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Introduction: Polyarticular juvenile idiopathic arthritis (pJIA) is a childhood-onset autoimmune disease. Immune cells contribute to persistent inflammation observed in pJIA. Despite the crucial role of monocytes in arthritis, the precise involvement of classical monocytes in the pathogenesis of pJIA remains uncertain. Here, we aimed to uncover the transcriptomic patterns of classical monocytes in pJIA, focusing on their involvement in disease mechanism and heterogeneity. Methods: A total of 17 healthy subjects and 18 premenopausal women with pJIA according to ILAR criteria were included. Classical monocytes were isolated, and RNA sequencing was performed. Differential expression analysis was used to compare pJIA patients and healthy control group. Differentially expressed genes (DEGs) were identified, and gene set enrichment analysis (GSEA) was performed. Using unsupervised learning approach, patients were clustered in two groups based on their similarities at transcriptomic level. Subsequently, these clusters underwent a comparative analysis to reveal differences at the transcriptomic level. Results: We identified 440 DEGs in pJIA patients of which 360 were upregulated and 80 downregulated. GSEA highlighted TNF-α and IFN-γ response. Importantly, this analysis not only detected genes targeted by pJIA therapy but also identified new modulators of immuno-inflammation. PLAUR, IL1B, IL6, CDKN1A, PIM1, and ICAM1 were pointed as drivers of chronic hyperinflammation. Unsupervised learning approach revealed two clusters within pJIA, each exhibiting varying inflammation levels. Conclusion: These findings indicate the pivotal role of immuno-inflammation driven by classical monocytes in pJIA and reveals the existence of two subclusters within pJIA, regardless the positivity of rheumatoid factor and anti-CCP, paving the way to precision medicine. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) often mimics symptoms of other diseases, and the interval between symptom onset and diagnosis may be long in some of these patients. Aims: To describe the characteristics associated with the time to SLE diagnosis and its impact on damage accrual and mortality in patients with SLE from a Latin American inception cohort. Methods: Patients were from a multi-ethnic, multi-national Latin-American SLE inception cohort. All participating centers had specialized lupus clinics. Socio-demographic, clinical/laboratory, disease activity, damage, and mortality between those with a longer and a shorter time to diagnosis were compared using descriptive statistical tests. Multivariable Cox regression models with damage accrual and mortality as the end points were performed, adjusting for age at SLE diagnosis, gender, ethnicity, level of education, and highest dose of prednisone for damage accrual, plus highest dose of prednisone, baseline SLEDAI, and baseline SDI for mortality. Results: Of the 1437 included in these analyses, the median time to diagnosis was 6.0 months (Q1–Q3 2.4–16.2); in 721 (50.2%) the time to diagnosis was longer than 6 months. Patients whose diagnosis took longer than 6 months were more frequently female, older at diagnosis, of Mestizo ethnicity, not having medical insurance, and having "non-classic" SLE symptoms. Longer time to diagnosis had no impact on either damage accrual (HR 1.09, 95% CI 0.93–1.28, p = 0.300) or mortality (HR 1.37, 95% CI 0.88–2.12, p = 0.200). Conclusions: In this inception cohort, a maximum time of 24 months with a median of 6 months to SLE diagnosis had no apparent negative impact on disease outcomes (damage accrual and mortality). [ABSTRACT FROM AUTHOR]

Objective: To determine the predictors of the occurrence of severe autoimmune hemolytic anemia (AIHA) and its impact on damage accrual and mortality in SLE patients. [ABSTRACT FROM AUTHOR]

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 (aβ2GPI) 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. [ABSTRACT FROM AUTHOR]

