Childhood-onset Systemic Lupus Erythematosus Patients Research Articles

Clinical profile, laboratory parameters and management outcomes in an eight-year-old female with childhood lupus nephritis

Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune disorder characterized by widespread inflammation of connective tissues affecting the skin, joints, kidneys, heart, lungs and nervous system. SLE is most often diagnosed in women during the second to fourth decades of life, but 15-20% cases are found in childhood. Renal involvement occurs in the majority of childhood onset SLE (cSLE) patients and is often fatal and hence constitutes an important determinant of prognosis. Multidisciplinary care is necessary for children with lupus nephritis in terms of immunosuppressive regimes with a common goal of achieving and maintaining renal remission. Despite a low prevalence rate of cSLE, it manifests with fatal complications like lupus nephritis in majority of cases. Renal biopsy is gold standard for staging of lupus nephritis, thus, deciding the modality of management and prognostication of cSLE.

Transmission disequilibrium analysis of whole genome data in childhood-onset systemic lupus erythematosus.

Childhood-onset systemic lupus erythematosus (cSLE) patients are unique, with hallmarks of Mendelian disorders (early-onset and severe disease) and thus are an ideal population for genetic investigation of SLE. In this study, we use the transmission disequilibrium test (TDT), a family-based genetic association analysis that employs robust methodology, to analyze whole genome sequencing data. We aim to identify novel genetic associations in an ancestrally diverse, international cSLE cohort. Forty-two cSLE patients and 84 unaffected parents from 3 countries underwent whole genome sequencing. First, we performed TDT with single nucleotide variant (SNV)-based (common variants) using PLINK 1.9, and gene-based (rare variants) analyses using Efficient and Parallelizable Association Container Toolbox (EPACTS) and rare variant TDT (rvTDT), which applies multiple gene-based burden tests adapted for TDT, including the burden of rare variants test. Applying the GWAS standard threshold (5.0 × 10-8) to common variants, our SNV-based analysis did not return any genome-wide significant SNVs. The rare variant gene-based TDT analysis identified many novel genes significantly enriched in cSLE patients, including HNRNPUL2, a DNA repair protein, and DNAH11, a ciliary movement protein, among others. Our approach identifies several novel SLE susceptibility genes in an ancestrally diverse childhood-onset lupus cohort.

Risk factors for mortality in 1528 Brazilian childhood-onset systemic lupus erythematosus patients.

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. 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. 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. 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.

A deeper look into the functions of right ventricle using three-dimensional echocardiography: the forgotten ventricle in children with systemic lupus erythematosus

Studies on the right ventricular dysfunction (RV) in systemic lupus erythematosus (SLE) patients are limited, particularly in the pediatric age group. The study aimed to identify subclinical RV alterations in childhood-onset SLE (c-SLE) using conventional and three-dimensional echocardiography (3DE). Forty SLE pediatric patients and 40 healthy controls were included. Disease activity and chronicity were evaluated by SLE disease activity index (SLEDAI) score and SLE damage index (SDI). Participants underwent detailed RV echocardiographic examination with conventional and 3DE assessment using 3D auto RV software. Patients included 35/40 (87.5%) females with mean age of 15.6 ± 1.7 years. Using conventional pulmonary artery systolic pressure echocardiography-derived measurement, none of the c-SLE patients had pulmonary hypertension. By 3DE, RV end-systolic and end-diastolic volumes (p = < 0.001, 0.02, respectively) were greater, whereas 3D-derived RV ejection fraction (p < 0.001), septal, and lateral longitudinal strain (both p < 0.001) were lower in SLE. SDI displayed a significant correlation with 3D auto RV ejection fraction (EF), tricuspid annular plane systolic excursion (TAPSE), fractional area change, and RV longitudinal strain (RVLS)-free wall (p = 0.01, 0.003, 0.007, and < 0.001, respectively). Cumulative SLEDAI score also showed a significant correlation with RV EF, TAPSE, FAC, and RVLS-free wall (p = 0.03, 0.007, 0.002, and < 0.001, respectively). By multivariate regression analysis, SDI remained an independent predictor of RVLS-free wall (ß coefficient − 0.4, p = 0.03) and TAPSE (ß − 0.5, p = 0.02). Conclusion: Subtle right ventricular myocardial dysfunction could be detected in childhood-onset SLE patients, especially via 3D-derived auto RV echocardiographic parameters, despite the absence of evident pulmonary hypertension. These parameters correlate with the SLE disease activity and chronicity scores.What is Known:•Diseases of the cardiovascular system are one of the most common causes of morbidity and mortality in SLE patients.•RV labeled the forgotten ventricle in many diseases, was also forgotten in SLE patients and has been rarely addressed in adults, with scarce research in pediatrics.What is New:•Right ventricular functions are affected in children with SLE in comparison to healthy controls, especially three-dimensional echocardiography-derived parameters, which is an aspect that has not been investigated in previous research in the pediatric age group.•Some of the detected myocardial dysfunctions of the right ventricle correlated with SLE disease activity and chronicity-related scores.

