Publications by authors named "Clovis A Silva"

169 Publications

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

Lupus 2021 Oct 25:9612033211054397. Epub 2021 Oct 25.

Division of Rheumatology, 117265Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil.

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%, = 0.0004) and neuropsychiatric domain (21% vs 7%, < 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, < 0.001) or neuropsychiatric damage (OR 9.480, 95% CI 5.481-16.399, <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, = 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), <0.001). 2019-EULAR/ACR score >25 was associated with more overall (SDI ≥ 1) (38% vs 25%, = 0.0002) and renal damage (11% vs 5%, = 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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http://dx.doi.org/10.1177/09612033211054397DOI Listing
October 2021

Systemic autoimmune myopathies: A prospective phase 4 controlled trial of an inactivated virus vaccine against SARS-CoV-2.

Rheumatology (Oxford) 2021 Oct 19. Epub 2021 Oct 19.

Division of Rheumatology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, SP, Brazil (BR).

Objectives: To evaluate immunogenicity and safety of an inactivated SARS-CoV-2 vaccine in systemic autoimmune myopathies (SAMs) and the possible influence of baseline disease parameters, comorbidities, and therapy on immune response.

Methods: This prospective controlled study included 53 patients with SAMs and 106 non-immunocompromised control group (CTRL). All participants received two doses of the Sinovac-CoronaVac vaccine (28-day interval). Immunogenicity was assessed by anti-SARS-CoV-2 S1/S2 IgG seroconversion (SC), anti-S1/S2 IgG geometric mean titer (GMT), factor increase GMT (FI-GMT), neutralizing antibodies (NAb) positivity, and median neutralizing activity after each vaccine dose (D0 and D28) and six weeks after the second dose (D69). Participants with pre-vaccination positive IgG serology and/or NAb and those with RT-PCR confirmed COVID-19 during the protocol were excluded from immunogenicity analysis.

Results: Patients and CTRL had comparable sex (P>0.99) and age (P=0.90). Immunogenicity of 37 patients and 79 CTRL naïve participants revealed at D69, a moderate but significantly lower SC (64.9% vs. 91.1%, P<0.001), GMT [7.9 (95%CI 4.7-13.2) vs. 24.7 (95%CI 30.0-30.5) UA/mL, P<0.001] and frequency of NAb (51.4% vs. 77.2%, P<0.001) in SAMs compared to CTRL. Median neutralizing activity was comparable in both groups [57.2% (IQR 43.4-83.4) vs. 63.0% (IQR 40.3-80.7), P=0.808]. Immunosuppressives were less frequently used among NAb+ patients vs. NAb- patients (73.7% vs. 100%, P=0.046). Type of SAMs, disease status, other drugs or comorbidities did not influence immunogenicity. Vaccine-related adverse events were mild with similar frequencies in patients and CTRL (P>0.05).

Conclusion: Sinovac-CoronaVac is safe and has a moderate short-term immunogenicity in SAMs, but reduced compared to CTRL. We further identified that immunosuppression is associated with diminished NAb positivity.

Clinical Trial Registration Number: #NCT04754698.
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http://dx.doi.org/10.1093/rheumatology/keab773DOI Listing
October 2021

Defining renal remission in an international cohort of 248 children and adolescents with lupus nephritis.

Rheumatology (Oxford) 2021 Oct 9. Epub 2021 Oct 9.

Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Objective: We studied the rate of remission of lupus nephritis (LN) in an international cohort of 248 children and adolescents with biopsy proven LN. Five different definitions from scientific studies and the definitions recommended by the American College of Rheumatology and Kidney Disease Improving Global Outcomes (KDIGO) were used.

Methods: Anonymized clinical data in patients with biopsy proven LN class ≥ III (International Society of nephrology/Royal Pathology Society-ISN/RPS) diagnosed and treated in the last 10 years in 23 international centers from 10 countries were collected. We compared the rate of patients in complete and partial remission applying the different definitions.

Results: The mean age at diagnosis was 11 years and 4 month and 177 were females.The number of patients in complete and partial remission varied a lot between the different definitions. At 24 months, between 50% and 78.8% of the patients were in full remission as defined by the different criteria. The number of patients in partial remission was low, between 2.3% and 25%. No difference in achieved remission was found between boys and girls or between children and adolescents (P > 0.05). Patients with East Asian ethnicity reached remission more often than other ethnicities (P = 0.03-0.0008). Patients treated in high income countries showed a higher percentage of complete remission at 12 and 24 months (P = 0.002-0.000001).

Conclusion: The rate of children and adolescents with LN achieving remission varied hugely with the definition used. Our results give important information for long awaited treatment studies in children and young people.
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http://dx.doi.org/10.1093/rheumatology/keab746DOI Listing
October 2021

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

J Clin Rheumatol 2021 Aug 5. Epub 2021 Aug 5.

From the Pediatric Rheumatology Unit Pediatric Psychiatric Unit, Instituto da Criança e do Adolescente Department of Psychiatry Division of Rheumatology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.

Objective: The aim of this study was to assess mental health in Latin American pediatric rheumatologists (LAPRs) during the COVID-19 pandemic.

Methods: 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.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1097/RHU.0000000000001782DOI Listing
August 2021

Immunogenicity and safety of the CoronaVac inactivated vaccine in patients with autoimmune rheumatic diseases: a phase 4 trial.

Nat Med 2021 10 30;27(10):1744-1751. Epub 2021 Jul 30.

Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil.