Introduction: The beneficial effect of hydroxychloroquine (HCQ) in decreasing LDL levels on Systemic Lupus Erythematosus (SLE) is well defined. The influence of this drug on HDL levels is still under debate and information about its effect on cholesterol reverse transport is lacking. Objective: To evaluate the effects of HCQ on HDL levels and the transfer of lipids to this lipoprotein in SLE. Methods: Nineteen SLE patients using only HCQ (SLE WITH HCQ), 19 SLE patients without any therapy (SLE WITHOUT THERAPY), and 19 healthy controls (CONTROL) were included. All three groups were premenopausal women age- and gender-matched. Serum lipids and apolipoproteins were determined by commercial kits. An in vitro transfer of four lipids (14C-Phospolipid, 3H-Cholesteryl ester, 3H-Triglyceride, and 14C-Unesterified cholesterol) from a radioactively labeled nanoemulsion donor to HDL was performed in all participants. Results: Groups had comparable mean age, weight, height, BMI(body mass index), and waist circumference (p >.05). Mean HDL levels were higher in SLE WITH HCQ group compared to SLE WITHOUT THERAPY(58.37 ± 14.04 vs 49.79 ± 8.0 mg/dL; p <.05) but lower than CONTROL (58.37 ± 14.04 vs 68.58 ± 9.99 mg/dL; p <.05). Total cholesterol (TC) and LDL levels were also significantly lower in SLE WITH HCQ compared SLE WITHOUT THERAPY(148.16 ± 16.43 vs 167.11 ± 30.18 mg/dL; p <.05, 75.05 ± 22.52 vs 96.05 ± 25.63 mg/dL; p <.05) and CONTROL (148.16 ± 16.43 vs 174.11 ± 23.70 mg/dL; p <.05, 75.05 ± 22.52 vs 88.53 ± 20.24 mg/dL; p <.05). The in vitro lipid transfer to HDL study revealed a significant difference among the three groups (p =.002) with a higher transfer of unesterified cholesterol(UC) in SLE WITH HCQ compared to SLE WITHOUT THERAPY(5.40 ± 1.05% vs. 4.44 ± 1.05%; p <.05). The latter was significantly decreased compared to CONTROL (5.40 ± 1.05% vs. 5.99 ± 1.71%; p <.05).The percentages of transfer of triacylglycerol (4.93 ± 0.69% vs. 4.50 ± 0.69% vs. 5.14 ± 1.01%; p =.054), esterified cholesterol (5.24 ± 0.70% vs. 4.96 ± 0.89% vs. 5.69 ± 1.27%; p =.079), and phospholipid (15.67 ± 1.03% vs. 15.34 ± 1.44% vs. 16.47 ± 1.89%; p =.066) were similar among groups. Conclusion: The present study is the first to demonstrate that HCQ promoted a higher transfer of unesterified cholesterol which may account for the increased HDL levels in lupus patients under HCQ. This desirable effect may underlie the reported reduced atherosclerosis in SLE. [ABSTRACT FROM AUTHOR]