Clinical efficacy and safety of sirolimus in childhood-onset systemic lupus erythematosus in real world.

To investigate the effectiveness and safety of sirolimus in childhood-onset systemic lupus erythematosus in a real world. This is a retrospective real world clinical study. All childhood-onset systemic lupus erythematosus patients treated with sirolimus in Children's Hospital of Hebei Province China were analyzed. They were treated with sirolimus and followed up regularly. The patients had systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, levels of antidouble-stranded DNA antibody, complement components C3 and C4, 24-hour proteinuria and corticosteroid reduction were recorded at baseline and at 6, 12, and 18 months. Adverse events were also collected. Thirty-two patients were enrolled in the study. SLEDAI-2K were improved on all time-points (P < .05). Complement levels increased and the levels of antidouble-stranded DNA antibody decreased during treatment. The mean dose of prednisone tapered and achieved significant reduction after 12 months therapy (15.4 ± 5.8 mg/d to 4.8 ± 2.1 mg/d; P < .05). Sirolimus was well tolerated and only 5 patients (15.6%) experienced adverse events, all of which were classified as infections (2 bacterial infection and 3 viral infections). No deaths, severe infusion reactions, or hypersensitivity reactions were found. Sirolimus use was associated with a decrease in disease activity and ability to tolerate tapering of oral glucocorticoid dose with a favorable risk-benefit profile.

Race, ethnicity and patient-reported outcomes in childhood-onset systemic lupus erythematosus.

This study assesses the association of race/ethnicity with the Patient-Reported Outcomes Measurement Information System (PROMIS®) in childhood-onset systemic lupus erythematosus (cSLE) patients from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. cSLE patients enrolled in the CARRA Registry within two years of cSLE diagnosis who met ACR and/or SLICC classification criteria for lupus were included. Baseline demographics, laboratory, and disease features as well as patient-reported outcomes were obtained. Multivariable linear regression analysis was used to examine the association of race and ethnicity with PROMIS scores at registry enrolment. 425 cSLE patients met inclusion criteria: 83.8% were female, 30.6% non-Hispanic White, 29.7% Black, 22.1% Hispanic. The mean age at diagnosis was 13.9 years (SD 2.5). Household income and highest parental education varied by race/ethnic group, as did frequency of rash, leukopenia, and anti-Smith antibodies. The cohort had low-moderate baseline disease activity (SLEDAI mean: 6.0 [SD 6.7]). The overall PROMIS Global Health mean T-score was 38.6 (SD 6.5), more than one standard deviation below the general population mean of 50. There was no association between race/ethnicity and PROMIS scores in multivariable linear regression analysis. In this multiethnic paediatric lupus cohort, PROMIS global health was lower when compared with the general paediatric US population. Moreover, PROMIS global health, pain interference, and physical function mobility did not vary across races/ethnicities.

Prognostic Factors at Diagnosis Associated With Damage Accrual in Childhood-Onset Systemic Lupus Erythematosus Patients.