CoronaVac, an inactivated SARS-CoV-2 vaccine, has been approved for emergency use in several countries. However, its immunogenicity in immunocompromised individuals has not been well established. We initiated a prospective phase 4 controlled trial (no. NCT04754698, CoronavRheum) in 910 adults with autoimmune rheumatic diseases (ARD) and 182 age- and sex-frequency-matched healthy adults (control group, CG), who received two doses of CoronaVac. The primary outcomes were reduction of ≥15% in both anti-SARS-CoV-2 IgG seroconversion (SC) and neutralizing antibody (NAb) positivity 6 weeks (day 69 (D69)) after the second dose in the ARD group compared with that in the CG. Secondary outcomes were IgG SC and NAb positivity at D28, IgG titers and neutralizing activity at D28 and D69 and vaccine safety. Prespecified endpoints were met, with lower anti-SARS-Cov-2 IgG SC (70.4 versus 95.5%, P < 0.001) and NAb positivity (56.3 versus 79.3%, P < 0.001) at D69 in the ARD group than in the CG. Moreover, IgG titers (12.1 versus 29.7, P < 0.001) and median neutralization activity (58.7 versus 64.5%, P = 0.013) were also lower at D69 in patients with ARD. At D28, patients with ARD presented with lower IgG frequency (18.7 versus 34.6%, P < 0.001) and NAb positivity (20.6 versus 36.3%, P < 0.001) than that of the CG. There were no moderate/severe adverse events. These data support the use of CoronaVac in patients with ARD, suggesting reduced but acceptable short-term immunogenicity. The trial is still ongoing to evaluate the long-term effectiveness/immunogenicity.
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http://dx.doi.org/10.1038/s41591-021-01469-5DOI Listing
October 2021

International Consensus For The Dosing Of Corticosteroids In Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis.

Arthritis Rheumatol 2021 Jul 19. Epub 2021 Jul 19.

Department of Pediatrics, Sao Paulo State University (UNESP), Botucatu, Brazil.

Objective: To develop a Standardized Steroid dosing Regimen (SSR) by physicians treating childhood-onset systemic lupus erythematosus (cSLE) complicated by lupus nephritis (LN), using consensus formation methodology.

Methods: Parameters influencing corticosteroid (CS) dosing were identified (Step-1). Data from children with proliferative LN were used to generate Patient Profiles (PP) (Step-2). Physicians rated change in activity of renal and extra-renal cSLE between two consecutive visits and proposed CS dosing (Step-3). Using PP ratings, the SSR was developed (Step-4) with refinements achieved in a physician focus group (Step-5). A second type of PP describing cSLE course for ≥4 months since kidney biopsy were rated to validate the SSR-recommended oral and intravenous CS-dosages (Step-6). PP adjudication was based on majority ratings for both renal and extra-renal disease courses, and consensus level was set at 80%.

Results: Degree of proteinuria, estimated glomerular filtration rate, change in renal and extra-renal disease activity, and time since kidney biopsy influenced CS dosing (Steps-1/2). Considering these parameters in 5,056 PP-ratings from 103 raters, and renal and extra-renal course definitions, CS-dosing rules of the SSR were developed (Steps-3-5). Validation of the SSR for up to 6 months post kidney biopsy was achieved with 1,838 PP-ratings from 60 raters who achieved consensus for oral and intravenous CS dosage as per the SSR (Step-6).

Conclusion: The SSR represents an international consensus on CS dosing for use in patients with cSLE and proliferative LN. The SSR is anticipated to be used for clinical care and standardize CS-dosage during clinical trials.
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http://dx.doi.org/10.1002/art.41930DOI Listing
July 2021

UHPLC-MS/MS Method for Determination of Hydroxychloroquine and Its Main Metabolites in Oral Fluid and Whole Blood for Therapeutic Drug Monitoring.

J Appl Lab Med 2021 07;6(4):868-880

Rheumatology Division Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.

Background: Hydroxychloroquine (HCQ) blood levels are used to monitor efficacy, safety, and patient adherence during treatment. Oral fluid has emerged as an alternative noninvasive, easily accessible, and low-complexity matrix for drug monitoring. However, there is no analytical method to measure HCQ in oral fluid. Therefore, we developed and validated an ultra-high-performance liquid chromatography-tandem mass (UHPLC-MS/MS) method for the measurement of HCQ and its main metabolites in oral fluid and compared to whole blood.

Methods: Ten microliters of matrices were used for sample preparation by protein precipitation with acetonitrile followed by online solid phase extraction. The validation process included assessment of lower limit of quantification, linearity, precision, recovery, matrix effect, interferences assessment, carryover, and sample dilution validation.

Results: The lower limit of quantification was 50 ng/mL for HCQ and metabolites in both oral fluid and whole blood. The calibration curve was linear from 50 to 2000 ng/mL (r2 = 0.999). The coefficient of variation for precision assay was 1.2% to 9.7% for intraday and 1.1% to 14.2% for interday for both HCQ and metabolites in oral fluid and whole blood samples at 150, 750, and 1250 ng/mL. The recovery was 85.3% to 118.5% for 150, 750, and 1250 ng/mL of HCQ and metabolites in both oral fluid and whole blood. Dilution factor up to 5-fold was validated for concentrations higher than the upper limit of quantification.