Objective: To date, the only study that has assessed the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2 mRNA) vaccine in systemic lupus erythematosus (SLE) observed a moderate response, but the sample size precluded an accurate analysis of the effect of individual drugs. Therefore, we evaluated the immunogenicity of an inactivated SARS‐CoV‐2 vaccine (Sinovac‐CoronaVac) and the influence of different medications in SLE. Safety was also assessed. Methods: We conducted a prospective controlled study of 232 SARS‐CoV‐2–naive SLE patients and 58 SARS‐CoV‐2–naive controls who were vaccinated with 2 doses of Sinovac‐CoronaVac with a 28‐day interval (day 0/day 28 [D0/D28]). Immunogenicity analysis at D0/D28 and D69 included anti‐SARS‐CoV‐2 S1/S2 IgG seroconversion (SC) and neutralizing antibodies (NAb) positivity. The influence of individual drugs on immune response and safety was assessed. Results: Patients and controls were well balanced for age (P = 0.771). At D69, SLE patients showed a moderate SC (70.2% versus 98.1%; P < 0.001) and moderate frequency of NAb positivity (61.5% versus 84.6%; P = 0.002), although both frequencies were lower than in controls. Factors associated with lower SC in univariate analysis at D69 were prednisone use (odds ratio [OR] 0.215 [95% confidence interval (95% CI) 0.108–0.427], P < 0.001) and mycophenolate mofetil (MMF) use (OR 0.201 [95% CI 0.107–0.378], P < 0.001), whereas hydroxychloroquine (HCQ) use led to a 2.5 increase in SC (P = 0.011). SLE patients who were receiving HCQ monotherapy had similar SC to controls at D69 (100% versus 98.1%; P = 1.000). In multivariate analysis, prednisone and MMF use were independently associated with lower SC (P < 0.001) and NAb positivity (P < 0.001). Safety analysis revealed no moderate/severe adverse events. Conclusion: Sinovac‐CoronaVac has a moderate immunogenicity in SARS‐CoV‐2–naive SLE patients with an excellent safety profile. We further demonstrate that HCQ may improve SC, whereas prednisone and MMF had a major deleterious effect in vaccine response, reinforcing the need to investigate the role of temporary MMF withdrawal or a vaccine‐booster dose (ClinicalTrials.gov identifier: NCT04754698). [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) and Primary Antiphospholipid Syndrome (PAPS) overlap clinical and immunological features. Therefore, misclassification of PAPS patients as SLE is a concern. The ACR/EULAR 2019 SLE classification has never been studied in PAPS. Objective: To verify if the ACR/EULAR 2019 SLE classification can correctly classify a PAPS patient as not having SLE and compare its performance with the SLICC 2012 SLE classification. Methods: One-hundred thrombotic PAPS patients who fulfilled the Sidney criteria were consecutively screened and those who attended the inclusion criteria were submitted to ACR/EULAR 2019 and SLICC 2012 classifications. Results: Sixty-seven PAPS patients were included in this study. The majority was female (89.6%) with median age at study inclusion of 45 years (35–53) and median PAPS disease duration of 13 years (8–19). PAPS correct classification was observed more often with ACR/EULAR 2019 than SLICC 2021 criteria (94.0% vs. 64.2%; p < 0.001). The 4 misclassified patients in ACR/EULAR 2019 were also misclassified in SLICC 2012. The comparison of misclassified patients to those correctly not classified as SLE resulted, for both criteria, in higher frequencies of hematological domain [ACR/EULAR 2019 (100% vs. 28.6%, p = 0.010) and SLICC 2012 (95.8% vs. 11.6%, p < 0.001)]. Further analysis of hematological manifestations revealed that for the ACR/EULAR 2019 leukopenia (100% vs. 22.2%, p = 0.004) and for the SLICC 2012 leukopenia/lymphopenia (91.7% vs. 7%, p < 0.001) were more frequent in misclassified group. Proteinuria (20.8% vs. 0%, p = 0.004) and low complement (45.8% vs. 20.9%, p = 0.033) were also more often observed in the incorrectly SLICC 2012 classified patients. Conclusion: ACR/EULAR 2019 had high accuracy for distinguishing PAPS from SLE, whereas the SLICC 2012 incorrectly classified more than one third of the PAPS patients as having SLE. [ABSTRACT FROM AUTHOR]

Introduction: Factors related to presentation of neuropsychiatric (NP) SLE manifestations, early in the course of the disease, and during follow up have not been clearly established. Purpose: To identify disease and non-disease related factors associated with NP manifestations in early SLE. Methods: We included 1193 patients from the GLADEL inception cohort free of NP involvement at cohort entry. We evaluated the association of demographic, clinical and laboratory data with NP involvement during follow-up. Statistical methods: Independent factors associated with NP involvement were identified using a multivariable Cox regression model. Results: Factors independently associated with NP manifestations were: mestizo ethnicity (HR 1.701, 95% CI 1.282–2.258, p = 0.0002), myalgias/myositis (HR 1.832, 95% CI 1.335–2.515, p = 0.0002), pneumonitis (HR 2.476, 95% CI 1.085–5.648, p = 0.0312), shrinking lung (HR 2.428, 95% CI 1.074–5.493, p = 0.0331) and hemolytic anemia (HR 1.629, 95% CI 1.130–2.347, p = 0.0089). Longer disease duration at cohort entry (13 to 24 months) was associated with a lower risk of developing NP manifestations (HR 0.642, 95% CI 0.441–0.934, p = 0.0206). Conclusions: Patients with myalgias/myositis, pneumonitis, shrinking lung and hemolytic anemia are at higher risk of NP involvement, whereas longer disease duration at cohort entry is associated with a lower risk of developing NP involvement. [ABSTRACT FROM AUTHOR]