ObjectivesTo associate prognostic factors present at diagnosis with damage accrual in childhood-onset systemic lupus erythematosus (cSLE) patients.MethodsWe designed a cohort study of eligible children age 16 or younger who fulfilled the 1997 American College of Rheumatology (ACR) classification criteria for SLE. Excluded were those with previous treatment of steroids or immunosuppressants. The diagnosis date was cohort entry. We followed up on all subjects prospectively for at least 2 years. Two experts assessed the disease activity with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and Mexican-SLEDAI (MEX-SLEDAI) every 3–6 months. Damage was measured annually, applying Pediatric Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) to their last visit. We analyzed prognostic factors by relative risks (RR) and used logistic regression to construct the clinimetric table.ResultsNinety patients with a median age of 11.8 years at diagnosis had a SLEDAI score of 15.5 (2–40) and a MEX-SLEDAI score of 12 (2–29); and of them, forty-eight children (53%) had SDI ≥ 2. The associated variables to damage (SDI ≥ 2) are as follows: neurologic disease RR 9.55 [95% CI 1.411–64.621]; vasculitis RR 2.81 [95% CI 0.991–7.973], and hemolytic anemia RR 2.09 [95% CI 1.280–3.415]. When these three features are present at diagnosis, the probability of damage ascends to 98.97%.ConclusionAt diagnosis, we identified neurologic disease, vasculitis, and hemolytic anemia as prognostic factors related to the development of damage in cSLE. Their presence should lead to a closer follow-up to reduce the likelihood of damage development.

Timing of Childhood-Onset Systemic Lupus Erythematosus Diagnosis Relative to Menarche and the Impact on Final Adult Height.

The aim of this study was to examine the impact of timing of a childhood-onset systemic lupus erythematosus (SLE) diagnosis relative to menarchal status, on final height, accounting for disease-associated factors. We conducted a cohort study of female patients age <18 years at childhood-onset SLE diagnosis, followed at a tertiary care pediatric center from July 1982 to March 2016 and restricted to patients with documented age of menarche and final height. We compared final height between patients diagnosed pre- and postmenarche. We tested the association of the timing of childhood-onset SLE diagnosis with final height, adjusted for ethnicity, in linear regression models. We performed subgroup analyses of patients with growth during follow-up, additionally adjusting for average daily corticosteroid dose and disease activity. Of 401 female childhood-onset SLE patients in the study, 115 patients (29%) were diagnosed premenarche and 286 (71%) postmenarche. Patients diagnosed premenarche were older at menarche compared with patients diagnosed postmenarche (mean ± SD age 13.5 ± 1.4 versus 12.5 ± 1.3 years; P < 0.001). The mean ± SD final height for girls diagnosed postmenarche (161.4 ± 6.9 cm) was greater than for those diagnosed premenarche (158.8 ± 7.3 cm; P=0.001). In regression analysis, those diagnosed postmenarche were significantly taller than those diagnosed premenarche, as adjusted for ethnicity and disease severity (mean ± SD β=2.6 ± 0.7 cm; P=0.0006). In this large cohort study of girls with childhood-onset SLE, patients diagnosed postmenarche achieved a taller final height than those diagnosed premenarche, even after accounting for ethnicity and disease severity.

The new 2019-EULAR/ACR classification criteria specific domains at diagnosis can predict damage accrual in 670 childhood-onset systemic lupus erythematosus patients.

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). 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). 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). 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.

Mental Health Impact in Latin American Pediatric Rheumatologists During the COVID-19 Pandemic.

The aim of this study was to assess mental health in Latin American pediatric rheumatologists (LAPRs) during the COVID-19 pandemic. A cross-sectional study was performed with 318 LAPRs based on an online, self-rated survey about clinical practice/mental health impacts during the COVID-19 pandemic. Validated self-reported scales for anxiety (Generalized Anxiety Disorder [GAD-7]) and depression (Patient Health Questionnaire [PHQ-9]) were evaluated. The response rate was 126 of 318 (40%), including 13 of 20 (65%) Latin American countries. Working on the COVID-19 frontline was reported by 27% of LAPRs. Anxiety and moderate/severe depression were observed in 49% and 25%, respectively. No LAPRs reported previous mental health disorders. Deaths of childhood-onset systemic lupus erythematosus and juvenile idiopathic arthritis patients with confirmed/suspected COVID-19 were reported by 8% and 2% of LAPRs, respectively. Further analysis of LAPRs revealed that the median current age was significantly lower in LAPRs with anxiety than in those without anxiety (39 [29-43] vs 45 [30-70] years, p = 0.029). Working on the frontline of COVID-19 (37% vs 17%, p = 0.015), feeling helpless (39% vs 17%, p = 0.009), and experiencing burnout (39% vs 11%, p = 0.0001) were factors significantly higher in LAPRs with anxiety. Median nighttime sleep abnormalities measured by the visual analog scale (VAS) (8 [0-10] vs 4 [0-10], p = 0.009) were significantly higher in the anxiety group, whereas the physical activity VAS was lower (0.5 [0-10] vs 3 [0-10], p = 0.005). A positive Spearman correlation was shown between the GAD-7 score and nighttime sleep abnormality VAS score (r = +0.348, p < 0.001), and a negative correlation was shown between the GAD-7score and physical activity VAS score (r = -0.192, p = 0.031). Anxiety and depression were relevant to the experience of LAPRs during the COVID-19 pandemic, impacting their mental health. Reporting information about mental health is essential to planning future preventive and health promotion strategies.

