Time to diagnosis in systemic lupus erythematosus: Associated factors and its impact on damage accrual and mortality. Data from a multi-ethnic, multinational Latin American lupus cohort.

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).

Neuromodulation with aerobic exercise reduces fatigue in systemic lupus erythematosus: a randomised, sham-controlled, double-blind study.

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.

Predictors of severe hemolytic anemia and its impact on major outcomes in systemic lupus erythematosus: Data from a multiethnic Latin American cohort.

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. METHODS: Factors associated with time to severe AIHA (hemoglobin level ≤7 g/dL) occurring from the onset of SLE symptoms were examined by Cox proportional hazards regressions. The association of severe AIHA with mortality was examined by logistic regression analyses while its impact on damage was by negative binomial regression. RESULTS: Of 1,349 patients, 49 (3.6%) developed severe AIHA over a mean (SD) follow-up time of 5.4 (3.8) years. The median time from the first clinical manifestation to severe AIHA was 111 days (IQR 43-450). By multivariable analysis, male sex (HR 2.26, 95% CI 1.02-4.75, p = 0.044), and higher disease activity at diagnosis (HR 1.04, 95% CI 1.01-1.08, p = 0.025) were associated with a shorter time to severe AIHA occurrence. Of the SLEDAI descriptors, only hematologic (leukopenia and/or thrombocytopenia) showed a certain trend toward significance in the multivariable analysis (HR 2.36, 95% CI 0.91-6.13, p = 0.0772). Severe AIHA contributed neither to damage nor to mortality. CONCLUSIONS: Severe AIHA occurs during the early course of SLE. Male sex and higher disease activity at diagnosis emerged as independent predictors of a shorter time to severe AIHA occurrence. Although not statistically significant, hematological abnormalities at SLE diagnosis could predict the occurrence of severe AIHA in a shorter time. Damage and mortality did not seem to be impacted by the occurrence of severe AIHA.

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.

Hydroxychloroquine increased cholesterol transfer to high-density lipoprotein in systemic lupus erythematosus: A possible mechanism for the reversal of atherosclerosis in the disease.

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.

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.

Incidence and risk factors for moderate/severe COVID-19 in rheumatic diseases patients on hydroxychloroquine: a 24-week prospective cohort.

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.

Avoiding misclassification of thrombotic primary antiphospholipid syndrome as systemic lupus erythematosus (SLE): What are the best-performing SLE classification criteria?

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.

Factors associated with neuropsychiatric involvement in Latin American patients with systemic lupus erythematosus.

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.

A longitudinal multiethnic study of biomarkers in systemic lupus erythematosus: Launching the GLADEL 2.0 Study Group.

Introduction: After more than 20 years of sustained work, the Latin American Group for the Study of Lupus (GLADEL) has made a significant number of contributions to the field of lupus, not only in the differential role that race/ethnicity plays in its course and outcome but also in several other studies including the beneficial effects of using antimalarials in lupus patients and the development of consensus guidelines for the treatment of lupus in our region. Methods: A new generation of "Lupus Investigators" in more than 40 centers throughout Latin America has been constituted in order to continue the legacy of the investigators of the original cohort and to launch a novel study of serum and urinary biomarkers in patients with systemic lupus erythematosus. Results: So far, we have recruited 807 patients and 631 controls from 42 Latin-American centers including 339 patients with SLE without renal involvement, 202 patients with SLE with prevalent but inactive renal disease, 176 patients with prevalent and active renal disease and 90 patients with incident lupus nephritis. Conclusions: The different methodological aspects of the GLADEL 2.0 cohort are discussed in this manuscript, including the challenges and difficulties of conducting such an ambitious project.

Short- and Long-Term Outcome of Systemic Lupus Erythematosus Peripheral Neuropathy: Bimodal Pattern of Onset and Treatment Response.

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.

Remission and Low Disease Activity Status (LDAS) protect lupus patients from damage occurrence: data from a multiethnic, multinational Latin American Lupus Cohort (GLADEL).

