Updates in the care and management of children and adolescents with systemic lupus erythematosus.

PURPOSE OF REVIEW: This narrative review offers an update of the most important recent articles published in the previous year of childhood-onset systemic lupus erythematosus (cSLE), focusing on care and management. RECENT FINDINGS: Age-related disparities may play a significant role in the clinical and laboratory characteristics of cSLE, as well as its performance in distinct classification criteria. Monogenic lupus is associated with higher disease damage scores and mortality rate compared to sporadic cSLE. Adolescent face unique challenges, with comorbid psychiatric diagnosis, low resilience and nonadherence posing relevant challenges. A recent international task force has outlined pivotal principles and points-to-consider for treat-to-target (T2T) in cSLE patients. While the past year did yield new randomized controlled trial for cSLE treatment, publications focused on broader management strategies, including the impact of ultraviolet radiation exposure, immunization, and strict blood pressure control. Additionally, case reports and series have evaluated the efficacy/safety profiles of both available and emerging treatments. SUMMARY: Current studies highlighted the various facets of cSLE, epidemiology, clinical, laboratory, classification criteria, adolescent issues, prognosis, surveillance, T2T approach and drug management. Despite notable progress, the scarcity of randomized trials emphasizes the need to delineate safer and more efficacious treatment modalities in cSLE.

Development of clinical and laboratory biomarkers in an international cohort of 428 children with lupus nephritis.

BACKGROUND: Lupus nephritis (LN) is a very severe manifestation of lupus. There is no consensus on which treatment goals should be achieved to protect kidney function in children with LN. METHODS: We retrospectively analyzed trends of commonly used laboratory biomarkers of 428 patients (≤ 18 years old) with biopsy-proven LN class ≥ III. We compared data of patients who developed stable kidney remission from 6 to 24 months with those who did not. RESULTS: Twenty-five percent of patients maintained kidney stable remission while 75% did not. More patients with stable kidney remission showed normal hemoglobin and erythrocyte sedimentation rate from 6 to 24 months compared to the group without stable kidney remission. eGFR ≥ 90 ml/min/1.73m2 at onset predicted the development of stable kidney remission (93.8%) compared to 64.7% in those without stable remission (P < 0.00001). At diagnosis, 5.9% and 20.2% of the patients showed no proteinuria in the group with and without stable kidney remission, respectively (P = 0.0001). dsDNA antibodies decreased from onset of treatment mainly during the first 3 months in all groups, but more than 50% of all patients in both groups never normalized after 6 months. Complement C3 and C4 increased mainly in the first 3 months in all patients without any significant difference. CONCLUSIONS: Normal eGFR and the absence of proteinuria at onset were predictors of stable kidney remission. Significantly more children showed normal levels of Hb and erythrocyte sedimentation rate (ESR) from 6 to 24 months in the group with stable kidney remission.

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.

International cohort of 382 children with lupus nephritis - presentation, treatment and outcome at 24 months.

BACKGROUND: Children with lupus have a higher chance of nephritis and worse kidney outcome than adult patients. METHODS: We retrospectively analyzed clinical presentation, treatment and 24-month kidney outcome in a cohort of 382 patients (≤ 18 years old) with lupus nephritis (LN) class ≥ III diagnosed and treated in the last 10 years in 23 international centers. RESULTS: The mean age at onset was 11 years 9 months and 72.8% were females. Fifty-seven percent and 34% achieved complete and partial remission at 24-month follow-up, respectively. Patients with LN class III achieved complete remission more often than those with classes IV or V (mixed and pure). Only 89 of 351 patients maintained stable complete kidney remission from the 6th to 24th months of follow-up. eGFR ≥ 90 ml/min/1.73 m2 at diagnosis and biopsy class III were predictive of stable kidney remission. The youngest and the oldest age quartiles (2y-9y, 5m) (14y, 2m-18y,2m) showed lower rates of stable remission (17% and 20.7%, respectively) compared to the two other age groups (29.9% and 33.7%), while there was no difference in gender. No difference in achieving stable remission was found between children who received mycophenolate or cyclophosphamide as induction treatment. CONCLUSION: Our data show that the rate of complete remission in patients with LN is still not high enough. Severe kidney involvement at diagnosis was the most important risk factor for not achieving stable remission while different induction treatments did not impact outcome. Randomized treatment trials involving children and adolescents with LN are needed to improve outcome for these children. A higher resolution version of the Graphical abstract is available as Supplementary information.