Conclusions: The validated method is specific, precise, and accurate to determine the analytical range for therapeutic monitoring of HCQ and its main metabolites in oral fluid and blood.
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http://dx.doi.org/10.1093/jalm/jfab031DOI Listing
July 2021

IS PET/MRI A RELIABLE TOOL FOR DETECTING VASCULAR ACTIVITY IN TREATED CHILDHOOD-ONSET TAKAYASU'S ARTERITIS (C-TA)? A MULTICENTER STUDY.

Rheumatology (Oxford) 2021 Mar 15. Epub 2021 Mar 15.

Paediatric Rheumatology Unit, Paediatrics Department, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.

Objectives: To assess whether 18F-fluordeoxiglucose-positron emission tomography/magnetic resonance imaging (18F-FDG-PET/MRI) with angiographic sequences can contribute to detecting vessel wall inflammation in patients with childhood-onset Takayasu's arteritis (c-TA) under immunosuppressive therapy.

Methods: Three-centre cross-sectional study was conducted. 18F-FDG-PET/MRI scans were performed in c-TA patients and in oncologic patients, who served as the control group. Clinical and laboratorial characteristics were also analysed.

Results: Seventeen c-TA patients (65% females) between the ages of 6 and 21 years, mean disease duration of 9.4 years were recruited. Only one patient presented clinical disease activity, and six (35.6%) had increased erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) levels. The most frequent magnetic resonance angiography (MRA) findings were stenosis and thickening, observed in 82.4% and 70.6% of c-TA patients, respectively. 18F-FDG-PET revealed 18F-FDG uptake higher than the liver in at least one arterial segment in 15 (88.2%) patients in a qualitative analysis and median standardized uptake value (SUVmax) of 3.22 (2.76-3.69) in a semi-quantitative analysis. c-TA patients presented significantly higher SUVmax than oncologic patients (p < 0.001). A positive correlation between SUVmax and CRP levels (Rho=0.528; p=0.029) was evidenced.

Conclusion: A state-of-the-art imaging modality was used in c-TA patients and revealed a strong arterial FDG uptake even in patients in apparent remission. We suppose that this finding may represent a silent activity in the vessel wall; however, we cannot exclude the possibility of arterial remodelling. Importantly, a negative imaging scan may help in immunosuppression withdrawal in daily clinical practice.
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http://dx.doi.org/10.1093/rheumatology/keab255DOI Listing
March 2021

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

Clin Rheumatol 2021 Sep 13;40(9):3651-3658. Epub 2021 Mar 13.

Pediatric Rheumatology Unit, Children's Institute, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, Sao Paulo, SP, 05403-000, Brazil.

Objective: 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.

Methods: 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.

Results: 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) cm, 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).

Conclusions: 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.
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http://dx.doi.org/10.1007/s10067-021-05677-9DOI Listing
September 2021

Laboratory-confirmed pediatric COVID-19 in patients with rheumatic diseases: A case series in a tertiary hospital.

Lupus 2021 04 2;30(5):856-860. Epub 2021 Mar 2.

Pediatric Rheumatology Unit, Instituto da Criança e do Adolescente, Hospital das Clinicas HCFMUSP, Faculdade Medicina, Universidade de Sao Paulo, SP, BR.

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http://dx.doi.org/10.1177/0961203321998427DOI Listing
April 2021

Hydroxychloroquine blood levels in stable lupus nephritis under low dose (2-3 mg/kg/day): 12-month prospective randomized controlled trial.

Clin Rheumatol 2021 Jul 24;40(7):2745-2751. Epub 2021 Jan 24.

Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Arnaldo, 455, 3° andar, sala 3192, Cerqueira César, Sao Paulo, SP, 01246-903, Brazil.

Introduction: The American Academy of Ophthalmology (2016-AAO) recommended hydroxychloroquine (HCQ) dose not to exceed 5 mg/kg/day (real body weight). Recently, it was reported that prescribed 2016-AAO dose provided adequate HCQ levels for most lupus nephritis (LN) patients, with low flare risk. However, the minimum HCQ dose required to keep adequate levels is unknown.

Objectives: To evaluate if a further reduction in 2016-AAO dose (2-3 mg/kg/day) would sustain 12-month HCQ levels in LN patients with stable inactive disease.

Methods: Seventy-three stable LN patients under prescribed full HCQ 2016-AAO dose for ≥6 months and adequate baseline HCQ levels (≥613.5 ng/mL) were divided in two groups: reduced 2016-AAO dose (2-3 mg/kg/day), n = 32, and full 2016-AAO dose (5 mg/kg/day), n = 41. All patients were assessed at baseline, 3, 6, and 12 months. HCQ levels were measured by liquid chromatography-tandem mass spectrometry. Flare was defined as augment ≥ 3 in SLE Disease Activity Index-2000 and/or change in treatment. Rigorous clinical/laboratorial surveillance was performed.

Results: Prospective evaluation revealed for reduced 2016-AAO dose group a decrease of HCQ levels from baseline to 3 months (1,404.9 ± 492.0 vs. 731.6 ± 385.0 ng/mL, p < 0.01), and sustained levels at 6 months (p = 0.273) and 12 months (p = 0.091) compared to 3 months. For the full 2016-AAO dose group, a decrease occurred only from baseline to 12 months (1343.5 ± 521.5 vs. 991.6 ± 576.3 ng/mL, p < 0.001). Frequencies of patients with inadequate levels at 6 months was higher in reduced 2016-AAO group than full 2016-AAO dose (59% vs. 24%, p = 0.005), as well as at 12 months (66% vs. 32%, p = 0.002). Six-month and 12-month flare frequencies were comparable for both groups (p > 0.05).

