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

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.

Chronic kidney disease in patients with childhood-onset systemic lupus erythematosus.

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.

Social impact of disease parameters and damage accrual in adult Brazilian patients with childhood-onset Systemic Lupus Erythematosus.

OBJECTIVES: To describe the frequency and investigate potential associations of unemployment, need of financial assistance and health-related quality of life in adult patients with childhood-onset Systemic Lupus Erythematosus (cSLE). METHODS: In this multicenter cross-sectional retrospective cohort study including cSLE adult patients, questionnaires were applied evaluating demographic characteristics, medical history, treatment, receipt of government financial assistance, work status, quality of life, economic classification, disease activity, and damage accrual. Disease activity and disease damage were measured at the study visit. RESULTS: Sixty-nine cSLE patients with a median age of 21 years from two Brazilian tertiary centers were included (median disease duration 9 years). Twenty-eight (40.6%) patients were unemployed and 16 (23.2%) were receiving financial assistance or retirement pension. Work unemployment was associated with higher damage scores (OR 1.83, 95% CI 1.08 to 3.09, p = 0.024), and the need of financial assistance was associated with longer disease duration (OR 1.15, 95% CI 1.00 to 1.31, p = 0.045) and worse economic score (OR 0.87, 95% CI 0.77 to 0.99, p = 0.038). Emotional health and body image perception were the most compromised domains of quality of life but showed no association with disease parameters. Disease activity, on the other hand, was inversely associated with symptoms scores (ß = -1.377, p = 0.014) and scores of adverse effects of medications (ß = -1.286, p = 0.020). CONCLUSION: cSLE is a disease with severe outcomes and high social burden that profoundly impacts patients. Damage accrual is a major contributor to unemployment during adulthood and its prevention must be central in the management of cSLE.

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

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.

Childhood-onset systemic lupus erythematosus-related antiphospholipid syndrome: A multicenter study with 1519 patients.

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.

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

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.

Autoimmune hepatitis in 847 childhood-onset systemic lupus erythematosus population: a multicentric cohort study.

OBJECTIVE: To evaluate autoimmune hepatitis (AIH) in a multicenter cohort of childhood-onset systemic lupus erythematosus (cSLE) patients. METHODS: This retrospective multicenter study included 847 patients with cSLE, performed in 10 Pediatric Rheumatology services of São Paulo state, Brazil. AIH was defined according to the International Autoimmune Hepatitis Group criteria (IAHGC). The statistical analysis was performed using the Bonferroni's correction (p < 0.0033). RESULTS: AIH in cSLE patients confirmed by biopsy was observed in 7/847 (0.8%) and all were diagnosed during adolescence. The majority occurred before or at cSLE diagnosis [5/7 (71%)]. Antinuclear antibodies were a universal finding, 43% had concomitantly anti-smooth muscle antibodies and all were seronegative for anti-liver kidney microsomal antibodies. All patients with follow-up ≥18 months (4/7) had complete response to therapy according to IAHGC. None had severe hepatic manifestations such as hepatic failure, portal hypertension and cirrhosis at presentation or follow-up. Further comparison of 7 cSLE patients with AIH and 28 without this complication with same disease duration [0 (0-8.5) vs. 0.12 (0-8.5) years, p = 0.06] revealed that the frequency of hepatomegaly was significantly higher in cSLE patients in the former group (71% vs. 11%, p = 0.003) with a similar median SLEDAI-2 K score [6 (0-26) vs. 7 (0-41), p = 0.755]. No differences were evidenced regarding constitutional involvement, splenomegaly, serositis, musculoskeletal, neuropsychiatric and renal involvements, and treatments in cSLE patients with and without AIH (p > 0.0033). CONCLUSIONS: Overlap of AIH and cSLE was rarely observed in this large multicenter study and hepatomegaly was the distinctive clinical feature of these patients. AIH occurred during adolescence, mainly at the first years of lupus and it was associated with mild liver manifestations.

Diffuse alveolar hemorrhage in childhood-onset systemic lupus erythematosus: a severe disease flare with serious outcome.

OBJECTIVE: To evaluate prevalence, clinical manifestations, laboratory abnormalities and treatment in a multicenter cohort study including 847 childhood-onset systemic lupus erythematosus (cSLE) patients with and without diffuse alveolar hemorrhage (DAH), as well as concomitant parameters of severity. METHODS: DAH was defined as the presence of at least three respiratory symptoms/signs associated with diffuse interstitial/alveolar infiltrates on chest x-ray or high-resolution computer tomography and sudden drop in hemoglobin levels. Statistical analysis was performed using Bonferroni correction (p < 0.0022). RESULTS: DAH was observed in 19/847 (2.2%) cSLE patients. Cough/dyspnea/tachycardia/hypoxemia occurred in all cSLE patients with DAH. Concomitant parameters of severity observed were: mechanical ventilation in 14/19 (74%), hemoptysis 12/19 (63%), macrophage activation syndrome 2/19 (10%) and death 9/19 (47%). Further analysis of cSLE patients at DAH diagnosis compared to 76 cSLE control patients without DAH with same disease duration [3 (1-151) vs. 4 (1-151) months, p = 0.335], showed higher frequencies of constitutional involvement (74% vs. 10%, p < 0.0001), serositis (63% vs. 6%, p < 0.0001) and sepsis (53% vs. 9%, p < 0.0001) in the DAH group. The median of disease activity score(SLEDAI-2 K) was significantly higher in cSLE patients with DAH [18 (5-40) vs. 6 (0-44), p < 0.0001]. The frequencies of thrombocytopenia (53% vs. 12%, p < 0.0001), intravenous methylprednisolone (95% vs. 16%, p < 0.0001) and intravenous cyclophosphamide (47% vs. 8%, p < 0.0001) were also significantly higher in DAH patients. CONCLUSIONS: This was the first study to demonstrate that DAH, although not a disease activity score descriptor, occurred in the context of significant moderate/severe cSLE flare. Importantly, we identified that this condition was associated with serious disease flare complicated by sepsis with high mortality rate.