Childhood-onset Systemic Lupus Erythematosus: Patients features and their transition into adulthood.

Systemic Lupus Erythematosus (SLE) is an autoimmune, multisystemic, chronic disease that is diffi cult to diagnose. Few studies describe its features in the South American pediatric population. Ob jective: to describe clinical and laboratory features, course, and treatment of childhood-onset SLE patients and their transition into adulthood. Retrospective study of patients diagnosed with SLE in a Children's Rheumatology Unit of a hospital in Santiago de Chile between 2001 and 2017. Epidemiological, clinical, laboratory, treatment received, evolution, complications and hospitalizations data were registered. It was considered severe SLE the cases with renal or cen tral nervous system involvement. 31 patients were studied, all with the disease longer than 6 months. The female/male ratio was 5.2/1. The median age of presentation was 12.5 years. In 94% of cases, the diagnostic delay was less than 6 months. The most frequent clinical characteristics were arthritis (87%), skin lesions (58%), and renal involvement (58%). The most frequent laboratory findings were positive antinuclear antibodies (100%), positive anti-dsDNA antibodies (74%), and hypocomplementemia (71%). Corticosteroids, hydroxychloroquine, and mycophenolate were the most commonly used drugs. There was no mortality in this group. 97% of patients had "satisfactory check-ups" during pediatric care and 59% in the adult one. The transition was scheduled in most cases. The results of this study were similar to other publications and is one of the few studies describing SLE in the Chilean pediatric population. In addition, it describes the transition into adulthood.

Long-term renal survival of paediatric patients with lupus nephritis.

Childhood-onset systemic lupus erythematosus (SLE) is more severe than adult-onset disease, including more frequent kidney involvement. This study aimed to investigate baseline clinical features, treatment modalities and short- and long-term renal outcomes of paediatric patients with lupus nephritis (LN). This study enrolled 53 LN patients out of 102 childhood-onset SLE patients followed at Hacettepe University between 2000 and 2020. The demographic and clinical data were reviewed retrospectively from the medical charts and electronic records. All SLE patients with renal involvement underwent renal biopsy either at the time of diagnosis or during follow-up. The median age at onset of SLE was 13.3 years [interquartile range (IQR) 10.4-15.8]. The median follow-up duration was 43.1 months (IQR 24.3-69.3). Of the 102 SLE patients, 53 (52%) had LN. The most frequent histopathological class was Class IV LN (54.7%), followed by Class III (22.6%). The proportion of patients who achieved either complete or partial remission was 77.3% and 73% at 6 and 12 months, respectively. In the overall LN cohort, 5- and 10-year renal survival rates were 92% and 85.7%, respectively. The remission rate at Month 6 was significantly higher in mycophenolate mofetil (MMF)- and cyclophosphamide (CYC)-treated groups than other combination therapies (P = 0.02). Although no difference was found between the CYC and MMF response rates (P = 0.57) in proliferative LN (Classes III and IV), the majority of Class IV patients (79%) received CYC as induction therapy. There was no difference between the response rates in any treatment regimens at Month 12 (P = 0.56). In the multivariate analysis, male gender, requiring dialysis at the time of LN diagnosis and failure to achieve remission at 6 and 12 months were found to be associated with poor renal outcome. Our study demonstrated that male gender, failure to achieve remission at 6 and 12 months and requiring dialysis at the time of diagnosis were the best predictors of poor renal outcome. Therefore appropriate and aggressive management of paediatric LN is essential to achieve and maintain remission.