Conclusions: Prescribed HCQ low-dose regimen (2-3 mg/kg/day) does not sustain, for most patients, 6- and 12-month adequate HCQ levels. Full 2016-AAO dose maintained HCQ levels way above this limit.

Trail Registration: ClinicalTrials.gov : NCT03122431, registered on April 20, 2017 Key Points • Reduced American Academy of Ophthalmology (2016-AAO) hydroxychloroquine (HCQ) dose (2-3 mg/kg/day, real body weight) is unable to sustain HCQ blood levels within the safe cut-off defined for flare risk. • Full 2016-AAO dose (5 mg/kg/day) maintains a safe pattern of HCQ levels up to 12 months.
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http://dx.doi.org/10.1007/s10067-021-05600-2DOI Listing
July 2021

Differences among Severe Cases of Sars-CoV-2, Influenza, and Other Respiratory Viral Infections in Pediatric Patients: Symptoms, Outcomes and Preexisting Comorbidities.

Clinics (Sao Paulo) 2020 30;75:e2273. Epub 2020 Nov 30.

Departamento de Pediatria, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR.

Objectives: Previous studies focusing on pediatric patients hospitalized with severe coronavirus disease 2019 (COVID-19) have been limited to small case series. We aimed to evaluate the characteristics of a large population of pediatric patients with severe COVID-19 and compare them with patients with severe cases of influenza and other respiratory viruses (ORV).

Methods: We performed a cross-sectional study of Brazilian data from the National Epidemiological Surveillance Information System, gathered from January 1st to July 14th, 2020. The sample included 4,784 patients (2,570 with confirmed COVID-19, 659 with influenza, 1,555 with ORV). Outcome measures included clinical features, preexisting comorbidities, pediatric intensive care unit admissions, need for ventilatory support, and death.

Results: Compared with the influenza and ORV groups, the COVID-19 group had a higher proportion of newborns and adolescents, as well as lower frequencies of fever, cough, dyspnea, respiratory distress, and desaturation. Although use of invasive ventilatory support was similar among groups, death rate was highest for COVID-19 (15.2% vs. 4.5% vs. 3.2%, p<0.001), with death risk more than three times the other groups (adjusted OR=3.7 [95% CI 2.5-5.6]). The presence of two or more comorbidities further increased this risk (OR=4.8 [95% CI 3.5-6.6]). Preexisting comorbidities were reported in 986 patients with severe COVID-19 (38%). Mortality rate among COVID-19 patients was significantly higher for almost all comorbidities reported.

Conclusion: Severe COVID-19 had a higher mortality rate than other viral respiratory illnesses, despite the lower frequency of fever, cough, dyspnea, respiratory distress, and desaturation. Death risk was strongly associated with preexisting comorbidities.
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http://dx.doi.org/10.6061/clinics/2020/e2273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688070PMC
December 2020

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

Autoimmun Rev 2020 Dec 22;19(12):102693. Epub 2020 Oct 22.

Pediatric Rheumatology Unit, Federal University of Pernambuco, Recife, BR, Brazil.

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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http://dx.doi.org/10.1016/j.autrev.2020.102693DOI Listing
December 2020

Abatacept induced long-term non-progressive reduction in gamma-globulins and autoantibodies: dissociation from disease activity control.

Clin Rheumatol 2020 Jun 11;39(6):1747-1755. Epub 2020 Jan 11.

Division of Rheumatology, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Arnaldo, no. 455, 3º and., 3190 - C. César, Sao Paulo, SP, 05403-010, Brazil.

Objectives: To evaluate long-term effects on gamma-globulins and autoantibodies of abatacept (ABA) versus tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients.

Method: Eighteen RA patients undergoing abatacept (ABA-RA) and 18 age/sex-matched patients treated with TNFi (TNFi-RA) were compared regarding clinical data, total gamma-globulins (TGG), specific subtypes (IgG, IgM, IgA), free light chains (FLC), IgM/IgG rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP3), and anti-mutated citrullinated vimentin (anti-MCV), assessed before and every 6 months, up to 24 months.

Exclusion Criteria: previous abatacept/rituximab or low TGG (< 0.7 g/dL).

Results: At baseline, female sex (78 vs. 78%), age (55 vs. 53 years), DAS28 (5.73 vs. 5.67), TGG (1.4 vs. 1.35 g/dL), IgG (1168 vs. 1079 mg/dL), IgM (107 vs. 113 mg/dL), IgA (333 vs. 322 mg/dL), kappa (342 vs. 249 mg/dL), lambda (170 vs. 150 mg/dL), IgM-RF (76 vs. 53 UI), IgG-RF (63 vs. 25 UI), anti-CCP3 (216 vs. 189 UI), and anti-MCV (202 vs. 102 UI) were comparable in ABA-RA and TNFi-RA (p > 0.05). Similar disease activity improvement was observed in both groups. In ABA-RA, significant decreases (p < 0.05) were observed in TGG (1.4 vs. 1.05 g/dL), IgG (1168 vs. 997), IgA (333 vs. 278 mg/dL), kappa (342 vs. 257 mg/dL), lambda (170 vs. 144 mg/dL), IgM-RF (76 vs. 37 UI), IgG-RF (65 vs. 24 UI), anti-CCP3 (216 vs. 183 UI), and anti-MCV (202 vs. 60 UI) at 6 months, without further decreases. In contrast, TNFi-RA showed no decrease in any of such parameters. ABA-RA also had more often transient IgG levels under the lower limit of normality (66.7% vs. 33.3%, p = 0.046). No severe infection occurred. DAS28, ESR, and CRP correlated significantly to gamma-globulins and FLC at baseline (p < 0.05), but these correlations were longitudinally lost in ABA-RA, but not in TNFi-RA.

