: To assess childhood-onset systemic lupus erythematosus-related antiphospholipid syndrome(cSLE-APS) in a large Brazilian population. METHODS: A retrospective observational cohort study was carried-out in 27 Pediatric Rheumatology university centers, including 1519 cSLE patients. RESULTS: cSLE-APS was observed in 67/1519 (4%) and was diagnosed at disease onset in 39/67 (58%). The median disease duration was 4.9 (0-17) years. Thrombosis recurrences were evidenced in 18/67 (27%) cSLE-APS patients. The most frequent thrombosis sites in cSLE-APS patients were: venous thrombosis in 40/67 (60%), especially deep vein thrombosis in 29/40 (72%); arterial thrombosis in 35/67 (52%), particularly stroke; small vessels thrombosis in 9/67 (13%) and mixed thrombosis in 3/67 (4%). Pregnancy morbidity was observed in 1/67 (1%). Non-thrombotic manifestation associated to cSLE-APS occurred in 21/67 (31%), mainly livedo reticularis in 14/67 (21%), valvar thickening in 4/67 (6%) and valvar vegetations not related to infections in 2/67 (3%). None of them had catastrophic APS. Further analysis demonstrated that the median of SLICC/ACR-DI [1(0-5) vs. 0(0-7),p < 0.0001] was significantly higher in cSLE-APS patients compared to cSLE without APS. The frequencies of cerebrovascular disease (40% vs. 1%,p < 0.0001), polyneuropathy (9% vs. 1%,p < 0.0001), SLICC/ACR-DI ≥1 (57% vs. 27%, p < 0.0001) and intravenous cyclophosphamide use (59% vs. 37%, p < 0.0001) were significantly higher in the former group. CONCLUSIONS: Our large multicenter study demonstrated that cSLE-APS was a rare condition, occurring during disease course with a high accrual damage. Central and peripheral neuropsychiatric involvements were distinctive features of this autoimmune thrombosis.

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BACKGROUND: Concerns about the safety and efficacy of vaccines in patients with autoimmune diseases (AID) have led to contradictions and low vaccination coverage in this population, who are at a higher risk of infections, including by human papillomavirus (HPV). Although HPV vaccines have been recommended for immunocompromised patients, there is still a lack of data to support its use for AID patients, such as juvenile dermatomyositis (JDM) patients. The aim of this study was to assess the safety and immunogenicity of the quadrivalent HPV (qHPV) vaccine in a cohort of JDM patients. METHODS: JDM patients aged from 9 to 20 years and healthy controls (HC) were enrolled to receive a 3-dose schedule of qHPV vaccine from March/2014 to March/2016. Study visits were performed before the first dose, 1 month after the second and third doses, and 6 months after the third dose. Participants completed a diary of possible adverse events for 14 days following each dose of vaccination (AEFV). Disease activity and current therapy were analyzed at each visit for JDM patients. In addition, serum samples from all participants were collected to test antibody concentrations against HPV16 and 18 at each visit. Participant recruitment was conducted in ten Brazilian centres. From 47 eligible JDM patients and 41 HC, 42 and 35, respectively, completed the 3-dose schedule of the vaccine, given that five JDM patients and two HC had received doses prior to their inclusion in the study. RESULTS: The AEFVs presented by the participants were mild and in general did not differ between JDM and HC groups. No severe AEFVs were related to the vaccination. Disease activity was stable, or even improved during the follow-up. One month after the third dose of the vaccine the JDM group presented seropositivity of 100% for HPV16 and 97% for HPV18, similarly to the HC group, who presented 100% for both serotypes (p = 1.000). Six months after the third dose the seropositivity for the patient group was 94% for both HPV types. CONCLUSIONS: The HPV vaccination in this cohort of JDM patients was safe and immunogenic. Since the seropositivity against HPV16 and 18 was very high after the 3-dose schedule, this regimen should be recommended for JDM patients. TRIAL REGISTRATION: Brazilian Clinical Trials Registry, number: RBR-9ypbtf . Registered 20 March 2018 - Retrospectively registered.