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.

Short-term Accrual 2019 European League Against Rheumatism/American College of Rheumatology Domains and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage in Lupus Patients With and Without Nephritis at Disease Onset.

OBJECTIVE: To determine in a historical inception cohort the impact of lupus nephritis at disease onset in short-term accrual 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) domains. The possible association with treatment and damage was also investigated. METHODS: One hundred thirty-three consecutive adult systemic lupus erythematosus patients according to the 2019 EULAR/ACR criteria were divided according to the presence (RENAL-lupus) or absence of renal involvement (NONRENAL-lupus) at disease onset. The 2019 EULAR/ACR score and Systemic Lupus International Collaborating Clinics/ACR (SDI) were longitudinally evaluated over 3 years. RESULTS: RENAL-lupus (n = 49 [36.8%]) and NONRENAL-lupus (n = 84 [63.2%]) were similar regarding age ( p = 0.704), female sex ( p = 0.313), and black race ( p = 0.506). At study entry, RENAL-lupus had higher 2019 EULAR/ACR total domains (30 [12-42] vs. 22 [10-36], p < 0.001) and used more often glucocorticoid ( p < 0.001), mycophenolate mofetil ( p = 0.007), and cyclophosphamide ( p = 0.001). After 3 years, a stable number of domain scores was observed for the RENAL-lupus (30 [12-42] vs. 30 [12-42], p = 0.125), whereas an increase was observed for the NONRENAL-lupus (22 [10-36] vs. 23 [10-40], p < 0.001) compared with baseline. Accordingly, RENAL-lupus patients had a lower frequency of additional domains (3/49 [6.1%] vs. 37/84 [44.0%], p < 0.0001). New kidney involvement occurred in 15 (44.1%) of 34 patients of the NONRENAL-lupus. Both groups evolved with a comparable increase in frequency of patients with damage (SDI ≥1) at the end of the study (23/49 [46.9%] vs. 34/89 [40.54%], p = 0.585) with a similar median of SDI (1 [0-4] vs. 0 [0-2], p = 0.132). CONCLUSIONS: The distinct pattern of accrual 2019 EULAR/ACR domains in patients with and without nephritis at disease onset suggests that close surveillance for additional organ involvement, including kidney, is mandatory in NONRENAL lupus in the first 3 years of disease. The unexpected comparable early damage in both groups despite milder disease and less intense immunosuppression in NONRENAL lupus reinforces the need for new and tailored therapies for these patients.

Is positron emission tomography/magnetic resonance imaging a reliable tool for detecting vascular activity in treated childhood-onset Takayasu's arteritis? A multicentre study.

OBJECTIVES: Toassess whether 18F-fluordeoxiglucose (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: A 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 laboratory characteristics were also analysed. RESULTS: Seventeen c-TA patients (65% females) between the ages of 6 and 21 years with a mean disease duration of 9.4 years were recruited. Only one patient presented clinical disease activity and six (35.6%) had increased ESR and/or 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 greater than the liver in at least one arterial segment in 15 (88.2%) patients in a qualitative analysis and a median maximum standardized uptake value (SUVmax) of 3.22 (interquartile range 2.76-3.69) in a semi-quantitative analysis. c-TA patients presented significantly higher SUVmax values than oncologic patients (P < 0.001). A positive correlation between SUVmax and CRP levels (ρ = 0.528, P = 0.029) was seen. 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 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.

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

OBJECTIVE: We studied the rate of remission of 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 ACR and Kidney Disease: Improving Global Outcomes were used. METHODS: Anonymized clinical data in patients with biopsy-proven LN class ≥III (International Society of Nephrology/Royal Pathology Society) diagnosed and treated in the last 10 years in 23 international centres 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 months, and 177 were females. The number of patients in complete and partial remission varied a great deal 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.