Conclusion: ABA, but not TNFi, induces a safe, persistent, long-term, and non-progressive reduction in gamma-globulins and autoantibodies, including anti-MCV. This pattern is dissociated from disease activity control.Key Points• ABA induces a long-term and non-progressive reduction in gamma-globulins and FLC, which occurs regardless of disease activity control.• ABA-induced reduction in gamma-globulins and FLC promotes a dissociation of such parameters and disease activity.• The same pattern of reduction is observed in autoantibodies: IgM-RF, IgG-RF, anti-CCP3, and anti-MCV.• Low transient IgG can be observed in RA patients treated with ABA, but does not correlate to infection.
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http://dx.doi.org/10.1007/s10067-020-04932-9DOI Listing
June 2020

LRBA deficiency: a new genetic cause of monogenic lupus.

Ann Rheum Dis 2020 03 18;79(3):427-428. Epub 2019 Dec 18.

Department of Pediatrics, Universidade de Sao Paulo, Sao Paulo, Brazil.

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http://dx.doi.org/10.1136/annrheumdis-2019-216410DOI Listing
March 2020

Lower genital tract infections in young female juvenile idiopathic arthritis patients.

Adv Rheumatol 2019 11 15;59(1):50. Epub 2019 Nov 15.

Pediatric Rheumatology Unit, Children's Institute, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, São Paulo, SP, 05403-000, Brazil.

Background: To evaluate human papillomavirus (HPV), Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections in juvenile idiopathic arthritis (JIA) patients.

Methods: After exclusion, 33 female adolescent and young JIA patients (ILAR criteria) and 28 healthy controls were selected for this study. Demographic data, gynecological, sexual function, cervical cytology and histological abnormalities were evaluated. JIA clinical/laboratorial parameters and treatment were also assessed. HPV-DNA, CT-DNA and NG-DNA testing in cervical specimens were performed by Hybrid Capture 2 assays.

Results: The mean current age was similar in JIA patients and controls (23.3 ± 6.24 vs. 26.1 ± 6.03 years, p = 0.09). The frequencies of sexual intercourse (76% vs. 89%, p = 0.201) and abnormal cervical cytology (24% vs. 11%, p = 0.201) were similar in JIA compared to controls. The higher frequency of HPV infection in JIA patients than controls (30% vs. 11%, p = 0.155) did not reach statistical significance. CT (0% vs. 7%, p = 0.207) and NG infections (0% vs. 4%, p = 0.459) were also alike in both groups. Further evaluation of JIA patients with abnormal and normal cervical cytology showed that the former group had a higher frequency of HPV infection (87% vs. 12%, p = 0.0002) with a low frequency of HPV vaccination (0% vs. 8%, p = 1.0). No differences were evidenced between these two JIA groups regarding demographic data, sexual function and clinical/laboratorial parameters. The frequencies of methotrexate (p = 0.206) and biological agent use (p = 0.238) were similar in both JIA groups.

Conclusions: To our knowledge, this was the first study to assess lower genital infections in JIA patients allowing the identification of HPV as main cause of cervical dysplasia. Methotrexate and biological agents do not seem to increase risk of lower genital tract infections in JIA patients.
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http://dx.doi.org/10.1186/s42358-019-0092-6DOI Listing
November 2019

Thalidomide and Lenalidomide for Refractory Systemic/Cutaneous Lupus Erythematosus Treatment: A Narrative Review of Literature for Clinical Practice.

J Clin Rheumatol 2021 Sep;27(6):248-259

From the Rheumatology Division.

Background: Thalidomide has shown exceptional results in systemic/cutaneous lupus erythematosus(SLE/CLE). Recently, lenalidomide has been also prescribed for SLE/CLE treatment. Literature regarding efficacy/adverse events for these drugs is scarce with a single systematic review and meta-analysis focused solely on thalidomide for refractory cutaneous lupus subtypes.

Objective: We, therefore, addressed in this narrative review the efficacy/adverse effects of thalidomide and lenalidomide for SLE and CLE. In addition, we provide a specialist approach for clinical practice based on the available evidence.

Results: Efficacy of thalidomide for refractory cutaneous lupus treatment was demonstrated by several studies, mostly retrospective with small sample size(≤20). The frequency of peripheral polyneuropathy is controversial varying from 15-80% with no consistent data regarding cumulative dose and length of use. Drug withdrawn results in clinical partial/complete reversibility for most cases (70%). For lenalidomide, seven studies (small sample sizes) reported its efficacy for SLE/CLE with complete/partial response in all patients with a mean time to response of 3 months. Flare rate varied from 25-75% occurring 0.5-10 months after drug withdrawn. There were no reports of polyneuropathy/worsening of previous thalidomide-induced neuropathy, but most of them did not perform nerve conduction studies. Teratogenicity risk exist for both drugs and strict precautions are required.

Conclusions: Thalidomide is very efficacious as an induction therapy for patients with severe/refractory cutaneous lupus with high risk of scarring, but its longstanding use should be avoided due to neurotoxicity. Lenalidomide is a promising drug for skin lupus treatment, particularly regarding the apparent lower frequency of nerve side effects.
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http://dx.doi.org/10.1097/RHU.0000000000001160DOI Listing
September 2021

Increased sMer, but not sAxl, sTyro3, and Gas6 relate with active disease in juvenile systemic lupus erythematosus.