OBJECTIVE: To evaluate disease activity statuses' (DAS') impact on systemic lupus erythematosus (SLE) outcomes. MATERIALS AND METHODS: Four DAS were defined: remission off-therapy: SLE Disease Activity Index (SLEDAI)=0, no prednisone or immunosuppressive drugs (IS); remission on-therapy: SLEDAI=0, prednisone ≤5 mg/day and/or IS (maintenance); low (L) DAS: SLEDAI ≤4, prednisone ≤7.5 mg/day and/or IS (maintenance); non-optimally controlled: SLEDAI >4 and/or prednisone >7.5 mg/day and/or IS (induction). Antimalarials were allowed in all. Predefined outcomes were mortality, new damage (increase of at least one Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI) point) and severe new damage (increase of at least 3 SDI points). Univariable and multivariable Cox regression models were performed to define the impact of DAS, as time-dependent variable, on these outcomes. RESULTS: 1350 patients were included, 79 died during follow-up, 606 presented new and 177 severe new damage. In multivariable analyses, remission (on/off-therapy) was associated with a lower risk of new (HR 0.60; 95% CI 0.43 to 0.85), and of severe new damage (HR 0.32; 95% CI 0.15 to 0.68); low disease activity status (LDAS) was associated with a lower risk of new damage (HR 0.66; 95% CI 0.48 to 0.93) compared with non-optimally controlled. No significant effect on mortality was observed. CONCLUSIONS: Remission was associated with a lower risk of new and severe new damage; LDAS with a lower risk of new damage after adjusting for other damage confounders.

Primary cardiac disease in systemic lupus erythematosus patients: protective and risk factors--data from a multi-ethnic Latin American cohort.

OBJECTIVES: The aim of this study was to assess the cumulative incidence, risk and protective factors and impact on mortality of primary cardiac disease in SLE patients (disease duration ≤2 years) from a multi-ethnic, international, longitudinal inception cohort (34 centres, 9 Latin American countries). METHODS: Risk and protective factors of primary cardiac disease (pericarditis, myocarditis, endocarditis, arrhythmias and/or valvular abnormalities) were evaluated. RESULTS: Of 1437 patients, 202 (14.1%) developed one or more manifestations: 164 pericarditis, 35 valvulopathy, 23 arrhythmias, 7 myocarditis and 1 endocarditis at follow-up; 77 of these patients also had an episode of primary cardiac disease at or before recruitment. In the multivariable parsimonious model, African/Latin American ethnicity [odds ratio (OR) 1.80, 95% CI 1.13, 2.86], primary cardiac disease at or before recruitment (OR 6.56, 95% CI 4.56, 9.43) and first SLICC/ACR Damage Index for SLE assessment (OR 1.31, 95% CI 1.14, 1.50) were risk factors for the subsequent occurrence of primary cardiac disease. CNS involvement (OR 0.44, 95% CI 0.25, 0.75) and antimalarial treatment (OR 0.62, 95% CI 0.44, 0.89) at or before recruitment were negatively associated with the occurrence of primary cardiac disease risk. Primary cardiac disease was not independently associated with mortality. CONCLUSION: Primary cardiac disease occurred in 14.1% of SLE patients of the Grupo Latino Americano de Estudio de Lupus cohort and pericarditis was its most frequent manifestation. African origin and lupus damage were found to be risk factors, while CNS involvement at or before recruitment and antimalarial treatment were protective. Primary cardiac disease had no impact on mortality.

Evidence for cardiac safety and antiarrhythmic potential of chloroquine in systemic lupus erythematosus.

AIMS: To perform a comprehensive evaluation of heart rhythm disorders and the influence of disease/therapy factors in a large systemic lupus erythematosus (SLE) cohort. METHODS AND RESULTS: Three hundred and seventeen consecutive patients of an ongoing electronic database protocol were evaluated by resting electrocardiogram and 142 were randomly selected for 24 h Holter monitoring for arrhythmia and conduction disturbances. The mean age was 40.2 ± 12.1 years and disease duration was 11.4 ± 8.1 years. Chloroquine (CQ) therapy was identified in 69.7% with a mean use of 8.5 ± 6.7 years. Electrocardiogram abnormalities were detected in 66 patients (20.8%): prolonged QTc/QTd (14.2%); bundle-branch block (2.5%); and atrioventricular block (AVB) (1.6%). Age was associated with AVB (P = 0.029) and prolonged QTc/QTd (P = 0.039) whereas anti-Ro/SS-A and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores were not (P > 0.05). Chloroquine was negatively associated with AVB (P = 0.01) as was its longer use (6.1 ± 6.9 vs. 1.0 ± 2.5 years, P = 0.018). Time of CQ use was related with the absence of AVB [odds ratio (OR) = 0.103; 95% confidence interval (CI) = 0.011-0.934, P = 0.043] in multiple logistic regression. Holter monitoring revealed abnormalities in 121 patients (85.2%): supraventricular ectopies (63.4%) and tachyarrhythmia (18.3%); ventricular ectopies (45.8%). Atrial tachycardia/fibrillation (AT/AF) were associated with shorter CQ duration (7.05 ± 7.99 vs. 3.63 ± 5.02 years, P = 0.043) with a trend to less CQ use (P = 0.054), and older age (P < 0.001). Predictors of AT/AF in multiple logistic regression were age (OR = 1.115; 95% CI = 1.059-1.174, P < 0.001) and anti-Ro/SS-A (OR = 0.172; 95% CI = 0.047-0.629, P = 0.008). CONCLUSIONS: Chloroquine seems to play a protective role in the unexpected high rate of cardiac arrhythmias and conduction disturbances observed in SLE. Further studies are necessary to determine if this antiarrhythmic effect is due to the disease control or a direct effect of the drug.