Cross-sectional study of plasma Axl, ferritin, IGFBP4 and sTNFR2 as biomarkers of disease activity in childhood-onset SLE: A study of the Pediatric Nephrology Research Consortium.

To evaluate the performance of 4 plasma protein markers for detecting disease activity in childhood-onset systemic lupus erythematosus (SLE) patients. Eighty-three consecutive pediatric patients fulfilling ≥4 ACR criteria for SLE and twenty-five healthy controls were prospectively recruited for serological testing of 4 protein markers identified by antibody-coated microarray screen, namely Axl, ferritin, IGFBP4 and sTNFR2. SLE disease activity was assessed using SLEDAI-2000 score. Fifty-seven patients had clinically active SLE (SLEDAI score ≥4, or having a flare). The plasma concentrations of Axl and ferritin were significantly higher in patients with active SLE than inactive SLE. Plasma Axl levels were significantly higher in active renal versus active non-renal SLE patients. Levels of Axl, ferritin and IGFBP4 correlated significantly with SLEDAI scores. Levels of Axl, IFGBP4 and sTNFR2 inversely correlated with plasma complement C3 levels. Only plasma Axl and ferritin levels correlated with degree of proteinuria. These markers were more specific, but less sensitive, in detecting concurrent SLE activity than elevated anti-dsDNA antibody titer or decreased C3. Ferritin and IGFBP4 levels were more specific for concurrent active lupus nephritis than anti-dsDNA or C3. Plasma ferritin was the best monitor of global SLE activity, followed by C3 then Axl, while both Axl and C3 were best monitors of clinical lupus nephritis activity. In childhood-onset SLE patients, plasma ferritin and Axl perform better than traditional yardsticks in identifying disease activity, either global or renal. The performance of these plasma markers should be explored further in longitudinal cohorts of SLE patients.

Clinical characteristics of cerebral venous sinus thrombosis in childhood-onset systemic lupus erythematosus patients: a single-centre study from China.

Cerebral venous sinus thrombosis (CVST) is a rare complication of childhood-onset SLE (cSLE) and is potentially fatal to the patient. In order to better define the characteristics of CVST in cSLE, we analysed a single-centre study of cSLE presenting with CVST. Clinical characteristics and laboratory findings of cSLE patients complicated with CVST from January 2006 to December 2019 were analysed through this retrospective, single-centre study. A total of 1395 records of cSLE patients were reviewed. Five patients (0.36%) had CVST. Headache (80%) was the most frequent symptom. The transverse sinus (45%) was the most frequent location of thrombus, followed by the sigmoid sinus (27%). The SLE disease activity index (SLEDAI) at the time of CVST was 11±3. The D-dimer was elevated in all 5 cases, only one patient was positive for ACL and anti-β2GP-I IgM. All the patients underwent MRV screen to confirm the diagnosis. All the patients had a favourable outcome after receiving glucocorticoid and immunosuppressant treatment, as well as anticoagulant therapy. CVST is relatively rare in cSLE and tends to occur in active lupus patients. Severe and persistent headache is an index of CVST. Early diagnosis and more intensive therapy for SLE, combined with anticoagulation therapy, could significantly improve the prognosis of CVST in cSLE.

Adrenal steroidogenesis and ovarian reserve in adult childhood-onset systemic lupus erytematosus patients.