Clin Rheumatol 2020 Feb 26;39(2):509-514. Epub 2019 Oct 26.

Laboratory of Medical Investigation (LIM-36), Instituto da Criança, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 647, 5° andar, Cerqueira Cesar, São Paulo, São Paulo, CEP:05403-900, Brazil.

Introduction/objectives: Tyro3, Axl, and Mer (TAM) receptors and ligands mediate apoptotic bodies engulfment which alteration has been related with juvenile systemic lupus erythematosus (JSLE) pathogenesis. Thus, the aim was to determine their soluble levels.

Methods: Serum sTyro3, sAxl, sMer, and Gas6 levels were measured using ELISA in 67 JSLE patients, 12 juvenile idiopathic arthritis (JIA) inflammatory and 20 healthy controls and related with SLEDAI-2K score, anti-dsDNA antibody, ESR, CRP, C3, C4 levels, and nephritis.

Results: JSLE patients with active disease (SLEDAI-2K> 4) had significantly increased sMer levels compared with healthy controls (median 8.4 vs. 6.0 ng/mL, p = 0.009) and inactive disease patients (5.2 ng/mL, p = 0.0003). sMer levels correlated with SLEDAI-2K (r = 0.44; p = 0.0004) and ESR (r = 0.24; p = 0.04), while sAxl correlated with SLEDAI-2K (r = 0.33; p = 0.008) and C4 levels (r = - 0.24; p = 0.04). JSLE patients taking glucocorticoid had increased sAxl and sMer levels. Moreover, sAxl correlated with sMer and sTyro3 levels. Patients with nephritis and those with focal or diffuse proliferative glomerulonephritis had these protein levels similar to healthy controls and patients without renal involvement. sTyro3 levels of JSLE patients taking glucocorticoid were decreased, and correlated with Gas6 and sAxl, while Gas6 levels correlated with age upon enrollment. JIA controls had protein levels similar to healthy controls and JSLE patients.

Conclusions: This study reinforces that sMer is increased in active JSLE patients, yet sMer and sAxl correlates with disease activity parameters, and their alterations are disease-specific. However, further studies are needed to determine exact roles of sTyro3 and Gas6 in disease pathogenesis. Key Points • sMer and sAxl serum levels are related with active disease in JSLE patients • sMer correlated with SLEDAI-2K score in JSLE • sTyro3, sAxl, sMer and Gas6 levels did not related with nephritis in JSLE patients • sTyro3 and Gas6 exact roles in JSLE are not established and further studies are needed.
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http://dx.doi.org/10.1007/s10067-019-04799-5DOI Listing
February 2020

Development and initial validation of the MS score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

Ann Rheum Dis 2019 10 11;78(10):1357-1362. Epub 2019 Jul 11.

Istituto Giannina Gaslini, Genova, Italy.

Objective: To develop and validate a diagnostic score that aids in identifying macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (sJIA).

Methods: The clinical and laboratory features of 362 patients with sJIA-associated MAS and 404 patients with active sJIA without evidence of MAS were collected in a multinational collaborative project. Eighty percent of the study population was used to develop the score and the remaining 20% constituted the validation sample. A Bayesian Model Averaging approach was used to assess the role of each clinical and laboratory variables in the diagnosis of MAS and to obtain the coefficients of selected variables. The final score, named MAS/sJIA (MS) score, resulted from the linear combination of these coefficients multiplied by the values of each variable. The cut-off that best discriminated MAS from active sJIA was calculated by means of receiver operating characteristic (ROC) curve analysis. Score performance was evaluated in both developmental and validation samples.

Results: The MS score ranges from -8.4 to 41.8 and comprises seven variables: central nervous system dysfunction, haemorrhagic manifestations, active arthritis, platelet count, fibrinogen, lactate dehydrogenase and ferritin. A cut-off value ≥-2.1 revealed the best performance in discriminating MAS from active sJIA, with a sensitivity of 0.85, a specificity of 0.95 and a kappa value of 0.80. The good performance of the MS score was confirmed in the validation sample.

Conclusion: The MS score is a powerful and feasible tool that may assist practitioners in making a timely diagnosis of MAS in patients with sJIA.
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http://dx.doi.org/10.1136/annrheumdis-2019-215211DOI Listing
October 2019

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

Clin Rheumatol 2019 Oct 13;38(10):2857-2863. Epub 2019 Jun 13.

Pediatric Rheumatology Unit, Federal University of Minas Gerais, Belo Horizonte, Brazil.

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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http://dx.doi.org/10.1007/s10067-019-04631-0DOI Listing
October 2019

Neutropenia During Tocilizumab Treatment Is Not Associated with Infection Risk in Systemic or Polyarticular-course Juvenile Idiopathic Arthritis.

J Rheumatol 2019 09 1;46(9):1117-1126. Epub 2019 Mar 1.

IRCCS Ospedale Pediatrico Bambino Gesù, Division of Rheumatology, Rome, Italy

Objective: To determine whether neutropenia is associated with increased risk for infection in patients with systemic juvenile idiopathic arthritis (sJIA) and polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with tocilizumab (TCZ).