Objectives: Transcranial direct current stimulation (tDCS) combined with aerobic exercise (tDCS-AE) effectively reduces fatigue in patients with fibromyalgia. However, no study has assessed this method in systemic lupus erythematosus (SLE) patients with significant fatigue. Therefore, we evaluated the safety and efficacy of tDCS-AE for significant fatigue symptoms in adult female SLE patients., Methods: This randomised, sham-controlled, double-blind study included 25 patients with SLE in remission or low disease activity (SLEDAI-2K £4) and with significant fatigue [≥36 points on the Fatigue Severity Scale (FSS) or ≥38 points on the Modified Fatigue Scale (MFIS)]. The patients received sham or tDCS for five consecutive days. The anode and cathode were positioned at M1 and Fp2, respectively (international 10-20 EEG system). tDCS was applied at an intensity of 2mA, and density of 0.057mA/cm2 in the tDCS-AE group. Both groups underwent combined low-intensity treadmill exercise. FSS, MFIS, pain visual analogue scale, physical activity, and sleep quality were evaluated at baseline and on days 7, 30, and 60. Adherence and safety were assessed using a standardised questionnaire., Results: Improvement in fatigue levels was observed in both groups. However, a sustained reduction in fatigue levels on days 30 and 60 occurred only with tDCS-AEs (p<0.05). No significant differences were observed in pain level, sleep quality, or physical activity. No disease flares occurred and the adverse effects were mild and transient. Finally, the patient's adherence to the treatment was satisfactory., Conclusions: Despite isolated AEs, there was an improvement in fatigue, however, only tDCS-AE maintained significant and sustained improvement.

Introduction: Polyarticular juvenile idiopathic arthritis (pJIA) is a childhood-onset autoimmune disease. Immune cells contribute to persistent inflammation observed in pJIA. Despite the crucial role of monocytes in arthritis, the precise involvement of classical monocytes in the pathogenesis of pJIA remains uncertain. Here, we aimed to uncover the transcriptomic patterns of classical monocytes in pJIA, focusing on their involvement in disease mechanism and heterogeneity., Methods: A total of 17 healthy subjects and 18 premenopausal women with pJIA according to ILAR criteria were included. Classical monocytes were isolated, and RNA sequencing was performed. Differential expression analysis was used to compare pJIA patients and healthy control group. Differentially expressed genes (DEGs) were identified, and gene set enrichment analysis (GSEA) was performed. Using unsupervised learning approach, patients were clustered in two groups based on their similarities at transcriptomic level. Subsequently, these clusters underwent a comparative analysis to reveal differences at the transcriptomic level., Results: We identified 440 DEGs in pJIA patients of which 360 were upregulated and 80 downregulated. GSEA highlighted TNF-α and IFN-γ response. Importantly, this analysis not only detected genes targeted by pJIA therapy but also identified new modulators of immuno-inflammation. PLAUR , IL1B , IL6 , CDKN1A , PIM1 , and ICAM1 were pointed as drivers of chronic hyperinflammation. Unsupervised learning approach revealed two clusters within pJIA, each exhibiting varying inflammation levels., Conclusion: These findings indicate the pivotal role of immuno-inflammation driven by classical monocytes in pJIA and reveals the existence of two subclusters within pJIA, regardless the positivity of rheumatoid factor and anti-CCP, paving the way to precision medicine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hounkpe, Sales, Ribeiro, Perez, Caparbo, Domiciano, Figueiredo, Pereira and Borba.)