Transcriptomic signatures of classical monocytes reveal pro-inflammatory modules and heterogeneity in polyarticular juvenile idiopathic arthritis.

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.

Anti-ribosomal P protein: a novel antibody in autoimmune hepatitis.

BACKGROUND: Autoantibodies to ribosomal P proteins (anti-rib P) are specific serological markers for systemic lupus erythematosus (SLE) and are associated with liver involvement in this disease. The similarity in autoimmune background between autoimmune hepatitis (AIH) and SLE-associated hepatitis raises the possibility that anti-rib P antibodies might also have relevance in AIH. AIMS: To evaluate the frequency and clinical significance of anti-rib P antibodies in a large AIH cohort. METHODS: Sera obtained at diagnosis of 96 AIH patients and of 82 healthy controls were tested for IgG anti-ribosomal P protein by ELISA. All of the sera were also screened for other lupus-specific autoantibodies, three patients with the presence of anti-dsDNA (n = 1) and anti-Sm (n = 2) were excluded. RESULTS: Moderate to high titres (>40 U) of anti-rib P antibody were found in 9.7% (9/93) of the AIH patients and none of the controls (P = 0.003). At presentation, AIH patients with and without anti-rib P antibodies had similar demographic/clinical features, including the frequency of cirrhosis (44.4 vs. 28.5%, P = 0.44), hepatic laboratorial findings (P > 0.05). Importantly, at the final observation (follow-up period 10.2 ± 4.9 years), the AIH patients with anti-rib P had a significantly higher frequency of cirrhosis compared with the negative group (100 vs. 60%, P = 0.04). CONCLUSION: The novel demonstration of anti-rib P in AIH patients without clinical or laboratory evidence of SLE suggests a common underlying mechanism targeting the liver in these two diseases. In addition, this antibody appears to predict the patients with worse AIH prognoses.

Bone erosions associated with systemic bone loss on HR-pQCT in women with longstanding polyarticular juvenile idiopathic arthritis.

OBJECTIVES: To analyze longstanding polyarticular juvenile idiopathic arthritis (pJIA) for possible associations between localized bone damage (erosions), and systemic bone loss. Besides, to compare the systemic bone mass of pJIA with healthy controls. METHODS: Thirty-four pJIA women and 99 healthy controls (HC) were included. Radius and tibia of all subjects were scanned by HR-pQCT. Volumetric bone mineral density (vBMD), bone microarchitecture, and -finite element parameters were analyzed. Patients underwent HR-pQCT of 2nd and 3rd metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the dominant hand, for bone erosions quantification. RESULTS: The mean age of patients was 31.5 ± 7.4yrs with a mean disease duration of 21.7 ± 9.2yrs. Bone erosions were detectable in 79% of patients. The number of bone erosions was positively correlated with cortical porosity (Ct.Po) at tibia (r = 0.575, p = 0.001), and radius (r = 0.423, p = 0.018); and negatively correlated with cortical vBMD at tibia (r=-0.420, p = 0.015). In a logistic regression analysis, adjusted for anti-CCP, the presence of bone erosions was independently associated with Ct.Po at radius (p = 0.018) and cortical vBMD at tibia (p = 0.020). Moreover, cortical and trabecular vBMD, trabecular number, and µ-finite element parameters were decreased in patients compared to HC (p < 0.05). CONCLUSION: Bone erosions in longstanding pJIA women were associated with decreased cortical bone parameters, and these patients showed systemic bone impairment at peripheral sites compared with healthy controls.