To assess overall adrenal mineralocorticoid/glucocorticoid/androgen steroidogenesis in childhood-onset systemic lupus erythematosus (cSLE) patients and the possible effect of prednisone on adrenal hormones and ovarian reserve. Fifty-one adult cSLE (ACR criteria) patients and 23 healthy controls were evaluated for adrenal steroidogenesis including mineralocorticoid (progesterone, deoxycorticosterone, aldosterone), glucocorticoid (17-OHprogesterone, 11-desoxycortisol, cortisol), and androgen (dehydroepiandrosterone-sulfate, androstenedione, total testosterone, and dihydrotestosterone) hormones. Ovarian reserve assessment included follicle-stimulating hormone (FSH), estradiol, anti-Müllerian hormone, ovarian volumes, and antral follicle count. The median of current age [29.11 (19-39.8) vs. 30.8 (19.6-42.1) years, p = 0.502] was similar in adult cSLE and controls. Regarding mineralocorticoid/glucocorticoid, the median of progesterone (p = 0.003), 17-OH progesterone (p < 0.001), and 11-desoxycortisol (p = 0.036) were significantly lower in patients compared to controls. All androgen steroidogenesis hormones were reduced in the former group [dehydroepiandrosterone-sulfate (p < 0.001), androstenedione (p = 0.001), total testosterone (p = 0.005), and dihydrotestosterone (p < 0.001)]. Further comparison of patients with and without current use of prednisone and controls revealed a predominant impact on adrenal glucocorticoid and androgen steroidogenesis with reduced levels of 17-OH progesterone [0.17 (0-0.5) vs. 0.27 (0.1-2.9) vs. 0.33 (0.1-0.8) ng/mL, p < 0.001], dehydroepiandrosterone-sulfate [0.155 (0-0.6) vs. 0.49 (0.1-1.6) vs. 1.11 (0.1-2.6) μg/mL, p < 0.001], androstenedione [0.56 (0.2-4.4) vs. 1.7 (0.5-4.5) vs. 2.33 (0.3-3.8) ng/mL, p < 0.001], total testosterone [12 (12-167) vs. 16 (12-28) vs. (16.5 (0-50) ng/d, p = 0.002], and dihydrotestosterone [92.68 (11.8-198.5) vs. 160.62 (37.9-842.1) vs. 188.3 (71.3-543.9) pg/ml, p < 0.001] in patients under this drug. In addition, patients with this therapy had reduced median ovarian volumes [4.14 (2-12) vs. 7.13 (2-25.7) vs. 5.18 (2.4-17.3) cm3, p = 0.028) that was not associated with cyclophosphamide cumulative dose (p > 0.05). The median prednisone dose was 15/mg/day (2.5-40). We provided novel evidence that cSLE patients have an overall androgen/glucocorticoid/mineralocorticoid adrenal suppression. Furthermore, low/moderate prednisone use seems to underlie these abnormalities and may also adversely affect ovarian reserve, independently of immunosuppressants. Key Points • cSLE patients have an overall androgen/glucocorticoid/mineralocorticoid adrenal suppression. • Low/moderate prednisone use may affect ovarian reserve, independently of immunosuppressants.

Clinical Team Perspectives on the Psychosocial Aspects of Transition to Adult Care for Patients With Childhood-Onset Systemic Lupus Erythematosus.

The transition from pediatric to adult care for youth with childhood-onset systemic lupus erythematosus (SLE) is a vulnerable period. Adverse outcomes during this transition include gaps in care, unscheduled health care utilization, loss of insurance, and high disease activity. The objective of this study was to examine the clinical care teams' perspective on the psychosocial factors associated with transition outcomes, which are poorly understood in this population. We conducted in-depth interviews with clinical care team members who interact with childhood-onset SLE patients during transfer from pediatric to adult rheumatology. A semistructured interview guide was used to prompt participants' perspectives about the psychosocial factors associated with the transition process for patients with childhood-onset SLE. Audio recordings were transcribed and analyzed using the constant comparative method. We stopped conducting interviews once thematic saturation was achieved. Thirteen in-depth interviews were conducted. Participants included pediatric rheumatologists (n = 4), adult rheumatologists from both academic and private practice settings (n = 4), nurses (n = 2), a nurse practitioner, a social worker, and a psychologist. We identified several themes deemed by clinical care teams as important during the transition, including the impact of the family, patient resilience and coping mechanisms, the role of mental health and emotional support, and the need for education, peer support, and social connectedness. We identified several psychosocial themes that clinical team members believe impact the transition of patients with childhood-onset SLE into adult care. The role of parental modeling, youth resilience, mental health and emotional care, improved childhood-onset SLE education, and structured peer support and social connectedness are highlighted, which may be amenable to interventions.

Predicting Macrophage Activation Syndrome in Childhood-onset Systemic Lupus Erythematosus Patients at Diagnosis.