SARS-CoV-2 vaccine in patients with systemic sclerosis: impact of disease subtype and therapy.

OBJECTIVE: To analyse the safety, immunogenicity and factors affecting antibody response to Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) vaccination in patients with SSc. METHODS: This is a phase 4 prospective study within a larger trial of two doses of inactivated SARS-CoV-2 vaccine (CoronaVac) in 51 SSc patients compared with 153 controls. Anti-SARS-CoV-2-IgG and neutralizing antibodies (NAb) were assessed at each vaccine shot (D0/D28) and 6 weeks after the second dose(D69), only in individuals with negative baseline IgG/NAb and those who did not have coronavirus-19(COVID19) during follow-up. Vaccine safety was also assessed in all participants. RESULTS: Patients and controls had comparable median ages [48(38.5-57) vs 48(38-57) years, P =0.945]. Patients had mostly diffuse SSc (68.6%) and the majority (74.5%) had interstitial lung disease. Most patients were under immunosuppressive therapy (72.5%), mainly MMF (52.9%). After full vaccination (D69), anti-SARS-CoV-2-IgG frequency (64.1% vs 94.2%, P < 0.001) and NAb positivity (53.8% vs 76.9%; P =0.006) were moderate, although lower than controls. The first dose response (D28) was low and comparable for both seroconvertion rates (SC) (P =0.958) and NAb positivity (P =0.537). SSc patients under MMF monotherapy vs other (no therapy/other DMARDs) had lower immunogenicity (SC: 31.3% vs 90%, P < 0.001) and NAb(18.8% vs 85%, P < 0.001). Multiple regression analysis confirmed that MMF use, but not disease subtype, is associated with insufficient seroconversion [odds ratio (OR)=0.056(95% CI: 0.009, 0.034), P =0.002] and NAb positivity [OR = 0.047(95% CI: 0.007, 0.036), P =0.002]. No moderate/severe side-effects were observed. CONCLUSION: CoronaVac has an excellent safety profile and moderate response to anti-SARS-CoV-2 vaccine in SSc. Vaccine antibody response is not influenced by disease subtype and is greatly affected by MMF, reinforcing the need for additional strategies to up-modulate vaccine response in this subgroup of patients. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT04754698.

Strong response after fourth dose of mRNA COVID-19 vaccine in autoimmune rheumatic diseases patients with poor response to inactivated vaccine.

OBJECTIVES: To assess immunogenicity of a heterologous fourth dose of an mRNA (BNT162b2) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in autoimmune rheumatic diseases (ARD) patients with poor/non-response to inactivated vaccine (Sinovac-CoronaVac). METHODS: A total of 164 ARD patients who were coronavirus disease 2019 (COVID-19) poor/non-responders (negative anti-SARS-CoV-2 S1/S2 IgG and/or neutralizing antibodies-NAb) to the third dose of Sinovac-CoronaVac received an additional heterologous dose of mRNA (BNT162b2) 3 months after last dose. IgG and NAb were evaluated before and after the fourth dose. RESULTS: Significant increases were observed after the fourth dose in IgG (66.4 vs 95.1%, P < 0.001), NAb positivity (5.5 vs 83.5%, P < 0.001) and geometric mean titre (29.5 vs 215.8 AU/ml, P < 0.001), and 28 (17.1%) remained poor/non-responders. Patients with negative IgG after a fourth dose were more frequently under rituximab (P = 0.001). Negative NAb was associated with older age (P = 0.015), RA (P = 0.002), SSc (P = 0.026), LEF (P = 0.016) and rituximab use (P = 0.007). In multiple logistic regression analysis, prednisone dose ≥7.5 mg/day (OR = 0.34; P = 0.047), LEF (OR = 0.32, P = 0.036) and rituximab use (OR = 0.19, P = 0.022) were independently associated with negative NAb after the fourth vaccine dose. CONCLUSIONS: This is the largest study to provide evidence of a remarkable humoral response after the fourth dose of heterologous mRNA SARS-CoV-2 vaccination in ARD patients with poor/non-response to the third dose of an inactivated vaccine. We further identified that treatment, particularly rituximab and prednisone, impaired antibody response to this additional dose. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, CoronavRheum #NCT04754698.

