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.

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.

Autoimmune endocrine disorders and coeliac disease in children and adolescents with juvenile idiopathic arthritis and rheumatic fever.

OBJECTIVES: There have been few studies on the association between childhood autoimmune and rheumatic diseases. Therefore, this study aims to assess the frequency of autoimmune thyroiditis (AT), coeliac disease (CD) and type 1 diabetes mellitus (T1DM) in children and adolescents with juvenile idiopathic arthritis (JIA) and rheumatic fever (RF). METHODS: This cross-sectional study includes 53 patients with JIA, 66 patients with RF and 40 healthy subjects controls. All subjects were evaluated for thyrotropin (TSH), triiodothyronine (T3), free thyroxine (FT4), antithyroglobulin (Tg) and antiperoxidase antibodies, fasting glucose, C-peptide, anti-glutamic acid decarboxylase (GAD), anti-islet cell (IA) and antitransglutaminase IgA (tTG) antibodies. Patients with thyroid dysfunction, positive anti-thyroid antibodies or tTG underwent thyroid ultrasonography and jejunal biopsy, respectively. RESULTS: In group 1 (n=53), 21 patients presented thyroid disorders (40%; 42% oligoarticular), either subclinical hypothyroidism (13%) or positive anti-thyroid antibodies (26%, 50% oligoarticular), significantly higher than in control group (p<0.009, OR=10.5, CI 1.29-85.2). In group 2 (n=66), thyroid disorders were identified in 11 patients, four (6%) with subclinical hypothyroidism and seven (11%) with positive anti-thyroid antibodies (p=0.06, compared with the control group). There were no cases of clinical overt hypothyroidism, positive anti-GAD or anti-IA, nor changes in serum C-peptide and glycemia. CD was confirmed in one patient from each group. CONCLUSIONS: Patients with JIA (especially the oligoarticular form) and RF should be investigated for thyroid dysfunction. Longitudinal studies could establish screening protocols for CD in patients with JIA and RF. The cost-effectiveness of T1DM screening is not justified in this population.

Hormone profile in juvenile systemic lupus erythematosus with previous or current amenorrhea.

To identify the underlying mechanism of amenorrhea in juvenile systemic lupus erythematosus (JSLE) patients, thirty-five (11.7%) JSLE patients with current or previous amenorrhea were consecutively selected among the 298 post-menarche patients followed in 12 Brazilian pediatric rheumatology centers. Pituitary gonadotrophins [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)] and estradiol were evaluated in 32/35 patients, and prolactin and total testosterone in 29/35 patients. Patient's medical records were carefully reviewed according to demographic, clinical and therapeutic findings. The mean duration of amenorrhea was 7.2 ± 3.6 months. Low FSH or LH was observed in 7/32 (22%) JSLE patients and normal FSH or LH in 25 (78%). Remarkably, low levels of FSH or LH were associated with higher frequency of current amenorrhea (57% vs. 0%, P = 0.001), higher median disease activity (SLEDAI) and damage (SLICC/ACR-DI) (18 vs. 4, P = 0.011; 2 vs. 0, P = 0.037, respectively) and higher median current dose of prednisone (60 vs. 10 mg/day, P = 0.0001) compared to normal FSH or LH JSLE patients. None of them had decreased ovarian reserve and premature ovarian failure. Six of 29 (21%) patients had high levels of prolactin, and none had current amenorrhea. No correlations were observed between levels of prolactin and SLEDAI, and levels of prolactin and SLICC/ACR-DI scores (Spearman's coefficient). We have identified that amenorrhea in JSLE is associated with high dose of corticosteroids indicated for active disease due to hypothalamic-pituitary-ovary axis suppression.

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.

Acute suppurative thyroiditis as the initial presentation of juvenile systemic lupus erythematosus.

We report an unusual case of acute suppurative thyroiditis associated with juvenile systemic lupus erythematosus (JSLE) onset. A 10 year-old girl presented with a painful voluminous swelling in the anterior cervical region with fever and dysphagia. She also had dysphonia, myalgia, swelling of the small joints of the hands, weight loss, and erythematous malar rash. Thyroid ultrasonography disclosed an ill-defined solid cystic area containing abundant echoes in suspension suggestive of an abscess in both lobes compatible with suppurative bacterial thyroiditis. Fine-needle aspiration biopsy showed a secretion with positive culture for Staphylococcus aureus. Endoscopic evaluation did not demonstrate pyriform sinus fistula. The child had no previous thyroid disease. Hormonal evaluation showed thyrotrophin (TSH) 13 microIU/ml and free thyroxine (FT4) 0.4 ng/dl. After laboratory confirmation of JSLE, high dose 'pulse' therapy was performed with methylprednisolone (30 mg/kg/day for 3 days), followed by prednisone (2 mg/kg/day). The acute thyroiditis was treated with oxacillin, metronidazole and amikacin which ameliorated the symptoms of infection followed by normalization of thyroid function with levothyroxine. In spite of the known association between autoimmune diseases and thyroid disorders, the coexistence of suppurative thyroiditis and JSLE is rare, generally occurring during the course of lupus and not at diagnosis.