Macrophage activation syndrome (MAS), a life-threatening inflammatory complication, is increasingly recognized in childhood-onset systemic lupus erythematosus (cSLE). It can be a challenge to differentiate active cSLE from MAS. We generated decision rules for discriminating MAS from active cSLE in newly diagnosed patients. We conducted a retrospective cohort study of consecutive, newly diagnosed, active cSLE patients with fever, requiring hospital admission to The Hospital for Sick Children from January 2003 to December 2007 (cohort 1) and January 2008 to December 2013 (cohort 2). All patients met ≥ 4 American College of Rheumatology or Systemic Lupus International Collaborating Clinics criteria, and were steroid-naïve and infection-free. MAS was diagnosed based on expert opinion. Recursive partitioning was applied to each cohort to derive a decision rule based on clinical and laboratory features, distinguishing MAS from non-MAS cSLE. Each decision rule was applied to the alternate, independent cohort. Sensitivity and specificity of these decision rules were compared to existing criteria. Cohort 1 (n = 34) and cohort 2 (n = 41) each had 10 patients with MAS. Recursive partitioning in cohort 1 identified ferritin ≥ 699 μg/L as the sole best discriminator between MAS and non-MAS patients (R2 = 0.48), and in cohort 2, ferritin ≥ 1107 μg/L was the best discriminator for MAS, followed by lymphocytes < 0.72 × 103/mm3 (R2 = 0.52). Cross-validation of our decision rules maintained 90-100% sensitivity and 65-85% specificity. Our decision rule demonstrated improved performance compared to preliminary guidelines for MAS in cSLE from the Lupus Working Group of the Paediatric Rheumatology European Society and familial hemophagocytic lymphohistiocytosis diagnostic criteria. Validation in independent cohorts is required.

Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in patients with childhood systemic lupus erythematosus: a real-world interventional multi-centre study.

This study aimed to assess the safety and immunogenicity of the quadrivalent human papillomavirus (qHPV) vaccination in childhood-onset systemic lupus erythematosus (cSLE) patients. 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. 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. 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.

Disease presentation of 1312 childhood-onset systemic lupus erythematosus: influence of ethnicity.

To evaluate the influence of ethnicity in presentation of childhood-onset systemic lupus erythematosus (cSLE) patients. 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). 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. 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.

Long-Term Clinical Outcomes in a Cohort of Adults With Childhood-Onset Systemic Lupus Erythematosus.

ObjectiveChildhood‐onset systemic lupus erythematosus (SLE) is a severe, lifelong, multisystem autoimmune disease. Long‐term outcome data are limited. This study was undertaken to identify clinical characteristics and health‐related quality of life (HRQoL) of adults with childhood‐onset SLE.MethodsPatients participated in a single study visit comprising a structured history and physical examination. Disease activity (scored using the SLE Disease Activity Index 2000 [SLEDAI‐2K]), damage (scored using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]), and HRQoL (scored using the Short Form 36 Health Survey) were assessed. Medical records were reviewed.ResultsIn total, 111 childhood‐onset SLE patients were included; the median disease duration was 20 years, 91% of patients were female, and 72% were white. Disease activity was low (median SLEDAI‐2K score 4), and 71% of patients received prednisone, hydroxychloroquine (HCQ), and/or other disease‐modifying antirheumatic drugs. The vast majority of new childhood‐onset SLE–related manifestations developed within 2 years of diagnosis. Damage such as myocardial infarctions began occurring after 5 years. Most patients (62%) experienced damage, predominantly in the musculoskeletal, neuropsychiatric, and renal systems. Cerebrovascular accidents, renal transplants, replacement arthroplasties, and myocardial infarctions typically occurred at a young age (median age 20 years, 24 years, 34 years, and 39 years, respectively). Multivariate logistic regression analysis showed that damage accrual was associated with disease duration (odds ratio [OR] 1.15, P < 0.001), antiphospholipid antibody positivity (OR 3.56, P = 0.026), and hypertension (OR 3.21, P = 0.043). Current HCQ monotherapy was associated with an SDI score of 0 (OR 0.16, P = 0.009). In this cohort, HRQoL was impaired compared to the overall Dutch population. The presence of damage reduced HRQoL scores in 1 domain. High disease activity (SLEDAI‐2K score ≥8) and changes in physical appearance strongly reduced HRQoL scores (in 4 of 8 domains and 7 of 8 domains, respectively).ConclusionThe majority of adults with childhood‐onset SLE in this large cohort developed significant damage at a young age and had impaired HRQoL without achieving drug‐free remission, illustrating the substantial impact of childhood‐onset SLE on future life.