Methods: Data up to Week 104 from 2 phase III trials of intravenous TCZ in sJIA (n = 112; ClinicalTrials.gov, NCT00642460) and pcJIA (n = 188; ClinicalTrials.gov, NCT00988221) were pooled. Worst common toxicity criteria grade and lowest observed absolute neutrophil count (ANC) were identified for each patient. Associations between patient characteristics and lowest observed ANC were tested using univariate regression analysis. Infection and serious infection rates per 100 patient-years (PY) in periods associated with grades 1/2 and 3/4 neutrophil counts were compared with rates associated with normal neutrophil counts.

Results: ANC decreased to grade ≥ 3 in 25.0% and 5.9% of sJIA and pcJIA patients, respectively, and decreases were transient. Young age (p = 0.047) and methotrexate use (p = 0.012) were positively associated with neutropenia in patients with sJIA but not in patients with pcJIA. The rate of serious infections in patients with sJIA (10.9/100 PY; 95% CI 6.8-16.5) tended to be higher than in patients with pcJIA (5.2/100 PY; 95% CI 3-8.5). No increase in rates of serious or nonserious infections was observed during periods of neutropenia in either trial.

Conclusion: Patients with JIA treated with TCZ experienced transient neutropenia that was not associated with an increased number of infections.
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http://dx.doi.org/10.3899/jrheum.180795DOI Listing
September 2019

Juvenile Sjögren's Syndrome: Clinical Characteristics With Focus on Salivary Gland Ultrasonography.

Arthritis Care Res (Hoboken) 2020 01 10;72(1):78-87. Epub 2019 Dec 10.

University of Bergen, Bergen, Norway.

Objective: Juvenile Sjögren's syndrome (SS) is a rare, poorly defined, and possibly underdiagnosed condition affecting children and adolescents. The aim of this study was to characterize symptoms and clinical findings of juvenile SS and to explore the clinical application of major salivary gland ultrasonography (SGUS) in patients with juvenile SS.

Methods: A cross-sectional multicenter study recruited patients with disease onset until age 18 years (n = 67). Disease characteristics were recorded, and unstimulated whole sialometry and SGUS examination of the parotid and submandibular salivary glands were performed.

Results: The female:male ratio was 58:9. The mean age at first symptom was 10.2 years and 12.1 years at diagnosis. Ocular and oral symptoms were noted in 42 of 67 patients (63%) and 53 of 66 patients (80%), respectively. The American-European Consensus Group or American College of Rheumatology/European League Against Rheumatism classification criteria for primary SS were fulfilled by 42 of 67 patients (63%). Pathologic SGUS findings were observed in 41 of 67 patients (61%); 26 of 41 SGUS+ patients (63%) fulfilled primary SS criteria. Salivary gland enlargements/parotitis were noted in 37 of 58 patients and were nonsignificantly associated with SGUS+ status (P = 0.066). The mean levels of saliva were 5.6 ml/15 minutes in SGUS- patients compared to 3.3 ml/15 minutes in the SGUS+ patients (P = 0.049). A total of 36 of 41 SGUS+ patients (88%) were anti-Ro/La+ compared to 14 of 26 SGUS- patients (54%) (P = 0.001). In addition, 24 of 39 SGUS+ patients (62%) were positive for rheumatoid factor (RF), whereas only 5 of 25 SGUS- patients (20%) were RF+ (P = 0.001).

Conclusion: Juvenile SS is characterized by a large spectrum of clinical symptoms and findings. Several glandular and extraglandular parameters such as hyposalivation, swollen salivary glands, and autoantibodies are associated with pathologic SGUS findings.
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http://dx.doi.org/10.1002/acr.23839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972604PMC
January 2020

American College of Rheumatology Provisional Criteria for Clinically Relevant Improvement in Children and Adolescents With Childhood-Onset Systemic Lupus Erythematosus.

Arthritis Care Res (Hoboken) 2019 05;71(5):579-590

University of Cincinnati, Cincinnati, Ohio.

Objective: To develop a Childhood Lupus Improvement Index (CHILI) as a tool to measure response to therapy in childhood-onset systemic lupus erythematosus (cSLE), with a focus on clinically relevant improvement (CRI ).

Methods: Pediatric nephrology and rheumatology subspecialists (n = 213) experienced in cSLE management were invited to define CRI and rate a total of 433 unique patient profiles for the presence/absence of CRI . Patient profiles included the following cSLE core response variables (CRVs): global assessment of patient well-being (patient-global), physician assessment of cSLE activity (MD-global), disease activity index score (here, we used the Systemic Lupus Erythematosus Disease Activity Index), urine protein-to-creatinine ratio, and Child Health Questionnaire physical summary score. Percentage and absolute changes in these cSLE-CRVs (baseline versus follow-up) were considered in order to develop candidate algorithms and validate their performance (sensitivity, specificity, area under the receiver operating characteristic curve [AUC]; range 0-1).

Results: During an international consensus conference, unanimous agreement on a definition of CRI was achieved; cSLE experts (n = 13) concurred (100%) that the preferred CHILI algorithm considers absolute changes in the cSLE-CRVs. After transformation to a range of 0-100, a CHILI score of ≥54 had outstanding accuracy for identifying CRI (AUC 0.93, sensitivity 81.1%, and specificity 84.2%). CHILI scores also reflect minor, moderate, and major improvement for values exceeding 15, 68, and 92, respectively (all AUC ≥0.92, sensitivity ≥93.1%, and specificity ≥73.4%).