Symptomatic polyautoimmunity at diagnosis of 1463 childhood-onset lupus: A Brazilian multicenter study.

OBJECTIVE: To evaluate symptomatic polyautoimmunity (PA) at childhood-onset systemic lupus erythematosus(cSLE) diagnosis, and its association with demographic data, disease activity, clinical manifestations and laboratorial abnormalities in a large Brazilian cSLE population. METHODS: A multicenter retrospective study was performed in 1463 cSLE(ACR criteria) patients from 27 Pediatric Rheumatology services. Symptomatic PA was defined according to the presence of more than one concomitant autoimmune disease(AD) and symptomatic multiple autoimmune syndrome(MAS) was defined as three or more AD. An investigator meeting was held to define the protocol. Demographic data, SLICC classification criteria and SLEDAI-2K were evaluated. RESULTS: At cSLE diagnosis symptomatic PA was observed in 144/1463(9.8%) and symptomatic MAS occurred in solely 10/1463(0.7%). In the former group the more frequently observed associated AD were Hashimoto thyroiditis n = 42/144(29%), antiphospholipid syndrome n = 42/144(29%), autoimmune hepatitis n = 26/144(18%) and type 1 diabetes mellitus n = 23/144(15.9%). Further comparisons between cSLE patients with and without PA showed a higher median age(p = 0.016) and lower mean SLICC criteria (p = 0.039) in those with PA. Additionally, these cSLE patients had less renal involvement(35% vs. 44%, p = 0.038) and red blood cell cast(6% vs. 12%, p = 0.042) and more antiphospholipid antibodies(29% vs. 15%, p < 0.0001). CONCLUSIONS: Approximately 10% of cSLE had symptomatic PA at diagnosis, particularly endocrine autoimmune disorders and antiphospholipid syndrome. Lupus was characterized by a mild disease onset and MAS was infrequently evidenced. Further studies are necessary to determine if this subgroup of cSLE patients have a distinct genetic background with a less severe disease and a better long-term outcome.

Anti-RO/SSA and anti-La/SSB antibodies: Association with mild lupus manifestations in 645 childhood-onset systemic lupus erythematosus.

BACKGROUND: To our knowledge there are no studies assessing anti-Ro/SSA and anti-La/SSB autoantibodies in a large population of childhood-systemic lupus erythematosus (cSLE) patients. METHODS: This was a retrospective multicenter cohort study performed in 10 Pediatric Rheumatology services, São Paulo state, Brazil. Anti-Ro/SSA and anti-La/SSB antibodies were measured by enzyme linked immunosorbent assay (ELISA) in 645 cSLE patients. RESULTS: Anti-Ro/SSA and anti-La/SSB antibodies were evidenced in 209/645 (32%) and 102/645 (16%) of cSLE patients, respectively. Analysis of cSLE patients with and without anti-Ro/SSA antibodies revealed higher frequencies of malar rash (79% vs. 71%, p=0.032), photosensitivity (73% vs. 65%, p=0.035), cutaneous vasculitis (43% vs. 35%, p=0.046) and musculoskeletal involvement (82% vs. 75%, p=0.046) in spite of long and comparable disease duration in both groups (4.25 vs. 4.58years, p=0.973). Secondary Sjögren syndrome was observed in only five patients with this antibody (2.5% vs. 0%, p=0.0035), two of them with concomitant anti-La/SSB. The presence of associated autoantibodies: anti-Sm (50% vs. 30%, p<0.0001), anti-RNP (39% vs. 21%, p<0.0001) and anti-ribossomal P protein (46% vs. 21%, p=0.002) was also significantly higher in patients with anti-Ro/SAA antibodies. Further evaluation of cSLE patients with the presence of anti-La/SSB antibodies compared to those without these autoantibodies showed that the frequency of alopecia (70% vs. 51%, p=0.0005), anti-Sm (59% vs. 31%, p<0.0001) and anti-RNP (42% vs. 23%, p<0.0001) were significantly higher in the former group. CONCLUSIONS: Our large multicenter cohort study provided novel evidence in cSLE that anti-Ro/SSA and/or anti-La/SSB antibodies were associated with mild manifestations, particularly cutaneous and musculoskeletal. Secondary Sjögren syndrome was rarely observed in these patients, in spite of comparable frequencies of anti-Ro/SSA and/or anti-La/SSB reported for adult SLE.