Influenza A/H1N1 vaccination of patients with SLE: can antimalarial drugs restore diminished response under immunosuppressive therapy?

OBJECTIVE: To assess the efficacy and safety of pandemic 2009 influenza A (H1N1) in SLE under different therapeutic regimens. METHODS: A total of 555 SLE patients and 170 healthy controls were vaccinated with a single dose of a non-adjuvanted preparation. According to current therapy, patients were initially classified as SLE No Therapy (n = 75) and SLE with Therapy (n = 480). Subsequent evaluations included groups under monotherapy: chloroquine (CQ) (n = 105), prednisone (PRED) ≥20 mg (n = 76), immunosuppressor (IS) (n = 95) and those with a combination of these drugs. Anti-H1N1 titres and seroconversion (SC) rate were evaluated at entry and 21 days post-vaccination. RESULTS: The SLE with Therapy group had lower SC compared with healthy controls (59.0 vs 80.0%; P < 0.0001), whereas the SLE No Therapy group had equivalent SC (72 vs 80.0%; P = 0.18) compared with healthy controls. Further comparison revealed that the SC of SLE No Therapy (72%) was similar to the CQ group (69.5%; P = 0.75), but it was significantly reduced in PRED ≥20 mg (53.9%; P = 0.028), IS (55.7%; P = 0.035) and PRED ≥20 mg + IS (45.4%; P = 0.038). The concomitant use of CQ in each of these later regimens was associated with SC responses comparable with SLE No Therapy group (72%): PRED ≥20 mg + CQ (71.4%; P = 1.00), IS + CQ (65.2%; P = 0.54) and PRED ≥20 mg + IS + CQ (57.4%; P = 0.09). CONCLUSION: Pandemic influenza A H1N1/2009 vaccine response is diminished in SLE under immunosuppressive therapy and antimalarials seems to restore this immunogenicity. Trial registration. www.clinicaltrials.gov, NCT01151644.

2019-EULAR/ACR classification criteria domains at diagnosis: predictive factors of long-term damage in systemic lupus erythematosus.

The objective of this study is to assess the role of the 2019-European League Against Rheumatism/American College of Rheumatology (2019-EULAR/ACR) classification criteria at diagnosis and its domains in predicting long-term damage in systemic lupus erythematosus(SLE). We performed a retrospective analysis using an electronic chart database utilized in routine clinical care of SLE patients and established in 2000 in a tertiary hospital. Two hundred and nine consecutive SLE patients with disease onset ≥18 years old and long disease duration were included. Cumulative damage at the last visit was scored using the SLICC/ACR-Damage Index (SDI). The median age at SLE diagnosis was 28 years (18-63), disease duration was 14 years (8-25), and 88% were females. Damage (SDI≥1) was observed in 116/209 (55%). Patients with (SDI≥1, n=116) and without damage (SDI=0, n=93) had similar median disease duration [14 (8-25) vs. 12 (8-25) years, p=0.090] and age at diagnosis [23 (18-55) vs. 23 (18-56) years, p=0.998]. No correlation was observed between total 2019-EULAR/ACR score at diagnosis and SDI at last visit (r=0.007, p=0.913). Presence of renal domain at diagnosis was associated with renal damage at last visit (OR=3.6, 95%CI 1.2-10.4, p=0.017) and antiphospholipid antibodies domain predicted neuropsychiatric damage (OR=3.0, 95%CI 1.2-7.6, p=0.015). A ROC analysis identified that a cut-off >24 in 2019-EULAR/ACR score could predict a trend for renal damage (p=0.077) with a lower renal survival (Kaplan-Meier curve) for patients above this limit (p=0.029). A multivariate logistic regression analysis revealed that 2019-EULAR/ACR score >24 at diagnosis (OR 4.583, 95%CI 1.052-19.962, p=0.043) was independently associated with renal damage. Specific domains in the 2019-EULAR/ACR criteria at diagnosis were associated with long-term organ-specific damage, particularly renal and neuropsychiatric harm. A 2019-EULAR/ACR score >24 predicted worse renal survival. Key Points • Presence of renal domain of the 2019-EULAR/ACR classification criteria at diagnosis was associated with long-term renal damage. • Presence of antiphospholipid antibodies domain at diagnosis was associated with long-term neuropsychiatric damage. • A 2019-EULAR/ACR overall score >24 at diagnosis was independently associated with renal damage and predicted worse renal long-term survival.