Conclusion: The CHILI is a new, seemingly highly accurate index for measuring CRI in cSLE over time. This index is useful to categorize the degree of response to therapy in children and adolescents with cSLE.
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http://dx.doi.org/10.1002/acr.23834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483875PMC
May 2019

Juvenile dermatomyositis: is periodontal disease associated with dyslipidemia?

Adv Rheumatol 2018 Sep 5;58(1):28. Epub 2018 Sep 5.

Pediatric Rheumatology Unit, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Rua Joel Jorge de Melo, 600 apto 121, Vila Mariana, São Paulo, SP, 04128-081, Brazil.

Background: Association between periodontal disease and dyslipidemia was recently reported in healthy adults. However, a systematic evaluation of concomitant periodontal diseases and lipid profile was not carried out in juvenile dermatomyositis (JDM). A cross-section study was performed in 25 JDM patients and 25 healthy controls, assessing demographic data, periodontal evaluation, fasting lipoproteins and anti-lipoprotein lipase antibodies. Disease parameters, laboratorial tests and treatment were also evaluated in JDM patients.

Results: The mean current age was similar in patients and controls (11.5 ± 3.75 vs. 11.2 ± 2.58 years,p = 0.703). Regarding lipid profile, the median triglycerides [80(31-340) vs. 61(19-182)mg/dL,p = 0.011] and VLDL[16(6-68) vs. 13(4-36)mg/dL,p = 0.020] were significantly higher in JDM patients versus controls. Gingival vasculopathy pattern was significantly higher in the former group (60% vs. 0%,p = 0.0001), as well as the median of gingival bleeding index (GBI) [24.1(4.2-69.4) vs. 11.1(0-66.6)%,p = 0.001] and probing pocket depth (PPD) [1.7(0.6-2.4) vs.1.4(0-2.12)mm,p = 0.006]. Comparison between JDM patients with and without dyslipidemia revealed that the median of dental plaque index (PI) [100(26.7-100) vs. 59(25-100)%,p = 0.022], PPD[1.9(0.6-2.4) vs. 1.4(1.2-1.8)mm,p = 0.024] and clinical attachment level (CAL) [1.31(0.7-1.7) vs. 0.8(0.6-1.7)mm,p = 0.005] were significantly higher in patients with dyslipidemia. Further analysis between JDM patients with and without gingivitis revealed that the median of current age [12.4 (8.3-18.4) vs. 9.2 (5.5-17.5) years, p = 0.034] and disease duration [7.09 ± 3.07 vs. 3.95 ± 2.1 years, p = 0.008] were significantly higher in the former group.

Conclusion: Our study showed that gingival inflammation seems to be related to dyslipidemia in JDM patients, suggesting underlying mechanisms for both complications.
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http://dx.doi.org/10.1186/s42358-018-0024-xDOI Listing
September 2018

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

Adv Rheumatol 2018 Nov 23;58(1):39. Epub 2018 Nov 23.

Pediatric Rheumatology Unit, Children's Institute, Faculdade de Medicina da Universidade de São Paulo (FMUSP), Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, São Paulo, SP, 05403-000, Brazil.

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.
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http://dx.doi.org/10.1186/s42358-018-0038-4DOI Listing
November 2018

Characterization of scrotal involvement in children and adolescents with IgA vasculitis.

Adv Rheumatol 2018 Nov 3;58(1):38. Epub 2018 Nov 3.

Pediatric Rheumatology Unit, Children's Institute, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, SP, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, São Paulo, SP, 05403-000, Brazil.

Objective: To characterize scrotal involvement in children and adolescents with IgA vasculitis.

Methods: A cross-sectional retrospective study included 296 IgA vasculitis (EULAR/PRINTO/PRES criteria) patients, 150/296 (51%) were males and assessed by demographic/clinical/laboratory and treatments. Scrotal involvement was defined by the presence of scrotal edema and/or pain/tenderness in physical examination and/or testicular Doppler ultrasound abnormalities.

Results: Scrotal involvement was observed in 28/150 (19%) IgA vasculitis patients. This complication was evidenced at IgA vasculitis diagnosis in 27/28 (96%). Acute recurrent scrotal involvement was observed in 2/150 (1%) and none had chronic subtype. Further analysis of patients with scrotal involvement at first episode (n = 27) compared to those without this complication (n = 122) revealed that the median age at diagnosis [4.0 (2.0-12) vs. 6 (1.3-13) years, p = 0.249] was similar in both groups. The frequency of elevated serum IgA was significantly lower in IgA vasculitis patients with scrotal involvement versus without this manifestation (18% vs. 57%, p = 0.017), whereas glucocorticoid (93% vs. 49%, p < 0.0001) and ranitidine use (63% vs. 30%, p = 0.003) were significantly higher in the former group.

Conclusions: The scrotal involvement occurred in almost one fifth of IgA vasculitis patients and was commonly evidenced as acute subtype at diagnosis. Scrotal signs/symptoms improved after a prompt use of glucocorticoid and was associated with low frequency of elevated IgA serum levels.
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http://dx.doi.org/10.1186/s42358-018-0039-3DOI Listing
November 2018

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

Adv Rheumatol 2018 Dec 13;58(1):43. Epub 2018 Dec 13.

Pediatric Rheumatology Unit, Children's Institute, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.

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.
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December 2018

Pediatric rheumatic disease patients: time to extend the age limit of adolescence?

Adv Rheumatol 2018 Sep 18;58(1):30. Epub 2018 Sep 18.

Pediatric Rheumatology Division, Sao Paulo State University (UNESP), Botucatu, Sao Paulo, Brazil.

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September 2018
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