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

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 titre (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 with CTRL. Median neutralizing activity was comparable in both groups [57.2% (interquartile range (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 with CTRL. We further identified that immunosuppression is associated with diminished NAb positivity. TRIAL REGISTRATION: COVID-19 CoronaVac in Patients With Autoimmune Rheumatic Diseases and HIV/AIDS (CoronavRheum), http://clinicaltrials.gov/ct2/show/NCT04754698.

Association between physical activity and immunogenicity of an inactivated virus vaccine against SARS-CoV-2 in patients with autoimmune rheumatic diseases.

OBJECTIVES: To investigate whether physical activity is associated with enhanced immunogenicity of a SARS-CoV-2 inactivated vaccine (Coronavac) in patients with autoimmune rheumatic diseases (ARD) (n = 898) and in non-ARD (n = 197) individuals without pre-existing immunogenicity to SARS-CoV-2. METHODS: This was a prospective cohort study within an open-label, single-arm, phase 4 vaccination trial. Immunogenicity was assessed after vaccination by measuring seroconversion rates of total anti-SARS-CoV-2 S1/S2 IgG (SC), geometric mean titers of anti-S1/S2 IgG (GMT), factor-increase in GMT (FI-GMT), frequency of neutralizing antibody (NAb), and median neutralizing activity. Physical activity (active being defined as ≥ 150 min/week) and sedentary behavior (>8h/day) were assessed by questionnaire. RESULTS: Physically active ARD patients (n = 494) were younger and less frequently used prednisone/biologics than inactive patients (n = 404). After controlling for covariates, active patients exhibited greater SC (OR: 1.4 [95%CI: 1.1-2.0]), GMT (32% [95%CI: 8.8-60) and FI-GMT (33% [95%CI: 9.6-63%]) vs. inactive. Cluster analysis (physical activity/sedentary status) revealed greater GMT (43.0% [95% CI: 11.0-84.0%) and FI-GMT (48.0% [95%CI: 14.0-92.0%]) in active/non-sedentary vs. inactive/sedentary ARD patients. A dose-response was observed, with greater benefits for the group of patients performing ≥ 350 min/week of physical activity (OR: 1.6 [95%CI: 1.1-2.4]; 41% [95%CI: 10-80%]; 35% [95%CI: 4.3-74], for SC, GMT, and FI-GMT, respectively) vs. the least active group (≤30 min/week). Greater SC (OR: 9.9 [95%CI: 1.1-89.0]) and GMT (26% [95%CI: 2.2-56.0%]) were observed in active vs. inactive non-ARD. CONCLUSIONS: A physically active lifestyle may enhance SARS-CoV-2 vaccine immunogenicity, a finding of particular clinical relevance for immunocompromised patients. TRIAL REGISTRATION: Clinicaltrials.gov #NCT04754698.

Care provided by nurses to patients with juvenile systemic lupus erythematosus.

OBJECTIVES: To describe the care provided by Brazilian nurses to patients with Juvenile Systemic Lupus Erythematosus (JSLE) using a self-administered questionnaire and to evaluate the possible association of demographic data and knowledge of the disease with availability of tools for diagnosis and treatment in Brazilian pediatric services. METHOD: This is a cross-sectional observational descriptive study that analyzed the care provided by Brazilian nurses to patients with JSLE based on the answers to a self-administered questionnaire. Questions included demographics of professionals, nursing consultation, usage of tools to assess disease activity, diagnostic criteria, general care, available practices, transition program, and practices needed for better care. RESULTS: A total of 111/373 (29.4%) questionnaires were completed, most professionals were female (90.1%). Hospitalization (45.9%) and poor medication adherence (27.9%) were the most reported problems, and lack of knowledge about the institutional transition process to adult care was mentioned by half of the professionals (50.5%). Comparisons of professionals on expected care of patients regarding the type of service, hospitalized patient care, and care provided to patients with JSLE did not reveal statistically significant differences (p > 0.05). Nurses who care for patients with JSLE are more likely to work in a public setting (14.5% vs. 36.8%, p = 0.048) and less likely to verify vaccination records (0.12.9% vs. 36.8%, p = 0.038). Nurses who worked in the inpatient setting with patients with JSLE were less likely to address pain concerns (11.7% vs. 61.6%, p < 0.0001) compared to nurses who didn't work with JSLE patients. However, they were more likely to discuss sunscreen use (54.9% vs. 25%, p < 0.05) and be part of a multi-disciplinary team (84.3 vs. 50%, p < 0.0001). CONCLUSIONS: This study demonstrates that the care provided by nurses to patients with JSLE does not consider all the resources available to assess the disease and occurs differently in the inpatient versus outpatient settings. Future research should address this gap in care. Lack of JSLE awareness was commonly reported among professionals, confirming the need for greater knowledge about JSLE, its treatment, and ways to improve adherence.