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., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To evaluate the incidence of COVID-19 and its main outcomes in rheumatic disease (RD) patients on hydroxychloroquine (HCQ) compared to household cohabitants (HC)., Methods: This is a 24-week nationwide prospective multi-centre cohort with a control group without RD and not using HCQ. All participants were monitored through scheduled phone interviews performed by health professionals. Details regarding COVID-19 symptoms, and epidemiological, clinical, and demographic data were recorded on a specific web-based platform. COVID-19 was defined according to the Brazilian Ministry of Health criteria and classified as mild, moderate or severe., Results: A total of 9,585 participants, 5,164 (53.9%) RD patients on HCQ and 4,421 (46.1%) HC were enrolled from March 29th, 2020 to September 30th, 2020, according to the eligibility criteria. COVID-19 confirmed cases were higher in RD patients than in cohabitants [728 (14.1%) vs. 427 (9.7%), p<0.001] in a 24-week follow-up. However, there was no significant difference regarding outcomes related to moderate/ severe COVID-19 (7.1% and 7.3%, respectively, p=0.896). After multiple adjustments, risk factors associated with hospitalisation were age over 65 (HR=4.5; 95%CI 1.35-15.04, p=0.014) and cardiopathy (HR=2.57; 95%CI 1.12-5.91, p=0.026). The final survival analysis demonstrated the probability of dying in 180 days after a COVID-19 diagnosis was significantly higher in patients over 65 years (HR=20.8; 95%CI 4.5-96.1) and with 2 or more comorbidities (HR=10.8; 95%CI 1.1-107.9 and HR=24.8; 95%CI 2.5-249.3, p=0.006, respectively)., Conclusions: Although RD patients have had a higher COVID-19 incidence than individuals from the same epidemiological background, the COVID-19 severity was related to traditional risk factors, particularly multiple comorbidities and age, and not to underlying RD and HCQ.

Background/objective: Our aim was to describe the short- and long-term outcome of peripheral neuropathy (PN) attributed exclusively to systemic lupus erythematosus (SLE)., Methods: Systemic lupus erythematosus patients with defined PN (clinical and electroneuromyography) were retrospectively evaluated at onset, 1-year, and 5-year follow-up using a standardized electronic chart database that started in 2000. Exclusion criteria were comorbidities, drugs, and infections. Age-, sex-, and disease duration-matched SLE patients without PN were selected as controls., Results: Lupus PN was identified in 38 (1.8%) of 2074 patients, and almost two thirds had PN onset in the first 5 years of SLE (63.2%). Peripheral neuropathy SLE had higher frequencies of cutaneous vasculitis (50% vs 21.1%, p = 0.002), lymphopenia (60.5% vs 36.8%, p = 0.027), anti-Sm (52.6% vs 27.6%, p = 0.013), and higher SLEDAI-2K scores (11.5 ± 10.5 vs 4.9 ± 6.7, p < 0.001) compared with controls. The most common type was polyneuropathy (71.1%) with sensory-motor pattern (68.4%). At PN diagnosis, all patients received glucocorticoid and 97.4% started immunosuppressive therapy (50% intravenous cyclophosphamide, 42.1% azathioprine). After 1-year follow-up, 92.1% had a favorable outcome with complete (36.8%) or partial remission (55.2%), in parallel with a decrease in prednisone dose (48.3 ± 17.9 vs 15.3 ± 13.4 mg/d, p < 0.001), symptomatic therapy (57.9% vs 29.7%, p = 0.02), and SLEDAI-2K score (11.5 ± 10.5 vs 1.7 ± 3.7, p < 0.001). SLEDAI-2K scores were higher in patients who had PN onset with less than 1 year of SLE duration, compared with those with more than 5 years of disease (21.3 ± 9.1 vs 3.9 ± 5.3, p < 0.001). Early-PN-onset group had a better response to treatment (complete remission at 1-year follow-up 61.5% vs 25%, p = 0.039). At 5-year follow-up, 89.3% remained with complete/partial remission., Conclusions: Peripheral neuropathy attributed to SLE itself is a rare manifestation with a bimodal pattern, characterized by a predominant early-onset group associated with high disease activity and a higher rate of complete remission, and a late-onset group with low disease activity and a partial therapy response., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)