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.

Gastrointestinal manifestations as initial presentation of acute leukemias in children and adolescents.

OBJECTIVE: this study aimed to determine the prevalence and characteristics of gastrointestinal manifestations on initial clinical presentation of acute leukemias (AL) in childhood. MATERIAL AND METHODS: this is a retrospective and descriptive study that assessed medical records of 354 patients with AL from January 1995 to December 2004. RESULTS: acute lymphoid leukemia (ALL) was diagnosed in 273 (77.1%) patients and acute non-lymphocytic leukemia (AML) in 81 (22.9%). There were 210 males (59.4%) and 144 females (40.6%). The most common presenting features were: abdominal pain (19.5% in ALL and 11.8% in AML), nausea and vomiting (14.9 in ALL and 14% in AML), abdominal distention (18.5 in ALL and 8.6% in AML; p 0.024), constipation (5% in ALL and 6.5% in AML), diarrhea (3.6% in ALL and 11.8% in AML; p 0.03%), and gastrointestinal bleeding (7.9% in ALL and 9.7% in AML). Ultrasound scanning was made in 61.1% and hepatomegaly was found on 33.6% and esplenomegaly on 28.5% of the patients with AL. Seventy-seven (21.7%) and 15 (4.2%) patients received nonsteroidal anti-inflammatory drugs and glucocorticoids before the diagnostic of AL. An association is well-defined between abdominal symptoms like nausea, vomiting and pain and use of this therapy but this association did not occurred clearly in this study. CONCLUSIONS: gastrointestinal symptoms are not very well-documented as initial manifestation of leukemia in children and should be considered on the differential diagnosis of gastrointestinal symptoms of unknown etiology in children.

Pregnancy outcome in juvenile systemic lupus erythematosus: a Brazilian multicenter cohort study.

OBJECTIVE: To determine pregnancy outcome and fetal loss risk factors in patients with juvenile systemic lupus erythematosus (JSLE). METHODS: A total of 315 female patients with JSLE followed in 12 Brazilian pediatric rheumatology centers were consecutively selected. Menarche was observed in 298 (94.6%) patients. Patients' medical records were reviewed for pregnancy outcomes and demographic, clinical, and therapeutic data. RESULTS: A total of 24 unplanned pregnancies occurred in 298 (8%) patients. The outcomes were 5 (21%) early fetal losses (prior to 16 wks gestation), 18 (75%) live births, and 1 (4%) death due to preeclampsia and premature birth. The frequencies of active diffuse proliferative glomerulonephritis, proteinuria > or = 0.5 g/day, and arterial hypertension at the beginning of pregnancy were higher in pregnancies resulting in fetal losses than in live births [60% vs 5% (p = 0.02), 60% vs 5% (p = 0.02), 60% vs 5% (p = 0.02), respectively]. JSLE pregnancies with fetal losses had a significantly higher mean SLE Disease Activity Index 2000 (SLEDAI-2K) at the start of pregnancy compared with those with live births (9.40 +/- 7.47 vs 3.94 +/- 6.00; p = 0.049). Four pregnancies were inadvertently exposed to intravenous cyclophosphamide therapy for renal involvement despite contraceptive prescriptions, resulting in fetal loss in 3 (p = 0.02). In multivariate analysis only intravenous cyclophosphamide use at start of pregnancy (OR 25.50, 95% CI 1.72-377.93, p = 0.019) remained as an independent risk factor for fetal loss. CONCLUSION: We identified immunosuppressive therapy as the major contributing factor for fetal loss in JSLE, reinforcing the importance of contraception.