Immunogenicity, safety, and antiphospholipid antibodies after SARS-CoV-2 vaccine in patients with primary antiphospholipid syndrome.

OBJECTIVE: Coronavirus disease 19 (COVID-19) has an increased risk of coagulopathy with high frequency of antiphospholipid antibodies (aPL). Recent reports of thrombosis associated with adenovirus-based vaccines raised concern that SARS-CoV-2 immunization in primary antiphospholipid syndrome (PAPS) patients may trigger clotting complications. Our objectives were to assess immunogenicity, safety, and aPL production in PAPS patients, after vaccinating with Sinovac-CoronaVac, an inactivated virus vaccine against COVID-19. METHODS: This prospective controlled phase-4 study of PAPS patients and a control group (CG) consisted of a two-dose Sinovac-CoronaVac (D0/D28) and blood collection before vaccination (D0), at D28 and 6 weeks after second dose (D69) for immunogenicity/aPL levels. Outcomes were seroconversion (SC) rates of anti-SARS-CoV-2 S1/S2 IgG and/or neutralizing antibodies (NAb) at D28/D69 in naïve participants. Safety and aPL production were also assessed. RESULTS: We included 44 PAPS patients (31 naïve) and 132 CG (108 naïve) with comparable age (p=0.982) and sex (p>0.999). At D69, both groups had high and comparable SC (83.9% vs. 93.5%, p=0.092), as well as NAb positivity (77.4% vs. 78.7%, p=0.440), and NAb-activity (64.3% vs. 60.9%, p=0.689). Thrombotic events up to 6 months or other moderate/severe side effects were not observed. PAPS patients remained with stable aPL levels throughout the study at D0 vs. D28 vs. D69: anticardiolipin (aCL) IgG (p=0.058) and IgM (p=0.091); anti-beta-2 glycoprotein I (aß2GPI) IgG (p=0.513) and IgM (p=0.468). CONCLUSION: We provided novel evidence that Sinovac-CoronaVac has high immunogenicity and safety profile in PAPS. Furthermore, Sinovac-CoronaVac did not trigger thrombosis nor induced changes in aPL production.

Primary dental care treatment in primary Sjögren's syndrome: a possible role in improving salivary flow rate.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is an inflammatory chronic disorder that mainly affects exocrine glands. Additionally, oral infections can aggravate the glandular dysfunction. However, data on primary dental care (PDC) treatment in pSS are scarce. This study aimed to appraise the impact of PDC on the Xerostomia Inventory (XI), unstimulated/stimulated salivary flow rates and salivary cytokine profile in pSS. METHODS: Fifty-two pSS patients and 52 sex- and age-matched control participants without systemic autoimmune diseases were included in a prospective study. At inclusion, all participants were assessed through a standardised protocol, measurement of salivary pro-inflammatory cytokines, and underwent PDC. Dental procedures included: oral hygiene guidance, restorative treatment of caries, surgical removal of residual roots and impacted or partially erupted teeth, cysts, supra and subgingival periodontal scaling and treatment of soft tissue disorders (removal of lesions and treatment of opportunistic infections). After 3 months, the clinical/laboratorial assessments were repeated. RESULTS: At inclusion, the Decayed, Missing and Filled Teeth (DMFT) index was higher in the pSS patients than in the control group (13.3±8.2 vs. 8.6±6.2, p=0.002), whereas periodontal parameters were comparable in both groups (p>0.05). After PDC, 26.9% of pSS patients showed a reduction of at least 6 points (clinical improvement) in XI, but mean XI remained unchanged (p=0.285). PDC resulted in an increase in mean unstimulated (p<0.001) and stimulated (p=0.001) salivary flow rates in pSS, with no change in salivary cytokine profile (p≥0.05). CONCLUSIONS: PDC promoted improvement in unstimulated and stimulated salivary flow rates in pSS. This novel finding reinforces the recommendation of this strategy for pSS patients. CLINICALTRIALS: gov (Identifier: NCT03711214).