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OBJECTIVE: This study aimed to assess the safety and immunogenicity of the quadrivalent human papillomavirus (qHPV) vaccination in childhood-onset systemic lupus erythematosus (cSLE) patients. METHODS: Volunteer cSLE patients aged 9-20 years and healthy controls (HC) were enrolled to receive a two- or three-dose qHPV vaccination schedule from March 2014 to March 2016. Study visits were performed before the first dose, one month after the second and third doses and one year after the first dose. In each study visit, disease activity and adverse events following vaccination were analyzed, and a serum sample was collected for testing antibody concentrations. Participant recruitment was conducted in 15 Brazilian paediatric rheumatology units. Of the 256 cSLE patients included, 210 completed the two- or three-dose schedules; 15 had previously received one dose, and 18 had received two doses of the vaccine. The analysis was based on intention-to-treat so that participants who did not complete the entire study protocol were also included. RESULTS: No severe adverse events were related to the vaccination. Disease activity was generally low and remained stable or even improved. The HC presented 100% seropositivity to HPV16 and HPV18, whereas the two- and three-dose cSLE groups presented 93% and 83% versus 97% and 91%, respectively. One year after the first dose, seropositivity of the three-dose cSLE group was 91% to HPV16 and 84% to HPV18. CONCLUSIONS: HPV vaccination in cSLE patients is safe and immunogenic. Since the seropositivity to HPV16 and HPV18 was higher for the three-dose schedule group, this regimen should be recommended for cSLE patients.

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OBJECTIVE: To evaluate the influence of ethnicity in presentation of childhood-onset systemic lupus erythematosus (cSLE) patients. METHODS: This multicenter study included cSLE patients (American College of Rheumatology criteria) followed in 27 Pediatric Rheumatology services of Brazil. Ethnicities were classified in four groups according to the parents' and all four grandparents' self-reported ethnicity. The statistical analysis was performed using the Bonferroni's correction (p < 0.0027). RESULTS: According to ethnic groups, 1537 cSLE patients were classified in Caucasian (n = 786), African-Latin American (n = 526), Asian (n = 8), and others/unknown (n = 217). Comparisons between 1312 African-Latin American and Caucasian revealed similar median age at cSLE diagnosis [12.2(2.6-18) vs. 12.1(0.3-18) years, p = 0.234], time interval to diagnosis [0.25(0-12) vs. 0.3(0-10) years, p = 0.034], and SLEDAI-2K score [14(0-55) vs. 14(0-63), p = 0.781] in both groups. The mean number of diagnostic criteria according to SLICC (6.47 ± 1.911 vs. 5.81 ± 1.631, p < 0.0001) and frequencies of maculopapular lupus rash (8% vs. 3%, p < 0.0001), palate oral ulcers (17% vs. 11%, p = 0.001), tongue oral ulcers (4% vs. 1%, p = 0.001), and nonscarring alopecia (29% vs. 16%, p < 0.0001) were significantly higher in African-Latin American, whereas malar rash (45% vs. 58%, p < 0.0001) was more frequent in Caucasian. The presence of anti-phospholipid antibody (23% vs. 12%, p < 0.0001), low complement levels (58% vs. 41%, p < 0.0001), and isolated direct Coombs test (10% vs. 5%, p = 0.001) was also significantly higher in the former group. CONCLUSIONS: Our study demonstrated that disease presentation severity of African-Latin American cSLE patients is comparable with Caucasian. Mucocutaneous manifestations and autoantibodies profile were the only distinctive features of the former group. The unique mixed background of Brazilian patients probably minimized race diversity spectrum of these patients. Key Points • Our study demonstrated that disease presentation severity of African-Latin American cSLE patients is comparable with Caucasian. • Mucocutaneous manifestations and autoantibodies profile were the only distinctive features of African-Latin American cSLE patients. • African-Latin American cSLE patients had more often anti-phospholipid antibodies and hypocomplementemia. • The unique mixed background of Brazilian patients probably minimized race diversity spectrum of these patients.

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