Gastrointestinal manifestations as initial presentation of acute leukemias in children and adolescents / Manifestaciones gastrointestinales como presentación de las leucemias agudas en niños y adolescentes

OBJECTIVE: this study aimed to determine the prevalence and characteristics of gastrointestinal manifestations on initial clinical presentation of acute leukemias (AL) in childhood. MATERIAL AND METHODS: this is a retrospective and descriptive study that assessed medical records of 354 patients with AL from January 1995 to December 2004. RESULTS: acute lymphoid leukemia (ALL) was diagnosed in 273 (77.1%) patients and acute non-lymphocytic leukemia (AML) in 81 (22.9%). There were 210 males (59.4%) and 144 females (40.6%). The most common presenting features were: abdominal pain (19.5% in ALL and 11.8% in AML), nausea and vomiting (14.9 in ALL and 14% in AML), abdominal distention (18.5 in ALL and 8.6% in AML; p 0.024), constipation (5% in ALL and 6.5% in AML), diarrhea (3.6% in ALL and 11.8% in AML; p 0.03%), and gastrointestinal bleeding (7.9% in ALL and 9.7% in AML). Ultrasound scanning was made in 61.1% and hepatomegaly was found on 33.6% and esplenomegaly on 28.5% of the patients with AL. Seventy-seven (21.7%) and 15 (4.2%) patients received nonsteroidal anti-inflammatory drugs and glucocorticoids before the diagnostic of AL. An association is well-defined between abdominal symptoms like nausea, vomiting and pain and use of this therapy but this association did not occurred clearly in this study. CONCLUSIONS: gastrointestinal symptoms are not very well-documented as initial manifestation of leukemia in children and should be considered on the differential diagnosis of gastrointestinal symptoms of unknown etiology in children.

Objetivo: el objetivo del estudio fue determinar la prevalencia y las características de las manifestaciones gastrointestinales en la presentación clínica inicial de las leucemias linfoides agudas (LLA) en la infancia. Materialy métodos: se trata de un estudio descriptivo y retrospectivo que evaluó los registros médicos de 354 pacientescon LLA de enero de 1995 a diciembre de 2004. Resultados: la (LLA) ha sido diagnosticada en 273 (77,1%) pacientes y leucemia mieloide aguda (LMA) en 81 (22,9%). Hubo 210 niños (59,4%) y 144 niñas (40,6%). Los síntomas más comunes de presentaciónhan sido los siguientes: dolor abdominal(19,5% en LLA y 11,8% en el LMA), náuseas y vómitos (14,9 en LLA y 14% en LMA, P 0.024), distensión abdominal (18,5 en LLA y 8,6% en LMA, p 0,024), estreñimiento (5% en LLA y 6,5% en LMA), diarrea (3,6% en LLA y 11,8% en LMA, p 0,03%) y hemorragia gastrointestinal (7,9% en LLA y 9,7% enLMA). La ecografía fue realizada en 61,1% de los pacientes encontrándose hepatomegalia en 33,6% y esplenomegalia en 28,5% con LLA. Setenta y siete (21,7%) y 15 (4,2%) pacientes recibieron los fármacos antiinflamatorios no esteroides y glucocorticoides antes del diagnóstico de LLA. Hay una asociación bien definidaentre síntomas abdominales como náuseas, vómitos y dolor y el uso de esta terapia pero esta asociación no seprodujo claramente en este estudio. Conclusiones: las manifestaciones gastrointestinales no están bien documentadas como manifestaciones iniciales de la leucemia en los niños y debe considerarse en el diagnóstico diferencial de los síntomas gastrointestinales de etiología desconocida en estas edades.

Imunodeficiência primária: quando investigar, como diagnosticar / Primary immunodeficiency: when to investigate, how to diagnose

O sistema imunológico normal possui duas ações de trabalho para manter a função normal do hospedeiro: a resposta imunológica inespecífica e a específica. Qualquer desequilíbrio em alguma parte da resposta imunológica pode resultar em uma inabilidade de controlar a infecção com doença subjacente. As imunodeficiências incluem uma variedade de doenças que deixam os pacientes mais susceptíveis a infecções e são classificadas em primárias e secundárias. Imunodeficiência primária deve ser suspeitada em todo o paciente com infecções recorrentes inexplicadas, infecções oportunistas, infecções que não respondem à terapia e que apresentam déficit pôndero-estatural. As imunodeficiências primárias incluem as doenças da imunidade humoral, os defeitos da célula T, os defeitos combinados da célula B e T, as doenças dos fagócitos e as deficiências do complemento..

The normal immune system has two arms work to maintain normal host function: nonspecific responses (innate immune responses) and immune specific response. Disruption of any part of the immune response can result in an inability to control infection and subsequent illness. Immunodeficiencies include a variety of disorders that render patients more susceptible to infections and are classified in primary and secondary. Primary immunodeficiency is suspected on the patient with unexplained recurrent infections, infections with opportunistic pathogens, infection with no response to therapy and failure to thrive. Common primary immunodeficiencies include disorders of humoral immunity, T-cell defects and combined B and T-cell defects, phagocytic disorders and complement deficiencies...