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

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.

Heart function in juvenile idiopathic arthritis patients: A biventricular two-dimensional speckle-tracking echocardiography study.

OBJECTIVES: We evaluated cardiac function in juvenile idiopathic arthritis (JIA) patients by 2D speckle-tracking echocardiography (2DSTE) and to assess possible associations with clinical, laboratorial, and treatment data. METHODS: A group of 42 JIA patients and 42 healthy controls were evaluated using both conventional echocardiography and 2DSTE. JIA patients underwent clinical and laboratory assessment. RESULTS: Conventional echocardiography data demonstrated normal left ventricular (LV) ejection fraction in both groups (71 vs. 71%; p = .69). 2DSTE analysis demonstrated that JIA patients presented significantly lower LV global systolic longitudinal strain (LVGLS) (-18.76 vs. -22%; p < .0001), LV systolic strain rate (LVSSR) (1.06 vs. 1.32 s-1; p < .0001), LV diastolic strain rate (LVDSR) (1.58 vs. 1.8 s-1; p < .0137), right ventricular global systolic strain (RVGLS) (-24.1% vs. -27.7%; p = .0002), and right ventricular systolic strain rate (RVSSR) (1.4 vs. 1.8 s-1; p = .0035). JIA patients under biological agents presented higher LVGLS (p = .02) and RVLS (p = .01). We also detected an association between LVGLS and C-reactive protein [CRP; -20% in normal CRP (10/42) vs. -18% in elevated CRP patients (32/42), p = .03]. CONCLUSIONS: JIA patients present different echocardiographic status from healthy patients. Moreover, our data suggest that JIA patients under biological agents present association with better cardiac function as shown by strain analysis.

Air pollution influence on serum inflammatory interleukins: A prospective study in childhood-onset systemic lupus erythematous patients.

OBJECTIVE: To assess the effect of individual exposure, in real-time, to traffic-related pollutants on serum interleukin levels of childhood-onset lupus erythematous systemic (c-SLE) patients. METHODS: A longitudinal and observational design was conducted in 12 repeated measures of serum samples and clinical evaluations (totaling 108 measurements) of c-SLE patients over 30 consecutive months. Real-time, individual exposure to fine particles (PM2.5) and nitrogen dioxide (NO2) was measured with portable monitors. Generalized estimating equation was used to evaluate the association between exposure to PM2.5 and NO2 and the following serum cytokine levels on the 7 days preceding clinical assessment and serum collection: MCP1, IL-6, IL-8, IL-10, IL-17, IFN-alpha, and TNF-alpha. Disease activity and other risk factors were also controlled. RESULTS: An interquartile range (IQR) increase in PM2.5 daily concentration was significantly associated with increased levels of TNF-alpha on the third, fourth, and seventh day after exposure; IL-10 on the third and fourth day after exposure; IL-17 on the third and seventh day after exposure; and INF-alpha on the third day after exposure (p < 0.05). An IQR increase in 7-day moving average of PM2.5 was associated with a 6.2 pg/mL (95% CI: 0.5; 11.8; p = 0.04) increase in serum IFN-alpha level. An unexpected significant association was observed between an IQR increase in NO27-day cumulative concentration and a decrease of 1.6 pg/mL (95% CI: -2.6; -0.7; p < 0.001) in serum IL-17. CONCLUSION: Real-time exposure to PM2.5 prospectively associated with increased serum TNF-alpha, INF-alpha, IL-10, and IL-17 levels in c-SLE patients.

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.

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

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.